Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:26]2[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][N:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[C:27]([C:32]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:33])=[N:28][CH:29]=[CH:30][N:31]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)c1nccnc1-c1ccccc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nccnc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3-Phenyl-pyrazine-2-carboxylic acid. LC-MS (basic): tR=1.18 min; [M+H]+=458.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>C(OCC)C>[CH3:1][SiH:2]([CH3:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH3:12])=[CH:6][CH:5]=1
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCOc1ccc([SiH](C)C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
A solution of 51 g of dimethyl-(4-ethoxyphenyl)-chlorosilane in 100 ml of absolute diethyl ether is added dropwise to a suspension of 2.55 g of lithium aluminum hydride in 30 ml of absolute diethyl ether under nitrogen at 15°-20° C. Stirring is carried out for 1 hour at 20° C., followed by refluxing for 1 hour. The reaction solution is cooled to 20° C. and poured into 200 ml of 2N sulfuric acid. The phases are separated and, after the aqueous phase has been washed several times with diethyl ether, the organic phases are combined and are evaporated down in a rotary evaporator. Distillation of the residue gives 29.0 g of dimethyl-(4-ethoxyphenyl)-silane (bp. 53° C./0.2 mbar).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH2:12])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:12][CH2:10][CH:7]1[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]1
Reactant: CC(C)N1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(C)N1CCC(CN)CC1
Yield: 76.2 %

Procedure:
Prepared from 1-isopropylpiperidine-4-carboxamide (2.5 g, 14.7 mmol) and LAH (1.12 g, 29.4 mmol) according to general the procedure used for Example 8 (Step B) to give 1.75 g of title compound as an oil.
Reaction SMILES: Cl.[NH:2]=[C:3]([NH2:5])[CH3:4].[Cl:6][C:7]1[N:12]=[C:11]([C:13](Cl)(Cl)[S:14]Cl)[CH:10]=[CH:9][N:8]=1.[OH-].[Na+].O>C(Cl)Cl>[Cl:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][N:5]=[C:3]([CH3:4])[N:2]=2)[CH:10]=[CH:9][N:8]=1
Reactant: ClSC(Cl)(Cl)c1ccnc(Cl)n1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1nsc(-c2ccnc(Cl)n2)n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
1-Imino-ethanamine hydrochloride (1:1) (0.08 mol) was added at 0° C. to a stirring mixture of intermediate 1 (0.07 mol) in DCM (300 ml). Sodium hydroxide (50%, 20 ml) was added dropwise at 0° C. The mixture was stirred at 5° C. for 1 hour. Water (300 ml) and DCM (300 ml) were added. The mixture was separated into its layers. The aqueous layer was washed twice with DCM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DCM). Two pure fractions were collected and their solvents were evaporated, yielding 3.5 g of 2-chloro-4-(3-methyl-1,2,4-thiadiazol-5-yl)pyrimidine (intermediate 2).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9]([OH:11])=[O:10].[N+:17]([O-])([O-:19])=[O:18].[K+]>>[F:6][C:7]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:14][CH:13]=[C:12]([F:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1c(F)cccc1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
Concentrated sulfuric acid (5 mL) was added into 2,6-difluoro benzoic acid (1.4 g, 9 mmol) and potassium nitrate (1 g, 9.9 mmol) was added gradually at 0° C. After the temperature of the reactant was elevated to a room temperature, the reactant was stirred for 24 hours. After pouring ice water into the reaction solution, extracting with ethylacetate, drying with sulfuric anhydride magnesium, and vacuum concentrating, the filtrate solid was washed with diethyl ether, and dried, so that 1.3 g of the target compound, 2,6-difluoro-3-nitro benzoic acid (percentage yield: 71%), was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:18]>C(N(CC)CC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:18])=[O:13])=[C:7]([O:15][CH3:16])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: COc1cc(C(C)(C)C)ccc1CC(=O)O
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)C)ccc1CC(=O)Cl
Reaction time: 0.5 h

Procedure:
To 0.52 g (0.23 mmol) of the product of Step A was added 10 mL CH2Cl2 and 1 mL triethylamine. The resulting solution was concentrated in vacuo to remove the solvent and excess triethylamine. The residual triethylammonium salt was re-dissolved in 10 mL CH2Cl2 and 1.0 mL of oxalyl chloride was added. After stirring 30 min the reaction mixture was evaporated in vacuo to afford the title compound which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:26][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:19]([CH3:20])[CH3:18])=[CH:28][CH:27]=1
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)Cc1ccc(N)cc1
Product: CCCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 62.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)butan-1-one (470 mg, 1.50 mmol) was reacted with 4-((dimethylamino)methyl)aniline (451 mg, 3 mmol) to afford the desired product (402 mg, 63%) as a yellow solid. ESI MS m/z 426 [C22H24BrN3O+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:16])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[C:34](O)=[O:35]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH:16][C:34]([C:25]2[CH:26]=[CH:27][C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]=2[OH:23])=[O:35])[CH2:13][C@H:12]1[C:17]1[O:18][C:19]([CH3:22])=[CH:20][N:21]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cnc([C@@H]2C[C@H](N)CN2C(=O)OCc2ccccc2)o1
Reactant: O=C(O)c1ccc2ccccc2c1O
Product: Cc1cnc([C@@H]2C[C@H](NC(=O)c3ccc4ccccc4c3O)CN2C(=O)OCc2ccccc2)o1

Procedure:
(2S,4S)-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4S)-4-amino-2-(5-methyl-oxazol-2-yl)-pyrrolidine-1-carboxylic acid benzyl ester and 1-hydroxy-naphthalene-2-carboxylic acid in an analogous manner to example 1. MS calcd. for C27H26N3O5 [(M+H)+] 472, obsd. 472.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][CH:10]=[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=3)[C:14](=[O:22])[NH:13][C:12]2=[O:23])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1.IC1C=C2C(=CC=1)C(=O)[NH:36]C(=O)C2=COC.NCC1C=CC(C2C=CC=CN=2)=C(O)C=1>>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][N:36]=[CH:26][CH:25]=1)[CH2:8][NH:9][CH:10]=[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([I:21])[CH:19]=2)[C:14](=[O:22])[NH:13][C:12]1=[O:23]
Reactant: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Agent: NCc1ccc(-c2ccccn2)c(O)c1
Product: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccncc2)c(O)c1
Yield: 40 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-Hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound is prepared from 6-iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (50 mg, 0.15 mmol) and 5-Aminomethyl-2-pyridin-2-yl-phenol (40 mg, 0.20 mmol) in 40% yield: MS (ESI): 498.1 (M+1)+1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH2:11][CH2:12][F:13])[N:7]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=3)[C:6]=2[CH:21]=1.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23].C(N(CC)CC)C>CS(C)=O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:13][CH2:12][CH2:11][O:10][C:8]1[N:7]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[N:15]=2)[C:6]2[CH:21]=[C:2]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=[CH:4][C:5]=2[N:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nccc(-n2c(OCCF)nc3ccc(Br)cc32)n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[Si](C)(C)C#Cc1ccc2nc(OCCF)n(-c3ccnc(N)n3)c2c1
Yield: 37.8 %

Procedure:
A solution of 4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.43 mmol), ethynyltrimethylsilane (126 mg, 1.28 mmol), bis(triphenylphosphine) palladium(II) dichloride (120 mg, 0.17 mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated with microwave radiation under nitrogen in a sealed tube at 80° C. for 40 min. The reaction mixture was diluted with 10 mL of dichloromethane and the solid material was removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column (ethyl acetate/petroleum ether, 3:1) to give 60 mg (38%) of 4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine as a yellow solid: LC-MS: m/z=+370 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=[C:10]([O:23][CH3:24])[CH:9]=1)[CH3:3].[CH2:26]([O:28][C:29]1[CH:34]=[C:33]([CH:35]=O)[CH:32]=[C:31]([O:37][CH2:38][CH3:39])[C:30]=1[C:40]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=1)[CH3:27].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:2]([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:9]=[C:10]([O:23][CH3:24])[CH:11]=[C:12]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:35][C:33]3[CH:32]=[C:31]([O:37][CH2:38][CH3:39])[C:30]([C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=4)=[C:29]([O:28][CH2:26][CH3:27])[CH:34]=3)[CH2:20][CH2:21]2)[CH:13]=1)[CH3:3]
Reactant: CCOC(=O)COc1cc(OC)cc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOC(=O)COc1cc(OC)cc(C(=O)NC2CCN(Cc3cc(OCC)c(-c4ccc(F)cc4)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), [3-methoxy-5-(piperidin-4-ylcarbamoyl)-phenoxy]-acetic acid ethyl ester hydrochloride (example 250b) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 609.3 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO>O>[N:7]1[CH:8]=[CH:9][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Solvent: CO
Solvent: O
Product: CC(O)c1ccncc1
Yield: 99.7 %

Procedure:
To a stirred solution of 4-acetylpyridine (2.50 g, 20.6 mmol) in methanol (25 ml) sodium borohydride (1.56 g, 41.2 mmol) was added in portions. After stirring overnight at RT water was added and the mixture was evaporated to dryness in vacuo. The product was taken into ethyl acetate. The solvent was evaporated to give 2.53 g of the title compound. 1H NMR (400 MHz, DMSO-d6): 1.32 (3H, d), 4.69-4.75 (1H, m), 5.38 (1H, d), 7.34 (2H, d), 8.49 (2H, d).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])[CH3:3].CN(C1C=CC=CN=1)C.[C:41](O)(=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45].O>N1C=CC=CC=1>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([NH:13][C:6]3[CH:5]=[C:4]([CH:2]([O:1][C:41](=[O:47])[CH2:42][CH2:43][C:44]([OH:46])=[O:45])[CH3:3])[C:9]([CH3:10])=[N:8][C:7]=3[O:11][CH3:12])=[O:15])[CH2:17][CH2:18]2)[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=1
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)O)c(C)nc3OC)CC2)c1
Reactant: O=C(O)CCC(=O)O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)OC(=O)CCC(=O)O)c(C)nc3OC)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
1-{[5-(1-Hydroxyethyl)-2-methoxy-6-methylpyridin-3-yl]aminocarbonyl}-4-(3,5-dimethoxyphenyl)piperazine(107 mg, 0.25 mmol) and dimethylaminopyridine(3 mg, 0.025 mmol) were dissolved in pyridine and anhydrous succinic acid(50 mg, 0.5 mmol) was added. The mixture was stirred at room temperature for 5 hrs. Distilled water was added into the above mixture. The above solution was extracted with CH2Cl2 and the organic phase washed with 1N-HCl and then concentrated under the reduced pressure to remove the solvent. The concentrate was purified by column chromatography(dichloromethane:methanol=20:1) to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1Br.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.[Na+].[Na+].[Na+].P(C1C=C(S([O-])(=O)=O)C=CC=1)(C1C=C(S([O-])(=O)=O)C=CC=1)C1C=C(S([O-])(=O)=O)C=CC=1.C(NC(C)C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.CN(C)C=O>[NH2:1][C:2]1[C:3]([C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[OH:12]
Reactant: COC(=O)c1cc(O)c(N)c(Br)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)c(N)c(-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
To a mixture of methyl 4-amino-3-bromo-5-hydroxybenzoate (1.0 g, 4.06 mmol), (4-fluorophenyl)-boronic acid (0.85 g, 6.1 mmol), 3,3′,3″-phosphinidynetris (benzensulfonic acid) trisodium salt (195.0 mg, 0.31 mmol), palladium(II) acetate (23.0 mg, 0.10 mmol) and diisopropylamine (0.58 mL, 4.06 mmol) were added N,N-dimethylformamide (15.2 mL) and water (5.1 mL). The mixture was heated to 80° C. After 18 h, the mixture was cooled to ambient temperature and ethyl acetate was added. The organic layer was washed with water (3×), brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) gave the title compound (0.27 g). LC-MS [M+1]=262.2.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH2:77])([CH3:68])([CH3:67])[CH3:66]>C(Cl)Cl>[C:65]([O:69][C:70](=[O:78])[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=1[NH:77][C:28]([C@H:9]1[C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:31])[C@:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[NH:10]1)=[O:30])([CH3:68])([CH3:66])[CH3:67]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (120 mg, 0.21 mmol) in methylene chloride (10 mL), HATU (Aldrich, 157 mg, 0.41 mmol) was added followed by the addition of DIPEA (110 uL, 0.62 mmol) and 2-amino benzoic acid t-butyl ester (Aldrich, 80 mg, 0.41 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 71 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]>>[Cl:33][C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20][CH2:19]2)[CH:37]=[C:36]([O:49][CH3:50])[C:35]=1[OH:51]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](CNC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (65 mg, 0.123 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (55 mg, 0.185 mmol) to afford the crude product (90 mg) as a yellow-green solid: ESI MS m/z 580 [C32H38ClN3O5+H]+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f14) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][O:5][CH2:6][CH:7]1[CH2:34][CH2:33][C:10]2[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[N:13][C:9]=2[CH2:8]1.ClC1C(C(F)(F)F)=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1>C(O)(=O)C.O>[Cl:1][C:2]1[C:38]([C:39]([F:41])([F:40])[F:42])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][O:5][CH2:6][CH:7]1[CH2:34][CH2:33][C:10]2[NH:11][CH:12]=[N:13][C:9]=2[CH2:8]1
Reactant: FC(F)(F)c1cccc(COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1Cl
Agent: FC(F)(F)c1cccc(COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1Cl
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(COCC2CCc3[nH]cnc3C2)c1Cl
Temperature: 70 °C

Procedure:
A solution of a mixture of 5-(2-chloro-3-(trifluoromethyl)benzyloxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(2-chloro-3-(trifluoromethyl)benzyloxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole in a mixture of acetic acid (9 ml) and water (1 ml) was heated to 70° C. for 2 hour. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 25 mg of the title compound.
Reaction SMILES: CC(C)([O-])C.[Na+].[F:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15][N:14]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[C:11]2=[CH:12][CH:13]=1.I[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1.O1CCOCC1>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].CC#N>[F:7][C:8]1[CH:9]=[C:10]2[C:16]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([C:34]5[CH:39]=[N:38][CH:37]=[CH:36][N:35]=5)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)[CH2:15][N:14]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[C:11]2=[CH:12][CH:13]=1
Reactant: Ic1cnccn1
Reactant: CN(C)C(=O)N1CC2(CCN(C3CCNCC3)CC2)c2cc(F)ccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CC2(CCN(C3CCN(c4cnccn4)CC3)CC2)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Pd2(dba)3 (0.5 mol %, 5.175 mg), ligand 12-(dicyclohexylphosphino)-2′ (N,N-dimethylamino) biphenyl (7.86 mg, 20 mol %), and sodium tert-butoxide (13.45 mg, 0.14 mmol) were weighed in air and transferred into a microwave tube. 5-fluoro-N,N-dimethyl-1′-(piperidin-4-yl)spiro[indoline-3,4′-piperidine]-1-carboxamide 4ba (36.0 mg, 0.1 mmol) and 2-iodo pyrazine (20.5 mg, 0.1 μmol) and 1 mL of dioxane were added. The tube was purged with N2 and stirred at 80° C. for 16 hours. The reaction was diluted with methanol, filtered (Whatman 0.2 μm PTFE) and subjected to reverse-phase HPLC purification [2-50% CH3CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.5 mL injected] to provide compound no. 52. 1H NMR (400 MHz, MeOD) 8.63 (d, J=2.6 Hz, 1H), 8.52 (s, 1H), 7.92 (d, J=3.0 Hz, 1H), 7.28-7.23 (m, 2H), 7.03-6.98 (m, 2H), 4.75-7.72 (m, 2H), 3.93 (s, 2H), 3.70-3.78 (m, 3H), 3.33-3.18 (m, 4H), 3.00 (s, 6H), 2.42-2.35 (m, 4H), 2.05-1.92 (m, 4H). LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 421.1, retention time 2.03 minutes.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([Cl:15])[N:5]=[CH:4][N:3]=1.[K+].[C:17]1([CH:23]=[CH:24][S:25]([NH-:28])(=[O:27])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.C(N(C(C)C)CC)(C)C.O.C(OCC)C>[Cl:15][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:28][S:25]([CH:24]=[CH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:26])=[O:27])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2c(Cl)ncnc2Cl)cc1
Reactant: [NH-]S(=O)(=O)C=Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=S(=O)(C=Cc1ccccc1)Nc1ncnc(Cl)c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A solution of 6.50 g of 4,6-dichloro-5-(4-chlorophenyl)-pyrimidine and 9.43 g of 2-phenyl-ethenesulfonamide potassium salt (Referential Example 1c) in 50 ml of DMSO and 4.4 ml of diisopropyl-ethylamine was stirred at rt for 65 h. The mixture was diluted with 500 ml of water and 250 ml of diethyl ether and was vigorously stirred for 15 min. The suspension was acidified by adding 8.5 g of citric acid monohydrate and stirring was continued at 5° C. for 30 min. The precipitate was collected and washed with water. The crude product was crystallised from 2-propanol at 2-3° C. The crystals were collected, washed with cold 2-propanol and dried to give 6.23 g of 2-phenyl-ethenesulfonic acid [6-chloro-5-(4-chloro-phenyl)-pyrimidin-4-yl]-amide as a white powder. LC-MS: tR=5.24 min, [M+H]+=405.89 (ES+), [M−H]−=403.92 (ES−).