Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[N:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]5)=[CH:22][CH:21]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:49]=[CH:50][CH:51]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31]5)=[CH:24][N:25]=4)[CH:18]=3)[N:13]([S:39]([C:42]3[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cn4)cnc32)cc1
Yield: 87.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(6-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazine-1-carboxylate (800 mg, 1.130 mmol) was deprotected in TFA/DCM (3/10 ml) to afford 600 mg (87.4% yield) of the titled compound. MS: m/z=608.2 (M+1).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][C@@H:7]([C:9]([F:12])([F:11])[F:10])[CH2:6][NH:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:33])=[CH:26][C:27]([C:31]#[N:32])=[N:28]2)=[CH:23][CH:22]=1>CC#N.O>[Cl:33][C:25]1[C:24]2[C:29](=[CH:30][C:21]([CH2:20][N:5]3[CH2:6][C@H:7]([C:9]([F:10])([F:12])[F:11])[O:8][C@H:3]([CH3:2])[CH2:4]3)=[CH:22][CH:23]=2)[N:28]=[C:27]([C:31]#[N:32])[CH:26]=1
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reactant: C[C@@H]1CNC[C@H](C(F)(F)F)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccc3c(Cl)cc(C#N)nc3c2)C[C@H](C(F)(F)F)O1
Temperature: 60 °C
Yield: 96 %

Procedure:
(2R,6R)-2-Methyl-6-(trifluoromethyl)morpholine hydrochloride (4-6, 500 mg, 2.432 mmol) and K2CO3 (739 mg, 5.35 mmol) were combined in CH3CN (10 ml) at rt. To this was added 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (2-4, 753 mg, 2.68 mmol) all at once as a solid then the mixture was heated to 60° C. overnight. The mixture was cooled to rt, diluted with H2O, and extracted with EtOAc (3×). The combined organic layers were filtered through a pad of Celite washing with EtOAc then concentrated. The crude product was subjected to silica gel chromatography (50 g, 0-10% EtOAc/hexanes, 15 minute gradient) to afford 4-chloro-7-(((2R,6R)-2-methyl-6-(trifluoromethyl)morpholino)methyl)quinoline-2-carbonitrile (4-7, 859, 96%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.26 (d, J=8.7 Hz, 1H); 8.11 (s, 1H); 7.83 (dd, J=8.6, 1.6 Hz, 1H); 7.78 (s, 1H); 4.09-4.01 (m, 1H); 3.79 (m, 3H); 2.90 (d, J=10.9 Hz, 1H); 2.73 (d, J=11.4 Hz, 1H); 2.28-2.17 (m, 1H); 2.03-1.92 (m, 1H); 1.20 (d, J=6.2 Hz, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:11]=2)[C:6]([CH3:31])([CH3:30])[CH2:5]1)(=O)C.Cl>O>[CH3:30][C:6]1([CH3:31])[C:7]2[C:12](=[CH:11][C:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[CH:9][CH:8]=2)[NH:4][CH2:5]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(NC(=O)c3ccccc3NCc3ccncc3)cc21
Agent: Cl
Solvent: O
Product: CC1(C)CNc2cc(NC(=O)c3ccccc3NCc3ccncc3)ccc21

Procedure:
N-(1-Acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (Example 2, 120 mg) was heated with HCl (5 N, 2.5 mL) and H2O (2.5 mL) to reflux for 2 h. The solvent was evaporated and the residue was washed with MeOH. The desired compound was collected after filtration as an off-white solid. MS: (ES+) 373 (M+H). Calc'd. for C23H24N4O-372.20.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[C:7]([S:18][CH3:19])=[N:8][C:9]([OH:17])=[C:10]([CH:16]=1)[C:11]([O:13]CC)=[O:12])#[N:5]>C(O)C.O>[C:4]([C:6]1[C:7]([S:18][CH3:19])=[N:8][C:9]([OH:17])=[C:10]([CH:16]=1)[C:11]([OH:13])=[O:12])#[N:5]
Reactant: CCOC(=O)c1cc(C#N)c(SC)nc1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1nc(O)c(C(=O)O)cc1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4.16 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a solution of 11.8 g (49.5 mmol) of ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate in 100 ml of ethanol and 100 ml of water. The reaction mixture is stirred at 60° C. for 2 hours. The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=1). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 9.9 g (95%) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in the form of a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a solution of 5-chloro-2-nitrophenol (40 g, 0.23 mol) in DMF (200 mL), K2CO3 (47.6 g, 0.345 mol) and iodomethane (49 g, 0.345 mol) were added and the resulting mixture was stirred at room temperature for 16 h. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether) to afford the desired product (30 g, 70% yield).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:36])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)cc1
Yield: 101.3 %

Procedure:
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (0.5 mL) and triethylamine (0.5 mL) was added. To this solution p-anisoyl chloride (60 mg, 0.35 mmol) dissolved in dichloromethane (0.5 ml) was added in one portion. The mixture was filtered and evaporated to afford 148 mg (100%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]2[N:17]3[C:13]([S:14][CH:15]=[CH:16]3)=[N:12][C:11]=2[CH3:18])=[O:9])[CH2:2]1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32](O)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[C:27]([C:32]([N:1]3[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8]([C:10]4[N:17]5[C:13]([S:14][CH:15]=[CH:16]5)=[N:12][C:11]=4[CH3:18])=[O:9])[CH2:2]3)=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1ccccc1-c1cccc(Cl)c1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCN(C(=O)c2ccccc2-c2cccc(Cl)c2)C1

Procedure:
prepared by reaction of (R)-6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid piperidin-3-ylamide with 3′-chloro-biphenyl-2-carboxylic acid.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10](Cl)=[CH:9][C:8](=[O:12])[N:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:6]=1)=[O:4].[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>ClC1C=CC=CC=1Cl.CCOC(C)=O>[Br:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:10]2[C:5]([C:3]([OH:2])=[O:4])=[N:6][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[CH:9]=2)=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: COC(=O)c1nn(-c2ccccc2)c(=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1Cl
Product: O=C(O)c1nn(-c2ccccc2)c(=O)cc1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 4-chloro-6-oxo-1-phenyl-1,6-dihydropyridazine-3-carboxylic acid methyl ester (0.250 g, 0.944 mmol) in 1,2-dichlorobenzene (3.8 mL) was added 4-bromo-2-fluoro aniline (0.561 g, 3.78 mmol), and cesium carbonate (0.615 mg, 1.89 mmol). The reaction mixture was heated to reflux. After 1 hour, the reaction mixture was cooled to room temperature. Water was added and the mixture was diluted with EtOAc. The aqueous layer was separated, acidified with 10% HCl solution, and extracted with EtOAc. The combined organic layers were dried (MgSO4), concentrated under reduced pressure, and triturated to give 0.153 g (43%) of the desired product.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][CH2:17][O:18][C:19]([C:21]1[C:22]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([OH:35])=[O:34])=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20].FC(F)(F)S(OC1C(C(OCOC)=O)=CC2C(=CC=CC=2)C=1)(=O)=O>CN(C)C=O.O>[CH3:15][O:16][CH2:17][O:18][C:19]([C:21]1[C:22]([C:31]2[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=2[C:33]([O:35][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:34])=[CH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20]
Reactant: BrCc1ccccc1
Reactant: COCOC(=O)c1cc2ccccc2cc1-c1ccccc1C(=O)O
Agent: COCOC(=O)c1cc2ccccc2cc1OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOC(=O)c1cc2ccccc2cc1-c1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Benzyl bromide (160 μl) and potassium carbonate (202 mg) were added to a solution of 2-(3-(methoxymethoxycarbonyl)naphthalen-2-yl)benzoic acid (410 mg) which was prepared by the same procedure as a series of reaction of Reference Example 4→Reference Example 5 using methoxymethyl 2-trifluoromethylsulfonyloxy-3-naphthalenecarboxylate, in dimethylformamid (5 ml). The mixture was stirred for 22 hours at room temperature. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=8:2) to give the title compound (498 mg) having the following physical data.
Reaction SMILES: I[C:2]1[C:3]([NH:8][C@@H:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[N:4][CH:5]=[CH:6][CH:7]=1.C1(C2C=CC=CC=2)C(O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O[C:37]([CH3:44])=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1.[Cu]I>[CH3:44][C:37]1[N:8]([C@@H:9]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])[C:3]2=[N:4][CH:5]=[CH:6][CH:7]=[C:2]2[C:38]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: C[C@@H](Nc1ncccc1I)C1CCOCC1
Reactant: CCOC(=O)C=C(C)O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1ccccc1-c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)n([C@H](C)C2CCOCC2)c2ncccc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
A re-sealable vial containing (S)- or (R)-3-iodo-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)pyridin-2-amine (0.333 g, 1.002 mmol), copper(I) iodide (0.0084 g, 0.044 mmol), biphenyl-2-ol (0.018 g, 0.106 mmol), and cesium carbonate (0.672 g, 2.062 mmol) was diluted with THF (3.5 mL). To the orange mixture was added ethyl 3-hydroxybut-2-enoate (0.25 mL, 1.977 mmol). The resultant blue-green contents were evacuated and purged with N2 (g) (3×). The vial was subsequently sealed and heated to 100° C. After 24 h, the reaction mixture was cooled to room temperature and filtered over a pad of Celite. The filter pad was washed with EtOAc (3×) and the filtrate was concentrated to give a thick brown oil. The resultant oil was purified on a Biotage system (50 g, gradient elution 2% EtOAc: 98% Hexanes to 15% EtOAc: 85% Hexanes, then 15% EtOAc: 85% Hexanes). The product (S)- or (R)-ethyl 2-methyl-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.257 g, 0.812 mmol, 81.0% yield) was isolated as a white foam. LRMS (M+H+) m/z: calcd 317.2. found 317.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19]C(=O)C)[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([OH:19])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(OC(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCOC(=O)c1ccc(OCc2ccccc2)c(O)c1
Reaction time: 2 h

Procedure:
The compound of step 2 (10 g, 31.8 mmol) was dissolved in methanol, potassium carbonate (88 mg, 0.636 mmol) was added and the mixture was stirred for 2 h under reflux. The solution was evaporated to dryness and the residue used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([F:42])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5].FC(F)(F)C(O)=O>>[CH3:43][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([F:42])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCc1ccc(-c2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)[C@@H](NC(=O)[C@H](C/C=C/c1ccc(-c2ccccc2)c(F)c1)CC(=O)OC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 72.4 %

Procedure:
According to the method of Preparation 1, tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-fluoro-(4-phenyl)phenyl]hexanoate (650 mg, 1.08 mmol) was treated with trifluoroacetic acid at 20° C. for 4 h to give the title compound (470 mg, 80%).
Reaction SMILES: [O:1]=[CH:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]=1[CH3:23])=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[BH4-].[Na+]>CO>[OH:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:22]=1[CH3:23])=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1
Reactant: Cc1c(C(=O)N[C@@H](CC=O)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(C(=O)N[C@@H](CCO)c2cccc(C(F)(F)F)c2)cnn1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 45.7 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-3-oxo-1-(3-trifluoromethyl-phenyl)-propyl]-amide (80 mg, 0.18 mmol) in methanol (3 mL) is added sodium borohydride (50 mg, 1.3 mmol). After 16 hours, the crude reaction mixture is purified directly by flash chromatography on silica gel (eluted with 4 to 10% MeOH/CH2Cl2) to afford 1-(4-chloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [(S)-3-hydroxy-1-(3-trifluoromethyl-phenyl)-propyl]-amide as a white solid (36 mg, 45%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[C:31]([NH2:34])(=[O:33])[CH3:32]>>[C:31]([NH:34][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4])(=[O:33])[CH3:32]
Reactant: CC(N)=O
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Product: CC(=O)NCC(=O)Nc1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and acetamide were reacted to give 211. MS: (ESI+) 484.1
Reaction SMILES: [F:1][C:2]1([F:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][CH2:12][C:13]#[CH:14])=[CH:10][C:4]=2[O:3]1.[N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]=[S:18]>C1COCC1>[F:15][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:12][C:13](=[CH2:14])[S:18]/[C:17]/3=[N:16]\[C:19](=[O:20])[O:21][CH2:22][CH3:23])=[CH:10][C:4]=2[O:3]1
Reactant: C#CCNc1ccc2c(c1)OC(F)(F)O2
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Product: C=C1CN(c2ccc3c(c2)OC(F)(F)O3)/C(=N/C(=O)OCC)S1

Procedure:
A solution of Example 1 (0.22 g, 1.05 mmol) and ethyl isothiocyanatoformate (0.11 mL, 1.05 mmol) in dry THF was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) δ ppm 1.32 (3H), 4.27 (2H), 4.70 (2H), 5.30 (2H), 7.00-7.25 (3H); MS (ESI) 343 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:31])[N:4]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:5]([CH3:22])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:11]=1[O:12][CH2:13][C:14](O)=[O:15].C[N:33]1CCO[CH2:35][CH2:34]1.ClC(OCC(C)C)=O.C(N)C>CC(N(C)C)=O>[Br:1][C:2]1[C:3](=[O:31])[N:4]([C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])[C:5]([CH3:22])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:11]=1[O:12][CH2:13][C:14]([NH:33][CH2:34][CH3:35])=[O:15]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2OCC(=O)O)c(Br)c(=O)n1-c1c(F)cccc1F
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: CC(=O)N(C)C
Product: CCNC(=O)COc1cc(F)ccc1COc1cc(C)n(-c2c(F)cccc2F)c(=O)c1Br
Yield: 50.8 %

Procedure:
To a cooled (−10° C.) solution of [2-({[3-bromo-1-(2,6-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridin-4-yl]oxy}methyl)-5-fluorophenoxy]acetic acid (from Step 4) (0.15 g, 0.30 mmol) in DMA (2.0 mL) was added 4-methylmorpholine (0.04 mL, 0.36 mmol) and isobutyl chloroformate (0.05 mL, 0.36 mmol). Ethylamine (0.04 mL, 0.45 mmol) was added after 20 minutes. DMF removed by distillation after 1 h. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a white solid (0.080 g, 51%). 1H NMR (CD3OD/400 MHz) δ7.60 (m, 1H), 7.53 (t, 1H, J=8.0 Hz), 7.23 (t, 2H, J=8.4 Hz), 6.82 (m, 2H), 6.71 (s, 1H), 5.42 (s, 2H), 4.61 (s, 2H), 3.31 (q, 2H, J=6.4 Hz), 2.10 (s, 3H), 1.09 (t, 3H, J=7.2 Hz). ESHRMS m/z 525.0616 and 527.0568 (M+H calculated for C23H21BrF3N2O4 requires 525.0631 and 527.0614).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH2:20]Br>CN(C=O)C>[F:15][C:16]([F:29])([F:30])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1)[CH2:20][O:4][CH2:3][C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:5][OH:6]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(CO)(CO)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(CO)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-phenylpropane-1,3-diol (3.37 g, 20.3 mmol) was dissolved in DMF, NaH (812 mg, 60%, 20.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. A DMF solution of 3,5-bistrifluoromethylbenzyl bromide (6.23 g, 20.3 mmol) was added in one portion and stirred for another 1 hour before it was quenched with water and extracted with ethyl acetate. The organic phase was washed with brine and dried with Na2SO4 before being concentrated. The crude product was purified by silica flash chromatography using 15% ethyl acetate in hexanes to yield 4.2 grams (52.8%) of the desired mono-alkylated product. 1H NMR (500 MHz, CDCl3) δ: 1.40 (s, 3 H) 1.78 (s, 1 H) 3.72 (d, J=9.16 Hz, 1 H) 3.82 (d, J=9.16 Hz, 1 H) 3.89 (m, 2 H) 4.64 (s, 2 H) 7.26 (m, 1 H) 7.37 (m, 4 H) 7.72 (s, 2 H) 7.79 (s, 1 H).
Reaction SMILES: [O:1]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][CH2:5]C.[CH3:21][O:22]N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)CC>>[CH3:21][O:22][C:19]1[CH:20]=[C:15]([C:2](=[O:1])[C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:4][CH3:5])[CH:16]=[CH:17][CH:18]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)c1cccc(OC)c1

Procedure:
was synthesised in the same way as 91c from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxobutan-2-ylcarbamate (95d, 250 mg, 1.02 mmol).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([O:14][CH2:15][CH3:16])[CH:4]=1>C(O)C>[CH2:15]([O:14][C:5]1[CH:4]=[C:3]([CH2:2][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16]
Reactant: CCOC(=O)c1ccc(CBr)cc1OCC
Solvent: CCO
Product: CCOC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1
Temperature: 50 °C
Yield: 177.1 %

Procedure:
A mixture of ethyl 4-bromomethyl-2-ethoxy-benzoate (4, 1 gm, 3.5 mmol), dichlorobis(1,2,5-triphenylphosphole)-palladium catalyst (0.1 gm), ethyl alcohol (5 ml) was heated to 50° C. with CO for 6-15 hrs. Catalyst was filtered and solvent was removed to yield the product ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate (1, 0.87 gm, 3.1 mmol, 88%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:11][C:12]([C:15]3[NH:16][C:17]([C:20]([O:22]C)=[O:21])=[CH:18][CH:19]=3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[O:4].CO.[OH-].[Na+]>O>[OH:4][C:3]([C:5]1[NH:9][C:8]([C:10]2[S:11][C:12]([C:15]3[NH:16][C:17]([C:20]([OH:22])=[O:21])=[CH:18][CH:19]=3)=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc(-c3ccc(C(=O)OC)[nH]3)s2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(-c2ccc(-c3ccc(C(=O)O)[nH]3)s2)[nH]1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
A mixture of compound 5 (1.56 g, 4.73 mmol), methanol (125 mL), NaOH (30 g) and H2O (80 mL) was refluxed. The reaction was cooled to room temperature and the methanol was removed under reduced pressure. The mixture was poured into ice water and acidified slowly using 1 M HCl until a solid precipitate resulted. Filtration and drying produced 1.29 g (4.3 mmol, 90%) of the green title compound. 1H-NMR (d-DMSO): δ 7.33 (s, 1H), 6.81 (dd, 1H), 6.37 (dd, 1H). 13C-NMR: δ162.2, 134.6, 132.0, 125.1, 124.4, 117.1, 108.8.