Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].[C:14]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:27]1([CH:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:25][CH2:26]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c2ccccc2n1CCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 4.5 parts of 1-(2-chloroethyl)-2,3-dihydro-1H-benzimidazol-2-one, 5 parts of 1-(diphenylmethyl)piperazine, 6.4 parts of sodium carbonate and 200 parts of 4-methyl-2-pentanone is stirred and refluxed overnight with water-separator. The reaction mixture is cooled and water is added. The precipitated product is filtered off and crystallized from a mixture of N,N-dimethylformamide and water, yielding 1-{2-[4-(diphenylmethyl)-1-piperazinyl]ethyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 218° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].C(N(CC)CC)C.Cl[C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20].[Cl-].[Na+]>C(Cl)(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:7][C:19](=[O:20])[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)OC(=O)Cl
Reactant: NCc1cccc(Br)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)OC(=O)NCc1cccc(Br)c1
Yield: 90.8 %

Procedure:
3.00 g of 3-bromobenzylamine hydrochloride suspended in chloroform (20 ml) was mixed with 2.86 g of triethylamine at room temperature. The resulting solution was stirred under cooling with ice while 1.82 g of isopropyl chloroformate was added dropwise and then stirred at room temperature for 2 hours. After the reaction, the reaction solution was poured into saturated aqueous sodium chloride, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated at ordinary pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 3.33 g of isopropyl N-(3-bromobenzyl)carbamate as a colorless transparent viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.Cl.Cl.Cl.[N:25]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][C:4]3[CH:18]=[CH:19][C:20]([F:21])=[C:2]([F:1])[CH:3]=3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:38][CH2:39]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3ccc(F)c(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,4-Difluoro-phenoxy)-1H-indole-2-carboxylic acid 149 (preparation see below) and amine 5.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2.[CH3:20]C1C=CC=C2C=1NC=C2>>[CH3:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=[CH:7]2
Reactant: Cc1cccc2cc[nH]c12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: Cc1cccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methyl-1H-indole.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:11])[NH:6]2.[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[NH:4][C:5](=[O:11])[NH:6]3)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]c(=O)[nH]c23)CC1

Procedure:
By reacting 6-chloro-7,9-dihydro-purin-8-one with piperidin-4-yl-carbamic acid tert-butyl ester according to the method of Example 4A, the title compound was obtained. LC/MS: (LCT) Rt 5.68 [M+H]+ 335.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:23][C:24]([F:39])([F:38])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][NH:29][CH3:30].[Cl-].[NH4+]>CN(C1C=CN=CC=1)C.ClCCl.O>[F:23][C:24]([F:38])([F:39])[C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:28][N:29]([CH3:30])[C:11](=[O:13])[C:10]1[C:14]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:8][CH:9]=1
Reactant: CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(N2CCOCC2)cc1Oc1ccccc1
Yield: 84 %

Procedure:
A mixture of 46 mg (0.15 mmol) 6-morpholin-4-yl-4-phenoxy-nicotinic acid, 43 mg (0.17 mmol) (3,5-bis-trifluoromethyl-benzyl)-methylamine, 32 mg (0.17 mmol) 1-(3-diaminopropyl)-3-ethyl-carbodiimide hydrochloride and a catalytic amount of 4-(N,N-dimethylamino)-pyridine in 3 ml dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with water, adjusted to pH 6 with saturated aqueous ammonium chloride solution and extracted with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated. Flash column chromatography afforded 68 mg (83%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]2)=[C:4]([N+:20]([O-])=O)[C:3]=1[O:23][CH3:24].O>C(O)(=O)C.[Fe]>[CH2:11]([C:24]1[O:23][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([F:8])=[C:5]([N:9]3[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=[N:10]3)[C:4]=2[N:20]=1)[CH:12]([CH3:16])[CH3:13]
Reactant: COc1c(Cl)cc(F)c(-n2ncc(C(F)(F)F)cc2=O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)Cc1nc2c(-n3ncc(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 166.9 %

Procedure:
A mixture of 2-(4-chloro-6-fluoro-3-methoxy-2-nitrophenyl)-5-trifluoromethylpyridazin-3-one (0.52 g) and iron powder (0.4 g) in acetic acid (30 ml) was stirred overnight at ambient temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with brine (×3) and dried over anhydrous sodium sulfate. The solvent was removed to give the title compound (0.46 g). 1H NMR (CDCl3, 300 MHz) 3.88 (3H, s), 4.19 (2H, br s), 6.67 (1H, d, J=9.6 Hz), 7.31 (1H, m), 8.10 (1H, d, J=2.2 Hz) ppm.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6].CCN(CC)CC.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>C(Cl)Cl>[C:18]([CH2:2][CH2:3][C:4]1[C:5]([NH:7][C:8](=[O:10])[CH:9]=1)=[O:6])(=[O:21])[CH:19]=[CH2:20]
Reactant: O=C1C=C(CCO)C(=O)N1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)CCC1=CC(=O)NC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxyethyl maleimide (5 g, 35.4 mmol) and Et3N (4.25 g, 43.0 mmol) was dissolved in 75 mL of methylene chloride and cooled to 0° C. Acryloyl chloride (3.20 g, 35.4 mmol) in 25 mL of methylene chloride was added dropwise over 30 minutes. The solution was stirred at room temperature for 30 minutes followed by refluxing for 1 hour. The triethylamine hydrochloride was removed by filtration and the yellow solution was concentrated. The yellow crystals were purified by sublimation yielding white crystals, m.p. 77-78° C. (5.00 g, 72.3%). 1H-NMR (CDCl3, δ, ppm): 3.81-3.87 (2H, --NCH2 --, t) 4.22-4.33 (2H, --OCH2 --, t), 5.81-5.85 (2H, CH2 =CH, cis), 6.00-6.13 (1H, CH2 =CH--, q), 6.34-6.42 (1H CH2 =CH, trans), 6.73 (2H, --OC--CH=CH--CO--, s). 13C-NMR (CDCl3, δ, ppm): 170.4 (2C, C=O, maleimide), 165.8 (1C, C=O, ester), 134.2 (2C, --CH=CH--), 131.45 (1C, --CH=), 127.9 (1C, CH2 =), 61.5 (1C, β--CH2 --), 36.8 (1C, α--CH2 --).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14](=[O:17])([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:1]([N:8]2[CH2:13][CH2:14][O:17][CH2:10][CH2:9]2)=[O:2])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 195 %

Procedure:
Amine preparation: a mixture of 4-morpholinocarbonyl chloride (0.38 ml), 1-BOC-piperazine (552 mg) and potassium carbonate (439 mg) in MeCN (7 mL) was stirred at room temperature for 3 h. The reaction mixture was then diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(morpholine-4-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (865 mg). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>[I-].[K+].O>[Cl:9][C:5]1[C:6]([O:8][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][C:2]([NH2:1])=[C:3]([F:10])[CH:4]=1
Reactant: BrC1CCCC1
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OC2CCCC2)c(Cl)cc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A two-necked, round-bottomed flask (25 cc) was charged with 5-amino-2-chloro-4-fluorophenol (1.015 g, 6.28 mmol), potassium carbonate (1.72 g, 12.4 mmol), potassium iodide (4.0 mg, 0.024 mmol) and solvent N,N-dimethylformamide (5 mL) and the mixture was stirred at 80° C. for 1 h. Subsequently, cyclopentyl bromide (1.00 g, 6.71 mmol) was added and the mixture was stirred at 80° C. for an additional 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and water (20 mL) was added, followed by extraction with toluene (20 mL×3). The organic layers were combined, washed with water (10 mL) and saturated brine (10 mL) and dried with anhydrous magnesium sulfate. After the desiccant was removed, the solvent was distilled off under vacuum to give 4-chloro-5-cyclopentyloxy-2-fluoroaniline (1.43 g, 6.23 mmol; yield=99.0%). BP: 143°-145° C./1.5 mmHg 1H-NMR(CDCl3, TMS,ppm): δ1.40-2.00(8H,m), 3.72(2H,s), 4.67(1H,m), 6.39(1H,d,JHF =9.0Hz), 7.04(1H,d,JHF =11.0Hz). IR (neat, cm-1): 3500, 3400, 1630, 1510, 1420, 1245, 1185.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:9]([C:11]3[CH:12]=[C:13]([N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][CH:16]=3)=[CH:10][C:3]=12.Br[C:30]1[C:31]([C:37]2[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=2)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=1>>[CH3:18][N:17]([CH3:19])[C:13]1[CH:12]=[C:11]([C:9]2[N:8]([S:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:21])=[O:22])[C:4]3=[N:5][CH:6]=[CH:7][C:2]([C:30]4[C:31]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C:44](=[O:48])[N:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=5)=[N:32][N:33]([CH2:35][CH3:36])[CH:34]=4)=[C:3]3[CH:10]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CN(C)c1cccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)c1
Product: CCn1cc(-c2ccnc3c2cc(-c2cccc(N(C)C)c2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1

Procedure:
Following the procedure described for Intermediate 32 with {3-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}dimethylamine. Using this product crude and following the procedure described in Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea provided the title product. ESMS [M+H]+: 634.6
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.C([O-])(O)=O.[Na+].[Br:18][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([F:29])=[C:23]([S:25](Cl)(=[O:27])=[O:26])[CH:24]=1>O.C(#N)C>[Br:18][C:19]1[C:20]([Cl:30])=[CH:21][C:22]([F:29])=[C:23]([S:25]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([CH3:12])([CH3:1])[CH2:3][CH2:4]2)(=[O:27])=[O:26])[CH:24]=1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (2.2 g, 13.66 mmol) in a mixture of water (60 mL) and acetonitrile (40 mL) containing NaHCO3 (3.44 g, 41.0 mmol), was added 5-bromo-4-chloro-2-fluoro-benzenesulfonyl chloride (4.2 g, 13.66 mmol) in acetonitrile (20 mL) slowly with vigorous stirring. After addition, the mixture was stirred for 3 hrs. The resulting precipitate was filtered, washed with hexane and dried to yield 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline as a light brown solid (5.0 g).
Reaction SMILES: C[Al](C)C.[Br:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:7]=1[NH2:8].[NH2:14][C:15]1[C:20]([C:21](OC)=[O:22])=[CH:19][C:18]([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:29]=2)=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[NH2:14][C:15]1[C:20]([C:21]([NH:8][C:7]2[C:9]([F:13])=[CH:10][CH:11]=[CH:12][C:6]=2[Br:5])=[O:22])=[CH:19][C:18]([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH:29]=2)=[CH:17][N:16]=1
Reactant: Nc1c(F)cccc1Br
Reactant: COC(=O)c1cc(-c2cnn(C3CCN(C)CC3)c2)cnc1N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CN1CCC(n2cc(-c3cnc(N)c(C(=O)Nc4c(F)cccc4Br)c3)cn2)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
2M Trimethylaluminium in toluene (0.75 ml) was added to a solution of 2-bromo-6-fluoro-aniline (0.229 g) in toluene (30 ml). The mixture was stirred for 30 minutes, then methyl 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylate (0.19 g) was added. The mixture was heated to 120° C. for 18 hours, allowed to cool and then quenched with 10% aqueous Rochelle's salt solution. The organic fraction was purified by SCX ion-exchange chromatography to give crude 2-amino-N-(2-bromo-6-fluorophenyl)-5-[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]pyridine-3-carboxamide; Mass Spectrum: M+H+ 472.1; RT 0.87 min.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2].Br[C:35]1[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=1>CN(C=O)C.C([O-])([O-])=O.[K+].[K+].CO.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([N:4]1[CH:8]=[C:7]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([NH2:43])=[O:42])=[N:39][CH:40]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:31])[C:10]2=[O:32])[C:6]([CH3:33])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(B4OC(C)(C)C(C)(C)O4)cc3c21
Reactant: NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(N)=O)nc4)cc3c21
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage 112.1.1, 34 mg, 0.075 mmol), 5-bromo-pyridine-2-carboxylic acid amide (Combi-Blocks, San Diego, USA, 20 mg, 0.099 mmol), and PdCl2(PPh3)2 (3.5 mg, 0.005 mmol) in DMF (0.9 ml) and 1 M aqueous K2CO3 (0.187 ml) was stirred under argon at 105° C. for 2.5 h. The RM was cooled to rt. The mixture was diluted with MeOH+3 drops TFA and purified directly by Prep.HPLC (H2O (0.1% TFA)/CH3CN 97:3 to 55:45). The fractions containing product were collected together and basified with NaHCO3 (0.3 g), before being concentrated. The resulting layer was extracted with DCM, washed with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a white solid. (HPLC: tR 2.44 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.00 (s, 1H), 8.75-8.69 (m, 1H), 8.24-8.19 (m, 1H), 8.18-8.07 (m, 2H), 8.07-7.98 (m, 3H), 7.75-7.67 (m, 1H), 7.61-7.56 (m, 1H), 4.61-4.48 (m, 1H), 3.58 (s, 3H), 1.97 (s, 3H), 1.45 (s, 3H), 1.43 (s, 3H))
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[CH:8]([OH:27])[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)=[C:10]([CH2:17][CH3:18])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:41](OC(=O)C)([F:43])[F:42]>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:41]([F:43])[F:42])=[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:10]([CH2:17][CH3:18])=[N:11]2
Reactant: CCC1=C(Cc2ccc(F)cc2)C(O)c2c(OCC(=O)OC)ccc(Cl)c2N1
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A mixture of [8-chloro-2-ethyl-3-(4-fluorobenzyl)-4-hydroxy-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.25 g), N,N-dimethylformamide (1.1 mL), potassium carbonate (0.51 g) and acetic acid chlorodifluoromethyl ester (0.33 mL) was stirred at 70° C. for 16 hours. The mixture was diluted with water, extracted with ethyl acetate and the combined extracts dried over sodium sulfate and then the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane gave title compound, 0.06 g.
Reaction SMILES: [CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]#[N:10])[N:4]=1.[C:19](OC)(=[O:27])[C:20]1[C:21](=[CH:23][CH:24]=[CH:25][CH:26]=1)[SH:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:3]1[CH:8]=[N:7][CH:6]=[C:5]([C:9]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19](=[O:27])[N:10]=2)[N:4]=1
Reactant: CN(CC(=O)OC(C)(C)C)c1cncc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(CC(=O)OC(C)(C)C)c1cncc(-c2nc(=O)c3ccccc3s2)n1
Yield: 26.5 %

Procedure:
tert-Butyl [methyl(6-cyano-2-pyrazinyl)amino]acetate (1.00 g, 4.03 mmol) and methyl thiosalicylate (1.36 g, 8.06 mmol) were dissolved in toluene (50 ml), and triethylamine (1.70 ml, 12.1 mmol) was added thereto. The mixture was refluxed for 18 hrs. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.41 g, 26%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH:14]=2)=[CH:4][C:3]=1[C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=2[F:34])[N:25]=[N:24][N:23]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:27]=1[N:26]1[C:22]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([C:8]3=[CH:14][CH2:13][NH:12][CH2:11][CH2:10][CH2:9]3)[CH:4]=2)=[N:23][N:24]=[N:25]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N)c(-c3nnnn3-c3cccc(F)c3F)c2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(C2=CCNCCC2)cc1-c1nnnn1-c1cccc(F)c1F

Procedure:
(E)-tert-Butyl 5-(6-amino-5-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-3-yl)-3,4-dihydro-2H-azepine-1(7H)-carboxylate (14 mg, 29.9 μmol, 1 eq.) was diluted in 1:1 TFA:DCM (1.5 mL) and the mixture stirred at room temperature for 2 hours. The reaction was concentrated and purified by reversed-phase HPLC purification to give 3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-((E)-2,5,6,7-tetrahydro-1H-azepin-4-yl)pyridin-2-amine in quantitative yield; 1H NMR (300 MHz, DMSO-d6): 9.0 (br s, 2H); 8.25 (m, 1H); 7.87-7.77 (m, 1H); 7.75-7.6 (m, 2H); 7.6-4.5 (m, 1H); 5.85 (m, 1H); 3.7 (m, 2H); 3.25 (m, 2H); 2.5 (m, 2H); 1.78 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10](O)=[O:11].S(Cl)([Cl:18])=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([Cl:18])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: CCCC(Cc1ccccc1Br)C(=O)O
Product: CCCC(Cc1ccccc1Br)C(=O)Cl

Procedure:
A 500-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a thermometer and a NaOH trap was charged with 277 mmol of 3-(2-bromophenyl)-2-propylpropionic acid and 200 ml of thionyl chloride, and the mixture was heated under reflux for 2 hours. Then, the excess thionyl chloride was removed by a single distillation, and the distillation of the residue under reduced pressure gave 77.4 g of a crude product having a boiling point of 130° to 135° C./1 mmHg as a pale brown transparent liquid. This acid chloride was used in the next reaction without further purification
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1.[CH3:15][C:16]1([CH3:23])[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1.Cl>CCCCCC.O1CCCC1>[Cl:14][C:9]1[CH:8]=[C:7]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]([CH3:23])([CH3:15])[CH2:17][CH2:18]2)[CH:12]=[CH:11][C:10]=1[OH:13]
Reactant: CC1(C)CCC(=O)CC1
Reactant: Oc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)CCC(O)(c2ccc(O)c(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
100 ml of a 1.6 M solution of n-butyllithium in hexane are added at −78° C. to 15.1 g of 4-bromo-2-chlorophenol in 150 ml of tetrahydrofuran, and the reaction mixture is stirred at −78° C. for 1 hour. 10.1 g of 4,4-dimethylcyclohexanone (compound 3.1) are added and the reaction mixture is stirred at −78° C. for a further 30 minutes and then at room temperature for 12 hours. The reaction mixture is hydrolysed with 1 N hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The solid obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/ethyl acetate mixture varying from 98/2 to 90/10 (v/v). 11.8 g of solid are obtained.