Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[N:6][C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:31])=[N:4]1.[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:55]=[CH:54][C:50]([C:51](O)=[O:52])=[CH:49][CH:48]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.S(=O)(=O)(O)[O-].[K+]>C(Cl)Cl>[CH2:32]([O:34][C:35]1[C:44]([O:45][CH3:46])=[CH:43][C:42]2[C:41]([C:47]3[CH:48]=[CH:49][C:50]([C:51]([N:28]4[CH2:29][CH2:30][CH:25]([N:11]5[C:12](=[O:24])[C:13]6[S:17][C:16]([C:18]7[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=7)=[CH:15][C:14]=6[N:9]([CH2:8][C:5]6[N:6]=[CH:7][N:3]([CH3:2])[N:4]=6)[C:10]5=[O:31])[CH2:26][CH2:27]4)=[O:52])=[CH:54][CH:55]=3)=[N:40][C@@H:39]3[CH2:56][CH2:57][S:58][CH2:59][C@@H:38]3[C:37]=2[CH:36]=1)[CH3:33]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cn1cnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5ncn(C)n5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 1-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (249 mg, compound B92), 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (210 mg; compound C10) and HATU (267 mg) in DCM (7.0 ml) is added DIPEA (0.28 ml). The reaction mixture is stirred at RT for 14 h. Aqueous potassium bisulfate solution (10% w/w, 10 ml) is added and the mixture is extracted with DCM. After filtration using a phase separator the organic layer is concentrated under reduced pressure and the residue is purified by preparative HPLC to yield the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:35]([NH:38][CH2:39][CH2:40][CH2:41][OH:42])(=[O:37])=[O:36])[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.C(N(C(C)C)CC)(C)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl>[CH3:52][S:53]([O:42][CH2:41][CH2:40][CH2:39][NH:38][S:35]([C:4]1[CH:5]=[C:6]([F:34])[C:7]([CH2:8][S:9][C:10]2[N:11]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:12]([C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=3)([CH3:16])[CH3:17])=[CH:13][N:14]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:37])=[O:36])(=[O:55])=[O:54]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCO)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)NCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Temperature: 25 °C
Yield: 78.4 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-N-(3-hydroxypropyl)benzenesulfonamide (910 mg, 1.42 mmol) and diisopropylethylamine (0.74 mL, 0.74 mmol) in DCM (6 mL) was added methanesulfonyl chloride (0.13 mL, 1.706 mmol) at −10° C. After the reaction was slowly warmed to ambient temperature over 30 min, it was extracted with DCM (10 mL). The combined extracts were washed with water (10 mL), dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography (Hex:EA=1:2) to give 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenylsulfonamido)propyl methanesulfonate (0.80 g, 78% yield) as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.63 (s, 1H), 7.39 (dd, J=8.27, 1.73 Hz, 1H), 7.27 (d, J=2.32 Hz, 2H), 6.89 (dd, J=10.97, 8.54 Hz, 1H), 6.84-6.74 (m, 2H), 6.58 (dd, J=8.09, 2.16 Hz, 1H), 6.53-6.45 (m, 1H), 6.41-6.33 (m, 2H), 5.26 (s, 1H), 4.42-4.29 (m, 2H), 4.23-4.08 (m, 3H), 3.78 (d, J=2.18 Hz, 4H), 3.21-3.10 (m, 2H), 3.10-2.99 (m, 4H), 2.00 (dd, J=11.78, 6.04 Hz, 2H), 1.65 (s, 7H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.C(OC(=O)C)(=O)C.[CH3:65][S:66]([CH3:68])=O>C(OCC)(=O)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][CH2:65][S:66][CH3:68])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: CS(C)=O
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCSC)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the FR-900506 substance (100 mg) in dimethyl sulfoxide (1.5 ml) was added acetic anhydride (1.5 ml), and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous sodium hydrogen carbonate, water and an aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to thin layer chromatography on silica gel (developing solvent: diethyl ether) to give 17-allyl-1,14-dihydroxy-23, 25-dimethoxy-13,19 21,27-tetramethyl-12-[2-(4-methylthiomethoxy-3-methoxycyclohexyl-1 -methylvinyl]-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (51 mg), 17-allyl-1-hydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl) -1-methylvinyl23, 25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18diene-2,3, 10,16-tetraone (18 mg) and 17-allyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21, 27-tetramethyl-12-[2-(4-methylthiomethoxy-3-methoxycyclohexyl)-1-methylvinyl] -11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (10 mg), respectively.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: CN(C)CCCCN
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCCN(C)C)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(4-dimethylamino-butyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1), N(1)-dimethyl-butane-1,4-diamine in an analogous manner to Example 1396. Product isolated as an orange solid (31 mg, 51%). m.p.=132-134° C.; LCMS (m/e) 566 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.35 (s, 1H), 8.68 (d, 1H, J=8.4 Hz), 8.51 (s, 1H), 8.09 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.47-7.38 (m, 1H), 7.36 (s, 1H), 7.30-7.22 (m, 1H), 7.13-6.93 (m, 3H), 3.56 (t, 2H, J=4.8 Hz), 3.51-3.42 (m, 2H), 3.39 (s, 3H), 2.98-2.85 (m, 4H), 2.82-2.67 (m, 6H), 2.35 (t, 2H, J=5.8 Hz), 2.21 (s, 6H), 1.81-1.71 (m, 2H), 1.71-1.61 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7])=[O:4].CO[CH:17](OC)[N:18](C)C>>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:7][N:18]=[CH:17][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Product: COC(=O)c1cnoc1-c1ccc(F)cc1
Yield: 86.3 %

Procedure:
A mixture of methyl 4′-fluorobenzoylacetate (10.02 g) and N,N-dimethylformamide dimethylacetal (8.63 g) was refluxed for 1.5 hr. The reaction mixture was concentrated, and the residue was dissolved in ethanol (150 ml). To the obtained solution was added hydroxylamine hydrochloride (6.75 g) and the mixture was refluxed for 5 hr. The reaction mixture was concentrated, dilute hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 5-(4-fluorophenyl)isoxazole-4-carboxylate (9.75 g, yield 91%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 92–93° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][CH:11]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[N+]=[N-].S([O-])([O-])(=O)=O.[Na+].[Na+]>CCOCC>[CH2:23]([O:22][CH2:21][CH:11]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][NH2:7])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCOCC(CN=[N+]=[N-])COCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCOCC(CN)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 0.87 g of lithium aluminum hydride in 80 ml of ether under argon is added, with stirring, over 30 minutes, a solution of 8.5 g of [[3- azido-2-[(hexadecyloxy)methyl]propoxy]methyl]benzene in 80 ml of ether. This mixture is refluxed for 3 hours, then cooled to 0° C. and 8 ml of saturated aqueous sodium sulfate solution is added. The mixture is filtered and the filtrate evaporated, to give 8.0 g of the desired compound as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:17])=[O:16])[CH:12]=2)[NH:7][C:6]=1[Si](C)(C)C.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][S:15]([NH:18][CH3:19])(=[O:16])=[O:17])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CNS(=O)(=O)Cc1ccc2[nH]c([Si](C)(C)C)c(CCCO)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(CCCO)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
To a solution of 0.0551 g (0.155 mmol, 1.0 equiv.) of 3-(3-hydroxypropyl)-2-trimethylsilyl-N-methyl-1H-indole-5-methanesulfonamide in 2 mL of methylene chloride at 0° C. was added 0.01 mL (0.155 mmol, 1.0 equiv.) of trifluoroacetic acid. After 15 minutes the reaction was allowed to warm to room temperature. After a total of thirty minutes the reaction was poured into 15 mL of ethyl acetate and washed with 5 mL of saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 0.0413 g (95%) of 3-(3-hydroxypropyl)-N-methyl-1H-indole-5-methanesulfonamide, homogeneous by 1H NMR and TLC.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([OH:23])=O)=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[NH2:24][C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34])[CH:28]=[CH:29][CH:30]=1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([NH:24][C:25]3[CH:26]=[C:27]([NH:31][C:32](=[O:44])[C@@H:33]([N:35]([CH3:43])[C:36](=[O:42])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH3:34])[CH:28]=[CH:29][CH:30]=3)=[O:23])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: C[C@@H](C(=O)Nc1cccc(N)c1)N(C)C(=O)OC(C)(C)C
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1

Procedure:
By using 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2) and (S)-tert-butyl (1-((3-aminophenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (B9), (S)-tert-butyl (1-((3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)phenyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (C7) was obtained as white solid in the same manner as that of Example 7, (9).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH:10]([CH3:29])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1.O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[N:16][C:17]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[C:18]([CH3:21])[C:19]=2[CH3:20])[CH:10]([CH3:29])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)C(=O)C2C)c1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCN(Cc3ccccc3)CC2C)c1C
Temperature: 50 °C

Procedure:
Treat a solution of 1-benzyl-4-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)-3-methylpiperazin-2-one (2.84 g, 7.02 mmol) in THF (70 mL) with borane-methyl sulfide complex (1.96 mL, 21.1 mmol). Heat the resulting mixture at 50° C. for 2 h. Cool the reaction mixture in an ice bath, add MeOH (20 mL) via a dropping funnel followed by 4 M HCl in 1,4-dioxane (20 mL). Heat the resulting mixture at 65° C. for 1 h. Concentrate the mixture under reduced pressure. Partition the residue between CH2Cl2 and saturated NaHCO3 (aq). Separate the layers, and extract the aqueous layer with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 0 to 3% 2 M NH3/MeOH in CH2Cl2) to afford the title compound as a waxy solid (2.45 g, 89%). ES/MS m/z 391.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:7]([CH:19]=[CH:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4-chlorophenyl)-5(pent-1-enyl)pyridine (Example 143) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.79 (t, J=7.0 Hz, 3 H), 1.08-1.38 (m, 18 H), 2.26 (m, 2 H), 3.22 (m, 1 H), 3.40 (m, 1 H), 4.31 (d, J=5.0 Hz, 1 H), 7.13 (d, J=8.0 Hz, 2 H), 7.42 (d, J=8.0 Hz, 2 H). mp 83-85° C. Rf=0.36 (10% ethyl acetate/n-hexane).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[N:9]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:8][CH2:7]2.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]2[C:11]=1[CH:10]([C:12]([OH:14])=[O:13])[N:9]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:8][CH2:7]2
Reactant: COc1ccc(Br)c2c1CCN(S(=O)(=O)c1ccc(Oc3ccc(F)cc3)cc1)C2C(=O)O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)C1c2c(Br)ccc(O)c2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 73 %

Procedure:
0.84 g (1.6 mmol) of 8-bromo-2-[4-(4-fluorophenoxy)benzenesulfonyl]-5-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (crude product, 21B) are dissolved in 20 ml of dichloromethane. At 0° C., a solution of 1.19 g (4.7 mmol) of boron tribromide in 10 ml of dichloromethane is added dropwise, and the solution is allowed slowly to reach room temperature. After two hours, it is washed twice with 2 N HCl and once with H2O, dried with MgSO4 and freed of solvent, resulting in 0.61 g of the title compound which can be reacted further without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:12]=1[C:13]#[N:14])(C)(C)C.O1CCOCC1>Cl>[NH2:7][C:8]1[S:9][C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][C:12]=1[C:13]#[N:14]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2cccnc2)cc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1cc(-c2cccnc2)sc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
tert-Butyl(3-cyano-5-pyridin-3-yl-2-thienyl)carbamate (800 mg, 2.07 mmol) was dissolved in 4M hydrochloric acid in dioxane (10.4 ml, 41.6 mmol) and the mixture was stirred at room temperature for 6 h. The mixture was quenched with 1N sodium hydroxide (50 mL) and extracted with ethyl acetate (3×100 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][O:75][CH2:74][CH2:73]2)[CH:69]=[CH:68][C:66]=1[NH2:67]>>[CH3:63][O:64][C:65]1[CH:71]=[C:70]([N:72]2[CH2:73][CH2:74][O:75][CH2:76][CH2:77]2)[CH:69]=[CH:68][C:66]=1[NH:67][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:32]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCOCC2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 46.1 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 2-methoxy-4-morpholinoaniline (Bionet) (0.14 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-methoxy-4-morpholin-4-yl-phenyl)-amide as a light yellow solid (Yield 0.13 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[Br:13]Br>CC(O)=O>[Br:13][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:11])[CH3:10])=[C:3]([CH3:12])[C:2]=1[Cl:1]
Reactant: CC(=O)Nc1cccc(Cl)c1C
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(Cl)c1C
Temperature: 0 °C
Reaction time: 24 h
Yield: 90.2 %

Procedure:
To a suspension of N-(3-chloro-2-methylphenyl)acetamide (35 g, 0.19 mol) in 350 mL of glacial AcOH cooled to 0° C. was added bromine (29.5 mL, 0.57 mol) dropwise. The ice bath was removed and the solution was stirred for 24 h and then poured into ice water with stirring. The solid was then filtered and dried to give the title compound (45 g, 90%) which was used for the next step without any further purification.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[NH:6]2.[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:29][C@@H:28]([NH2:40])[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(O)C>[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:29][C@@H:28]([NH:40][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[NH:6]3)[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc3[nH]c(-c4cccc(Cl)c4)nc23)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 83.5 %

Procedure:
A solution of 6-chloro-8-(3-chlorophenyl)-9H-purine (155 mg, 0.58 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine (200 mg, 0.56 mmol) (Example 128, steps a-c), and N,N-diisopropylethylamine (0.20 mL, 1.17 mmol) in ethanol (2.00 mL) was microwaved at 160° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (275 mg, 76%) as a light yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH2:17])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]1[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[C:13]([C:14](=[O:18])[C:15]=1[CH2:16][NH:17][C:32]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:33])=[CH:12][CH:11]=[C:10]([Cl:19])[CH:9]=2)=[O:5]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1c(CNC(=O)N2CCOCC2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 50 mL flask, 3-aminomethyl-7-chloro-1-phenyl-1H-quinolin-4-one hydrochloride salt (intermediate I) (50 mg, 0.132 mmol) and morpholine-4-carbonyl chloride (21.7 mg, 0.145 mmol) were combined with CH2Cl2 (5 mL) and stirred at 0° C. for 10 min. Then N,N-diisopropylethylamine was added at 0° C. over 1 hr. The reaction mixture was stirred at and stirred at 0° C. for 4 hr. The reaction mixture was concentrated. The crude product was purified using preparative reverse phase HPLC to yield the product 7-chloro-3-{[(morpholine-4-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quino-line-2-carboxylic acid methyl ester. MS calcd. for C23H23ClN3O5 [(M+H)+] 456.1, obsd. 455.9.