Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC(C)c4ccccc4)C(=O)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-(4′-{3-methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and benzoyl chloride.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[Br:27][C:28]1[CH:29]=[C:30]([OH:37])[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O>O>[Br:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[O:37][C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Cl
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cc(Br)cc([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (250 mg), 3-bromo-5-nitrophenol (170 mg), potassium carbonate (138 mg), and N-methylpyrrolidone (5 mL) was stirred at 100° C. for 4 hours. To the reactant was added water, followed by extraction with ethyl acetate. The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol=1:0-9:1) to obtain 5-(3-bromo-5-nitrophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (336 mg) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6]1([CH3:32])[CH2:10][CH2:9][CH:8]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]1([CH3:31])[CH3:30].[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[C:14]([SiH2:13][O:12][C:11]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:8]1[CH2:9][CH2:10][C:6]([CH:5]=[CH:4][CH2:3][OH:2])([CH3:32])[C:7]1([CH3:31])[CH3:30])([CH3:15])([CH3:16])[CH3:17]
Reactant: COC(=O)C=CC1(C)CCC(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)C1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1CCC(C)(C=CCO)C1(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
Intermediate (5) (11.12 g, 23.92 mmol) in CH2Cl2 (150 mL) at −78° C. was added dropwise diisobutylaluminium hydride (1.5 M solution in toluene; 63.8 mL, 95.67 mmol) over a period of 30 minutes. After stirring at −78° C. for 2 hours, the reaction mixture was allowed to warm to −55° C. over a period of 2 hours and the reaction was quenched by the addition of a 2 N K—Na-tartrate solution (100 mL). H2O (400 mL) was added and the aqueous layer was extracted with Et2O (4×150 mL). The combined organic layers were dried over anhydrous MgSO4, the solvent removed in vacuo and the resulting residue was purified over silica (n-hexane/ethyl acetate, 85:15) to afford 10.34 g (99% yield) of the desired intermediate (6) as a colourless oil which was characterized as follows:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:29][C:30]#[N:31].CI>O1CCCC1>[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:29]([CH3:1])[C:30]#[N:31]
Reactant: N#CCc1cccc(F)c1F
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to −10° C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to −78° C. and a solution of 2.00 g (13 mmol) 2,3-difluorophenyl-acetonitrile in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at −78° C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+.), 152.1 (((M-CH3)+.), 100%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][NH:12][C:11]1=[O:15])([CH3:6])([CH3:5])[CH3:4].[C:17]1([S:23]([N:26]2[C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=3[CH:28]=[C:27]2[CH2:36]Br)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:3]([O:7][C:8](=[O:16])[NH:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:36][C:27]2[N:26]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:34]3[CH:33]=[CH:32][N:31]=[C:30]([Cl:35])[C:29]=3[CH:28]=2)[C:11]1=[O:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=S(=O)(c1ccccc1)n1c(CBr)cc2c(Cl)nccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cc3c(Cl)nccc3n2S(=O)(=O)c2ccccc2)C1=O
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.081 g, 2.02 mmol, 60% mineral oil dispersion) is added to a solution of [2-oxopyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (0.404 g, 2.02 mmol) in DMF (5 mL) at 0° C. The mixture is stirred for 10 minutes, then cannulated dropwise to a solution of 1-benzenesulfonyl-2-bromomethyl-4-chloro-1H-pyrrolo[3,2-c]pyridine (0.74 g, 1.92 mmol) in DMF (10 mL) at 0° C. The resulting yellow solution is stirred for 1 hour at 0° C. then quenched with saturated ammonium chloride solution and diluted with EtOAc. The organic layer is washed with water and brine, then dried over MgSO4, filtered and concentrated. The solid product (0.94 g, 1.86 mmol) is used in the subsequent step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12](=[O:15])[NH:13][CH3:14])=[C:7](B(O)O)[O:8][C:4]=2[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1I>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[C:6]([C:12]([NH:13][CH3:14])=[O:15])=[C:7]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=3[F:26])[O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc(I)c(F)c1
Reactant: CNC(=O)c1c(B(O)O)oc2cc(N)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N)c(Br)cc12
Temperature: 15 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a mixture of (6-amino-5-bromo-3-(methylcarbamoyl)benzofuran-2-yl)boronic acid (4.78 g, 11.46 mmol), K3PO4.3H2O (8.32 g, 31.25 mmol) and 2,4-difluoro-1-iodobenzene (2.50 g, 10.42 mmol) in DMF (25 mL) was added Pd(dppf)Cl2 (380 mg, 0.52 mmol) under N2, and then the mixture was stirred at 15° C. for 3 hours. After the solvent was removed, EtOAc/H2O (10 mL/20 mL) was added to the mixture. After stirring 15 minutes, the resulting solid was filtered to give the product of 6-amino-5-bromo-2-(2,4-difluorophenyl)-N-methylbenzofuran-3-carboxamide (2.80 g, yield: 70%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.06 (d, J=1.6 Hz, 1H), 7.74 (d, J=10.4 Hz, 1H), 7.70 (s, 1H), 7.41 (s, 1H), 7.24 (s, 1H), 7.00 (s, 1H), 5.58 (br s, 2H), 2.76 (s, 3H). MS (M+H)+: 281/283
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38](Br)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]>>[OH:25][CH2:26][C:27]([NH:30][S:31]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[CH:39]=1)(=[O:33])=[O:32])([CH3:29])[CH3:28]
Reactant: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2)(281 mg, 1.0 mmol) according to general procedure II. Obtained as a light-brown solid (200 mg, 35%). MS (ISP) 566.2 [(M+H)+]; mp 200-201° C.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([O-])([O-])=[O:13].[K+].[K+]>CO>[Br:1][C:2]1[C:3](=[O:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([OH:13])[CH:5]=2
Reactant: O=C1C(Br)=Cc2ccccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1C(Br)=Cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1 to 1.2 eq of the 2-bromo-1H-indenone prepared in Step 4 is dissolved in MeOH, and then K2CO3 (1 to 2 eq) is added thereto. The resulting mixture is stirred at room temperature for 2 to 7 h, to obtain the 2-bromo-6-hydroxy-1H-indenone of formula 8 in which acetyl group is removed.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]=[CH:4][C:5](O)=[O:6].[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1>>[CH:10]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:5](=[O:6])[CH:4]=[CH:3][C:2]([F:9])([F:8])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)C=CC(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)C=CC(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 4,4,4-trifluorobut-2-enoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder (19.6% yield). 1H NMR (500 MHz, CDCl3) δ 8.09, 8.00, 7.00, 6.81, 3.96-3.88, 3.78, 3.57, 1.53, 0.76, 0.48, 0.10. MS (ES+) m/z 398 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:3]1.[OH-].[Na+].CO>O>[OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: COC(=O)CCCCCCC1=CC(O)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 16 h

Procedure:
A mixture of 0.240 part of methyl 3-hydroxy-5-oxocyclopent-1-eneheptanoate, 10 parts by volume of 0.1 N sodium hydroxide and 7.9 parts of methanol is allowed to stand at room temperature for 16 hours, then diluted with water and extracted with ethyl acetate. The aqueous layer is acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over anhydrous sodium sulfate and stripped of solvent under reduced pressure. Chromatography of the crude product on silica gel with 50% ethyl acetate-benzene affords 3-hydroxy-5-oxocyclopent-1-eneheptanoic acid, melting at about 47°-48.5°. That compound is characterized further by absorption in the ultravoilet spectrum at about 222 millimicrons with a molecular extinction coefficient of about 7700 and a maximum in the nuclear magnetic resonance spectrum at about 87.2 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([CH3:17])[CH:16]=1)[C:5]([C@H:7]1[CH:11]([CH3:12])[CH2:10]OC1=O)=[O:6].[ClH:18].C(=O)(O)[O-].[Na+]>>[Cl:18][CH2:10][C@H:11]([CH3:12])[CH2:7][C:5]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:16]=[C:15]([CH3:17])[CH:14]=1)=[O:6]
Reactant: Cl
Reactant: Cc1cc(C)cc(C(=O)[C@@H]2C(=O)OCC2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C)cc(C(=O)C[C@@H](C)CCl)c1
Reaction time: 1 h

Procedure:
To a solution of (R)-3-(3,5-dimethylbenzoyl)-4-methyldihydrofuran-2-one (2.42 g in 15 mL dioxane) was added 15 mL conc. hydrochloric acid and the mixture heated to reflux on an oil bath. After one hour, the reaction was poured into cold, saturated aqueous sodium bicarbonate. Additional solid sodium bicarbonate was added until all acid was neutralized. This was then extracted with ethyl acetate, washed with brine. Concentration in vacuo provided the title compound (2.12 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][C@H:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([N:1]3[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][C@H:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]([C:28]([NH2:30])=[O:29])[CH2:20]4)[CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: NC(=O)N1C[C@@H](CCBr)c2ccccc21
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)N1C[C@@H](CCN2CCN(c3ccc4[nH]ccc4c3)CC2)c2ccccc21
Yield: 45.3 %

Procedure:
A mixture of 5-(piperazin-1-yl)-1H-indole (3.37 g, 0.017 mol), (S)-3-(2-bromoethyl)-2,3-dihydro-1H-indole-1-carboxylic acid amide (3.0 g, 0.11 mol), potassium carbonate (2.31 g, 0.017 mol) in butanone (450 mL) was boiled under reflux for 12 h. The mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (ethyl acetate/ethanol/triethylamine 70:25:5). The purified residue was precipitated from ethyl acetate to give the title compound as a white solid (3.0 g). Assignment of the optical rotation was done in dimethyl sulfoxide.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:18][C:19]([F:37])([F:36])[C:20]1[CH:21]=[C:22]([C:30](=O)[C:31]([F:34])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1.[OH-].[Ca+2].[OH-].CN(C)C=O>COC(C)(C)C>[F:18][C:19]([F:36])([F:37])[C:20]1[CH:21]=[C:22]([C:30]([C:31]([F:34])([F:33])[F:32])=[CH:2][C:1]([C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]([C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=2)=[O:3])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: COC(=O)c1ccc(C(C)=O)c2ccccc12
Agent: [Ca+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: COC(=O)c1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)c2ccccc12
Reaction time: 10 h

Procedure:
A mixture of methyl 4-acetyl-1-naphthalenecarboxylate (5.36 g, 23.5 mmol), 1-[3,5-bis(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (7.28 g, 23.5 mmol), calcium hydroxide (1.40 g, 18.9 mmol), N,N-dimethylformamide (16 mL) and tert-butyl methyl ether (32 mL) was boiled with provision of the apparatus comprising a ten-plate Oldershaw column and decanter described in Example 1, Step A for removal of the tert-butyl methyl ether/water azeotrope. As the decanter trap contained an amount of tert-butyl methyl ether sufficient to dissolve all of the water formed by the reaction, the condensate in the trap did not separate into layers containing predominately water and predominately tert-butyl methyl ether. Tert-butyl methyl ether was removed by gradually draining the decanter trap until the pot temperature was 85° C. To maintain this temperature, tert-butyl methyl ether was added as needed to compensate for loss of solvent from the apparatus. The total time from beginning heating the reaction mixture to stopping distillation, not including a shutdown period overnight, was about 10 h. During this time period no additional calcium hydroxide was added to the reaction mixture.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)[C:8]([O:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:9])[CH2:3]1.[ClH:26].[CH:27](=[NH:31])OCC>C(O)C>[ClH:26].[F:25][C:2]1([F:1])[CH2:6][CH2:5][C@@H:4]([C@@:7]([OH:24])([C:17]2[CH:18]=[CH:19][C:20]([Br:23])=[CH:21][CH:22]=2)[C:8]([O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH:27]=[NH:31])[CH2:15][CH2:16]2)=[O:9])[CH2:3]1
Reactant: CCOC=N
Reactant: O=C(OC1CCNCC1)[C@](O)(c1ccc(Br)cc1)[C@@H]1CCC(F)(F)C1
Agent: Cl
Solvent: CCO
Product: N=CN1CCC(OC(=O)[C@](O)(c2ccc(Br)cc2)[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 60.1 %

Procedure:
To a solution of 13 mg of piperidin-4-yl (2R)-2-((1R)-3,3-difluorocyclopentyl)-2-hydroxy-2-(4-bromophenyl)ethanoate in 1 ml of anhydrous ethanol, 4 mg of ethyl formimidate hydrochloride was added, followed by 13 hours' stirring at room temperature. The reaction liquid was condensed to dry solid. Purifying the crude product on silica gel column chromatography (eluent: chloroform/methanol=10/1), 9 mg of the title compound was obtained as a colorless solid.
Reaction SMILES: Cl.[C:2]1([CH2:8][C:9](=[NH:13])[O:10][CH2:11][CH3:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl.CCOC(C)=O>[CH2:18]([O:17][C:15]([N:13]=[C:9]([O:10][CH2:11][CH3:12])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16])[CH3:19]
Reactant: CCOC(=N)Cc1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)N=C(Cc1ccccc1)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Ethyl 2-phenylacetimidate hydrochloride (1.7 g, 8.5 mmol) was dissolved in DCM (10.6 mL) and cooled to 0° C. TEA (7.1 mL, 51.1 mmol) was added dropwise the mixture was stirred for 1 h. Ethyl chloroformate (1.6 g, 14.8 mmol) was added and the reaction mixture was allowed to warm to RT and stirred for 12 h. The mixture was diluted with EtOAc (100 mL) and the solids were removed by filtration through diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL) and the combined filtrates were concentrated in vacuo to afford ethyl N-ethoxycarbonyl-2-phenylacetimidate (1.9 g, 93%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6): δ 7.27-7.26 (m, 5H), 4.01-4.00 (m, 4H), 3.70 (s, 2H), 1.18-1.08 (m, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]([N:40]5[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]5[CH3:46])=[O:39])=[CH:34][N:33]=4)[C:28](=[O:47])[N:27]([CH3:48])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1COCCN1C(=O)c1ccc(Nc2cc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 136d (140 mg, 0.21 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (16 mg, 0.63 mmol). The mixture was stirred at room temperature for 1 h and quenched with water (2 mL). It was then evaporated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 136 (40 mg, 28%) as a white solid. MS-ESI: [M+H]+ 654.3. 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.57 (d, J=5.0 Hz, 1H), 8.53 (d, J=2.5 Hz, 1H), 8.25 (d, J=2.5 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.65-7.63 (m, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.53 (d, J=5.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.91-4.89 (m, 1H), 4.45-4.39 (m, 2H), 4.17-4.13 (m, 1H), 3.79-3.67 (m, 2H), 3.58-3.53 (m, overlap, 5H), 3.41-3.36 (m, 1H), 3.29-3.25 (m, 1H), 1.39 (s, 9H), 1.22 (d, J=7.5 Hz, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:40])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][C:35]([F:38])([F:37])[F:36])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:39])[CH:14]=2)[CH:9]=1>C1COCC1.O>[Cl:39][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][C:35]([F:37])([F:36])[F:38])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)c3ccccc3OC(F)(F)F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)c2ccccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 112.8 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.23 mmol) was added to a stirred solution of {6-chloro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (0.032 g, 0.058 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {6-chloro-3-methyl-4-[4-(2-trifluoromethoxy-benzenesulfonyl)-phenyl]-naphthalen-2-yl}-acetic acid (0.035 g, 92%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. s, 1 H) 8.36 (d, J=7.82 Hz, 1 H) 8.06 (d, J=8.80 Hz, 2 H) 7.88-7.99 (m, 3 H) 7.74 (t, J=7.80 Hz, 1 H) 7.62 (d, J=8.10 Hz, 1 H) 7.55 (d, J=7.83 Hz, 2 H) 7.48 (d, J=7.82 Hz, 1 H) 6.94 (s, 1 H) 3.84 (s, 2 H) 2.05 (s, 3 H) MS calcd. for C26H19ClF3O5S [(M+H)+] 535, obsd. 535.3.