Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1.Br[C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[N:33][CH:34]=1>CC(O)C.C(=O)(O)[O-].[Na+].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>[NH2:38][S:35]([C:31]1[CH:30]=[C:29]([C:17]2[CH:16]=[C:15]3[C:11]([CH:12]=[N:13][NH:14]3)=[C:10]([NH:9][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[S:3][CH:4]=3)=[O:8])[CH:18]=2)[CH:34]=[N:33][CH:32]=1)(=[O:37])=[O:36]
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ncc23)cs1
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: [Na+]
Solvent: CC(C)O
Product: Cc1nc(C(=O)Nc2cc(-c3cncc(S(N)(=O)=O)c3)cc3[nH]ncc23)cs1
Temperature: 120 °C

Procedure:
2-Methyl-N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-4-yl]-1,3-thiazole-4-carboxamide (23 mg, 0.06 mmol), 5-bromo-3-pyridinesulfonamide (18 mg, 0.078 mmol) and Pd(PPh3)4 (7 mg, 0.006 mmol) were combined in IPA (0.5 ml) and 1 M sodium bicarbonate (aq) (0.18 ml). The reaction was heated in a Biotage microwave at 120° C. for 10 mins. After cooling the solvent was removed under a stream of nitrogen and the solid partitioned between water (10 ml) and ethyl acetate:DCM (3×10 ml, 1:1, v/v). A few drops of brine were added to aid separation. The organic layers were combined, passed through a hydrophobic frit and dried under a stream of nitrogen. The residue was dissolved in MeOH:DMSO (0.5 ml, 1:1, v/v) and purified by MDAP (Method B). The solvent was removed under a stream of nitrogen to give the title compound, 1.5 mg.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]([CH3:25])[CH3:24])[CH:17]=2)=[C:10]([CH3:26])[CH:9]=1)=[O:6].[OH-].[K+]>CO.O>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:11]2[C:10]([CH3:26])=[CH:9][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:27])=[O:2])=[CH:13][C:12]=2[CH3:14])=[CH:17][C:18]=1[CH:23]([CH3:25])[CH3:24]
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(C)C)c2)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-[4-(4-hydroxy-3-isopropyl-phenoxy)-3,5-dimethyl-phenyl]-malonamic acid methyl ester (29 mg, 0.08 mmol) in a mixture of MeOH (1 mL) and H2O (1 mL) was added 3 N KOH (0.9 mmol, 0.3 mL). After stirring at RT for 4 h, H2O (10 mL) was added. The solution was washed with EtOAc (2×10 mL) and acidified with 1 N HCl. The aqueous solution was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried and concentrated to give the title compound of Step E and Example 1 (20 mg) as a white solid. MS (APCI−) Calc.: 357.1, Found: 356.1 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:18][N:17]=[C:16]([CH3:19])[N:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:21]>C(Cl)Cl.C(OCC)C>[ClH:21].[ClH:21].[CH3:19][C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[S:18][N:17]=1
Reactant: Cc1nsc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1nsc(N2CCC(N)CC2)n1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of [1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester (256 mg, 0.86 mmol) in CH2Cl2 (8.6 mL) was added at room temperature under stirring a 2 M HCl solution in diethyl ether (4.3 mL) and was stirred at room temperature over night. The solvent was removed under reduced pressure. The crude product was treated twice with diethyl ether to yield the title compound as a yellow semi-solid (260 mg, 100%)
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[N:13][C:12]([C:18]([OH:20])=O)=[CH:11]3)=[CH:5][CH:4]=1.Cl.[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH2:45])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28](=[O:46])[C@@H:29]([NH:45][C:18]([C:12]1[N:13]=[CH:14][C:15]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:22][CH:21]=1)=[CH:17][CH:16]=2)=[O:20])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[C:39]([Cl:44])[CH:38]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(F)c(Cl)c2)cc1
Reactant: O=C(O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)NC(=O)c1cc2cc(Oc3ccc(C(F)(F)F)cc3)ccc2cn1
Yield: 26.9 %

Procedure:
A solution of 6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carboxylic acid (0.050 g, 0.149 mmol) in DMF (2.0 mL) was treated with 2(S)-amino-3-(3′-chloro-4′-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.051 g, 0.164 mmol), HBTU (0.062 g, 0.164 mmol), and DIEA (0.112 mL) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using Hexanes:EtOAc 88:12 to give 0.025 g of 3-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-(2S)-{[6-(4-trifluoromethyl-phenoxy)-isoquinoline-3-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([N:15]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]2=[O:27])=[N:11][N:12]([CH3:14])[CH:13]=1)=O)(C)(C)C.C(OCC)(=O)C.CO.[ClH:36]>>[ClH:36].[NH2:8][C:9]1[C:10]([N:15]2[CH2:19][CH2:18][NH:17][C:16]2=[O:27])=[N:11][N:12]([CH3:14])[CH:13]=1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(N2CCN(C(=O)OC(C)(C)C)C2=O)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(N)c(N2CCNC2=O)n1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
tert-Butyl 3-(4-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-2-oxoimidazolidine-1-carboxylate (7.61 g) was dissolved in 2M hydrogen chloride methanol solution (50 mL), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was ice-cooled, ethyl acetate (50 mL) was added thereto, and the precipitate was collected by filtration, and dried under reduced pressure to give the title compound (4.15 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6](Br)[CH:7]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[C:10]1([C:2]2[CH:3]=[C:4]([Cl:9])[CH:5]=[C:6]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:7]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cc(Br)cc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cc(-c2ccccc2)cc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 163.3 %

Procedure:
Into a 1 L four-necked glass flask equipped with a thermometer, a reflux condenser and a stirrer, 3,5-dibromochlorobenzene 20.0 g (74.0 mmol), phenylboronic acid 27.0 g (222 mmol), 2.0 mol/l sodium carbonate aqueous solution 285 ml (570 mmol), and toluene:tetrahydrofuran (1:1) solution 500 ml were added, and nitrogen was passed through the solution for 2 hours and 30 minutes. Tetrakistriphenylphosphine palladium(0) 4.28 g (3.70 mmol) was then added, which was reacted for 28 hours at 73 to 75° C. with stirring followed by further addition of phenylboronic acid 4.10 g (33.6 mmol) and tetrakistriphenylphosphine palladium(0) 1.10 g (950 μmol) and reaction for 24 hours at 73 to 75° C. with stirring. After completion of the reaction, the reaction mixture was cooled down to room temperature and separated with the addition of water and toluene, and after the water layer was extracted with toluene and after the organic layers were combined and washed with water, it was dried with anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica-gel column chromatography (eluent: hexane) to obtain 3,5-diphenylchlorobenzene 16.0 g as white solid (isolation yield; 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:13]N1C(=O)CCC1=O>FC(C1C=CC=CC=1)(F)F.C(OCC)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:12][Br:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: FC(F)(F)c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)ccc1CBr
Temperature: 90 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of methyl 5-bromo-2-methylbenzoate (5.27 g) in trifluoromethylbenzene (50.0 mL) were added AIBN (0.04 g) and N-bromosuccinimide (4.50 g), and the mixture was stirred at 90° C. for 4 hr under argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (4.89 g).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: N#Cc1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
A mixture of 90 (1.63 g, 11.4 mmol), 3,4-dihydro-2H-pyran (2.87 g, 34.2 mmol), and p-TsOH.H2O (196 mg, 1.14 mmol) in THF (60 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography with eluting with petroleum ether/EtOAc (1:1) to afford 2.48 g (95.9%) of 1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carbonitrile (92) as yellow oil: MS (ESI) m/z=228.1 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[OH:11])=O.C([O-])(=O)C.[Na+].Cl.[NH2:18][OH:19]>C(O)C>[OH:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[N:18][OH:19])[C:7]#[N:8]
Reactant: N#Cc1ccc(C=O)c(O)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(C=NO)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of 4-formyl-3-hydroxy-benzonitrile (CAS 84102-89-6) (6.90 g) in dry ethanol (165 ml) was added sodium acetate (4.23 g) and hydroxylamine hydrochloride (3.58 g). The mixture was stirred at rt for 1 h. The solvent was evaporated and the product was purified by flash chromatography (cyclohexane/EtOAc 8:2=>1:1) to give 3-hydroxy-4-(hydroxyimino-methyl)-benzonitrile (4.70 g). Light yellow solid. MS 162.0 ([M]+)
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:3][C:4]2[N:5]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)=[CH:21][C:20]=1[O:26][CH3:27]
Reactant: COc1cc(O)ccc1Cl
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a mixture of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (150 mg, 0.5 mmol), 4-chloro-3-methoxyphenol (158 mg, 1 mmol) and DMSO (1 mL) was added K2CO3 (415 mg, 3 mmol). The reaction was stirred at ambient temperature for 8 h before diluting with water (10 mL). A solution of 1N HCl was added until the mixture was only slightly basic (pH 8) before extracting with EtOAc (30 mL). The EtOAc phase was washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2, hexanes/EtOAc) to afford the title compound (194 mg, 97%) as a white solid: ESI MS m/z 397 [C18H15Cl3N2O2+H]+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[S:26][CH:25]=[C:24]([CH2:27][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)[CH:23]=1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2.5 g), (5-chloro-3-thienyl)methanol (2.48 g) and tributylphosphine (5.63 g) in THF (150 ml) was added 1,1′-(azodicarbonyl)dipiperidine (7.03 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed With brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then ETOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (1.15 g) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]#[N:11])[CH2:5][CH2:4]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:11][CH2:10][CH2:9][CH:6]1[CH2:5][CH2:4][C:3]([N:2]([CH3:1])[CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC#N)CC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(CCN)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4-Dimethylamino-4-phenylcyclohexylidene)acetonitrile (1.16 g, 4.8 mmole) was dissolved in methanol (30 ml). Nickel(II) chloride hexahydrate (2.28 g, 9.6 mmole) was added to this solution. NaBH4 (1.82 mg, 48 mmole) was then added in portions with stirring and ice water cooling. Once addition was complete, stirring was continued at RT for 1 h. The resultant black nickel boride was removed by suction filtration after addition of 2M hydrochloric acid (15 ml) and washed with 2M hydrochloric acid (3×10 ml). The hydrochloric, aqueous-methanolic solution was reduced to half its volume in order to remove the methanol. The remaining aqueous phase was extracted with ether (3×10 ml) to remove neutral substances. The aqueous phase was then alkalised by addition of conc. aqueous ammonia solution and again extracted with ether (3×20 ml). The combined extracts were washed with saturated NaCl-solution (30 ml), dried over Na2SO4 and then evaporated. The resultant crude product could be purified by column chromatography [silica gel 60 (100 g); MeOH (1000 ml)]. However, this did not result in separation of the diastereoisomers. [4-(2-Aminoethyl)-1-phenylcyclohexyl]dimethylamine was obtained as a colorless oil in a yield of 643 mg (54%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:19]>>[Cl:1][C:2]1[CH:10]=[C:9]([C:11](=[O:15])[N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([Cl:16])[C:3]=1[C:4]([Cl:19])=[O:5]
Reactant: CN(C)C(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 2,6-dichloro-4-(dimethylcarbamoyl)benzoic acid (65 mg, 0.21 mmol) in SOCl2 (3 mL) was heated to reflux for overnight and then cooled to room temperature. The mixture was concentrated under reduced pressure to give crude 2,6-dichloro-4-(dimethylcarbamoyl)benzoyl chloride (70 mg, yield: 100%), which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([Cl:18])=[O:15])=[CH:11][O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1conc1-c1ccc(F)cc1
Product: O=C(Cl)c1conc1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 0.3 g of Compound 8D in 1.05 mL of thionyl chloride was refluxed for 1 h under N2 atmosphere. After cooling to r.t., the solvent was evaporated to dryness and the so obtained crude 3-(4-fluorophenyl)isoxazole-4-carbonyl chloride dissolved in 10 mL of chloroform. Afterwards a solution of 0.48 g of Compound 8B and 0.6 mL of triethylamine in 10 mL of chloroform was added and the resulting mixture stirred at r.t. for 18 h. The solvent was washed with water, dried (sodium sulphate), filtered and evaporated in vacuo. The crude was purified by flash chromatography (ethyl acetate-2N ammonia in methanol 95:5) to give 0.607 g (79.8%) of the title compound. M.p.: 122.4-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(-n2ccc(-c3cccc(Cl)c3)n2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(-c2ccn(-c3ccc(Cl)c(CBr)c3)n2)c1

Procedure:
A mixture of 1-(3-methyl-4-chlorophenyl)-3-(3-chlorophenyl)-1H-pyrazole (i.e. the product of Step A) (1.7 g, 5.61 mmol), N-bromosuccinimide (1.1 g, 6.17 mmol) and benzoyl peroxide (30 mg, 0.12 mmol) in 100 mL of carbon tetrachloride was irradiated with a sun lamp for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (10 to 20% gradient of ethyl acetate in hexanes as eluant) to give the title compound as a white solid (0.37 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH:31]=[CH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:21]4[N:22]=[N:23][C:24]([N:27]5[CH2:28][CH:29]=[CH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1ccc(N2CC=CCC2)nn1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Product: C1=CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nn2)CC1
Yield: 20 %

Procedure:
Compound 409 was prepared from compound 4 and compound 410 using chemistry similar to that described in example 1. The yield is 20%. 1H NMR (500 MHz, CD3OD) δ ppm 9.68 (1 H, d, J=1.5 Hz), 9.36 (1 H, s), 9.36 (1 H, d, J=0.5 Hz), 8.69 (3 H, t, J=2.2 Hz), 8.60-8.72 (1 H, m), 8.22 (1 H, d, J=10.5 Hz), 8.08 (1 H, dd, J=10.0, 1.0 Hz), 6.02-6.09 (1 H, m, J=8.1, 4.1, 4.1, 2.0 Hz), 5.89 (1 H, dddd, J=8.4, 3.4, 3.3, 1.5 Hz), 5.50 (2 H, t, J=8.8 Hz), 4.17 (3 H, qd, J=2.7, 2.6 Hz), 3.87 (3 H, t, J=5.7 Hz), 2.47-2.60 (3 H, m), 2.37-2.43 (2 H, m, J=6.1, 6.1, 3.5, 2.2 Hz), 2.15-2.35 (7 H, m), 1.87-1.99 (3 H, m); LCMS-ESI (POS), M/Z, M+1: Found 413.2, Calculated 413.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH3:27])[N+:12]=2[O-])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O:32]C(=O)C)(=[O:31])[CH3:30]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[C:14]([CH2:25][CH3:26])=[C:13]([CH2:27][O:32][C:29](=[O:31])[CH3:30])[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(C)[n+]([O-])c(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12
Product: CCc1c(COC(C)=O)nc(-c2ccc(OC)c(OC)c2)c2cc(OC)c(OC)cc12

Procedure:
421.5 g (1.1 M) of 1-(3,4-dimethoxyphenyl-3-methyl-4-ethyl-6,7-dimethoxy-isoquinoline N-oxide and 1.1 liters of acetic anhydride are refluxed for 2.5 hours, then the solution is evaporated at reduced pressure. The residue is recrystallized first from 1.2 liters of 99% ethanol, then the resulting product (414.5 g, m. p. 115° to 120° C.) is repeatedly recrystallized from one liter of 99% ethanol. Yield 393.7 g (84.1%), m.p. 129° to 131° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:10])[C:8]=1[F:9])[NH2:5].N1C=CC=CC=1.Cl[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:18](=[O:19])[O:20][CH3:21])[CH:6]=[C:7]([Br:10])[C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: Nc1cc(Br)c(F)c(Br)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1cc(Br)c(F)c(Br)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
3,5-dibromo-4-fluoroaniline (1.6 g, 4.16 mmol) was dissolved in DCM (41.6 ml). Pyridine (0.90 ml, 11.13 mmol) was added and the reaction mixture cooled to 0-5° C. Methyl chloroformate (0.66 ml, 8.52 mmol) was added drop wise via syringe. The reaction mixture was stirred at 0-5° C. for 1 hour. The reaction mixture was diluted with additional 50 ml dichloromethane and washed with 0.5 M citric acid twice, NaHCO3 solution once and brine once, then dried over MgSO4, filtered and evaporated to dryness. Chromatography on silica (gradient from 100% hexanes to 100% DCM) gave methyl (3,5-dibromo-4-fluorophenyl)carbamate (1.22 g) as a colorless fluffy solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: C#Cc1ccc(Br)cc1
Agent: [Na]
Product: Brc1ccc(/C=C\C(SC(/C=C\c2ccc(Br)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl benzylsulfide. The title compound was obtained in 80% yield following oxidation. 1HNMR (CDCl3) δ 4.52 (2H, s), 6.80 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3=[N:16][CH:17]=[CH:18][C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[C:14]3[NH:13][C:12]=2[CH3:32])=[O:10])[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:29]1([CH2:28][O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[C:11]([C:9]([NH:8][C@H:5]4[CH2:6][CH2:7][C@@H:2]([NH:1][C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:3][CH2:4]4)=[O:10])=[C:12]([CH3:32])[NH:13][C:14]=23)[CH2:30][CH2:31]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ccnc2c1C(=O)N[C@H]1CC[C@@H](N)CC1
Product: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (example D.f6) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.