Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([Si](C)(C)[O:6][CH:7]1[CH2:10][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:11]2)[CH2:8]1)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH:7]1[CH2:8][C:9]2([CH2:14][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:11]2)[CH2:10]1
Reactant: CCOC(=O)C1CC2(CC(O[Si](C)(C)C(C)(C)C)C2)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1CC2(CC(O)C2)CN1C(=O)OCc1ccccc1
Temperature: 45 °C

Procedure:
To a solution of 7-ethyl 6-(phenylmethyl) 2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-6-azaspiro[3.4]octane-6,7-dicarboxylate (151) (1.87 g, 4.2 mmol) in THF (20 mL) was added glacial acetic acid (0.48 mL), followed by TBAF (8.5 mL, 1M solution in THF) and the reaction heated to 45° C. for 18 h. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 followed by brine, and then dried over MgSO4 and concentrated in vacuo to afford the title compound as a clear oil in quantitative yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.48 (m, 5H) 4.83-5.15 (m, 3H) 3.88-4.34 (m, 4H) 3.35-3.47 (m, 2H) 2.02-2.39 (m, 3H) 1.65-1.96 (m, 3H) 1.00-1.22 (m, 3H). LC-MS ESI (M+H)+=334.17.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=C>>[CH3:13][O:12][C:8]([CH2:9][N:1]([CH2:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:8]([O:12][CH3:13])=[O:11])=[O:11]
Reactant: C=CC(=O)OC
Reactant: NCc1cccs1
Product: COC(=O)CN(CC(=O)OC)Cc1cccs1

Procedure:
2-Aminomethylthiophene and methyl acrylate are reacted in similar manner so that described in Examples 19 to give 2-[N,N-di(methoxycarbonylmethyl)aminomethyl]thiophene. b. 2-[N,N-Di(methoxycarbonylethyl)aminomethyl]thiophene is cyclized and decarboxylated in a similar manner to that described in Example 19 to give N-(2thienylmethyl)-4-piperidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([O:26]C(=O)C(F)(F)F)[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH:17]=[CH:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].C(N(CC)CC)C>CO>[C:1]([O:4][CH2:5][C:6](=[O:40])[C@:7]1([O:35][C:36](=[O:39])[CH2:37][CH3:38])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:33])[CH:17]=[CH:18]2)[C@@H:13]([CH3:34])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](OC(=O)C(F)(F)F)C[C@@]21C
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)O[C@]1(C(=O)COC(C)=O)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Yield: 79.1 %

Procedure:
3.5 g of 21-acetoxy-6α-methyl-17-propionyloxy-11β-trifluoroacetoxy-1,4-pregnadiene-3,20-dione is stirred in 80 ml of methanol and 4.2 ml of triethylamine for 4 hours at room temperature. The crude product is purified on 600 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone), thus isolating 2.3 g of 21-acetoxy-11β-hydroxy-6α-methyl-17-propionyloxy-1,4-pregnadiene-3,20-dione.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][O:35][CH3:36].[I-].[K+]>CN(C=O)C.C(N(CC)CC)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][N:29]([CH2:33][CH2:34][O:35][CH3:36])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: COCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Yield: 19.3 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (50 mg, 0.122 mmol) in 2 mL of DMF, triethylamine is added (34 uL, 0.244 mmol) followed by 1-bromo-2-methoxyethane (36 uL, 0.256 mmol). A spatula tip of potassium iodide was added and the reaction heated at 60° C. for 48 hours. The reaction was cooled and then partitioned between EtOAc (50 mL) and water (25 mL). The organic layer was washed with water (5×15 mL) to remove DMF. The EtOAc layer was the dried with Na2SO4 and then concentrated to yield an off-white solid. The solid was recrystallized from EtOAc-hexanes to yield 11 mg (19%) of title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.88 (s, 1 H), 7.80 (d 1 H), 7.58 (s, 1 H), 7.35 (m, 5 H), 7.15 (d, 1 H), 6.66 (s, 1 H), 5.64 (s, 2 H), 3.80 (m, 2H), 3.45 (t, 2H), 3.30-3.05 (m, 6 H), 2.70-2.50 (m, 2 H), 2.25 (m, 1 H), 1.97 (m, 1H); ES-MS m/z 468.2 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: Cl.C[N:3](C)[CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.O.[NH2:16]N.[OH-].[Na+]>CO>[C:8]1([C:6]2[CH2:5][CH2:4][NH:3][N:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NN
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C2=NNCC2)cc1
Temperature: 50 °C

Procedure:
Under N2 atmosphere, 3-dimethylamino-1-phenyl-propan-1-one hydrochloride (37.2 g) was dissolved in warm MeOH (75 mL), and slowly added to a solution of hydrazine hydrate (23 mL) and 50% aqueous NaOH (12 mL) in MeOH (30 mL) stirred at 50° C. The mixture was refluxed for 2 hours and evaporated under reduced pressure. Ice water was added to the residue and after stirring for 5 minutes the formed solid was filtered off. The residue was taken up in Et2O, dried over Na2SO4, and evaporated to dryness under reduced pressure to give 19.7 g of a yellow oil being 80% pure, which was used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](N3CCN(CCCS(C)(=O)=O)CC3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:49])([CH3:48])[CH3:47])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:55]1([CH2:61][C:62]([N:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)=[O:63])[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:54])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:58]3[CH2:57][CH2:56][N:55]([CH2:61][C:62](=[O:63])[N:64]4[CH2:65][CH2:66][CH2:67][CH2:68]4)[CH2:60][CH2:59]3)=[O:22])[C:10]([C:36]3[C:37]([O:51][CH2:52][CH3:53])=[CH:38][C:39]([Cl:50])=[C:40]([S:42]([NH:45][C:46]([CH3:47])([CH3:48])[CH3:49])(=[O:44])=[O:43])[CH:41]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1
Product: CCOc1cc(Cl)c(S(=O)(=O)NC(C)(C)C)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(5-tert-butylsulfamoyl-4-chloro-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 45) was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OJ-H 3×25 cm, 35° C. at 100 bar, eluting with 15% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H50N6O5SCl3 [(M+H)+] 831.2624, observed 831.2625.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.CCCCCCC>CN(C=O)C>[Si:18]([O:8][CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CC(O)CC1CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Product: CCOC(=O)C1CC(O[Si](C)(C)C(C)(C)C)CC1CC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of ethyl 2-ethyl-4-hydroxycyclopentanecarboxylate (10.0 g, 53.7 mmol) in DMF (18 mL) was added TBDMS-Cl (9.72 g, 64.5 mmol) and imidazole (9.15 g, 134 mmol). The reaction mixture was stirred at ambient temperature for about 3 h. Heptane (50 mL) was added to the reaction and the layers were separated. The bottom layer was extracted with heptane (2×30 mL). The combined organic extracts were washed with water (2×30 mL), brine (30 mL), dried over anhydrous MgSO4, filtered and concd to give ethyl 4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylate (15.87 g, 52.8 mmol, 98%) as a colorless oil; 1H NMR (400 MHz, CDCl3) δ 4.13 (m, 3H), 2.79 (m, 1H), 2.09 (m, 1H), 1.99 (m, 3H), 1.50-1.24 (m, 6H), 0.89 (m, 12H), 0.05 (s, 6H).
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C(=O)([O-])O.[Na+].[CH3:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][C:26]3[N:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][CH:27]=3)=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16]2)=[CH:12][CH:11]=1>C(O)C>[CH3:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH2:25][C:26]3[N:31]=[C:30]([C:32](=[N:3][OH:2])[NH2:33])[CH:29]=[CH:28][CH:27]=3)=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:16]2)=[CH:12][CH:11]=1
Reactant: [NH3+]O
Reactant: Cc1ccc2c(Cc3cccc(C#N)n3)c(-c3ccccc3)[nH]c2c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Yield: 90.4 %

Procedure:
To a suspension of hydroxylammonium chloride (27.6 mg) in ethanol (1 mL) was added sodium hydrogen carbonate (33.4 mg), and this mixture was heated under reflux for 45 minutes. Then, a solution of 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carbonitrile (61 mg) in ethanol (1.3 mL) was added dropwise thereto under ice-cooling, and the mixture was heated under reflux for additional 3.5 hours. The reaction mixture was left to be cooled and concentrated under reduced pressure. To the residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (60.8 mg). 1H-NMR (CDCl3) δ ppm: 2.47 (3H, s), 4.42 (2H, s), 5.64 (2H, br s), 6.48-6.84 (1H, br), 6.90-6.97 (1H, m), 7.08-7.14 (1H, m), 7.18-7.23 (1H, m), 7.32-7.49 (4H, m), 7.52 (1H, t, J=7.8 Hz), 7.54-7.61 (2H, m), 7.66-7.74 (1H, m), 8.06 (1H, br s). ESI-MS (m/z): 357 (M+H)+
Reaction SMILES: C(OC(=O)[N:7]([C:20]1[C:21]2[N:22]([CH:37]=[CH:38][N:39]=2)[C:23]([C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[N:29]=[C:28](F)[CH:27]=2)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.CC([O-:45])(C)C.[K+].Cl>C1COCC1.O>[F:33][C:32]([F:35])([F:34])[C:30]1[NH:29][C:28](=[O:45])[CH:27]=[C:26]([C:23]2[N:22]3[CH:37]=[CH:38][N:39]=[C:21]3[C:20]([NH:7][C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[CH:10][CH:9]=3)=[N:25][CH:24]=2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2cc(F)nc(C(F)(F)F)c2)n2ccnc12
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1cc(-c2cnc(Nc3ccc(N4CCOCC4)cc3)c3nccn23)cc(C(F)(F)F)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.3 %

Procedure:
To a solution of [5-(2-fluoro-6-trifluoromethyl-pyridin-4-yl)imidazo[1,2-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)carbamic acid tert-butyl ester (92 mg, 0.12 mmol) in THF (0.5 mL) is added KOtBu (26 mg, 0.23 mmol) and the mixture is stirred at rt for 20 min. HCl (12 M aq., 0.1 mL) is added and the mixture is diluted with water (10 mL) and concentrated under reduced pressure. The residue is dissolved in THF (5 mL) and HCl (12 M aq., 0.5 mL) is added and the mixture is stirred at rt for 5 h. NaHCO3 (sat. aq.) is added until the pH is 7 and the mixture is extracted with DCM (3×10 mL). The extracts are dried over Na2SO4 and evaporated under reduced pressure to afford a pale orange solid. This is purified by preparative HPLC to afford the title compound as a yellow solid (9.5 mg). LCMS: Rt=1.04 min (100%), m/z (ESI) 457 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]([CH3:7])[CH2:5][OH:6].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1>C1COCC1>[Cl:8][C:9]1[N:10]=[C:11]([O:6][CH2:5][CH:4]([NH2:3])[CH3:7])[CH:12]=[CH:13][CH:14]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)COc1cccc(Cl)n1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Sodium hydride (60 wt. percent oil dispersion, 560 mg, 14 mmol) was added to a stirred solution of 2-aminopropanol (1.2 mL, 14 mmol) in THF (25 mL). After 30 minutes, 2,6-dichloropyridine (2.0 g, 14 mmol) was added and the reaction heated at reflux for 8 hours. After cooling, the reaction was quenched with aqueous 1N hydrochloric acid and washed with ether (3×30 mL). The pH of the aqueous phase was then raised to 10-11 with 50 wt. percent aqueous sodium hydroxide and extracted with ether (3×50 mL). The organics were dried (MgSO4), filtered and solvent removed in vacuo leaving 2.2 g of a yellow oil.
Reaction SMILES: Cl.[CH2:2]([NH:4][C@@H:5]1[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:9]=2[S:8](=[O:19])(=[O:18])[N:7]([CH2:20][CH2:21][CH2:22]OC)[CH2:6]1)[CH3:3].[BrH:25]>>[Br:25][CH2:22][CH2:21][CH2:20][N:7]1[CH2:6][CH:5]([NH:4][CH2:2][CH3:3])[C:10]2[CH:11]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:13][C:9]=2[S:8]1(=[O:19])=[O:18]
Reactant: Br
Reactant: CCN[C@H]1CN(CCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: Cl
Product: CCNC1CN(CCCBr)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Yield: 96 %

Procedure:
A stirred solution of (+)-(R)-4-ethylamino-3,4-dihydro-2-(3-methoxypropyl)-2H-thieno-[3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide hydrochloride (4.5 g, 110.7 mmol) in 48% HBr (20.0 mL) was heated at 80° C. for 72 h. The reaction mixture was concentrated in vacuo at 60° C. bath temperature to give a pale tan solid (4.8 g, 96%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:24])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:11][C:10]2([CH3:23])[CH3:22])=[O:4].[NH2:25][C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:27]([C:26]1([NH:25][C:17]2[CH:16]=[C:15]([CH:12]3[CH2:11][C:10]([CH3:22])([CH3:23])[C:9]4[C:14](=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([Cl:24])[CH:8]=4)[NH:13]3)[CH:20]=[CH:19][CH:18]=2)[CH2:31][CH2:30]1)([OH:29])=[O:28]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Reactant: CC(C)(N)C(=O)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)CC(c2cccc(NC3(C(=O)O)CC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A solution of 2-(3-bromo-phenyl)-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (408.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(1-carboxy-cyclopropylamino)-phenyl]-6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (78.6 mg, 18.9%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 417.1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:4]([OH:17])[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:20][C:19]1([CH3:21])[CH2:18][C:3]2[C:2]([CH3:1])=[C:7]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH3:15])=[C:5]([CH3:16])[C:4]=2[O:17]1
Reactant: C=C(C)Cc1c(C)c(Nc2ccccc2)c(C)c(C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1Nc1ccccc1)CC(C)(C)O2
Yield: 69.2 %

Procedure:
To a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-4-phenylaminophenol (1.40 g, 4.98 mmol) in methanol (30 ml) was added conc. hydrochloric acid (10 ml) with ice-cooling and the mixture was heated with reflux in an argon atmosphere. The reaction mixture was cooled, neutralized with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with a saturated saline solution and concentrated. The residue was recrystallized from isopropyl ether to obtain the desired compound (0.97 g, yield: 69.3%), m.p. 148°-150° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:21](Cl)(=[O:23])[CH3:22].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:20][C:21](=[O:23])[CH3:22])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccnc(C)c2)c1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cccc(C)c2)c(-c2ccnc(C)c2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
To a solution of [4-(3-methylphenyl)-5-(2-methyl-4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.061 g, 0.50 mmol) in N,N-dimethylacetamide (15 mL) was added acetyl chloride (0.19 mL, 2.7 mmol), and the mixture was stirred for 14 hours at 80° C. An aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the deposited solid was filtrated. The resulted solid was washed with water, then, dried. The crude crystal was recrystallized from ethanol, to obtain a title compound (0.39 g, yield 67%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([O:16]C(C)(C)C)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9]1>ClCCl>[CH:8]1([CH:13]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[C:14]([OH:16])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reaction time: 8 h

Procedure:
At room temperature, 22.67 ml (294.3 mmol) of trifluoroacetic acid were added slowly to a solution of 6.6 g (14.7 mmol) of tert-butyl cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetate in 90 ml of dichloromethane, and the mixture was stirred overnight. The solvent was then removed under reduced pressure, and the residue was taken up in 100 ml of ethyl acetate and extracted with 50 ml of water. The organic phase was dried over magnesium sulfate. After filtration, the solvent was removed under reduced pressure. This gave 4.8 g (12.23 mmol, 83% of theory) of a colorless solid.
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1.CO.C=O.[C:48]([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]([CH3:48])[CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([NH2:15])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:2][CH2:3]1
Reactant: [BH3-]C#N
Reactant: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(C)cnc(CN2N=C3CC(N(C)C4CC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
A mixture composed of di-tert-butyl {8-(cyclopropylamino)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 60 (400 mg), methanol (2 mL), a 35% formalin solution (111 μL), acetic acid (156 μL) and molecular sieves 3A was stirred at room temperature for 40 minutes. Then, sodium cyanoborohydride (163 mg) was added, and the mixture was stirred at room temperature for 14 hours. The molecular sieves were separated off by filtration, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (233 mg, 84%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1C)O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:21][C:23]3[S:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:25][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)s3)cc21

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester was reacted with [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield {6-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as white solid.