Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[NH2:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23]([C:27]([NH2:29])=[O:28])=[N:24][NH:25][CH:26]=1>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13](=[O:14])[NH:15][C:16]1[CH:17]=[C:18]([CH:30]=[CH:31][CH:32]=1)[CH2:19][CH2:20][NH:21][C:22]1[C:23]([C:27]([NH2:29])=[O:28])=[N:24][NH:25][CH:26]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1n[nH]cc1NCCc1cccc(N)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1n[nH]cc1NCCc1cccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)c1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
A solution of 0.14 ml of 1-fluoro-2-isocyanato-4-trifluoromethylbenzene is added at 20° C. to a solution of 0.25 g of 4-[(3-aminobenzyl)methylamino]-1H-pyrazole-3-carboxamide in 25 ml of anhydrous THF. The reaction medium is stirred for 12 hours at 20° C. and then diluted with 100 ml of ethyl acetate. The organic phase is washed with 50 ml of distilled water, and is then separated out by settling of the phases, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is chromatographed on a column of silica (15 g of Merck cartridge silica with a particle size of 15 to 45 μm, column diameter 2.2 cm, 5 ml fractions, flow rate of 10 ml/min, eluent 95/5 dichloromethane/methanol—by volume). Fractions 35 to 95 are combined and evaporated to dryness under reduced pressure. 0.02 g of 4-({3-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]benzyl}methylamino)-1H-pyrazole-3-carboxamide is obtained in the form of a solid. ([M+H]+): 451). RT: 3.55 min (Method A).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Fc1ccccc1CBr
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 120 h
Yield: 41.7 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 2-fluoro-benzyl bromide (58 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight and then allowed to stand at room temperature for five days. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(2-fluoro-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (63 mg, 42%) as a white solid. APCI-MS (M+H) 315.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:31][CH2:30]2)=[C:25]([CH:28]=1)[C:26]#[N:27]>>[C:26]([C:25]1[CH:28]=[C:21]([NH:20][C:15]([C:12]2[CH:11]=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:18])[CH:4]=3)[C:13]=2[CH3:14])=[O:17])[CH:22]=[CH:23][C:24]=1[N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:36][CH2:37][O:38][CH2:39][CH2:40]2)[CH2:31][CH2:30]1)#[N:27]
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1cccc(C(F)(F)F)c1
Yield: 25.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-trifluoromethylphenyl)-5-methylpyrazole-4-carboxylic acid (2.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (2.4 g), the title compound (1.0 g) was obtained, melting point: 215–216° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)[N:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=3)=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C1COCC1>[C:29]([C:27]1[CH:28]=[C:24]([NH:23][C:21]([NH:20][C:17]2[CH:16]=[N:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)=[O:22])[N:25]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)[N:26]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Temperature: 60 °C

Procedure:
Place 4-{5-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-ureido]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (565 mg, 1.06 mmol) in THF (10 mL). Add 4 M HCl in dioxane (2.65 mL, 10.6 mmol) and heat to 60° C. for 3 hours. Cool the reaction to room temperature and load onto a Varian™ SCX column. Wash the column with MeOH and then flush off the product with 2 M NH3 in MeOH.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[OH:20][CH2:21][CH2:22][NH2:23]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([S:9]([NH:23][CH2:22][CH2:21][OH:20])(=[O:11])=[O:10])[CH:6]=[N:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Reactant: NCCO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1cncc(Br)c1

Procedure:
A cooled (0° C.) solution of 5-bromopyridine-3-sulfonyl chloride hydrochloride (3.00 g, 10.2 mmol) in DCM (50 ml) was slowly treated with triethylamine (4.3 ml) and stirred until a clear solution was obtained. This solution was treated dropwise with 2-hydroxyethylamine (0.68 g, 0.68 mL) and stirred at RT for 16 hours. The reaction mixture was washed successively with water and brine, the organic layer was dried with sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography (silica) eluting with 20% ethyl acetate in petroleum ether, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].COC(=O)C1C=C([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)C=C([N+]([O-])=O)C=1N>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1N
Product: COC(=O)c1cc(-c2ccncc2)cc2[nH]c(N)nc12
Yield: 50 %

Procedure:
0.25 g (50% overall yield) of 2-amino-6-pyridin-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester was synthesized according to procedures described for the synthesis of 2-Amino-1H-benzoimidazole-4-carboxylic acid methyl ester (intermediate A) starting from 0.5 g (1.8 mmol) of above synthesized 2-Amino-3-nitro-5-pyridin-4-yl-benzoic acid methyl ester. LCMS: 269 (M+1)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:18][CH:17]=1.[O:41]1[CH:45]=[CH:44][C:43]([CH:46]=O)=[N:42]1.C(OCC)C>C1COCC1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[CH:24][N:25]([CH:35]3[CH2:40][CH2:39][N:38]([CH2:46][C:43]4[CH:44]=[CH:45][O:41][N:42]=4)[CH2:37][CH2:36]3)[C:26]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][CH3:34])[N:28]=2)=[CH:20][CH:21]=1
Reactant: O=Cc1ccon1
Reactant: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCNCC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1nccc(-c2c(-c3ccc(F)cc3)ncn2C2CCN(Cc3ccon3)CC2)n1
Reaction time: 1.5 h

Procedure:
Sodium triacetoxyborohydride (135 mg, 0.637 mmol) was added to a solution of 4-[4-(4-fluorophenyl)-1-piperidin-4-yl-1H-imidazol-5-yl]-N-methylpyrimidin-2-amine (C8) (150 mg, 0.426 mmol) and isoxazole-3-carbaldehyde (49.6 mg, 0.511 mmol) in THF (10 mL). After 90 minutes at room temperature, the reaction was concentrated in vacuo and partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide a thick oil. Purification via silica gel chromatography (Eluants: ethyl acetate followed by 10% methanol in ethyl acetate) provided a viscous oil, which was reconcentrated from diethyl ether to afford the product as a white solid. Yield: 77 mg, 0.18 mmol, 42%. LCMS m/z 434.6 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.99-2.09 (m, 2H), 2.16-2.22 (m, 4H), 3.03 (m, 2H), 3.05 (d, J=5.1 Hz, 3H), 3.69 (s, 2H), 4.67 (br m, 1H), 5.17 (m, 1H), 6.41 (d, J=5.1 Hz, 1H), 6.41 (d, J=1.7 Hz, 1H), 7.00 (dd, J=8.7, 8.7 Hz, 2H), 7.46 (dd, J=8.7, 5.4 Hz, 2H), 7.77 (s, 1H), 8.16 (br d, J=4.5 Hz, 1H), 8.40 (d, J=1.6 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][C:20]=3[O:19][CH3:18])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1ccncc1B(O)O
Reactant: CCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCNC(=O)c1nnc2c(-c3cnccc3OC)cccc2c1N
Yield: 25.6 %

Procedure:
The title compound was prepared from 4-amino-8-bromo-N-ethyl-cinnoline-3-carboxamide (70.0 mg, 0.237 mmol) and 4-methoxy-3-pyridine boronic acid (153.0 mg, 0.3439 mmol) according to Method A except that the extraction was carried out with methylene chloride rather than ethyl acetate and the flash column was eluted with a gradient of 10to 60% methanol in dichloromethane. The concentrated product was then recrystallized from chloroform (with a few drops of methanol) and hexanes to afford the title compound as a yellow solid (19.6 mg, 26% yield). 1H NMR (300.132 MHz, CDCl3) δ 8.58 (d, J=5.7 Hz, 1H), 8.52-8.43 (bm, 1H), 8.46 (s, 1H), 7.92 (app quintet, J=4.0 Hz, 1H), 7.74 (dd, J=4.9, 0.9 Hz, 2H), 6.96 (d, J=5.8 Hz, 1H), 3.78 (s, 3H), 3.53 (dq, J=5.8, 7.3, Hz, 2H), 1.27 (t, J=7.3 Hz, 3H). MS APCI, m/z=324 (M+H). HPLC 1.42 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17].[N:18]([Si](C)(C)C)=[N+:19]=[N-:20].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[N:17]1[NH:18][N:19]=[N:20][C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: N#CCCCCN1C(=O)c2ccccc2C1=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCc1nn[nH]n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To a solution of 5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentanenitrile (6.84 g, 30 mmol) and azidotrimethylsilane (14 mL, 108 mmol) in toluene (40 mL) was added dibutyltin oxide (2.1 g, 6.0 mmol). The mixture was heated at 100° C. for 48 h, concentrated, and flash chromatographed on silica gel column, eluting with EtOAc/DCM (30 and 60%) followed by methanol/DCM (2.5 and 5%) to give the title compound (6.72 g, 83% yield) as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncn4)cc(=O)n3C)CCO2)cc1
Yield: 90.4 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (0.30 g, 1.35 mmol), 2-chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (0.40 g, 1.75 mmol) and triethylamine (0.56 ml, 4.05 mmol) in tetrahydrofuran(6 ml) was refluxed for several hours. The reaction mixture was removed in vacuo. The residue was dissolved in 1N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate as the eluent to give the title compound (463 mg, 90%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[Cl:19].[Cl-].[NH4+]>C(O)C.O.[Fe]>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]([Cl:19])=[CH:11][C:12]([NH2:16])=[C:13]([F:15])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Oc2ccncc2Br)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(Oc2ccncc2Br)cc1F
Temperature: 70 °C

Procedure:
To a solution of 3-bromo-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (2.00 g, 5.75 mmol) in ethanol/water (9:1, 50 mL) was added iron powder (2.00 g, 35.8 mmol) followed by ammonium chloride (2.00 g, 37.4 mmol). The mixture was heated at 70° C. for 2 h. The reaction mixture was filtered, and the solids were washed with EtOAc. The filtrate was evaporated to dryness. The residue was taken in ethyl acetate and washed with water and dried. The solvent was evaporated to provide 4-(3-bromopyridin-4-yloxy)-5-chloro-2-fluorobenzenamine as light brownish oil (0.98 g, 53.6% yield). MS (ESI) m/z: 317.0/319.0 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH3:26])[C:17]([C:27](=[O:45])[N:28]([CH2:30][C:31]3[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[C:33]([C:41]([F:44])([F:43])[F:42])[CH:32]=3)[CH3:29])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:36]=[C:31]([CH:32]=[C:33]([C:41]([F:42])([F:43])[F:44])[CH:34]=1)[CH2:30][N:28]([CH3:29])[C:27]([C:17]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])=[CH:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[N:15][CH:16]=1)=[O:45]
Reactant: Cc1ccccc1-c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(C2=CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 62.2 %

Procedure:
A solution of 258 mg (0.407 mmol) 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-o-tolyl-3′,6′-dihydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (Example 41) and 0.26 ml (3.2 mmol) trifluoroacetic acid in 2 ml dichloromethane was heated at reflux for 4 h. After cooling to room temperature the mixture was diluted with dichloromethane and washed with 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated. Column chromatography afforded 135 mg (62%) of the title compound as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: O=C(O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 39.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-chloro-4-fluorophenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (115 mg, 0.23 mmol) obtained in step 2 and ethanesulfonamide (123 mg, 1.17 mmol), the title compound (53 mg, 39%) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[S:10].[H-].[Na+].Cl[C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][N:18]=1
Reactant: O=Cc1cnc(Cl)s1
Reactant: S=c1[nH]c2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1cnc(Sc2nc3ccccc3[nH]2)s1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
1,3-Dihydro-benzimidazole-2-thione (1.0 g, 6.66 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 479 mg (9.99 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 2-Chloro-1,3-thiazole-5-carbaldehyde (983 mg, 6.66 mmol) is then added and the reaction mixture is stirred at room temperature for 2 h, upon which it is filtered. The solid is washed with tetrahydrofuran and dried under reduced pressure. The residue is diluted with water and extracted twice with ethyl acetate and once with dichloromethane. The organic extracts are combined, dried on magnesium sulfate, filtered and concentrated under reduced pressure. 1.23 g of 2-(1H-benzimidazol-2-ylsulfanyl)-thiazole-5-carbaldehyde is obtained as a pale yellow powder. mp: 188° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16](Br)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:16]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH3:26])[CH:19]=[CH:18]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Temperature: 110 °C
Yield: 72.9 %

Procedure:
Pd(PPh3)4 (69 mg, 0.06 mmol) was added to a mixture (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-tert-butoxyethyl pivalate (5E) (325 mg, 0.75 mmol), 4-chlorophenylboronic acid (175 mg, 1.1 mmol), K2CO3 (1.3 mL 2 M in water, 2.6 mmol) in 1,2-dimethoxyethane (10 mL). The reaction mixture was flushed with nitrogen, heated at 110° C. for 30 min under microwave, and then the volatile component was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product (256 mg, 73%). LCMS-ESI+ (m/z): 468.3, 469.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[C:16]([OH:20])(=[O:19])[CH2:17][SH:18]>>[C:16]([CH2:17][S:18][S:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[C:12]([Cl:15])([Cl:14])[Cl:13])([OH:20])=[O:19]
Reactant: O=C(O)CS
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: O=C(O)CSSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 85.6 %

Procedure:
As in Example 1, 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 18.4 g of thioglycolic acid. After the solvent has been distilled off and the residue recrystallized from toluene, there is obtained 62 g of carboxymethyldithio-4-nitro-2-trichloromethylbenzene; m.p.: 140° C.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[C:5](I)=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]#[N:25])=[C:19](B(O)O)[CH:20]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:24]#[N:25])=[C:19]([C:5]2[C:4]([O:3][CH:2]([F:13])[F:1])=[CH:9][N:8]=[C:7]([O:10][CH3:11])[CH:6]=2)[CH:20]=1
Reactant: N#Cc1ccc(Cl)cc1B(O)O
Reactant: COc1cc(I)c(OC(F)F)cn1
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(OC(F)F)cn1

Procedure:
460 mg (purity 90%, 1.38 mmol) of 5-(difluoromethoxy)-4-iodo-2-methoxypyridine and 299 mg (1.65 mmol, 1.2 eq.) of 5-chloro-2-cyanophenylboronic acid in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. The crude product was purified by flash chromatography (IR-50SI, petroleum ether/ethyl acetate 10-15%). Yield: 230 mg (purity 80%, 43% of theory)
Reaction SMILES: [N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl[C:17]1[CH:22]=[C:21]([O:23][C@H:24]([CH3:46])[CH2:25][O:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:20]=[C:19]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:18]=1>>[N:1]1([C:5]([C:7]2[O:11][C:10]([S:12]([NH:15][C:17]3[CH:22]=[C:21]([O:23][C@H:24]([CH3:46])[CH2:25][O:26][C:27]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:20]=[C:19]([S:47][CH2:48][C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=4[F:56])[N:18]=3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: NS(=O)(=O)c1ccc(C(=O)N2CCC2)o1
Product: C[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)Oc1cc(NS(=O)(=O)c2ccc(C(=O)N3CCC3)o2)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared from 5-(azetidin-1-ylcarbonyl)furan-2-sulfonamide (the product of step iii) (0.40 g) and 4-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-[(1R)-1-methyl-2-(triphenylmethoxy)ethoxy]-pyrimidine (the product of Example 13, step iii) (0.41 g) according to the procedure outlined in Example 1, step iv). Yield: 0.25 g
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH3:30])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:33])[CH3:36]
Reactant: CCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-ethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A175) and ethyl chloroformate the title compound was obtained as colorless solid.