Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][NH2:13])=[CH:6][C:7]=1[CH:8]1[CH2:11][CH2:10][CH2:9]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([F:23])[CH:22]=1)[CH:18]=O>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:12][N:13]=[CH:18][C:17]2[CH:16]=[C:15]([F:14])[CH:22]=[C:21]([F:23])[CH:20]=2)=[CH:6][C:7]=1[CH:8]1[CH2:9][CH2:10][CH2:11]1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NNc1cc(C2CCC2)c(Cl)nn1
Agent: Cl
Product: Fc1cc(F)cc(C=NNc2cc(C3CCC3)c(Cl)nn2)c1

Procedure:
3-Chloro-4-cyclobutyl-6-hydrazinopyridazine (0.502 g, 2.53 mmol) and 3,5-difluorobenzaldehyde (285 ml, 2.78 mmol) were stirred in 0.2M hydrochloric acid (10 ml) for 2 hours. This product was then collected by filtration and dried (0.81 g, 99%). MS (ES+) 323 [MH]+, 325 [MH]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:31]=[CH:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 45.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-difluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (0.51 g) in dichloromethane (6 ml) was added TFA (6 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (ethyl acetate/heptane) yielded the title compound as a white solid (0.21 g, 42%). MS (ISP) 506.1 [(M+H)+]; mp 204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.[CH:22]1([C:25]2[O:29][N:28]=[C:27]([CH2:30][NH2:31])[N:26]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[O:29][N:28]=[C:27]([CH2:30][NH:31][C:19]([C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13]([O:14][CH2:15][CH:16]4[CH2:17][CH2:18]4)=[CH:12][N:11]=3)=[O:21])[N:26]=2)[CH2:24][CH2:23]1
Reactant: NCc1noc(C2CC2)n1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Product: O=C(NCc1noc(C2CC2)n1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and [(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]amine (CAS Registry No. 1082420-52-7), LC-MS (UV peak area/ESI) 100%, 426.132 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].[Cl:20]C1C=CC=C(F)C=1C(O)=O>>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1Cl

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2-chloro-6-fluorobenzoic acid as the starting acid to give 4-(2-chloro-6-fluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (4.42 g) as a pale blue solid. (LC/MS: Rt 2.35, [M+H]+ 283.94).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([C:14]=1[Cl:15])=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:36]1[N:41]=[CH:40][C:39]([NH:42][CH:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[CH:38][CH:37]=1>>[Cl:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:36]3[CH:37]=[CH:38][C:39]([NH:42][CH:43]4[CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:40][N:41]=3)[CH:12]=2)[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:6]=1[C:4]([OH:3])=[O:5]
Reactant: Brc1ccc(NC2CCCC2)cn1
Reactant: CCOC(=O)c1c(Cl)c2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1-c1ccc(OC(C)C)cc1
Product: CC(C)Oc1ccc(-n2c(C(=O)O)c(Cl)c3cc(-c4ccc(NC5CCCC5)cn4)ccc32)cc1

Procedure:
The title compound was prepared in accordance with Example 8(b) from 3-chloro-1-(4-isopropoxyphenyl)-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 35, Method 1, step (c)) and 6-bromopyrid-3-ylcyclopentylamine (see Example 45(b)), followed by ester hydrolysis according to Example 35, Method 3, step (b).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].CC(C)=[O:17].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=1)[C:2]([OH:17])=[O:1])#[N:7]
Reactant: CC(C)=O
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: N#Cc1cc(C(=O)O)cc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 84.6 %

Procedure:
3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (2.70 g, 13.4 mmol) synthesized by the method described in Japanese Patent Unexamined Publication (Kokai) No. 2003-221376 was dissolved in acetone (30 mL), the solution was added with 2 M Jones reagent (26.8 mL, 53.6 mmol), and the mixture was stirred for 12 hours. The reaction mixture was added with water (15 mL) for dilution, and then extracted with ether. The organic layers were combined, and inversely extracted with 2 M aqueous sodium hydroxide, and then the aqueous layer was added with 1 M hydrochloric acid for neutralization, and extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3-cyano-5-(trifluoromethyl)benzoic acid (2.44 g, 85%) as colorless solid.
Reaction SMILES: C(Cl)(=O)C.CN([CH2:8][N:9]([CH3:11])[CH3:10])C.[Cl:12][C:13]1[C:21]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2.[OH-].[Na+]>ClCCl>[CH3:11][N:9]([CH2:8][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:13]=2[Cl:12])[NH:17][CH:16]=1)[CH3:10]
Reactant: CN(C)CN(C)C
Reactant: Clc1c(OCc2ccccc2)ccc2[nH]ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)Cl
Solvent: ClCCl
Product: CN(C)Cc1c[nH]c2ccc(OCc3ccccc3)c(Cl)c12
Reaction time: 0.08 h
Yield: 50.6 %

Procedure:
Acetyl chloride (6.42 g, 81.7 mmol) was added dropwise to a stirred solution of bis-dimethylamino-methane (BDAM) (8.34 g, 81.7 mmol) in dry dichloromethane (100 ml), while cooling in an ice bath. After 5 minutes, a solution of 4-chloro-5-benzyloxyindole (15.6 g, 60.7 mmol) in dichloromethane (100 ml) was added, dropwise, followed by addition of 10% aqueous sodium hydroxide (300 ml) after a further 10 minutes. The mixture was extracted with dichloromethane, and the extracts dried (Na2SO4) and stripped to a crude solid which was purified by chromatography (SiO2 ; CHCl3 /MeOH/NH4OH) and recrystallised from ethanol to give 3- dimethylaminomethyl-4-chloro-5-benzyloxyindole (9.66 g), m.p. 137°-9° C.
Reaction SMILES: C(OC([N:8]1[C:20]2[CH2:19][CH:18]([C:21]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])([F:26])[C:22](=[O:25])[NH:23][CH3:24])[CH2:17][CH2:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=2)=O)(C)(C)C.[H-].[Na+].Br[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[C:30]1([S:27]([C:21]([CH:18]2[CH2:17][CH2:16][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([Cl:36])[CH:13]=4)[NH:8][C:20]=3[CH2:19]2)([F:26])[C:22]([N:23]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH3:24])=[O:25])(=[O:28])=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNC(=O)C(F)(C1CCc2c(n(C(=O)OC(C)(C)C)c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C(F)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 59.5 %

Procedure:
60 mg (0.112 mmol) of (RS,SR)-2-(benzenesulfonyl-fluoro-methylcarbamoyl-methyl)-6-chloro-1,2,3,4-tetrahydro-carbazole-9-carboxylic acid tert-butyl ester (from example 59.1) in 3 mL of THF were treated with 7 mg (0.168 mmol, 1.5 eq) of NaH (55% in oil) at 0° C. over 40 min. 38 mg (0.224 mmol, 2eq) of bromomethly-benzene were added and the reaction mixture was stirred over night at RT. The solvent was evaporated, the residue was dissolved in 3 mL of CH2Cl2, 1 mL of TFA was added, and the reaction mixture was stirred over night at RT. Evaporation of the solvent and purification of the residue by preparative HPLC (C18 column) yielded 35 mg (60%) of (RS,SR)-2-benzenesulfonyl-N-benzyl-2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)-2-fluoro-N-methyl-acetamide as a white solid, MS: 525 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)([CH:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH3:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[N:10]2[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)C=CC=CC=1.[OH-].[Na+].O>C1COCC1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]2[C:17]([CH2:9][N:10]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:11]2=[O:20])=[CH:16][CH:15]=1
Reactant: COc1ccc(CN2C(=O)c3cc(OC)ccc3C2P(=O)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3ccc(OC)cc3C2=O)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
A mixture of 3-(diphenyl-phosphinoyl)-6-methoxy-2-(4-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (1.49 g, 3.1 mmol) in THF (40 mL) containing a solution of sodium hydroxide (2.5 M, 12.4 mL, 30.8 mmol) was heated under reflux for 14 h. The solution was then cooled to RT and water (40 mL) added. The mixture was extracted with diethyl ether and the combined organic extracts washed with water and brine. The organic layer was then dried over sodium sulphate, filtered and evaporated. The residue was then purified by chromatography (SiO2, Hexane:Acetone 6:4) to afford the title product (661 mg, 76%) as a light yellow solid. MS m/e=283.2 (M).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].C1C=CC=CC=1.[C:22]([OH:26])([CH3:25])([CH3:24])[CH3:23]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CC(C)(C)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 49 %

Procedure:
The crude 3,4-dinitrobenzoyl chloride, 500 ml. of benzene, 25 ml. of pyridine and 22 g. (0.3 mole) of t-butyl alcohol were reacted as in Example 2 (A), second paragraph, to provide 33 g. (49 percent yield) of t-butyl 3,4-dinitrobenzoate.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:19]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: c1ccc(CNCc2ccccc2)cc1
Product: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3[nH]2)cc1
Temperature: 170 °C

Procedure:
2-Chloro-1H-benzo[d]imidazole (1 g) was added to a neat solution of dibenzylamine (7 mL) and heated to 170° C. for 1.5 hours in a Biotage microwave synthesizer. The reaction mixture was concentrated to dryness and purified via flash column chromatography to afford 0.6 g of N,N-dibenzyl-1H-benzo[d]imidazol-2-amine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O>O1CCCC1>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[C:26]3[C:22](=[CH:21][C:20]([O:27][CH3:28])=[CH:19][C:18]=3[Cl:17])[CH2:23][CH2:24]2)[C:3](=[O:15])[N:4]([CH:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CCC(COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Cl)c2c(c1)CCN2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Cl)c32)c1=O
Reaction time: 18 h
Yield: 20.7 %

Procedure:
To 3,5-dichloro-1-[1-(methoxymethyl)propyl]-2(1H)-pyrazinone (1.0 g), prepared as described in Scheme 4, and 7-chloro-5-methoxyindoline hydrochloride (0.92 g), prepared as described in U.S. Pat. No. 6,245,769, stirring in anhydrous tetrahydrofuran (25 mL, 0° C.) was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 11.9 mL, dropwise). The reaction mixture was allowed to come to ambient temperature and stirred 18 hours. Water was added, and the mixture was extracted with three portions of ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was chromatographed on silica gel using ethyl acetate/hexane (1:4) as eluent to afford the title compound (329 mg). mp 131-133° C. 1H-NMR (CDCl3) δ: 0.93 (3H, t, J=7.3 Hz), 1.83 (2H, m), 3.09 (2H, t, J=7.6 Hz), 3.35 (3H, s), 3.56 (1H, dd), 3.67 (1H, dd), 3.78 (3H, s), 4.34 (2H, t, J=7.7 Hz), 4.94 (1H, m), 6.74 (2H, s), 6.99 (1H, s). MS (APCI+) m/z 398 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:12]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29]Cl>CC(C)=O>[C:17]([O:16][C:14](=[O:15])[CH2:13][N:12]1[C:11]2[CH:21]=[CH:22][CH:23]=[CH:24][C:10]=2[N:9]=[C:8]1[S:7][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[O:26][CH3:25])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: COc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccccc1CSc1nc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A suspension of K2CO3 (31.4 mg, 0.23 mmol) in acetone (3 ml) containing tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 30 mg, 0.11 mmol) and 2-methoxybenzyl chloride (17.8 mg, 15.8 μl, 0.11 mmol) is stirred at rt overnight. Filtration over Celite and evaporation of the solvent in vacuo affords the pure title compound (27 mg) in 62% yield as a yellow oil: tR=7.47 min (LC-1), MS (pos.): m/z 385.20 [M+H]+; 1H NMR (DMSO-d6): δ (ppm) 1.37 (s, 9H, tBu), 3.90 (s, 3H, OCH3), 4.53 (s, 2H, SCH2), 4.92 (s, 2H, CH2CO2), 6.87 (t, 1Harom), 7.03 (d, 1Harom), 7.21 (m, 2Harom), 7.28 (t, 1Harom), 7.40 (d, 1Harom), 7.50 (m, 1Harom), 7.64 (m, 1Harom).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=1)=O.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.ClC(Cl)C.C([O-])(O)=O.[Na+]>[C:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:1][C:3]2[CH:4]=[C:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=[C:7]([CH3:9])[CH:8]=2)[CH2:23][CH2:22]1)(=[O:20])[CH3:19]
Reactant: Cc1cc(C=O)cc(NC(=O)OC(C)(C)C)c1
Reactant: CC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(=O)N1CCN(Cc2cc(C)cc(NC(=O)OC(C)(C)C)c2)CC1

Procedure:
To a solution of tert-butyl 3-formyl-5-methylphenylcarbamate (200 mg, 0.85 mmol) and acetylpiperazine (131 mg, 1.02 mmol) in 0.1 mL HOAc and 4 mL dichloroethane was added NaBH(OAc)3 (216 mg, 1.02 mmol) at room temperature. After 2 hours additional acetylpiperazine (131 mg, 1.02 mmol) and NaBH(OAc)3 (216 mg, 1.02 mmol) were added. After 2 hours the mixture was diluted with saturated NaHCO3. The layers were separated and the aqueous extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (5% MeOH/CH2Cl2) gave tert-butyl 3-[(4-acetylpiperazin-1-yl)methyl]-5-methylphenylcarbamate as a white foam:
Reaction SMILES: CO[C:3](=[O:31])[N:4]=[C:5](SC)[C:6](=[N:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1)[C:7]1[CH:16]=[C:15]([O:17][CH3:18])[C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[F:19].[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[NH:41][NH2:42])=[O:35].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:33][C:34]([C:36]1[S:37][CH:38]=[CH:39][C:40]=1[N:41]1[C:3](=[O:31])[NH:4][C:5]([CH:6]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[C:7]2[CH:16]=[C:15]([O:17][CH3:18])[C:10]3[O:11][CH2:12][CH2:13][O:14][C:9]=3[C:8]=2[F:19])=[N:42]1)=[O:35]
Reactant: COC(=O)c1sccc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)c2c(c1F)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sccc1-n1nc(C(Nc2ccc(C#N)cc2)c2cc(OC)c3c(c2F)OCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of 2 g of [2-(4-cyanophenylimino)-2-(5-fluoro-8-methoxy-2,3-dihydrobenzo[1,4]dioxin-6-yl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 24 ml of DMF there were added 720 mg of 3-hydrazinothiophene-2-carboxylic acid methyl ester and 1.2 ml of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere.
Reaction SMILES: C(OC(=O)C[CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])C.[CH2:30]([O:32][C:33](=[O:40])[CH2:34][CH2:35]CN=C=O)[CH3:31]>>[CH2:30]([O:32][C:33](=[O:40])[CH2:34][CH2:35][CH2:6][NH:7][C:8]([NH:10][C:11]1[S:12][C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:18]=2)=[C:14]([CH3:16])[N:15]=1)=[O:9])[CH3:31]
Reactant: CCOC(=O)CCCN=C=O
Reactant: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1
Product: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)c2)s1

Procedure:
The titled compound is prepared by an analogous procedure to 3-{3-[4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-yl]-ureido}-propionic acid ethyl ester (Example 14) by replacing ethyl 3-isocyanatopropionate with 4-isocyanato-butyric acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)=[O:10])[CH3:23]
Reactant: CCO
Reactant: Nc1ccc(C(=O)O)nc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(N)cn1
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of 5-amino-pyridine-2-carboxylic acid (1.0 g, 5.9 mmol) in ethanol (15.0 ml) was treated with concentrated sulfuric acid (0.30 ml) and stirred at reflux overnight. The mixture was cooled to 0° C. and treated with 1M Na2CO3 until pH 8 was reached (4.0 ml). A precipitate formed, which was filtered washing with ethanol/water 2:1, and dried under vacuum, yielding 5-amino-pyridine-2-carboxylic acid ethyl ester (1.03 g, 89%) as a white solid, MS (EI): m/e=196.0 (M+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Si:30]([CH3:47])([CH3:46])[C:31]#[C:32][Sn](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:32]#[C:31][Si:30]([CH3:47])([CH3:46])[CH3:29])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)c(Cc3ccccc3)cnc12
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Temperature: 120 °C

Procedure:
A solution of 3-benzyl-4-(3-bromo-phenyl)-8-trifluoromethyl-quinoline (1.0 g, 23 mmol) and trimethyl-tributylstannanylethynyl-silane (1.3 g, 34 mmol) in toluene (25 mL) is treated with Pd(PPh3)4 (270 mg) and heated at 120° C. for 3 h. The reaction is then cooled and concentrated in vacuo. The residue is chromatographed with 10:90 ethyl acetate:hexane to afford 3-benzyl-8-trifluoromethyl-4-(3-trimethylsilanylethynylphenyl)-quinoline as an oil. MS (ESI) m/z 460.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:22]3[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccncc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-pyridine-boronic acid to give (5-methyl-1H-pyrazol-3-yl)-(1-pyridin-4-yl-isoquinolin-3-yl)-amine. LC-MS m/e 302(MH+).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[C@H:6]([NH2:40])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1>CO.O1CCCC1>[NH2:40][C@H:6]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:20][CH3:21])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:32])([CH3:33])[CH3:34])=[C:24]([CH3:36])[CH:23]=3)[CH2:37][CH3:38])=[CH:15][C:14]=2[CH3:39])=[CH:11][CH:12]=1)[C:5]([OH:41])=[O:4]
Reactant: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)OC)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@@H](N)C(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.094 mL, 0.094 mmol) was added to a solution of (R)-amino-(4′-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 167-(3); 16.6 mg, 0.031 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for two days. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol:water=4:2:0.6) to give the target compound as a colorless oil (15.2 mg, 95%).