Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=1)=[O:40]>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[N:42]=[CH:43][N:44]([CH3:46])[CH:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CON(C)C(=O)c1cn(C)cn1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@H](C)O1
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3cn(C)cn3)c(F)c2F)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,3-difluorophenyl]-2,6-dimethylmorpholine (Intermediate 3) and N-methoxy-N,1-dimethyl-1H-imidazole-4-carboxamide
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl:16][C:17]1[CH:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH2:30])[CH:20]=[CH:19][C:18]=1[C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C.C1(C)C=CC=CC=1.C(Cl)Cl.CCOC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[NH:30][C:9](=[O:11])[CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:20]=[CH:19][C:18]=1[C:31](=[O:32])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39]
Reactant: O=C(O)COc1ccccc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2NC(=O)COc2ccccc2)cc1Cl
Reaction time: 3 h

Procedure:
A solution of 2-phenoxyacetic acid (75 mg, 0.49 mmol), thionylchloride (72 μL, 1.0 mmol) and one drop of DMF in toluene (2.0 mL) was refluxed for 30 min. The reaction mixture was concentrated in vacuo and the resulting crude acid chloride was dissolved in dry DCM (2.0 ml). The solution was added slowly to a cooled (0° C.) solution of {2-chloro-4-[(2-aminophenyl)amino]phenyl}(2-methylphenyl)methanone (0.150 g, 0.45 mmol) (disclosed in WO 98/32730) and triethylamine (135 mg, 1.33 mmol) in dry DCM (5.0 ml). The solution was allowed to reach room temperature. The reaction mixture was stirred for 3 h and then poured into a mixture of NaHCO3 (aq.) and EtOAc. The aqueous phase was extracted with more EtOAc (×2). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using DCM as the eluent to afford the title compound as a yellow oil.
Reaction SMILES: C1COCC1.[BH4-].[Na+].[OH:8][C@@:9]([C:41]1[CH:50]=[CH:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:51]([NH:53][CH3:54])=[O:52])[CH:47]=2)[CH:42]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[CH2:10][C:11](OC(C)C)=[O:12].[Cl-].[NH4+]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.O>[OH:8][C:9]([C:41]1[CH:42]=[C:43]2[C:48](=[CH:49][CH:50]=1)[CH:47]=[C:46]([C:51]([NH:53][CH3:54])=[O:52])[CH:45]=[CH:44]2)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CC(=O)OC(C)C)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1ccc2cc(C(O)(CCO)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
3 mL of THF and 0.17 g (1.25 mmol, 8 eq) of zinc chloride were added to 0.095 g (2.51 mmol, 8 eq) of sodium borohydride. The mixture was stirred at 25° C. for 10 minutes. 0.2 g (0.31 mmol) of isopropyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate was added. The mixture was stirred at 40° C. for 31 hours. After cooled to 25° C., 3 droplets of water was added dropwise, 11 mL of water, 1 mL of an aqueous saturated ammonium chloride solution and 12 mL of ethyl acetate were added, and the layers were separated. The organic layer was washed successively with a mixed solution of 1 mL of an aqueous saturated ammonium chloride solution and 8 mL of water, and 8 mL of water 2 times. After concentrated under reduced pressure, the concentration residue was loosened with 4 mL of water, and crystals were filtered. Vacuum drying (40° C.) to a constant weight afforded 0.15 g of 6-[1,3-dihydroxyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (yield 76%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[NH:31][C:32](=[O:33])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: NC(=O)c1[nH]c2ncccc2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1

Procedure:
40.56 mg of solid white 3-{4-[3-(2-chloro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and 2-chloro-5-trifluoromethylphenyl isocyanate.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl[CH2:5][C:6]1[CH:26]=[CH:25][C:9]([CH2:10][C:11]2[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[N:13][C:14]([NH2:18])=[N:15][C:16]=2[CH3:17])=[C:8]([O:27][CH3:28])[CH:7]=1>CS(C)=O.CN(C=O)C.C([O-])(O)=O.[Na+]>[NH2:18][C:14]1[N:15]=[C:16]([CH3:17])[C:11]([CH2:10][C:9]2[CH:25]=[CH:26][C:6]([CH2:5][C:1]#[N:2])=[CH:7][C:8]=2[O:27][CH3:28])=[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:13]=1
Reactant: [C-]#N
Reactant: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CCl)cc1OC
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 62.2 %

Procedure:
Potassium cyanide (0.53 g) was added to a solution of the product from step (vi) (0.99 g) in DMSO (10 mL) and DMF (10 mL) under nitrogen. The resulting mixture was stirred at rt for 20 h and diluted with saturated aqueous NaHCO3 (50 mL). The mixture was extracted with EtOAc and the combined organic phase was washed with water and brine, dried, filtered and evaporated. The crude product was purified by chromatography, eluting with 5% MeOH in DCM to afford the subtitle compound as an orange solid 0.6 g.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:17]2=[N:16][C:15]=1[CH3:31])=[O:13])(=[O:10])=[O:9])(=O)C.CO.[OH-].[Na+]>C1COCC1>[CH:25]1([CH2:24][O:23][C:22]2[C:17]3[N:18]([C:14]([C:12]([NH:11][S:8]([CH2:7][CH2:6][CH2:5][OH:4])(=[O:10])=[O:9])=[O:13])=[C:15]([CH3:31])[N:16]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NS(=O)(=O)CCCO
Reaction time: 8.5 h
Yield: 34.8 %

Procedure:
To 130 mg of 3-[({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)sulfonyl]propyl acetate were added 2 ml of methanol, 2 ml of THF, and 1 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring for 8.5 hours. The solvent was evaporated under reduced pressure and to the obtained residue were added water and 1 M hydrochloric acid. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained purified product were added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 41 mg of 8-(cyclohexylmethoxy)-N-[(3-hydroxypropyl)sulfonyl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [I:1][C:2]1[C:3]([C:8](O)=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C(CO)=CC(F)=C(Cl)N=1>>[I:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1I
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1ncccc1I
Yield: 10.6 %

Procedure:
Compound 51A (10 mg, 10%) was prepared from 3-iodo-pyridine-2-carboxylic acid (100 mg, 0.4 mmol) ) using a procedure similar to the synthesis of 1A. HPLC Rt=0.3 min
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5].ClS([N:49]=[C:50]=[O:51])(=O)=O.C(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C.O.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>[NH2:2][C@:3]([N:49]=[C:50]=[O:51])([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@@](N)(N=C=O)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Yield: 63.5 %

Procedure:
To a solution of HCl.H-Thr-D-Trp(CHO)-Phe-NMeBzl (0.94 g) and triethylamine (0.153 g) in acetonitrile (12 ml), was added chlorosulfonyl isocyanate (0.214 g) under cooling with Dry ice and carbon tetrachloride bath. The solution was stirred at the same temperature for an hour and then stirred under ice-cooling. Chlorosulfonyl isocyanate (0.214 g) was added at this temperature, after stirring for fifteen minutes, water (3 ml) was added. The pH was adjusted to pH 4 with sodium hydrogencarbonate and the mixture was stirred for an hour. After evaporation of acetonitrile, the product was extracted with ethyl acetate under saturation with sodium chloride. The organic layer was washed with sodium chloride solution and concentrated. The residue was dissolved in CH3CN-H2O (8:2) (20 ml) and applied to a column of ®TOYO PEARL HW-40 (26 mmφ, 400 ml) and eluted with CH3CH-H2O (7:3), and fractionated. The main fraction was collected, and after evaporation of acetonitrile, n-butanol and ethyl acetate was added and the organic layer was separated and concentrated to give H2NCO-Thr-D-Trp(CHO)-Phe-NMeBzl (600 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([C:27]([F:28])([F:29])[F:30])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(C(F)(F)F)cc1N
Product: COc1ccc(C(F)(F)F)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-amino-4-methoxybenzotrifluoride (55 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (56 mg, 70%). 1H NMR (CDCl3): 9.66 (dd, J=0.6, 2.1 Hz, 1H), 8.95 (s, 1H), 8.75 (dd, J=1.8, 4.8 Hz, 1H), 8.73–8.69 (m, 1H), 7.67 (s, 1H), 7.46–7.42 (m, 1H), 7.41–7.37 (m, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.93 (s, 1H), 3.99 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH3:31][C:32]([CH3:37])([CH3:36])[C:33](Cl)=[O:34].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:31][C:32]([CH3:37])([CH3:36])[C:33]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)=[O:34]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.363 mmol) in pyridine (5 mL) was added dropwise 2,2-dimethylpropanoyl chloride (49 μL, 0.399 mmol), and the mixture was stirred at room temperature for 16 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and precipitated from ethyl acetate/hexane to give the title compound (90 mg, 50%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([SH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.BrC1SC2C=CC=CC=2N=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([S:11][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: Clc1nc2ccccc2s1
Reactant: COC(=O)C(S)c1ccccc1
Agent: Brc1nc2ccccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Sc1nc2ccccc2s1)c1ccccc1

Procedure:
18.2 g of 2-mercapto-2-phenylacetic acid methyl ester is added to a suspension of 2.4 g of NaH in 200 ml of DMF and the mixture is stirred until the evolution of gas has ceased. 17 g of 2-chlorobenzothiazole (or 21.5 g of 2-bromobenzothiazole) is then introduced. The mixture is stirred for 5 hours at 80° and is worked up in the customary manner to give 2-(benzothiazol-2-ylthio)-2-phenylacetic acid methyl ester, in the form of an oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH:34][CH2:35][C:36]1[CH:37]=[C:38]([S:42][C:43]2[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=2)[CH:39]=[CH:40][CH:41]=1.[OH:51][C:52]1[C:57]([CH3:58])=[C:56](O)[CH:55]=[CH:54][C:53]=1[C:60](=[O:62])[CH3:61]>C1COCC1.C(OCC)(=O)C>[C:60]([C:53]1[CH:54]=[CH:55][C:56]([O:34][CH2:35][C:36]2[CH:37]=[C:38]([S:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[N:47][CH:48]=3)[CH:39]=[CH:40][CH:41]=2)=[C:57]([CH3:58])[C:52]=1[OH:51])(=[O:62])[CH3:61]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)cn1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(OCc2cccc(Sc3ccc(C#N)nc3)c2)c(C)c1O
Reaction time: 8 h
Yield: 73 %

Procedure:
Add triphenylphosphine (1.84 g, 7.02 mmol) and diisopropylazodicarboxylate (1.42 g, 7.02 mmol) to a solution of 5-(3-(hydroxymethyl)phenylthio)picolinonitrile (1.70 g, 7.02 mmol) and 1-(2,4-dihydroxy-3-methylphenyl)ethanone (1.17 g, 7.02 mmol) in THF (35.1 mL). Stir overnight. Dilute with ethyl acetate. Wash the mixture with water and brine. Dry, filter and concentrate to afford the title compound (2.00 g, 73%). Use as is. MS (APCI-neg) m/z (rel intensity): 390 (M+H, 100%).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1([C:39]([O:41]C)=[O:40])[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[C:25]([CH:26]4[CH2:28][CH2:27]4)=[CH:24][N:23](S(C4C=CC(C)=CC=4)(=O)=O)[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.CCOC(C)=O>[C:3]([O:7][C:8]([NH:10][C:11]1([C:39]([OH:41])=[O:40])[CH2:12][CH2:13][N:14]([C:17]2[C:18]3[C:25]([CH:26]4[CH2:27][CH2:28]4)=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3c2c(C2CC2)cn3S(=O)(=O)c2ccc(C)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]cc(C4CC4)c23)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 68.2 %

Procedure:
2M sodium hydroxide solution (5.00 mL) was added to methyl 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylate (Intermediate 63) (780 mg, 1.37 mmol) in THF (10 mL) at 20° C. The resulting solution was stirred at 40° C. for 24 hours. The reaction mixture was diluted with EtOAc (50 mL) and the aqueous layer was collected and acidified to pH4 with 2M HCl solution. The aqueous layer was extracted with DCM (2×50 mL) and the organic layers combined and washed with saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product 4-(tert-butoxycarbonylamino)-1-(5-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (375 mg, 68.2%) as a cream solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.C[Si]([C:14]#[CH:15])(C)C.C(N(CC)C(C)C)(C)C>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1CCCC1=O>[C:14]([C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[CH:15]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(F)cc1I
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(F)cnc1N
Temperature: 70 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (751 mg, 3.16 mmol) described in Manufacturing Example 173-1-1, trimethylsilylacetylene (874 μL, 6.32 mmol), copper (I) iodide (60.2 mg, 0.32 mmol), N,N-diisopropylethylamine (1.07 mL, 6.32 mmol), and N-methylpyrrolidinone (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (183 mg, 0.16 mmol), which was stirred for 3 hours under nitrogen atmosphere at 70° C. This reaction solution was cooled to room temperature, and then partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue thus obtained was purified by NH silica gel column chromatography and then silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (129 mg, 30%).
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@@H:10]([OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O)(=O)C1C=CC=CC=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.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C#C[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,5S)-N-Boc-3-Hydroxy-5-ethynyl-pyrrolidine (200 mg, 0.95 mmol) (Example 99C), benzoic acid (138 mg, 0.11 mmol) and triphenyl phosphine (373 mg, 1.42 mmol) in 15 mL of THF was added diisopropyl azodicarboxylate (287 mg, 1.42 mmol) at 0° C. The mixture was allowed to slowly warm up to room temperature and stirred for 18 hrs. The reaction mixture was then concentrated and the residue was directly passed through a silica gel column with a 0-30% EtOAc in hexanes gradient. The intermediate benzoate ester was dissolved in 6 mL of MeOH and then K2CO3 (260 mg, 1.89 mmol) was added. The mixture, after overnight stirring, was filtered and concentrated to a residue which after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient afforded (3S,5S)-N-Boc-5-ethynyl-3-hydroxy-pyrrolidine. (Yield 170 mg, 85%).
Reaction SMILES: [N:1]([C@@H:4]([C@H:19]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:5](N1[C@@H](C2C=CC=CC=2)COC1=O)=[O:6])=[N+:2]=[N-:3].OO.[Li+].[OH-].S([O-])([O-])=[O:40].[Na+].[Na+].C([O-])(O)=O.[Na+]>C1COCC1.O>[N:1]([C@@H:4]([C@H:19]([C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=1)[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:5]([OH:40])=[O:6])=[N+:2]=[N-:3]
Reactant: O=S([O-])[O-]
Reactant: [N-]=[N+]=N[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(F)cc1)c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of (4S)-3-[(2S,3S)-2-azido-3-(3,5-difluorophenyl)-3-(4-fluorophenyl)propanoyl]-4-phenyl-1,3-oxazolidin-2-one (3.1 g, 6.7 mmol) in 45 mL of THF and 15 mL of water was cooled to 0° C. in an ice-water bath. To the stirred solution was added hydrogen peroxide (2.7 mL of a 30% solution in water, 27 mmol) and LiOH (0.32 g, 13 mmol), and the mixture was stirred at 0° C. for 45 min. The reaction was quenched by the addition of a solution of sodium sulfite (3.4 g, 27 mmol) in 20 mL of water, followed by 67 mL of a 0.5 M solution of aqueous NaHCO3 (33 mmol). The stirred mixture was warmed to ambient temperature and most of the THF was removed in vacuo. The aqueous mixture was extracted with two portions of CH2Cl2 to remove the chiral auxiliary. The aqueous phase was then acidified to pH 1 with the addition of 6 N HCl and extracted with two portions of EtOAc. The combined EtOAc layers were dried (MgSO4), filtered, and the solvent was removed in vacuo to give a gum.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][C:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=34)[S:5]2(=[O:17])=[O:16])[CH2:34][CH:35]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: Fc1ccc2[nH]cc(CC3=CCNCC3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CC=C(Cc2c[nH]c3ccc(F)cc23)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 11.6 %

Procedure:
The procedure is as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2 g), 4-[(5-fluoro-3-indolyl)methyl]-1,2,3,6-tetrahydropyridine hydrochloride (2 g) and sodium bicarbonate (1.3 g) in a mixture of dimethylformamide (70 cc) and tetrahydrofuran (45 cc). The mixture is heated to boiling for 20 hours and then cooled to a temperature in the region of 20° C. After purification by flash chromatography on a silica column under a stream of nitrogen at moderate pressure (0.5-1.5 bar) with dichloromethane and then ethyl acetate as eluents, 2-{2-[4-((5-fluoro-3-indolyl)methyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (0.4 g) is obtained in the form of a yellow oil, which is converted to an acid oxalate, m.p. 128° C.