Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24](O)=[O:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:24](=[O:25])[CH2:23][C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)[CH2:7]1
Reactant: O=C(O)Cc1ccco1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(Cc1ccco1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Yield: 57.9 %

Procedure:
Example 38 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 1 (0.056 g) and 2-furylacetic acid (0.025 g) to give the title compound (0.044 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH:24]([CH3:26])[CH3:25])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)=O>ClCCCl.C(O)(=O)C>[CH3:25][CH:24]([CH3:26])[C@@H:16]([NH:15][CH2:27][C:29]1[CH:34]=[CH:33][N:32]=[C:31]2[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:36]=[C:37]([C:38]([O:40][CH3:41])=[O:39])[C:30]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)[C@@H](N)C(=O)N1CCCC1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)N3CCCC3)C(C)C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-3-methyl-1-(pyrrolidin-1-yl)butan-1-one (84 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (128 mg, 85%). [M+H] calc'd for C24H34N4O5, 459; found, 459.6.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-])=O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]>C(O)C.[Pd]>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of 5-methyl-2-nitrobenzoic acid (20 g, 110 mmol) in ethanol was added 10% Pd/C (1 g). The mixture was stirred overnight at room temperature under hydrogen atmosphere. The solution was filtered through celite and evaporated under reduced pressure to yield 16 g (96%) of white solids. M.P. 162° C. 1H NR (DMSO-d6): δ 2.13 (s, 3H), 6.65 (d, J=8.6 Hz, 1H), 7.06 (dd, J=8.6, 1.8 Hz, 1H), 7.48 (d, J=1.1, 1H). EIMS m/z 174 (M+1), 152 (M+23).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]([N:28]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][CH3:35])[CH2:29]1)([CH3:27])[CH3:26]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:34]([CH2:33][CH:30]4[CH2:31][CH2:32][N:28]([CH:25]([CH3:27])[CH3:26])[CH2:29]4)[CH3:35])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: CNCC1CCN(C(C)C)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CC3CCN(C(C)C)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(1-isopropylpyrrolidin-3-yl)-N-methylmethanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (br. s., 5H) 2.09 (br. s., 1H) 2.42 (s, 3H) 2.60-2.78 (m, 1H) 2.90-3.09 (m, 4H) 3.09-3.44 (m, 5H) 7.44 (d, J=8.49 Hz, 1H) 7.47 (s, 1H) 7.76-7.80 (m, 1H) 7.85 (d, J=7.33 Hz, 1H) 8.30 (d, J=8.34 Hz, 1H) 8.45 (br. s., 1H) 8.55 (d, J=8.59 Hz, 1H); ESI-MS m/z [M+H]+ 459.2.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7](Cl)=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]([C:3]2[N:4]=[CH:5][NH:6][C:2]=2[CH3:1])=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1[nH]cnc1C(=O)Cl
Solvent: c1ccncc1
Product: Cc1[nH]cnc1C(=O)Nc1cccc(Cl)c1

Procedure:
Under a dry nitrogen atmosphere a solution of 5-methyl-1H-imidazole-4-carboxylic acid chloride (1.5 g, 0.01 mole) and 3-chloroaniline (1.3 g, 0.01 mole) in 25 ml of pyridine was stirred at ambient temperature for two days. The reaction mixture was then concentrated under reduced pressure, and the residue was slurried with aqueous saturated sodium bicarbonate. The resultant solid was collected by filtration, washed with water, and recrystallized, yielding N-(3-chlorophenyl)-5-methyl-1H-imidazole-4-carboxamide; (0.5 g; mp, 199°-202°).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:32]=[N+:33]=[N-:34].C1C=CC=CC=1.[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH2:63][S:64][CH3:65])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53]O)=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>O1CCCC1>[CH3:41][O:42][C:43](=[O:66])[C@H:44]([CH2:62][CH2:63][S:64][CH3:65])[NH:45][C:46](=[O:61])[C:47]1[CH:52]=[CH:51][C:50]([CH2:53][N:32]=[N+:33]=[N-:34])=[CH:49][C:48]=1[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: [N-]=[N+]=N
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CO)cc1-c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CN=[N+]=[N-])cc1-c1ccccc1
Temperature: 25 °C

Procedure:
To triphenylphosphine (1.0 equivalent) in tetrahydrofuran (THF) at −78° C. is added diethyl azodicarboxylate (1.0 equivalent) in THF. To this mixture is added a solution of hydrazoic acid in benzene (2.0 equivalents) and then the resultant compound from Example 16D (1.0 equivalent). After one hour the mixture was warmed to room temperature, stirred until the reaction is judged complete by TLC analysis, evaporated and chromatographed on silica gel to afford the title product.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22]>>[CH:21]([NH:24][C:3]([C:5]1[N:6]=[C:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Br:20])[NH:8][C:9](=[O:12])[C:10]=1[OH:11])=[O:4])([CH3:23])[CH3:22]
Reactant: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Reactant: CC(C)N
Product: CC(C)NC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1O
Yield: 24.3 %

Procedure:
The compound was prepared according to the same procedure as in Example 21 using 2-(2-bromo-benzyl)-5-hydroxy-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid methyl ester (0.08 g; 0.236 mmol) and isopropylamine (0.4 ml; 4.7 mmol). This gave the title compound as a white solid (0.021 g; 24%). LCMS: m/z=367 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:6](N)([NH2:9])(=[O:8])=[O:7]>O1CCOCC1>[N:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCCC1

Procedure:
Pyrrolidine (3.37 g) and sulfamide (7.10 g) in 1,4-dioxane (110 ml) were heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the resulting solid suspended in CHCl3. The suspension was filtered and the filtrate concentrated in vacuo to afford the subtitle compound as a white solid. Yield: 5.35 g.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([C:17]([N+:22]([O-:24])=[O:23])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:26]1([NH2:29])[CH2:28][CH2:27]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:17]([N+:22]([O-:24])=[O:23])=[C:4]2[C:3]=1[N:29]([CH:26]1[CH2:28][CH2:27]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)c(Cl)c(F)c(F)c1[N+](=O)[O-]
Reactant: NC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2c(Cl)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
The ethyl 2-(3-chloro-2,4,5-trifluoro-6-nitrobenzoyl)-3-ethoxyacrylate prepared in the previous step was dissolved in 200 ml of t-butanol and treated with 5.0 g (88 mmol) of cyclopropylamine. The reaction mixture was warmed to 45° C. and stirred for three hours at that temperature. The solution was then cooled to room temperature and treated with a slurry of 9.4 g (84 mmol) of potassium t-butoxide in 50 ml of t-butanol. The mixture was stirred at 60° C. for five hours; the suspension was filtered, and the solid was washed with water and ether to give 21.7 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[S:27][C:28]([CH:31]([CH3:33])[CH3:32])=[N:29][N:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>ClCCl>[CH:31]([C:28]1[S:27][C:26]([NH:25][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][NH:13][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[N:30][N:29]=1)([CH3:33])[CH3:32]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)c1nnc(NS(=O)(=O)c2ccc(CCN)cc2)s1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)NCCc2ccc(S(=O)(=O)Nc3nnc(C(C)C)s3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
21.4 mg 4-Methoxy-benzoyl chloride and 50 mg 4-(2-Amino-ethyl)-N-(5-isopropyl-[1,3,4]thiadiazol-2-yl)-benzene sulfonamide hydrochloride were dissolved in 2 ml dichloromethane and stirred at room temperature for two hours. The reaction mixture was diluted by addition of 50 ml dichloromethane, washed three times with portions of 30 ml water and then dried over MgSO4. The solvent was removed in vacuo. The residue was purified by RP-HPLC to obtain 21.4 mg N-{2-[4-(5-isopropyl-[1,3,4]thiadiazol-2-ylsulfamoyl)-phenyl]-ethyl}-4-methoxy-benzamide.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20](=S)[CH2:21][C:22](=O)[CH3:23])=[O:4].S(O)(O)(=O)=O.[CH2:31]([NH:39][NH2:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:39]([CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:40]=[C:22]([CH3:23])[CH:21]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1C(=S)CC(C)=O
Reactant: NNCCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 253c) was reacted with 2-phenethyl-hydrazine sulfate (CAS Reg. No. 56-51-4) to give the title compound as orange oil. MS (ESI): m/z=488.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:24]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[C:15](=[O:17])[C@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:13][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)C(=O)OC
Reactant: NCc1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(Cc2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48 %

Procedure:
(S)-Dimethyl 2-((7-chloro-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (120 mg, 0.33 mmol) was dissolved in DMF (1.0 mL). 4-Aminomethylpyridine (100 μL, 1.0 mmol) was added to the mixture. Reaction stirred at room temperature for 24 hours. Mixture was diluted with ethyl acetate. Mixture was washed twice with water and once with brine. Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was dissolved in toluene (4 mL). Acetic acid (1 mL) was added to the mixture. Reaction was heated at reflux for 3.5 hours. Mixture was cooled to room temperature then diluted with ethyl acetate. Material was washed once with water and twice with aqueous sodium bicarbonate. Aqueous was made basic with sodium bicarbonate. Back extracted from the aqueous twice with ethyl acetate. Combined organics were dried (magnesium sulfate), filtered and concentrated in vacuo. Residue was purified with silica gel chromatography eluting dichloromethane and 2N ammonia in methanol. Title compound was obtained as yellow solid in 48% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=O)[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-:16][C:17]#[N:18].[K+].Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[C:11](=[O:13])[NH:18][C:17](=[O:16])[NH:10]2)=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: N#C[O-]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc([N+](=O)[O-])cc2)N1
Yield: 82 %

Procedure:
A solution of p-nitrophenylalanine (4.2 g, Fluka) and potassium cyanate (1.62 g) in water (6 ml) was refluxed for 1 hour. C.HCl (3 ml) was added and the mixture refluxed for a further 10 minutes, then cooled, diluted with water and filtered. The residue was washed with water and dried to give the desired product as a straw-coloured solid (3.85 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:1][C@H:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: N[C@H]1CCCC[C@H]1C(=O)O
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CCCC[C@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 28.5 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 429.6 mg (3 mmol) of cis-2-amino-1-cyclohexane-carboxylic acid with 1.15 g of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 387.9 mg of cis-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclohexanecarboxylic acid in 28% yield. MS: 455.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[N:16][C:17](Cl)=[CH:18][CH:19]=1)=[O:13].[N:21]1([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[N:16][C:17]([N:24]2[CH2:25][CH2:26][N:21]([C:27](=[O:28])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:36])[F:37])[CH2:22][CH2:23]2)=[CH:18][CH:19]=1)=[O:13]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCc1ccc(F)cc1F)c1ccc(Cl)nn1
Product: O=C(NCCc1ccc(F)cc1F)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid [2-(2,4-difluorophenyl)ethyl]amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid (33% yield). m.p. 179-181° C. 1H NMR (400 MHz, CDCl3) δ 8.04, 7.91, 7.75, 7.61, 7.37, 7.30-6.89, 4.09-3.66, 3.38-3.32, 2.88. MS (ES+) m/z 520 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH:9]([CH3:11])[CH3:10].Br[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]>>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:24])[C:17]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH:9]([CH3:11])[CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Fc1cccc(F)c1Br
Reactant: C=Cc1cc(OC)c(C(C)C)c(OC)c1
Product: COc1cc(C=Cc2c(F)cccc2F)cc(OC)c1C(C)C

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-i-propylphenyl)ethene and 1-bromo-2,6-diflurobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[OH:6])[O:3][CH3:4].[CH3:31][C:32](OC(C)=O)=[O:33].O>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([O:19][C@H:18]([CH2:20][O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[C@H:5]1[O:6][C:32](=[O:33])[CH3:31])[O:3][CH3:4]
Reactant: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COC1(C)O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OC(C)=O

Procedure:
To the solution of raw oil from Step 2 above (173.6 g, 0.3600 mol) in 1.379 L pyridine, were added Ac2O (33.970 mL, 0.3600 mol) and DMAP (1.3766 g, 0.01127 mol). After 21 hours of stirring at room temperature 1.4 L H2O were added. The solution was acidified with 1.45 L concentrated HCL. The acidified product was extracted with EtOAc, dried with MgSO4 and concentrated in vacuo. The residue was isolated as 85.75 g (0.1636 mol) of clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][C:33](Cl)=[O:34]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:33](=[O:34])[CH2:32][C:28]4[S:27][CH:31]=[CH:30][CH:29]=4)[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: O=C(Cl)Cc1cccs1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)Cc5cccs5)c4)CC3)cccc2n1
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 2-thienylacetyl chloride.
Reaction SMILES: [CH3:1][N:2]([C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:4].[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[CH:6]4[CH2:7][CH:5]4[C:3](=[O:4])[N:2]([CH3:1])[C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:22])=[CH:14][CH:15]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CC1C(=O)N(C)[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CC4C(=O)N(C)[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 2-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-cyclopropanecarboxylic acid methyl-((R)-1-phenyl-ethyl)-amide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(O)CCCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][C@H:28]([NH2:31])[C@H:27]([F:32])[CH2:26]2)=[CH:21][C:20]=1[O:33][CH3:34].Cl[C:36]1[N:41]=[C:40]([C:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[NH:44][CH:43]=2)[C:39]([Cl:51])=[CH:38][N:37]=1>>[NH2:31][C@H:28]1[CH2:29][CH2:30][N:25]([C:22]2[CH:23]=[CH:24][C:19]([NH:18][C:36]3[N:41]=[C:40]([C:42]4[C:50]5[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=5)[NH:44][CH:43]=4)[C:39]([Cl:51])=[CH:38][N:37]=3)=[C:20]([O:33][CH3:34])[CH:21]=2)[CH2:26][C@H:27]1[F:32]
Reactant: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1N
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCO
Product: COc1cc(N2CC[C@H](N)[C@H](F)C2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Yield: 34.9 %

Procedure:
1-Pentanol (2 mL) was injected into a microwave vial charged with p-toluenesulfonic acid (0.180 g, 0.95 mmol), (3R,4S)-1-(4-amino-3-methoxyphenyl)-3-fluoropiperidin-4-amine (Intermediate 48) (0.091 g, 0.38 mmol), and 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 2) (0.1 g, 0.38 mmol). The reaction was microwaved at 140° C. for 1 h. The solution was concentrated under reduced pressure. The crude residue was dissolved in DCM (15 mL) and washed with a sat. Na2CO3 solution. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated to give a crude liquid. The crude material was purified using silica gel chromatography (2-10% MeOH and 1% NH4OH in DCM) to give the title product (0.062 g, 35.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])([O-:11])=[O:10].Cl>CC(O)C>[ClH:1].[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:15][C:14]2[CH:16]=[CH:17][CH:18]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[CH:7]=1
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 84 °C
Yield: 36 %

Procedure:
250 mg of 4,6-Dichloropyrimidine and 178 mg of m-nitroaniline were dissolved in 2.5 mL of i-PrOH and 0.25 mL of 37% HCl were added. The mixture obtained was refluxed (84° C.) for 4 hours under nitrogen atmosphere. A colorless precipitate was formed which was collected by filtration. 6-Chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride in the form of bright yellow crystals was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=2)[O:3]1.[NH2:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][N:21]=1>C(#N)C>[F:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:9]([B:4]3[O:3][C:2]([CH3:18])([CH3:1])[C:6]([CH3:8])([CH3:7])[O:5]3)=[CH:10][CH:11]=2)[CH:25]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Reactant: Nc1cc(F)ccn1
Solvent: CC#N
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(F)ccn3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.9 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (1.688 mmol, 450 mg) in acetonitrile (24.8 mL) was added 2-amino-4-fluoropyridine (4.22 mmol, 473 mg). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated to a small volume, 3% aq. citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2×15 mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated to afford 542.2 mg of N-(4-fluoropyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (94%) as an off-white solid.