Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:28][CH2:27][N:26](CC4C=CC=CC=4)[CH2:25][C:14]=3[N:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[CH2:28][CH2:27][NH:26][CH2:25][C:14]=3[N:15]=[C:16]([CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[N:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCN(Cc2ccccc2)C3)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nc(CN3CCOCC3)nc3c2CCNC3)cc1
Yield: 77.1 %

Procedure:
Catalytic amount palladium hydroxide on carbon powder (20% Pd, moisture ea. 60%) was added to the solution of N-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine (240 mg, 0.51 mmol) in methanol and was stirred at hydrogen atmosphere over night at room temperature. Reaction solution was filtered through celite and filtrate was concentrated to yield the product as a white powder (150 mg, 77%).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([O:25][C:26](OC4C=CC=CC=4)=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:35])=[N:13]2)=[CH:8][CH:7]=1.C(OC(C)C)(C)C>C(#N)C>[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([N:16]3[CH:24]([O:25][C:26]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:35])=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: NC1CC1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: O=C(NC1CC1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 81.4 %

Procedure:
Cyclopropylamine (2.85 g.) is added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (4.3 g.) in acetonitrile (43 cc.), and the suspension obtained is stirred for 20 hours at a temperature of about 20° C. Diisopropyl ether (85 cc.) is then added, after which the insoluble product is filtered off and washed with diisopropyl ether (2 × 10 cc.). Recrystallisation from acetonitrile (130 cc.) gives 2-(7-chloro-1,8-naphthyridin-2-yl)-3-cyclopropylaminocarbonyloxy-isoindolin-1-one (3.2 g.) melting at 220° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(O)C>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CNCc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Methyl 4-(Aminomethyl)benzoate (6.88 g, 34.2 mmol) and 4-hydroxybenzaldehyde (4.60 g, 37.7 mmol) were dissolved in ethanol (300 mL), the mixture was heated to reflux for 6 hours, sodium borohydride (2.07 g, 54.7 mmol) was added at room temperature, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane. The resulting organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was reprecipitated with dichloromethane-hexane to give the title compound (4.90 g; yield, 52%) as a white solid.
Reaction SMILES: C[N:2]([N:22]=O)[C:3]1[CH2:14][N+:13]([O-:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=1.[CH2:24]([OH:26])[CH3:25]>C(N(CC)CC)C>[C:24]([NH:22][NH:2][C:3]1[CH2:14][N+:13]([O-:15])=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[N:4]=1)(=[O:26])[CH3:25]
Reactant: CN(N=O)C1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1
Reactant: CCO
Solvent: CCN(CC)CC
Product: CC(=O)NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=[N+]([O-])C1

Procedure:
A mixture of 3.3 g. of N-nitrosochlordiazepoxide, 30 ml. of ethanol, 3 ml. of triethylamine and 2 g. of acetyl hydrazide was refluxed for 24 hours. The solvent was removed and replaced by n-butanol. After additional 24 hours of reflux, the reaction mixture was evaporated. The residue was slurried with methylene chloride. The insoluble material was collected and recrystallized from methylene chloride/ethanol to yield 2-(2-acetylhydrazino)-7-chloro-5-phenyl-3H-1,4-benzodiazepine 4-oxide. The methylene chloride soluble part was chromatographed over 70 g. of silica gel using 10 percent ethanol in methylene chloride. Crystallization of the clean fractions from ethyl acetate yielded 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,5-a][1,4]benzodiazepine 5-oxide with a melting point of 278°-282°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1>>[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=[CH:6][C:5]([NH:9][C:10]2[C:11]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2ccccc2)cc1
Reactant: Brc1ccccc1Br
Product: c1ccc(-c2ccc(Nc3ccccc3Nc3ccc(-c4ccccc4)cc3)cc2)cc1
Yield: 78.8 %

Procedure:
The synthesis is carried out in accordance with the general procedure in accordance with Example 2 from 56.6 g (240 mmol) of 1,2-dibromobenzene and 85.4 g (505 mmol) of 4-aminobiphenyl. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 78 g (189 mmol) of a crystalline solid. The overall yield is 80%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:32]=[CH:31][C:23]([CH2:24][N:25]2[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]2)=[CH:22][CH:21]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C(=O)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:17][C:4]1[CH:3]=[C:2]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:34])([F:33])[F:18])=[CH:32][CH:31]=3)[CH:29]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)(=[O:10])=[O:9]
Reactant: Nc1cnn(Cc2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2cnn(Cc3ccc(C(F)(F)F)cc3)c2)cc1F
Temperature: 120 °C

Procedure:
4-Bromo-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (0.337 g, 1.00 mmol), 1-(4-Trifluoromethyl-benzyl)-1H-pyrazol-4-ylamine (0.242 g, 1.00 mmol), Tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.040 mmol), and 9,9-DIMETHYL-4,5-BIS(DIPHENYLPHOSPHINO)XANTHENE (0.069 g, 0.12 mmol), were mixed in anhydrous N,N-Dimethylacetamide (10 mL, 100 mmol). The solution was sparged with argon for 10 minutes. Sodium tert-butoxide (0.290 g, 3.02 mmol) was added and the reaction was heated in the microwave for 5 minutes at 120° C. The crude reaction was partitioned between 1N HCl and chloroform. The organic phase was separated and the aqueous phase washed a second time with chloroform. The combined organic phase was washed with brine and dried over magnesium sulfate, then evaporated onto celite. The product was purified by column chromatography, chloroform to 10% methanol-chloroform gradient elution. Product fractions were combined and evaporated to a residue. The product was purified by reverse phase HPLC. (Phenomenex 100×21.2 mm 10 micron C18 column. 20 mL/min. Gradient 85% A to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA.).
Reaction SMILES: [F:1][C:2]([F:16])([C:12]([F:15])([F:14])[F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[B]1OC2C(=CC=CC=2)O1.Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O.C1(C)C=CC=CC=1.ClCCl>[F:16][C:2]([F:1])([C:12]([F:13])([F:14])[F:15])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [B]1Oc2ccccc2O1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O[C@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Temperature: -78 °C
Reaction time: 7 h
Yield: 92.8 %

Procedure:
To a solution of 2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-one (13.0 g, 53 mmol) in a mixture 1:1 of dichloromethane and toluene (160 mL) at room temperature, 1M solution of S-methyl-CBS-oxazaborolidine in toluene (5.3 mL, 5.3 mmol) was added at room temperature. The reaction mixture was cooled at −78° C. and catecholborane (7.62 g, 63 mmol) was added. After stirring for 7 h at −78° C., a 4 M solution of HCl in dioxane (18 mL) was added. After allowing the reaction mixture to warm to room temperature, water (5 mL) was added, stirred for 5 min and 10% solution of sodium metabisulfite (25 mL) was added. The heterogeneous mixture was stirred for 15 min and the solid was separated by filtration. The solution was concentrated on rotovap to reduce the amount of dichloromethane and then the residue was diluted with hexanes (100 mL). The resulting solution was washed with a 10% solution of sodium metabisulfite (100 mL) and brine (100 mL). After drying over magnesium sulfate, the solution was concentrated and the crude was purified on a silica gel column, using dichloromethane as eluent to give (R)-2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-ol as an oil (12.01 g).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(C(C)C)CC)(C)C.O>CN1C(=O)CCC1>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[CH:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:30])([F:29])[F:31])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulphonyl chloride (0.23 ml) was added dropwise to a solution of 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.77 g) and diisopropylethylamine (1.2 ml) in NMP (6 ml). The mixture was stirred at room temperature for 3 hours. After adding cold water (20 ml), solid product was collected by filtration, washed with cold ethanol (20 ml) to give 2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (0.89 g).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1>NCCC(C)C>[C:16]([NH:1][C@H:2]([C:13]([NH:1][CH2:2][CH2:3][CH:4]([CH3:12])[CH3:5])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)CCN
Product: CC(C)CCNC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 196.3 %

Procedure:
In substantially the same manner as in Example 5, 1-amino-3-methylbutane (405 μl) was condensed with Fmoc-Trp-OH (1.35 g, Peptide Institute, Inc.) to give N-(Fmoc-L-tryptophanyl)-1-amino-3-methylbutane (1.54 g) as a white powder (yield 98%). A portion (1.44 g) of this product was, in substantially the same manner as in Example 17, subjected to deprotection of Fmoc group, which was then condensed with (2S,3S)-ethyl hydrogen transepoxysuccinate as obtained in Reference Example 8 (432 mg) to yield the title compound (compound 88; 734 mg) as a white powder (yield 72%).
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][NH:27][C:26](=O)[CH2:25]1)=[O:23].[CH3:31][C:32]1[N:33]=[N:34][S:35][C:36]=1[C:37]([NH:39][NH2:40])=O>ClCCl>[Cl:13][C:14]1[C:19]([F:20])=[C:18]([Cl:21])[CH:17]=[CH:16][C:15]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]2[C:37]([C:36]3[S:35][N:34]=[N:33][C:32]=3[CH3:31])=[N:39][N:40]=[C:26]2[CH2:25]1)=[O:23]
Reactant: Cc1nnsc1C(=O)NN
Reactant: O=C1CN(C(=O)c2ccc(Cl)c(F)c2Cl)CCN1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1nnsc1-c1nnc2n1CCN(C(=O)c1ccc(Cl)c(F)c1Cl)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethyloxonium tetrafluoroborate (330 mg, 1.738 mmol) was added to a suspension of 4-[(2,4-dichloro-3-fluorophenyl)carbonyl]-2-piperazinone (I37) (460 mg, 1.580 mmol) in dry Dichloromethane (DCM) (3.9 ml). The reaction mixture was stirred at room temperature 45 mins—mixture became clear. 4-Methyl-1,2,3-thiadiazole-5-carbohydrazide (300 mg, 1.896 mmol, commercially available) was added and the resulting reaction mixture was stirred at room temperature 2 h 10 min. The solvent was evaporated under reduced pressure. The residue was dissolved in 1-butanol (3.90 ml) and the reaction mixture was stirred at reflux for 17 h. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with water (2×25 mL), sat. NaHCO3 (25 mL) and brine (2×25 mL). The resulting organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by MDAP (basic method). The resulting residue was triturated with ether (5×2 mL) and then dried under vacuum at 50° C. to afford the desired product in 117.4 mg as a cream powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([CH3:17])=[CH:12][C:13]=1[C:14](=[O:16])[NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([Cl:18])[CH:20]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)c(NC(=O)OC(C)(C)C)s1
Reactant: Nc1cccc(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27.3 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-5-methyl-thiophene-3-carboxylic acid (1.16 g, 4.49 mmol) in dimethylformamide (50.00 ml) was treated with 3-chloro aniline (0.86 g, 6.73 mmol), DIPEA (1.74 g, 13.47 mmol) and TBTU (2.16 g, 6.73 mmol) and stirred at room temperature for 48 h. The volatiles were evaporated and the residue purified by flash chromatography (heptane/ethyl acetate), to yield [3-(3-chloro-phenylcarbamoyl)-5-methyl-thiophen-2-yl]-carbamic acid tert-butyl ester (0.45 g, 27%) as a yellow solid, MS (ISP): m/e=368.6 (M+H+)
Reaction SMILES: [NH2:1][C:2](=O)[C:3]([CH3:45])([O:5][C:6]1[CH:7]=[C:8]([C@@:13]([NH:32][C:33](=[O:44])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)([C:21]2[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:10][C:11]=1[F:12])[CH3:4]>CN(C=O)C.S(Cl)(Cl)=O.O.CCOC(C)=O>[C:2]([C:3]([O:5][C:6]1[CH:7]=[C:8]([C@@:13]([NH:32][C:33](=[O:44])[C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)([C:21]2[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[C:23]([F:31])[CH:22]=2)[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[CH:10][C:11]=1[F:12])([CH3:45])[CH3:4])#[N:1]
Reactant: CC(C)(Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F)C(N)=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)Oc1cc([C@@](Cc2ccccc2)(NC(=O)c2cccc(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)ccc1F
Reaction time: 0.67 h
Yield: 55 %

Procedure:
To a solution of (R)—N-(1-(3-(1-amino-2-methyl-1-oxopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 274, 30 mg, 0.046 mmol) in DMF (1 mL) at room temperature was added thionyl chloride (3 drops). The reaction mixture was stirred for 40 min and diluted with H2O and EtOAc. The organic layer was washed with H2O, saturated NaHCO3, H2O and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, hexanes/EtOAc) to give pure (R)—N-(1-(3-(2-cyanopropan-2-yloxy)-4-fluorophenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(trifluoromethyl)benzamide (Example 275, 16 mg, yield: 55%). LCMS: RT=2.21 min [M+H] 633.3 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [CH2:1]([N:3]=[C:4]=[O:5])[CH3:2].[NH2:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[C:16]([S:20]([NH2:23])(=[O:22])=[O:21])=[C:15]([Cl:24])[CH:14]=2)=[C:10]([CH3:12])[N:11]=1>CN(C)C=O>[Cl:24][C:15]1[CH:14]=[C:13]([C:9]2[S:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[N:11][C:10]=2[CH3:12])[CH:18]=[C:17]([Cl:19])[C:16]=1[S:20]([NH2:23])(=[O:22])=[O:21]
Reactant: Cc1nc(N)sc1-c1cc(Cl)c(S(N)(=O)=O)c(Cl)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc(C)c(-c2cc(Cl)c(S(N)(=O)=O)c(Cl)c2)s1

Procedure:
Ethyl isocyanate (0.015 ml, 0.19 mmol) is added to a stirred solution of 4-(2-amino-4-methyl-thiazol-5-yl)-2,6-dichloro-benzenesulfonamide (Example 26) (0.043 g, 0.127 mmol) in dry dimethylformamide (1.0 ml) under argon. After heating at 85° C. for 3 hours more ethyl isocyanate (0.015 ml, 0.19 mmol) is added and heating continued for a further hour. The reaction is concentrated in vacuo and the product is purified by chromatography on silica eluting with ethyl acetate-hexane (1:1 increasing to 4:1) to give the title compound. MH+ (TOF, MS, ES+): 408.9, 410.9, 412.8
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=[O:6].[BH4-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(CO)cc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an ice-cooled suspension of 3-fluoro-4-methanesulfonyl-benzaldehyde (1.3 g, 6.44 mmol) in ethanol (5 ml) under an inert atmosphere of Argon is added sodium borohydride (0.275 g, 7.27 mmol) portionwise over 2-3 minutes. After stirring for 4 hours, the reaction mixture is poured carefully onto ice-cold water and acidified to pH 1 using 1M HCl. The product is extracted into ethyl acetate (80 ml) and this organic portion is washed with brine, dried over MgSO4 and the solvent is removed in vacuo to give an oil which solidifies on drying to yield the titled compound.
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([NH2:13])[CH:3]=1.[F:14][C:15]([F:27])([F:26])[O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])O.[Na+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:7]1([N:6]2[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[C:17]([O:16][C:15]([F:14])([F:26])[F:27])[CH:18]=3)=[CH:3][C:4]([NH2:13])=[N:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1cc(I)n(-c2ccccc2)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: COCCOC
Product: Nc1cc(-c2cccc(OC(F)(F)F)c2)n(-c2ccccc2)n1
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of 5-iodo-1-phenyl-1H-pyrazol-3-ylamine (605 mg) in ethylene glycol dimethyl ether (12 ml) were sequentially added 3-(trifluoromethoxy)phenyl boronic acid (481 mg), a 2M aqueous solution of sodium carbonate (6 ml), tricyclohexylphosphine (119 mg), palladium acetate (48 mg), and the mixture was stirred for 2 hours at reflux. This reaction mixture was cooled to room temperature, and a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and then the mixture was filtered through Celite. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (298 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[F:40])=[CH:29][CH:28]=1)[CH2:10][C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])[CH3:15])=[O:12])=O)(C)(C)C.Cl>O1CCOCC1>[NH2:8][C@H:9]([CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=2[F:40])=[CH:31][CH:32]=1)[CH2:10][C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:18])[CH3:15])=[O:12]
Reactant: CC(OC(=O)C[C@@H](Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)OC(C)(C)C)OC(=O)OC1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(OC(=O)C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)OC(=O)OC1CCCCC1
Temperature: 23 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
To (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-((tert-butoxycarbonyl)amino)-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoate (2.02 g, 3.49 mmol) was added 9 mL of 4M HCl in 1,4-dioxane. The reaction mixture was stirred at 23° C. for approximately 1 hour. The reaction mixture was evaporated approximately to dryness to afford (3R)-1-(((cyclohexyloxy)carbonyl)oxy)ethyl 3-amino-4-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)butanoate (approximately 1.73 g, 104%) and taken directly to the next step. LCMS (ES+) C25H29ClFNO5: Calc.: 477.2; Found: 478.2[M+H]+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:20](=[CH:21][CH:22]=2)[O:19][C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:12][C:11]3=[O:23])[CH:5]=[N:4]1.[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([C:33](O)=[O:34])[CH:30]=[C:29]([O:36][CH2:37][CH3:38])[C:28]=1[C:39]1[CH:44]=[CH:43][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:41][CH:40]=1)[CH3:25]>>[CH2:37]([O:36][C:29]1[CH:30]=[C:31]([C:33]([N:16]2[CH2:15][CH2:14][C:13]3([CH2:12][C:11](=[O:23])[C:10]4[C:20](=[CH:21][CH:22]=[C:8]([C:6]5[CH:5]=[N:4][N:3]([CH3:2])[CH:7]=5)[CH:9]=4)[O:19]3)[CH2:18][CH2:17]2)=[O:34])[CH:32]=[C:27]([O:26][CH2:24][CH3:25])[C:28]=1[C:39]1[CH:40]=[CH:41][C:42]([C:45]([O:47][CH3:48])=[O:46])=[CH:43][CH:44]=1)[CH3:38]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Reactant: Cn1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)cn1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cnn(C)c4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1

Procedure:
In the same manner as in Example 25, the intended compound was obtained as a colorless solid using 6-(1-methyl-1H-pyrazol-4-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride and 2,6-diethoxy-4′-(methoxycarbonyl)biphenyl-4-carboxylic acid.