Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)(=O)c1cccc(-c2cccn3nc(N)nc23)c1
Product: CS(=O)(=O)c1cccc(-c2cccn3nc(Nc4ccc(N5CCOCC5)cc4)nc23)c1

Procedure:
The title compound was prepared from 8-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.3468 mmol) and 4-(4-bromo-phenyl)-morpholine (101.0 mg, 0.4172 mmol) in a manner analogous to Step 2d and was isolated as a pale yellow solid (0.025 g, 16%). MP=202-204° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.68 (t, J=1.6, 1H), 8.46 (dd, J=6.9, 0.9 Hz, 1H), 8.39-8.35 (m, 1H), 8.01-7.98 (m, 1H), 7.73 (dd, J=7.7, 7.7 Hz, 1H), 7.67 (dd, J=7.5, 0.8 Hz, 1H), 7.56-7.50 (m, 2H), 7.01-6.94 (m, 3H), 6.72 (s, 1H), 3.90-3.86 (m, 4H), 3.14-3.10 (m, 7H). MS=450 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]2[N:6]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[CH2:7][CH2:8][CH2:9][C:10](=O)[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH:15]([O:14][C:12]([N:6]1[CH2:7][CH2:8][CH2:9][CH:10]([NH:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:4]2[CH:3]=[C:2]([CH3:1])[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:5]1=2)=[O:13])([CH3:17])[CH3:16]
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2=O
Reactant: Nc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2Nc1cccnc1
Temperature: 130 °C
Reaction time: 96 h
Yield: 13.2 %

Procedure:
Add isopropyl 7-methyl-5-oxo-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (Example 3, Step 8) (1.16 g, 3.52 mmol), 3-aminopyridine (465 mg, 5.10 mmol), p-toluenesulfonic acid (210 mg, 1.10 mmol) and toluene (8.0 mL) to a sealed tube and stir vigorously for 4 days at 130° C. Evaporate the toluene, dissolve the residue with MeOH (10.0 mL), and add sodium borohydride (146 mg, 3.86 mmol) portionwise. Reflux overnight and evaporate the MeOH. Partition the resulting residue between water (10 mL) and EtOAc (10 mL). Wash the organic layer with 2-mL portions of water and brine, dry (MgSO4), and concentrate. Purify via column chromatography (silica gel; 30% to 70% EtOAc:hexanes to 100% EtOAc gradient) to give 189 mg (13%) of the title compound as a white solid. APCI MS m/z 408 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:15]1([S:21][O:12][C:11](=[O:13])[CH2:10][CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(CC(=O)O)O[Si](C)(C)C(C)(C)C
Reactant: Sc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CC(=O)OSc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of 3.18 g (19.2 mmol) of (-)-3-t-butyldimethylsilyloxybutyric acid and 2.26 ml (22 mmol) of thiophenol dissolved in 100 ml of methylene chloride, 4.53 g (22 mmol) of N,N'-dicyclohexylcarbodiimide was added. After stirring the mixture at room temperature for 2 hours, the resultant was filtered and the filtrate was concentrated and distilled (110° to 116° C./0.3 mmHg) to give 5.00 g of (-)-3-t-butyldimethylsilyloxybutyric acid phenylthio ester (yield: 83%).
Reaction SMILES: [I:1]I.N(OCCC(C)C)=O.[C:11]([O:15][C:16]([N:18]1[C:22]([CH3:23])=[CH:21][C:20](N)=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[C:22]([CH3:23])=[CH:21][C:20]([I:1])=[N:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: II
Reactant: Cc1cc(N)nn1C(=O)OC(C)(C)C
Agent: CC(C)CCON=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(I)nn1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 16.6 %

Procedure:
Iodine (0.774 g, 3.0 mmol) was dissolved in DCM (5 mL) then isoamyl nitrite (0.682 mL, 5.1 mmol) was added followed by the slow addition of 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (0.50 g, 2.54 mmol) as a solution in DCM (4 mL). The reaction mixture was stirred at room temperature for 1.5 hours and then poured onto saturated sodium thiosulfate solution. The phases were separated and the aqueous layer was extracted with DCM (×3). The organics were washed with brine then dried over sodium sulfate, filtered and evaporated. The crude material was purified by chromatography on a silica II cartridge, eluting with 2-6% ethyl acetate in pentane to give 3-iodo-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester as a solid (0.13 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[N:7][CH:8]=1)#N.[OH2:20]>C(O)=O.[Ni]>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[N:7][CH:8]=1)=[O:20]
Reactant: N#Cc1ccc(Oc2cccc3c2CCC3=O)nc1
Reactant: O
Agent: [Ni]
Solvent: O=CO
Product: O=Cc1ccc(Oc2cccc3c2CCC3=O)nc1

Procedure:
To a solution prepared by suspending 4.6 g of 4-[(5-cyano-2-pyridinyl)oxy]-1-indanone obtained in Reference Example 59 in 4.4 ml of water and 11 ml of formic acid, 2.6 g of raney nickel was added at 60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-])=O)=[N:11][CH:12]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.Cl.C(O)C>O>[NH2:18][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:2]=1[Cl:1])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)c([N+](=O)[O-])c2)cn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccc(Cl)c(N)c2)cn1
Temperature: 85 °C
Reaction time: 2 h
Yield: 66.4 %

Procedure:
A mixture of 5-(4-chloro-3-nitrophenoxy)-2-nitropyridine (3.80 g, 12.9 mmol), reduced iron (4.84 g, 86.7 mmol), 6N hydrochloric acid (2 mL), ethanol (20 mL) and water (4 mL) was stirred at 85° C. for 2 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (2.02 g, 66%) as a gray solid.
Reaction SMILES: C[O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.C([N:71]1[CH2:78][CH2:77][CH2:76][C@H:72]1[C:73]([OH:75])=O)(OC(C)(C)C)=O>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:20][C:21]([CH:23]3[CH2:32][C:31]4[CH:30]=[C:29]5[O:33][CH2:34][C@H:35]([C:37]6[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=7)=[CH:41][CH:42]=6)[O:36][C:28]5=[CH:27][C:26]=4[CH2:25][N:24]3[S:53]([C:56]3[S:60][C:59]([NH:61][C:73]([C@@H:72]4[CH2:76][CH2:77][CH2:78][NH:71]4)=[O:75])=[N:58][C:57]=3[CH3:62])(=[O:54])=[O:55])=[O:22])[C:3]([OH:63])=[O:2])=[CH:11][CH:10]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: Cc1nc(NC(=O)[C@@H]2CCCN2)sc1S(=O)(=O)N1Cc2cc3c(cc2CC1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (18 mg) was prepared from (S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester and boc-L-proline according to General Procedures L, C, and B. LCMS (m/z): 1008.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([NH:14][C@H:15]([CH3:18])[CH2:16][OH:17])[N:8]=1.[Cl:22]NC(=O)CCC(N)=O>CC(O)=O>[Cl:22][C:10]1[C:11]([OH:13])=[N:12][C:7]([S:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=2)=[N:8][C:9]=1[NH:14][C@H:15]([CH3:18])[CH2:16][OH:17]
Reactant: NC(=O)CCC(=O)NCl
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2cccc(Cl)c2)n1
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1nc(SCc2cccc(Cl)c2)nc(O)c1Cl
Reaction time: 3 h

Procedure:
The product of Example 3 (0.22 g) was dissolved in AcOH (10 ml), N-chlorosuccinamide (90 mg) added and stirred for 3 h. The volatiles were removed under reduced pressure and the residue purified by reverse phase HPLC with gradient elution in acetonitrile/0.02M ammonium hydroxide (90% to 50% aqueous phase) to yield the title product as a white solid. Yield 0.1 g.
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@H:6]([OH:19])[CH2:5]1.[C:20]([O:24][C:25]([N:27]([CH:40]([CH3:42])[CH3:41])[CH2:28][C@H:29]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:30](O)=[O:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:29]([C:30]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:31])[CH2:28][N:27]([CH:40]([CH3:41])[CH3:42])[C:25](=[O:26])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:34][CH:35]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)C[C@H]3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (2.92 g, 9.51 mmol) and (S)-3-(tert -butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (3.25 g, 9.51 mmol) in DCM (40 mL) and DIEA (5.0 mL, 28.7 mmol) was stirred at room temperature for 10 minutes. HBTU (3.61 g, 9.51 mmol) was added to the mixture. The mixture was stirred at room temperature for 1 hour. The solvent was removed, and the residue was dissolved in ethyl acetate (500 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by EtOAc-DCM/MeOH (20:1) to give tert-butyl (S)-2-(4-chlorophenyl)-3-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (3.68 g, 69%.) LC/MS (APCI+) m/z 558.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[C:25]([CH3:38])=[C:26]([CH2:30][NH:31][S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH:27]=[N:28][CH:29]=1>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[C:25]([CH3:38])=[C:26]([CH2:30][NH:31][S@@:32]([C:34]([CH3:36])([CH3:35])[CH3:37])=[O:33])[CH:27]=[N:28][CH:29]=1
Reactant: Cc1c(Br)cncc1CN[S@](=O)C(C)(C)C
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(F)cc21
Product: Cc1c(CN[S@](=O)C(C)(C)C)cncc1-c1cc2c(cc1F)N(C)C(=O)CC2

Procedure:
In analogy to the procedure described for the preparation of example 45, 7-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-22) has been coupled to (R)-2-methyl-propane-2-sulfinic acid (5-bromo-4-methyl-pyridin-3-ylmethyl)-amide (intermediate A-59) to give the title compound as a brown amorphous solid. MS: 404.5 (M+H+).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][C:18]#[N:19]>>[CH:1]1([CH2:7][O:8][C:9]2[N:14]=[C:13]([CH:15]([OH:16])[CH2:17][C:18]#[N:19])[CH:12]=[CH:11][N:10]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: O=Cc1ccnc(OCC2CCCCC2)n1
Product: N#CCC(O)c1ccnc(OCC2CCCCC2)n1

Procedure:
CH3CN addition to 2-(cyclohexylmethoxy)pyrimidine-4-carbaldehyde following the method described in Example 6 gives 3-(2-(cyclohexylmethoxy)pyrimidin-4-yl)-3-hydroxypropanenitrile.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12]C(O)=O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=1.[S:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]1>C(O)CCC.ClCCl>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:16])[CH:8]=2)[N:3]=[C:2]([N:20]2[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[S:17][CH2:18][CH2:19]2)[CH:11]=1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)cc(CC(=O)O)c2c1
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)cc(C)c2c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
A solution of (2-chloro-6-methylquinolin-4-yl)acetic acid (118 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine (247 mg, 1.5 mmol) in n-butanol (0.2 mL) was heated with stirring in a sealed 0.5 mL of microwave process vial for 2 hours at 160° C. After being cooled to room temperature, the reaction mixture was diluted with dichloromethane (50 mL), washed with a saturated aqueous solution of sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 100 mg of the desired product (yield was 62%). MS (ESI+) [(M+H)+] 321.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Br[C:31]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=1[CH:33]=[O:34]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:7]=[C:8]([C:31]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:32]=2[CH:33]=[O:34])[C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCc2ccccc2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-benzyloxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-5-(trifluoromethyl)benzaldehyde.
Reaction SMILES: C([O:4][C:5]1[C:9]2[CH:10]=[C:11](Cl)[CH:12]=[C:13](CN3CCN(C)CC3)[C:8]=2[O:7][CH:6]=1)(=O)C.O.Cl>CO>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5](=[O:4])[CH2:6]1
Reactant: CC(=O)Oc1coc2c(CN3CCN(C)CC3)cc(Cl)cc12
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1COc2ccccc21
Temperature: 80 °C
Reaction time: 4 h
Yield: 141 %

Procedure:
A solution of 5-chloro-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3-yl acetate (0.12 g, 0.37 mmol) in methanol (8.0 mL) was added with water (2.0 mL) and concentrated hydrochloric acid (0.20 mL), and the mixture was stirred at 80° C. for 4 hours. The solvent was evaporated under reduced pressure, then the residue was dissolved in ethyl acetate, and the solution was successively washed with water, saturated aqueous sodium hydrogencarbonate, and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain 5-chloro-7-[(4-methylpiperazin-1-yl)methyl)]benzofuran-3(2H)-one (0.070 g, 67%).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([C:19](O)=[O:20])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:26]1[CH:27]=[CH:28][C:24]([NH:23][C:19]([C:8]2[C:7](=[O:22])[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:11]3[N:12]=[C:13]([NH:17][CH3:18])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=2)=[O:20])=[N:25]1
Reactant: Nc1cc[nH]n1
Reactant: CNc1nc(C)c2cc(C(=O)O)c(=O)n(C3CCCC3)c2n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1nc(C)c2cc(C(=O)Nc3cc[nH]n3)c(=O)n(C3CCCC3)c2n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 110 μL of 0.1 M solution of example 89 in DMF in a test tube (10×95 mm) was added 100 μL of 0.1 M solution of 3-aminopyrazole in DMF followed by 110 μL each of 0.1 M solution of HATU and triethylamine, respectively. The reaction mixture was stirred at 80° C. for 8 h. After the removal of the solvent in vacuo, the residue was reconstituted in 1.2 mL of DMSO and subjected to HPLC purification to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15]>CC(C)=O>[CH3:7][O:6][C:4]([C:3]1[C:2]2[N:11]([C:13]([CH3:17])=[C:14]([CH3:15])[CH:1]=2)[CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(=O)C(C)Br
Reactant: COC(=O)c1cccnc1C
Solvent: CC(C)=O
Product: COC(=O)c1cccn2c(C)c(C)cc12
Temperature: 25 °C

Procedure:
A solution of methyl 2-methylnicotinate (4.9 g, 32.1 mmol) and 3-bromo-2-butanone (4.8 g, 32.1 mmol) in acetone (40 ml) were warmed to reflux for 3 d. Cooled to RT and partially purified the remaining residue via column chromatography (silica gel, 5-10% EtOAc/hexanes). The product-containing fractions were combined and concentrated to give the desired product.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:34](O)=[O:35])[CH:24]=[CH:25][CH:26]=[C:27]2[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34]([C:23]2[CH:24]=[CH:25][CH:26]=[C:27]3[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29][C:28]=23)=[O:35])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: CC(C)Oc1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)Oc1cccc(CC(NC(=O)c2cccc3c2C=CCCC3)C(O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[3-(isopropyloxy)phenyl]-1-propanol (0.46 g, 1.5 mmol) and 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (0.34 g, 1.8 mmol) in acetonitrile (20 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g, 2.1 mmol) and 1-hydroxybenzotriazole hydrate (0.32 g, 2.1 mmol), and the mixture was stirred at room temperature for 5 hrs. To the reaction solution was added water (100 ml), and the mixture was extracted with- ethyl acetate (100 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the objective substance (0.55 g, 77%) as crystals.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[NH:19][CH2:18][CH2:17][S:16]3(=[O:24])=[O:23])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1>CS(C)=O.C(OCC)(=O)C>[C:3]1([CH2:9][C@H:10]2[C@@:15]3([CH2:21][C:20](=[O:22])[N:19]([CH2:31][C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:17][S:16]3(=[O:23])=[O:24])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1cccnc1
Reactant: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=C1C[C@]2(CCCC[C@H]2Cc2ccccc2)S(=O)(=O)CCN1Cc1cccnc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
A stirred suspension of sodium hydride (5.5 g, 60% dispersion in mineral oil) in dimethyl sulfoxide (400 ml) was heated at 60° C. for 1 hour under nitrogen atmosphere. (1S,6S)-1-Phenylmethyl-11-oxo-7-thia-10-azaspiro[5.6]-dodecane 7,7-dioxide (40.0 g) and 3-pyridylmethyl chloride (25 g) were added to the nearly clear solution and the mixture was allowed to stand at room temperature for 15 minutes. The mixture was diluted with ethyl acetate (2 l) and washed with saturated aqueous sodium bicarbonate (2 l) and brine (2 l). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate and recrystallized from ethanol to give (1S,6S)-1-phenylmethyl-10-(3-pyridylmethyl)-11-oxo-7-thia-10-azaspiro[5.6]dodecane 7,7-dioxide (14.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)=[O:4].C([Li])CCC.CON(C)[C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.CCCCCC>[C:29]([C:7]1[CH:8]=[C:9]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:20])([CH3:19])[CH3:1])(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: CN1CCN(c2ccc(NC(=O)C(C)(C)C)cc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(NC(=O)C(C)(C)C)c(C(=O)c3ccccc3)c2)CC1
Temperature: -70 °C
Reaction time: 3 h
Yield: 16.6 %

Procedure:
A solution of 1.375 g (5 mmol) of 2,2-dimethyl-N-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionamide was dissolved in 25 ml tetrahydrofuran and cooled to −70° C. Under argon 7.8 ml (12.5 mmol) of a 1.6 M n-butyl lithium solution in hexane was added slowly at this temperature. The cooling bath was removed and the mixture was stirred for 3 h at room temperature. The reaction mixture was cooled down again to −70° C. and a solution of 1.234 g N-methoxy-N-methyl benzamide (7.2 mmol) in 5 ml tetrahydrofuran was added slowly at −70° C. After 10 min the cooling bath was removed and stirring was continued at room temperature for 1 hour. Water (50 ml) was added to quench the reaction and the mixture was extracted with diethylether (three times 50 ml). The organic layer was dried with magnesium sulfate and evaporated to give a brown oil, which was purified by flash chromatography with dichloromethane/methanol to yield 315 mg (17%)of the product as a light orange solid.