Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:35]=[CH:34][C:9]([CH2:10][NH:11][C:12]2[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=3)[N:13]=2)=[CH:8][C:7]=1[Cl:36].C(N(CC)C(C)C)(C)C.[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH2:56])([CH3:49])([CH3:48])[CH3:47].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:46]([O:50][C:51](=[O:59])[NH:52][CH2:53][C:54]([CH3:58])([CH3:57])[CH2:55][NH:56][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([NH:24][C:14]2[N:13]=[C:12]([NH:11][CH2:10][C:9]3[CH:34]=[CH:35][C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:7]([Cl:36])[CH:8]=3)[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])[N:15]=2)=[CH:33][CH:32]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a 100 mL round-bottom flask charged with the 4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid prepared above (13.0 mmol) was added CH2Cl2 (65 mL), and then N,N-diisopropylethylamine (7.95 mL, 45.5 mmol). The flask was cooled with a 0° C. bath. To the solution was added tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (3.16 g, 15.6 mmol), and then 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 6.43 g, 16.9 mmol). The bath was removed and the solution was allowed to warm to room temperature with stirring for 1 h. The solution was transferred to a 1 L separatory funnel and was diluted with EtOAc (500 mL). The solution was washed with aq. 2M HCl (2×100 mL), and then with sat. aq. NaHCO3 (100 mL), and then with sat. aq. NaCl (100 mL). The organic solution was dried over MgSO4; filtered; and then concentrated in vacuo. The resulting solid residue was subjected to SiO2 chromatography (hexanes:EtOAc, 1:1) to afford tert-butyl(3-(4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate as a colorless solid (8.77 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.5 Hz, 2H), 7.76-7.66 (m, 1H), 7.62 (dd, J=15.6, 8.5 Hz, 2H), 7.35 (s, 1H), 7.22-7.15 (m, 1H), 6.96-6.89 (m, 1H), 5.16-5.04 (m, 1H), 4.73 (dq, J=12.2, 8.4 Hz, 2H), 4.57 (d, J=5.3 Hz, 2H), 4.19-4.14 (m, 2H), 3.69-3.61 (m, 2H), 3.28-3.18 (m, 2H), 3.00-2.92 (m, 2H), 2.36 (sxt, J=5.8 Hz, 2H), 1.46 (d, J=2.0 Hz, 9H), 0.91 (d, J=3.3 Hz, 6H); MS m/z=774.25 (M+1)+.
Reaction SMILES: [CH2:1]([N:5]([C:14](=[O:24])[C@@H:15]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:16])[NH:6][C:7](=[O:13])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:2]([CH3:4])[CH3:3].[OH2:25].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CO>[C:26]1([CH3:36])[CH:27]=[CH:28][C:29]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:30][CH:31]=1.[OH:25][NH:6][C:7]([C@H:8]([C@@H:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]([NH:6][N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:14](=[O:24])[C@@H:15]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:16])=[O:13])[CH2:9]/[CH:10]=[CH:36]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:13]
Reactant: O
Reactant: CC(C)CCC(=O)NN(CC(C)C)C(=O)[C@H](N)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@H](N)Cc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 0.288 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-phenylalanyl)valerohydrazide in 3 ml of methanol was treated with 0.099 g of p-toluenesulphonic acid monohydrate. The mixture was stirred for 3 hours at room temperature and evaporated. The residue was triturated with diethyl ether and then with hexane, filtered off and dried to give 0.232 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methyl-2′-(D-phenylalanyl)valerohydrazide p-toluenesulphonate in the form of a pale yellow solid.
Reaction SMILES: ClC1C=CC(O[CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=CC=1.Cl.N[C@@H](CCN1CC([C:40](=[O:49])[C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([F:48])[CH:42]=2)C1)CO>>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]([CH:7]2[CH2:8][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:10]2)=[O:49])=[CH:42][C:43]=1[F:48]
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Reactant: N[C@H](CO)CCN1CC(C(=O)c2ccc(Cl)c(F)c2)C1
Agent: Cl
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(C(=O)c3ccc(Cl)c(F)c3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-(4-chloro-3-fluoro-benzoyl)-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][N:5]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC.CN(C=O)C.O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][N:5]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Clc1ccc(OCc2ccccc2)cn1
Reaction time: 2 h
Yield: 87.7 %

Procedure:
Sodium hydride (55% in oil, 236 mg, 5.40 mmol) washed in Hexane and 2-Chloro-5-hydroxypyridine (350 mg, 2.70 mmol) was suspended in dry DMF (20 ml). After 10 minutes at room temperature Benzylbromide (0.32 ml, 2.70 mmol) was added and the mixture was stirred for an additional 2 hrs. The reaction was diluted with water and extracted with EtOAc (3*50 ml). The combined organic layers were washed with water and brine, and dried over Na2SO4. The solvent was removed by rotary evaporation, affording 520 mg (88%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([O:21]CC)=[O:20])[N:9]=1.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=[O:20])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2scc(C)c2Cl)n(CC(C)C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1csc(-c2nn(CC(=O)O)c(=O)n2CC(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg (1.96 mmol) of ethyl 2-[3-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetate from Example 248A are placed in 10 ml methanol and treated with 1 ml of 20% aqueous potassium hydroxide. This is stirred overnight at room temperature, the reaction mixture is then adjusted to pH 6 with 1 N hydrochloric acid and directly purified by preparative HPLC [Method 12]. 555 mg (86% of theory) of the target compound are thus obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH:32]1(O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(O)cc3)oc2C)cc1
Reactant: OC1CCCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(OC4CCCCC4)cc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.4 %

Procedure:
To a 0° C. solution of 2-(4-{2-[2-(4-hydroxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.60 g, 1.41 mmol), cyclohexanol (0.212 g, 2.11 mmol) and triphenyl phosphine (0.55 g, 2.10 mmol) in THF (18 mL) was added diisopropyl azodicarboxylate (0.43 g, 2.12 mmol) in THF (2 mL). The reaction was warmed to room temperature and stirred under N2 for 18 h. Silica gel was added directly to the reaction mixture and the solvent removed in vacuo to absorb the crude product onto the silica gel. The crude product was then purified by flash chromatography (3/1 hexanes/EtOAc) to afford 0.339 g (47%) 2-(4-{2-[2-(4-cyclohexyloxy-phenyl)-5-methyl-oxazol-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. 1H NMR (500 MHz, CDCl3) δ 7.94-7.85 (m, 2H), 6.92 (d, 2H, J=9.0 Hz), 6.82-6.75 (m, 4H), 4.32-4.23 (m, 1H), 4.21-4.16 (m, 4H), 2.98-2.90 (m, 2H), 2.39 (s, 3H), 2.05-1.95 (m, 2H), 1.85-1.78 (m, 2H), 1.62-1.51 (m, 3H), 1.52 (s, 6H), 1.42-1.25 (m, 3H), 1.27 (t, 3H, J=7.23 Hz); MS (ES+) Calc'd for C30H38NO6: Found m/e 508.3 (M+1, 100%).
Reaction SMILES: [Na].[OH:2][CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.[CH3:16][C:17]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)[O:19][N:18]=1>C1C=CC=CC=1>[CH:14]1[C:15]2[CH:3]([O:2][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:20]3[O:19][N:18]=[C:17]([CH3:16])[CH:21]=3)[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: Cc1cc(CCCCCCCBr)on1
Agent: [Na]
Solvent: c1ccccc1
Product: Cc1cc(CCCCCCCOC2c3ccccc3-c3ccccc32)on1

Procedure:
The sodium salt of 9-hydroxyfluorene was made by reacting sodium metal in anhydrous benzene before the etherization with 7-(3-methylisoxazol-5-yl)-heptyl bromide in the same solvent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:24]([O:26]C)=[O:25])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(c2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)CC1
Temperature: 70 °C
Yield: 79.6 %

Procedure:
Methyl 1-(4-((4-(4-fluorophenyl)piperazin-1-yl)methyl)phenyl)cyclopropanecarboxylate (2.26 g) was dissolved in ethanol (18 ml) and a solution of sodium hydroxide (0.49 g) in water (4.6 ml) was added, and the mixture was heated at 70° C. for 2 hr. The solvent was evaporated, and the residue was dissolved in water (200 ml). The solution was neutralized with hydrochloric acid and extracted with ethyl acetate (300 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (1.73 g) as white crystals, m.p.=74-77° C.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([CH3:18])[CH:4]=1)=O.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:14][C:8]([O:7][C:6]1[CH:16]=[CH:17][C:3]([CH2:1][NH:26][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[CH:4][C:5]=1[CH3:18])([CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
To a solution of ethyl 2-(4-formyl-2-methylphenoxy)-2-methylpropanoate (0.563 g, 2.25 mmol) in CH2Cl2 (10 mL) under nitrogen at room temperature, was added 4-trifluoromethylbenzyl amine (0.34 mL, 2.37 mmol). The resulting solution was stirred for 30 minutes prior to addition of sodium triacetoxyborohydride (0.668 g, 3.15 mmol). After 18 h stirring the reaction mixture was quenched by cautious addition of sat. sodium bicarbonate aq. (30 mL) and extracted CH2Cl2 (2×50 mL). The organic solution was dried (MgSO4) and the solvent removed in vacuo. Purification by SPE (Silica, 20 g) eluting 9:1 cyclohexane:EtOAc afforded the title compound as a colourless oil (0.485 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:23]=[CH:22][C:14]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>ClCCl>[C:25]([Si:28]([CH3:30])([CH3:29])[O:21][CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][C:14]1[CH:13]=[CH:12][C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([NH:2][CH3:1])=[CH:8][CH:7]=2)=[CH:23][CH:22]=1)([CH3:27])([CH3:26])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNc1ccc(C=Cc2ccc(OCCOCCO)cc2)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CNc1ccc(C=Cc2ccc(OCCOCCO[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Compound 3a (45 mg, 0.14 mmol) and TBDMSCl (33 mg, 0.22 mmol) were dissolved in dichloromethane (10 ml) followed by imidazole (20 mg, 0.29 mmol). The solution was stirred at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (1.5% methanol in dichloromethane) to afford 7a (56 mg, 91%): 1H NMR δ 7.40 (m, 4H), 6.90 (m, 4H), 6.75 (d, 2H, J=7.9 Hz), 4.15 (t, 2H), 3.88 (t, 2H), 3.82 (t, 2H), 3.66 (t, 2H), 2.85 (s, 3H), 0.92 (s, 9H), 0.09 (s, 6H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]([S:8][C:9]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[CH:14]=[C:13]([CH3:24])[C:10]=1[C:11]#[N:12])[CH3:7]>>[CH2:6]([S:8][C:9]1[CH:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[CH:14]=[C:13]([CH3:24])[C:10]=1[C:11]([NH2:12])=[O:2])[CH3:7]
Reactant: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C#N
Reactant: O=S(=O)(O)O
Product: CCSc1cc(N2CCOC[C@H]2C)cc(C)c1C(N)=O
Temperature: 100 °C

Procedure:
Concentrated sulfuric acid (5 ml) is added to 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzonitrile (0.11 g, 0.40 mmol) at RT and the resulting mixture is heated at 100° C. for 4 h. Upon completion (monitored by TLC), the reaction is slowly quenched with ice at 0° C. The mixture is basified with aqueous ammonia (pH=10). The aqueous part is extracted with ethyl acetate (3×10 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and evaporated to get 2-ethylsulfanyl-6-methyl-4-[(3R)-3-methyl-morpholin-4-yl]-benzamide which is used in the next step without further purification (0.075 g, 0.26 mmol, 55%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:15][CH2:16][C:17]([NH2:19])=[O:18].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[C:17]([CH2:16][NH:15][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])(=[O:18])[NH2:19]
Reactant: NCC(N)=O
Reactant: O=C(O)c1cccc2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: NC(=O)CNC(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of quinoline-8-carboxylic acid (3.45 mmol), glycinamide hydrochloride (3.45 mmol), NMM (41.43 mmol) and HOAt (4.14 mmol) in DMF (17 mL) at room temperature was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (4.14 mmol). After stirring at room temperature overnight, the reaction mixture was purified by HPLC to afford the title compound as a white solid. MH+230.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]=[S:27]1(=[O:35])[CH2:30][C:29]([CH2:33][NH2:34])([CH2:31][NH2:32])[CH2:28]1>>[NH2:32][CH2:31][C:29]1([CH2:33][NH:34][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:30][S:27](=[O:35])(=[O:26])[CH2:28]1
Reactant: NCC1(CN)CS(=O)(=O)C1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(CN)CS(=O)(=O)C3)c2c1

Procedure:
The title compound was prepared in analogy to Example 6-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (1,1-dioxidothietane-3,3-diyl)dimethanamine. MS obsd. (ESI+) [(M+H)+] 501, 1H NMR (400 MHz, CD3Cl) δ ppm 7.958-7.939 (d, J=7.6 Hz, 1 H), 7.651-7.633 (d, J=7.2 Hz, 1 H), 7.482-7.415 (m, 2 H), 7.308-7.270 (t, J=7.2 Hz, 1 H), 7.235-7.215 (d, J=8.0 Hz, 1 H), 7.134 (s, 1 H), 6.646 (s, 1 H), 5.065 (s, 2 H), 4.701-1.250 (brs, 2 H), 3.924-3.890 (m, 4 H), 3.659-3.646 (d, J=5.2 Hz, 2 H), 3.491 (s, 2 H), 3.320 (s, 2 H), 2.323 (s, 3 H).
Reaction SMILES: [C:1]([O:9][CH2:10][C@:11]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:34])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:32])([CH3:31])[C@@H:20]([OH:33])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[C:1]([O:9][CH2:10][C@:11]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:12]1[C@@H:13]1[C@@:26]([CH3:29])([CH2:27][CH2:28]2)[C@@:25]2([CH3:30])[C@@H:16]([C@:17]3([CH3:34])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:31])([CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(COC(=O)c3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 7.25 h
Yield: 96.4 %

Procedure:
To a solution of ((1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-3a-yl)methyl benzoate (8.6 g, 15.73 mmol) in CH2Cl2 (100 ml) was added PCC (5.09 g, 23.59 mmol). After 7.25 h of stirring at rt, the mixture was filtered through a pad of celite and silica gel and was washed with dichloromethane then with 1:1 EtOAc:hexanes. The filtrate was concentrated under reduced pressure to give the title compound as a white foam (8.26 g, 15.16 mmol, 96% yield). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.05 (d, J=7.32 Hz, 2H),7.56 (t, J=7.48 Hz, 1H), 7.44 (t, J=7.63 Hz, 2H), 4.72 (s, 1H), 4.61 (s, 1H), 4.52 (d, J=10.99 Hz, 1H), 4.09 (d, J=11.29 Hz, 1H), 2.45-2.58 (m, 2H), 2.34-2.43 (m, 1H), 1.86-2.10 (m, 4H), 1.70 (s, 3H), 1.10 (s, 3H), 1.06 (s, 3H), 1.04-1.82 (m, 18H), 1.02 (s, 3H), 1.01 (s, 3H), 0.94 (s, 3H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=2[F:11])[NH2:7])[CH2:3][CH2:2]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1.O>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:7][C:13](=[O:14])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(C2CC2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(F)c(C2CC2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.5 %

Procedure:
Add 3-cyclopropyl-4-fluoro-aniline (600 mg, 3.97 mmol), phenyl chloroformate (620 mg, 3.97 mmol) and pyridine (314 mg, 3.97 mmol) in DCM (30 mL), stir at room temperature (25° C.) for 4 hrs. After the reaction is complete, add water (15 mL), extract with EtOAc (15 mL×2), combine the organic layers, wash with 1M HCl solution (15 mL) and brine (15 mL) sequentially, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give a crude product (350 mg) which is used directly without further purification.
Reaction SMILES: [OH-].[Li+:2].[OH:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)[C:6]([O:8]C)=[O:7].O1CCCC1>O.CO>[OH:3][CH2:4][CH:5]([C:10]1[CH:11]=[C:12]([C:20]([F:21])([F:23])[F:22])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1)[C:6]([O-:8])=[O:7].[Li+:2]
Reactant: COC(=O)C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C([O-])C(CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 176.5 %

Procedure:
Lithium hydroxide (168 mg, 4 mmol) in water (2 mL) was added to a solution of (RS)-methyl α-(hydroxymethyl)-3,5-bis(trifluoromethyl)benzeneacetate (Description 7, 500 mg, 1.6 mmol) in methanol (4 mL). Methanol (2 mL) and tetrahydrofuran (2 mL) were added and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and the residue was dried azeotropically by evaporating toluene (×2) to to give the crude title compound as a colorless gum (870 mg), which was used without further purification. 1H NMR (400 MHz, CD3OD) δ 3.73–3.79 (1H, m), 3.85–3.92 (1H, m), 4.02–4.06 (1H, m), 7.80 (1H, s) and 7.98 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[C:14](OC)(=[O:19])[CH2:15][C:16]([CH3:18])=O>C(OCC)(=O)C>[CH3:18][C:16]1[C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH2:7][C:2]=2[NH:1][C:14](=[O:19])[CH:15]=1
Reactant: COC(=O)CC(C)=O
Reactant: NC1=CC(=O)CC(c2ccsc2)C1
Solvent: CCOC(C)=O
Product: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccsc1)C2
Temperature: 170 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of 1-amino-5-(thiophen-3-yl)cyclohexen-3-one (4.75 g) and methyl acetoacetate (10 g) was stirred at 170° C. for 18 hours and cooled, and to the mixture was added ethyl acetate. Precipitated crystals were filtered and washed with ethyl acetate to give 4-methyl-7-(thiophen-3-yl)-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (1.4 g) as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:23])[CH2:4]1.[Cl:24][C:25]1[C:34]([CH:35]=O)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[Cl:24][C:25]1[C:34]([CH2:35][NH:1][CH2:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH2:10][N:11]3[C:20]4[C:15](=[N:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=4)[CH:14]=[CH:13][C:12]3=[O:23])[CH2:4]2)=[N:33][C:32]2[NH:31][C:30](=[O:37])[CH2:29][O:28][C:27]=2[CH:26]=1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CN)C3)c2c1
Reactant: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNCc4nc5c(cc4Cl)OCC(=O)N5)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
To a solution of 1-{2-[(3S)-3-(Aminomethyl)-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one (0.149 g, 0.472 mmol) in 1:1 (MeOH/CH2Cl2) (25 mL) were added 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003064421, Example 15(c)) (0.100 g, 0.472 mmol) and sodium sulphate (0.100 g) and the resulting solution stirred for 18 hours at ambient temperature. Na(OAc)3BH (0.300 g, 1.42 mmol) was added and the solution stirred an additional 2 h. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil and then further purified by HPLC(CH3CN/H2O) to yield the title compound as a white powder (0.041 g, 17%).