Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH2:10])=[O:9].Cl.C(O[CH:15](OCC)[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:20][CH2:19]1)C>C(O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH:15]3[NH:10][C:8](=[O:9])[C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[NH:1]3)[CH2:19][CH2:20]2)=[O:25])=[CH:31][CH:30]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CCOC(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)OCC
Agent: Cl
Solvent: CCO
Product: O=C1NC(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)Nc2ccccc21
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 9 parts of 2-aminobenzenecarboxamide, 12 parts of concentrated hydrochloric acid and 120 parts of absolute ethanol is stirred and refluxed for 2 hours. Then there are added 3.6 parts of [1-(3,3-diethoxypropyl)-4-piperidinyl](4-fluorophenyl)methanone and stirring at reflux is continued overnight. The reaction mixture is evaporated and the residue is stirred with water. The whole is alkalized with ammonia and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized twice from 4-methyl-2-pentanone, yielding 1.9 parts (19%) of 2-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,3-dihydro-4(1H)-quinazolinone; mp. 153.4° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)CCC>[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH:24][C:2]1[C:3]2[C:10]([CH3:11])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(-c2[nH]c3ncnc(Cl)c3c2C)cc1
Reactant: Nc1cccc(Cl)c1
Solvent: CCCCO
Product: COc1ccc(-c2[nH]c3ncnc(Nc4cccc(Cl)c4)c3c2C)cc1
Reaction time: 8 h

Procedure:
4 g of 4-chloro-5-methyl-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 8.45 ml of 3-chloro-aniline are heated under reflux in 400 ml of n-butanol for 20 hours. The brown solution is concentrated, the desired product already precipitating. The solution is stored overnight in a refrigerator and the product is filtered off with suction and washed with hexane/ethyl acetate, yielding the title compound in the form of colourless crystals; m.p. 265-268° C.; FAB-MS: (M+H)+ =365.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH:8]1[CH2:12][CH2:11][C@@H:10]([C:13]2[N:14]=[N:15][NH:16][N:17]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2nn[nH]n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C1C[C@@H](c2nn[nH]n2)CN1
Reaction time: 8 h
Yield: 62.9 %

Procedure:
(R)-3-(2H-Tetrazol-5-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg, 2.51 mmol) was dissolved in methanol (20 mL), 4M HCl in dioxane (1.13 ml, 4.52 mmol) was then added dropwise. The solution was stirred overnight. The reaction was concentrated in vacuo. The residue was purified by reverse phase HPLC to afford (R)-5-pyrrolidin-3-yl-2H-tetrazole (220 mg, 1.58 mmol, 63%) as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1([OH:33])[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:37]>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=1[C:20]1([O:33][CH3:37])[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1(c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
To a solution of tert-butyl 4-(2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)phenyl)-4-hydroxypiperidine-1-carboxylate (526 mg; 1.07 mmol) in tetrahydrofuran (6 mL) at 0° C. was added sodium hydride (75 mg; 60% dispersion in mineral oil). The reaction was stirred for 10 minutes. Then iodomethane (0.10 mL; 1.61 mmol) was added. The reaction was stirred for 72 hours at room temperature. The reaction was quenched with water and 2N hydrochloric acid. The reaction was extracted with ethyl acetate. The organic layer was washed with water and brine. It was dried sodium sulfate and concentrated under reduced pressure. The residue was purified by 40 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-20% ethyl acetate in heptane) to give 540 mg (99.8% yield) of a colorless gum. MS (ES+): Calc: 503.6, Found: 445.4 (M−1BuH). 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (s, 1H), 7.49, (dd, J=7.88, 8.30 Hz, 1H), 7.31 (d, J=8.30 Hz, 1H), 5.03 (s, 2H), 4.03 (bs, 2H), 3.16 (bs, 2H), 2.97 (s, 3H), 2.15 (d, J=12.86 Hz, 2H), 1.85 (bs, 2H), 1.48 (s, 9H), 0.98 (s, 9H), 0.14 (s, 6H).
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](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][O:26][CH2:27][C:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1>>[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]([NH:32][CH2:31][C:28]4([CH2:27][O:26][CH3:25])[CH2:30][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCC1(CN)CC1
Product: COCC1(CNC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

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-(methoxymethyl)cyclopropyl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.36-0.44 (m, 2H) 0.52-0.60 (m, 2H) 2.43 (s, 3H) 3.22-3.28 (m, 5H) 3.35 (s, 2H) 7.66 (d, J=7.83 Hz, 1H) 7.73 (s, 1H) 7.77 (br. s., 1H) 8.08-8.26 (m, 1H) 8.42 (d, J=6.57 Hz, 2H) 8.64 (t, J=5.56 Hz, 1H) 8.88-8.94 (m, 1H) 12.96-13.46 (m, 1H). MS m/z [M+H]+ 418.2
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH:3]=1.[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1>[S:15]([O:8][CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)([C:12]1[CH:13]=[CH:14][C:9]([CH3:19])=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CC1=CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=CCC(OS(=O)(=O)c2ccc(C)cc2)CC1
Reaction time: 2 h

Procedure:
To a solution of alcohol 4C (R=methyl) (10 g) and p-toluenesulfonyl chloride (20.8 g) in anhydrous tetrahydrofaran (21 mL) at 0° C. is added anhydrous pyridine (21 mL). The reaction is allowed to stir in an ice bath for 2 hours, and is then allowed to stand at −20° C. for a further 16 hours. The reaction mixture is then poured into 2M HCl (75 mL) and extracted with ethyl acetate. The combined organic layers are extracted with brine and dried over sodium sulfate. The solvent is removed in vacuo.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=1>C(Cl)Cl.N1C=CC=CC=1>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([C:21]([F:22])([F:23])[F:24])[CH:12]=2)[C:8]([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Reactant: Nc1ccccn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccccn2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (73 mg, 0.2 mmol) and triphenylphosphine (79 mg, 0.3 mmol) in methylene chloride (5.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (60.5 mg, 0.34 mmol). After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminopyridine (28.2 mg, 0.3 mmol) and pyridine (1 drop). The resulting reaction mixture was stirred at 25° C. for 48 h. The reaction mixture was then diluted with methylene chloride (50 mL). The organic layer was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (2×25 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo. High pressure liquid chromatography (Chromegasphere SI-60, 10 μM, 60 Å, 25 cm×23 cm ID, 50/50 heptane/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyridin-2-yl propionamide (54.2 mg, 61.5%) as a white solid: mp 86-89° C.; EI-HRMS m/e calcd for C21H23F3N2O3S (M+) 440.1383, found 440.1381.
Reaction SMILES: [CH:1](=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([CH2:13][C:14]([N-:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:25])[CH:19]=1)=[O:15])#[N:12]>>[OH:25][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][C:21]=1[OH:24])[CH2:17][NH:16][C:14](/[C:13](=[CH:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)/[C:11]#[N:12])=[O:15]
Reactant: O=CC=Cc1ccccc1
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Product: N#C/C(=C\C=C\c1ccccc1)C(=O)NCc1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding cinnamaldehyde (0.018 ml, 0.14 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (Example 2, 0.03 g, 0.14 mmol). After refluxing for 2 h and recrystallization from ethanol, a yellow solid was obtained (0.027 g, 59%). The product gave the following analytical data:
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Cl:39][CH2:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=[O:43].N1C=CC=CC=1>ClCCCl>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:42](=[O:43])[C:41]([CH3:46])([CH3:45])[CH2:40][Cl:39])[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Reactant: CC(C)(CCl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)C(C)(C)CCl)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 82.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), chloropivaloyl chloride (166 mg) and pyridine (86 μl) were added, and the mixture was refluxed for 2 hours 30 minutes. The reaction mixture was successively washed with water,1N hydrochloric acid, and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=2:1), to thereby obtain 509 mg of the titled compound (Yield: 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Fc1cccc(C(F)(F)F)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(C(F)(F)F)n1

Procedure:
The title compound, MS: m/e=362.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-6-trifluoromethyl-pyridine.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[CH3:19][NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([CH3:34])[CH:23]=1>>[F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH3:19])=[O:35])=[CH:23][C:24]=3[CH3:34])[CH2:33][CH2:32]2)[CH:5]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)c(C)c1

Procedure:
Using 403A and N,3-dimethyl-4-(piperazin-1-yl)benzamide 298 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36-1.49 (m, 3H) 2.26 (s, 3H) 2.52-2.62 (m, 4H) 2.74 (d, J=4.55 Hz, 3H) 2.89 (br. s., 4H) 3.41-3.50 (m, 2H) 4.74 (q, J=6.65 Hz, 1H) 6.81 (s, 2H) 6.92-7.37 (m, 2H) 7.56-7.66 (m, 2H) 8.23 (d, J=4.55 Hz, 1H) 10.81 (s, 1H). ESI-MS: m/z 475.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][C:7]([C:9]3[C:10]([NH2:17])=[N:11][CH:12]=[C:13]([N+:15]#[C-:16])[CH:14]=3)=[CH:8][C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>O1CCCC1.C(OCC)(=O)C>[NH2:17][C:10]1[C:9]([C:7]2[S:6][C:5]3[CH:18]=[CH:19][C:2]([NH:1][C:28]([NH:27][C:24]4[CH:25]=[CH:26][C:21]([Cl:20])=[C:22]([C:30]([F:32])([F:31])[F:33])[CH:23]=4)=[O:29])=[CH:3][C:4]=3[CH:8]=2)=[CH:14][C:13]([N+:15]#[C-:16])=[CH:12][N:11]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: [C-]#[N+]c1cnc(N)c(-c2cc3cc(N)ccc3s2)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: [C-]#[N+]c1cnc(N)c(-c2cc3cc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the stirring mixture of 3-(5-aminobenzo[b]thiophen-2-yl)-5-isocyanopyridin-2-amine (1.064 g, 4 mmol, 1 eq) in anhydrous tetrahydrofuran (25 mL) under nitrogen atmosphere was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (904 mg, 1 eq) and the reaction mixture was stirred at room temperature for three hours. The reaction was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted and concentrated under reduced pressure to lesser amount, to which was added a small amount of EtOAc-Hex (2:1). Upon a filtration, 1-(2-(2-amino-5-isocyanopyridin-3-yl)benzo[b]thiophen-5-yl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea was obtained as white solid in the amount of 1.37 g.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[C:8](Cl)[N:7]=[C:6]([S:11][CH3:12])[N:5]=1>ClCCl>[Cl:3][C:4]1[N:5]=[C:6]([S:11][CH3:12])[N:7]=[C:8]([NH:1][NH2:2])[CH:9]=1
Reactant: CSc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: ClCCl
Product: CSc1nc(Cl)cc(NN)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.2 %

Procedure:
Referring to Scheme 2, anhydrous hydrazine (164 mg, 162 μl, 5.1 mmol) and dichloromethane (3 ml) were cooled to −78° C. 4,6-Dichloro-2-(methylthio)pyrimidine (1 g, 5.1 mmol) was slowly added. The mixture was allowed to stir for 10 minutes then the bath was replaced with an ice bath and the solution allowed to slowly reach 0° C. The precipitate was filtered and washed with DCM. 1-(6-Chloro-2-(methylthio)pyrimidin-4-yl)hydrazine (624 mg, 64%) was obtained. [M+H] calc'd for C5H7ClN4S, 191; found, 191.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[C:11]([C:13](=[O:32])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[N:10]([CH3:33])[CH:9]=1)(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[NH2:7][C:8]1[CH:12]=[C:11]([C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2/[CH:21]=[CH:22]/[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)=[O:32])[N:10]([CH3:33])[CH:9]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(N)cc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
(E)-(5-{2-[2-(1H-indazol-3-yl)vinyl]phenylcarbamoyl}-1-methyl-1H-pyrrol-3-yl) carbamic acid tert-butyl ester (15 mg, 0.033 mmol) was dissolved in methylene chloride (1.0 mL) and trifluoroacetic acid (100 μL) was added thereto followed by stirring at room temperature for 5 hours. Then, the mixture was concentrated and dried to obtain Compound 76 (11.3 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22](O)=[O:23])[N:8]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]>>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:10](=[O:20])[N:9]([CH2:21][C:22]([NH:25][CH2:26][CH:27]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CN)c1ccccc1C(F)(F)F
Reactant: O=C(O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Product: CC(C)(C)OC(=O)NC(CNC(=O)Cn1nc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1ccccc1C(F)(F)F

Procedure:
Analogously to the procedure of Example 63, 54 mg (146 μmol) of [3-(5-chloro-2-thienyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetic acid [for the preparation see Example 154A in WO 2007/134862] were reacted with 49 mg (161 μmol) of tert-butyl {2-amino-1-[2-(trifluoromethyl)phenyl]ethyl}carbamate. This gave 64 mg (67% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH2:21])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[O:23])=[C:4]([CH3:36])[CH:3]=1.[C:37](Cl)(=[O:39])[CH3:38].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18]([NH:21][C:37](=[O:39])[CH3:38])(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)=[O:23])=[C:4]([CH3:36])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(S(N)(=O)=O)cnn12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Temperature: 50 °C
Yield: 13.5 %

Procedure:
7-(4-Fluoro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.098 g, 0.175 mmol) obtained in Example 1 step 5 was dissolved in pyridine (2 mL), 4-(dimethylamino)pyridine (0.023 g, 0.189 mmol) and acetyl chloride (0.25 mL, 3.50 mmol) were added, and the mixture was stirred with heating at 50° C. for 2 hr. 1 mol/L Hydrochloric acid was added dropwise to the reaction mixture, and the mixture was extracted 3 times with chloroform. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to give the title compound (0.013 g, 14%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[CH3:26][C:24]1[NH:23][N:22]=[C:21]([NH:20][C:12]2[N:11]=[C:10]([O:8][C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[C:19]3[C:14]([CH:13]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:25]=1
Reactant: Cc1ccc(O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methyl-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (5-methyl-1H-pyrazol-3-yl)-(1-p-tolyloxy-isoquinolin-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1.[Cl:27]CCl.[ClH:30].O1CCOCC1>CO>[ClH:27].[ClH:30].[ClH:27].[Br:1][C:2]1[N:3]=[C:4]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH:6]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCN2CCCC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Brc1cn(CCN2CCCC2)c(C2CCNCC2)n1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
Combine tert-butyl 4-(4-bromo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (0.80 g, 1.87 mmol), dichloromethane (20 mL), methanol (8 mL), and 4M hydrochloric acid in dioxane (9.36 mL, 20.0 eq) under nitrogen and let stir at room temperature. After 1.5 hours, concentrate in vacuo to give the title compound (0.82 g, 100%). MS (ES) m/z=327 [M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][C:3]=1[O:19][CH3:20].Cl[C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1>>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)=[C:3]([O:19][CH3:20])[CH:4]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: COc1cc(-c2c(C)sc3ncnc(N)c23)ccc1N
Product: COc1cc(-c2c(C)sc3ncnc(N)c23)ccc1Nc1ccc2ccccc2n1
Temperature: 25 °C
Yield: 4.1 %

Procedure:
A mixture of Example 70A (100 mg, 0.35 mmol) and 2-chloroquinoline (62 mg, 0.38 mmol) was heated to 200° C. under nitrogen for 20 minutes, cooled to room temperature, and partitioned between saturated NaHCO3 and dichloromethane. The aqueous phase was extracted three times with dichloromethane and the combined organic extracts were dried (Na2SO4), filtered, and concentrated. The concentrate was triturated with diethyl ether to provide 6 mg (5%) of the desired product. MS(ESI(+)) m/e 414 (M+H)+; 1H NMR (DMSO-d6) δ 9.08 (d, 1H, J=8.2 Hz); 8.70 (s, 1H); 8.28 (s, 1H); 8.08 (d, 1H, J=8.8 Hz); 7.73 (t, 2H, J=8.8 Hz); 7.61-7.56 (m, 1H); 7.44 (d, 1H, J=9.1 Hz); 7.34-7.29 (m, 1H); 7.06 (d, 1H, J=2.0 Hz); 7.02-6.99 (m, 1H); 3.93 (s, 3H); 2.37 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](Cl)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].[CH3:21][C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>CN1CCCC1=O>[CH3:21][C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:12]2[CH:13]=[C:14]3[C:9]([C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6][N:5]3[C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][C:11]=2[F:16])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CC(C)(C)N1CCNCC1
Solvent: CN1CCCC1=O
Product: CC(C)(C)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C(C)(C)C)CC1
Temperature: 100 °C
Yield: 22.3 %

Procedure:
A mixture of 0.45 g (1.51 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-7-chloro-6-fluoro-4-oxo-3-quinolinecarboxylic acid and 0.65 g (4,56 mmoles) 1-(1,1-dimethylethyl)piperazine in 2 mL N-methylpyrrolidone were heated 5 hours at 100° C. The solvent was evaporated under reduced pressure. The residue was tritured in water. The precipitate was recrystallized in ethanol to give 0.136 g of titled compound. MP>270° C.