Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([F:31])[CH:33]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: OCc1cccc(F)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
2-Bromo-4-nitrophenol (4.86 g, 0.0223 mol), triphenylphosphine (7.6 g, 0.0290 mol), 3-fluorobenzylalcohol (3.65 g, 0.0290 mol) were combined and dissolved in THF (89 mL). The reaction temperature was cooled to 0° C. and DIAD (4.50 g, 0.0290 mol) was added. The reaction was allowed to warm slowly to room temperature and stirred for 3 hours before it was diluted with water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (200 mL×2). The organic extracts were combined and washed with brine, followed by drying over sodium sulfate. The volatiles were removed in vacuo and the residual semi-solid was treated with diethyl ether. The solids were removed by filtration. The volatiles from the resulting filtrate were removed in vacuo and the material was purified using EtOAc:Hexanes (90/10) in a biotage LC system to afford the title compound as a yellow solid (3.73 g, 68% yield). 1H NMR (DMSO-d6) δ 8.43 (d, 1H); 8.26 (m, 1H); 7.45 (m, 1H); 7.38 (d, 1H); 7.30 (m, 2H); 7.17 (m, 1H); 5.39 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:15](=[O:18])[CH2:16][CH3:17])[CH:3]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(Br)ccn1
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
To a solution of 4-bromo-2-aminopyridine (580 mmol) in 1.5 L dichloromethane was added pyridine (1.16 mol). The mixture was stirred for 20 min. Propionyl chloride (669 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 5 h. Water was added and the reaction mixture was extracted with dichloromethane. The combined organic layer was washed with brine, dried and concentrated. The residue was recrystallized from hexane/ethyl acetate (6:1) to afford 112 g of N-(4-bromopyridin-2-yl)propanamide (85% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH3:21])[CH:12]=2)[OH:10])=[CH:5][CH:4]=1>C(Cl)Cl.O=[Mn]=O>[CH3:22][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:20][CH3:21])[CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOc1cc(C(O)c2ccc(N(C)C)cc2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(N(C)C)cc2)ccc1OC
Yield: 17.1 %

Procedure:
To a stirred solution of (4-dimethylamino-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanol (1.29 g, 4.3 mmol) in CH2Cl2 (30 mL) at room temperature was added activated MnO2 powder (2.1 g, 24 mmol) and kept adding 2˜3 equivalents of MnO2 every 3˜5 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (4-dimethylamino-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone as an brown oil (0.22 g, 17% yield): 1H NMR (CDCl3) δ 1.48 (t, J=7 Hz, 3H, CH2CH3), 3.08 (s, 6H, N(CH3)2), 3.95 (s, 3H, OCH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 6.67-6.71 (m, 2H, Ar), 6.88-6.92 (m, 1H, Ar), 7.34-7.39 (m, 2H, Ar), 7.77-7.80 (m, 2H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6]([CH3:9])=[CH:7][CH:8]=1.[Br:15]N1C(=O)CCC1=O>>[Br:15][CH2:9][C:6]1[C:5]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc(OC)ccc1C
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1cc(OC)ccc1CBr

Procedure:
Reaction of ethyl 4-methoxy-o-toluate with N-bromosuccinimide as described in Example 1a provides ethyl α-bromo-4-methoxy-o-toluate as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Product: Clc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, light brown solid (29 mg, 22%), MS (ISP) m/z=405.4 [(M+H)+], mp 182° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-phenyl)-1H-benzo[d]imidazole (intermediate H) (100 mg, 325 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (79.6 mg, 358 μmol).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[C:4](O)=[N:3][CH:2]=1.S(Cl)([Cl:14])=O>CN(C)C=O>[Cl:14][C:4]1[C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2cnccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1ncnc2cnccc12
Yield: 99.4 %

Procedure:
A suspension of pyrido[3,4-d]pyrimidin-4-ol (33)(1.47 g, 10 mmol) in thionylchloride (30 ml) and dimethylformamide (50 μl, cat.) was heated to reflx (90° C.) for 1 hour. The mixture was then cooled and concentrated in vacuo and then diluted with CH2Cl2 (50 ml) which caused a suspension to form. The solid was removed by filtration, washed with cold CH2Cl2 (10 ml) to give the title compound (1.65 g, 99.4%) in sufficiently pure form to be used without any further purification. m/z (LC-MS, ESP): 166 [M+H]+, R/T=2.82 mins.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:21])=[CH:15][CH:14]=1.[OH-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:21])=[CH:15][CH:14]=1
Reactant: OCc1ccccc1B(O)O
Reactant: O=C(Nc1ccc(Br)cc1)[C@H]1CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccccc2CO)cc1)[C@H]1CN2CCC1CC2

Procedure:
A mixture of 90 mg (0.58 mmol) of 2-(hydroxymethyl)phenylboronic acid, 120 mg (0.39 mmol) of (3R)-N-(4-bromophenyl)-1-azabicyclo[2.2.2]octane-3-carboxamide, 1.16 ml (1.16 mmol) of 1N sodium hydroxide solution, 30 mg (0.04 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 1 ml of DMF is heated at 80–85° C. for 42 h. The solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel 60 (mobile phase: dichloromethane→dichloromethane/methanol/ammonia 80:20:2). 56 mg (39% of theory) of the title compound are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O-])=[O:16])=[CH:13][CH:12]=1)=[O:8])([O-:3])=[O:2].O.[NH2:24][NH2:25]>CCO>[NH:24]([C:15]([C:14]1[CH:18]=[CH:19][C:11]([CH2:10][NH:9][C:7](=[O:8])[C:6]2[CH:20]=[CH:21][CH:22]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:12][CH:13]=1)=[O:16])[NH2:25]
Reactant: NN
Reactant: O=C([O-])c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CNC(=O)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a suspension of 4-{[(3-nitrobenzoyl)amino]methyl}benzoate (500 mg, 1.59 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.16 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with EtOH (2×2 mL), EtOH/water (2×2 mL)and water (2×2 mL), and drying under vacuo at 70° C. for 5 hrs gave 379 mg of the title compound (76%) as a pale yellow solid in 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].C(#N)C.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:50]=[CH:51][CH:52]=1)[O:24][C:25]1[N:26]=[C:27]([NH:36][C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:39][CH:38]=2)[C:28]([C:33]([NH2:35])=[O:34])=[N:29][C:30]=1[CH2:31][CH3:32]>C(OCC)(=O)C.CN1CCCC1=O.CN(C)C=O>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([NH:20][C:21]1[CH:22]=[C:23]([CH:50]=[CH:51][CH:52]=1)[O:24][C:25]1[N:26]=[C:27]([NH:36][C:37]2[CH:38]=[CH:39][C:40]([N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)=[CH:41][CH:42]=2)[C:28]([C:33]([NH2:35])=[O:34])=[N:29][C:30]=1[CH2:31][CH3:32])=[O:8]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(N)c1
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cccc(NC(=O)/C=C/CN(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a mixture of trans-4-dimethylaminocrotonic acid hydrochloride (113 mg) and acetonitrile (1.9 mL) were added oxalyl dichloride (55 μL) and N,N-dimethylformamide (2 droplets) under ice-cooling, followed by stirring at room temperature for 2 hours. To a mixture of 5-(3-aminophenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (190 mg) and N-methylpyrrolidone (3.8 mL) was added a solution of the acid chloride prepared above under ice-cooling, followed by stirring at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and then washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic phase was dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1). Ethyl acetate was added thereto and the precipitated solid was collected by filtration and then dried under reduced pressure to obtain 5-(3-{[(2E)-4-(dimethylamino)buta-2-enoyl]amino}phenoxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (107 mg) as a pale yellow solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[F:34])[C:22]([NH2:35])=[CH:21][N:20]=1>C1COCC1>[CH3:13][O:14][C:15]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:16]=1[CH2:17][NH:18][C:19]1[N:24]=[C:23]2[C:22]([NH:35][C:1](=[O:2])[N:25]2[CH2:26][C:27]2[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=2[F:33])=[CH:21][N:20]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(CNc2ncc(N)c(NCc3c(F)cccc3F)n2)c(OC)c1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncc3[nH]c(=O)n(Cc4c(F)cccc4F)c3n2)c(OC)c1

Procedure:
Carbonyldiimidazole (0.93 g) was added to a solution of N2-(2,4-dimethoxybenzyl)-N4-(2,6-difluorobenzyl)pyrimidine-2,4,5-triamine (54) in THF (20 mL) and the resultant mixture stirred at RT overnight, then the solvents were removed under reduced pressure and the taken up in EtOAc and washed trice with water. The organics were dried, filtered and evaporated and purified via column chromatography, elution with 2.5 and 4% MeOH/DCM, to yield 2-(2,4-Dimethoxybenzylamino)-9-(2,6-difluorobenzyl)-7H-purin-8(9H)-one (55) (0.58 g), MH+=428.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[N:5]1[C:10]2[NH:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3[CH2:14][C:15](=[O:16])[C:9]=2[CH:8]=[CH:7][CH:6]=1>O.C(O)(=O)C>[NH:5]1[C:10]2=[N:11][C:12]3[CH:20]=[N:19][CH:18]=[CH:17][C:13]=3/[C:14](=[N:1]/[OH:3])/[C:15](=[O:16])[C:9]2=[CH:8][CH:7]=[CH:6]1
Reactant: O=N[O-]
Reactant: O=C1Cc2ccncc2Nc2ncccc21
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2ccc[nH]c-2nc2cnccc2/c1=N/O
Reaction time: 1.5 h
Yield: 87 %

Procedure:
A solution of sodium nitrite (3.3 g, 0.048 mol) in water (14.4 mL) was added dropwise to a solution of 6,11-dihydro-5H-dipyrido[2,3-b:4′,3′-f]azepin-5-one (4.22 g, 0.02 mol) in acetic acid (80 mL) at room temperature. After the addition was completed, the reaction was stirred for 1.5 hours and 100 mL of water was then added. The mixture was stirred for additional 10 minutes, filtered and dried to give 4.18 g of the desired product. 1H NMR (400 MHz, CD3OD): δ 8.70 (s, 1H), 8.48-8.51 (m, 2H), 8.32 (d, 1H, J=5.2 Hz), 7.56 (d, 1H, J=5.6 Hz), 7.07 (dd, 1H, J1=8 Hz, J2=4.8 Hz). MS [M+H]=241.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:17].[C:18]1([CH2:24][C:25](=[NH:29])OCC)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.C(Cl)(Cl)Cl>[ClH:17].[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25](=[NH:29])[CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1COc1cccnc1N
Reactant: CCOC(=N)Cc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1COc1cccnc1NC(=N)Cc1ccccc1
Yield: 9.5 %

Procedure:
A mixture of 2-amino-3-(2-methylbenzyloxy)pyridine (5.2 g, 24.2 mmol) and ethyl phenylacetimidate hydrochloride (5.32 g, 26.7 mmol) in ethanol (80 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave an oil which was taken up in chloroform, filtered to remove an insoluble white solid, and purified by flash chromatography (chloroform/methanol) to obtain the product (0.85 g), m.p. 175°-178° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:10][CH3:11])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>>[Cl:1][C:2]1[C:3]([S:10][CH2:11][Cl:13])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1
Reactant: CSc1nc(Cl)c(Cl)nc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: ClCSc1nc(Cl)c(Cl)nc1Cl
Temperature: 0 °C

Procedure:
A mixture of 22.6 grams (0.1 mole of 3,5,6-trichloro-2-methylthiopyrazine and 20 grams (0.1 mole) of phosphorus pentachloride were heated at reflux (170° C) in an oil bath until the phosphorus pentachloride ceased to sublime. An additional 18 grams (0.095 mole) of phosphorus pentachloride were incrementally added until the reaction was complete (6 days). The reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with a saturated sodium bicarbonate solution followed by washing with a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The chloroform was removed by evaporation and the yellow-orange oil which remained was recrystallized from hexane. The 3,5,6-trichloro-2-(chloromethylthio)pyrazine product was recovered in a yield of 8.0 grams (~30 percent of theoretical) and melted at 68°-70° C. Upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 22.80, 0.88 and 10.83 percent, respectively, as compared with the theoretical contents of 22.72, 0.76 and 10.61 percent, respectively, calculated for the above-named compound.
Reaction SMILES: [SH:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][SH:8])=[O:4].[C:14](Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].Cl>[OH-].[Na+]>[C:14]([S:8][CH2:7][C@@H:6]([C:9]([OH:11])=[O:10])[NH:5][C:3](=[O:4])[C:2]([S:1][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(S)C(=O)N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)C(=O)SC[C@H](NC(=O)C(C)(C)SC(=O)C(C)(C)C)C(=O)O
Yield: 16.3 %

Procedure:
N-(2-Mercapto-2-methylpropanoyl)-L-cysteine (11.2 g, 0.05 mol) is dissolved in N sodium hydroxide (50 ml) and pivaloyl chloride (17.0 g, 0.13 mol) and aqueous N sodium hydroxide (150 ml) are added dropwise at 0° C. with stirring under a nitrogen atmosphere. After the addition, the mixture is stirred for 1 hour at room temperature and acidified with 6 N hydrochloric acid. The produced oil is extracted with ethyl acetate and the organic layer is washed with water, dried and concentrated to dryness under reduced pressure to yield 3.2 g (16.4%) of S-pivaloyl-N-(S-pivaloyl-2-mercapto-2-methylpropanoyl)-L-cysteine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[C:10]1[CH:15]=[C:14](Br)[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:46][CH3:47])=[C:41](B(O)O)[CH:42]=1)([CH3:36])[CH3:35].C(O)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH2:1]([O:8][C:9]([C:10]1[CH:15]=[C:14]([C:41]2[CH:42]=[C:37]([CH:34]([CH3:36])[CH3:35])[CH:38]=[CH:39][C:40]=2[O:46][CH3:47])[C:13]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:11]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)OCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 84 %

Procedure:
A mixture of 2,4-bis-benzyloxy-5-bromo-benzoic acid benzyl ester (503 mg, 1 mmol) and 5-isopropyl-2-methoxy-phenylboronic acid (388 mg, 2 mmol) was heated in a mixture of toluene (5 ml), ethanol (5 ml) and saturated NaHCO3 (5 ml) under nitrogen in the presence of a catalytic amount of Pd(PPh3)4 (60 mg, 0.052 mmol) at 80° C. for 2-3 h. After the reaction was complete, the reaction mixture was extracted with ethyl acetate (25 ml×3), and the combined organics were washed with water and brine and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography on silica gel to provide 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid benzyl ester (481 mg, 84%). M.p.: 139-141° C.; 400 MHz 1H NMR (CDCl3) δ: 7.44-7.22 (m, 16H), 7.17 (dd, J=8.0, 2.4 Hz, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.58 (s, 1H), 5.32 (s, 2H), 5.11 (s, 2H), 5.04 (s, 2H), 3.71 (s, 3H), 2.87 (hept, J=7.2 Hz, 1H), 1.23 (d, J=7.6 Hz, 6H); LCMS: 573 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]([Cl:14])[C:3]=1[C:4]([OH:6])=[O:5].Cl.[OH-].[Na+]>O>[NH2:11][C:10]1[C:2]([Cl:1])=[C:3]([C:7]([Cl:14])=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(Cl)c(C(=O)O)c1Cl
Temperature: 60 °C

Procedure:
2,6-Dichloro-3-nitro-benzoic acid (10 g, 42 mmol, Step a) was added to concentrated hydrochloric acid (100 mL), followed by stannous chloride dihydrate (38 g, 169 mmol). The reaction mixture was heated at 60° C. for 1 hour. The reaction mixture was diluted with water (500 mL) and extracted with ethyl acetate (2×300 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford the crude product (sticky material). The crude material was dissolved in water (200 mL, turbid solution) and treated slowly with aqueous sodium hydroxide (20%) solution till precipitation while maintaining the pH 1-2 (dense precipitate was observed). The precipitate was filtered and filtrate was extracted with ethyl acetate (2×200 mL) and dried over anhydrous sodium sulfate and concentrated under vacuum to yield 3-amino-2,6-dichloro-benzoic acid as a creamish solid (6 gm, 69%).
Reaction SMILES: CS(O[C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)=O.[NH2:23][C:24]1[C:25]([CH3:30])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(#N)C>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:6]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cnc2c(OC)nccc2c1OS(C)(=O)=O
Reactant: Cc1ccccc1N
Solvent: CC#N
Product: CCOC(=O)c1cnc2c(OC)nccc2c1Nc1ccccc1C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Ethyl 4-methanesulfonyloxy-8-methoxy-1,7-naphthyridin-3-carboxylate (261 mg and o-toluidine (0.17 nl) were dissolved into 7 ml of acetonitrile and the solution was heated to reflex for 30 minutes. After cooling the mixture, the solvent was evaporated under reduced pressure and the beside was dissolved into chloroform. The solution was washed with water and then saturated sodium bicarbonate, dried, and concentrate under reduced pressure. The residue was subjected to silica gel column chromatography using a mixture of hexane:ethyl acetate (2:1) as an eluant to give yellow titled compound (180 mg, 67%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH3:27].CO.C(Cl)(Cl)Cl>C(O)C.C(Cl)(Cl)Cl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][N:17]([CH2:26][CH3:27])[CH2:16][CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 24 h
Yield: 74.1 %

Procedure:
In 100 ml of ethanol were added 2.77 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35), 1.66 g of anhydrous potassium carbonate and 5.45 g of ethyl bromide, and the reaction was carried out at an external temperature of 70° C. for 24 hours. After the reaction solution was filtered, the filtrate was condensed and the residue was dissolved in 50 ml of chloroform, and the solution was extracted twice with a 2N aqueous hydrochloric acid solution. The aqueous hydrochloric acid layer was rendered alkaline, extracted twice with 50 ml of chloroform, and the chloroform layer extracted was washed with water and dried with anhydrous magnesium sulfate. After the chloroform was distilled therefrom, the residue obtained was subjected to a silica gel column chromatography (silica gel: 100 g; solvent: 2% methanol-chloroform) to give 2.26 g of 1-(5-isoquinolinesulfonyl)-4-ethylpiperazine, i.e., Compound (42) in a yield of 74%.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[C:8]([CH3:13])[C:6]=2[N:7]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>C(O)CCC>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([NH:12][C:10]2[CH:9]=[C:8]([CH3:13])[C:6]3[NH:7][C:3]([CH3:2])=[N:4][C:5]=3[CH:11]=2)[CH:20]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1nc2c(C)cc(N)cc2[nH]1
Agent: Cl
Solvent: CCCCO
Product: Cc1nc2cc(Nc3cc(Cl)ncn3)cc(C)c2[nH]1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 3.00 g (15.2 mmol) 2,7-dimethyl-benzimidazol-5-ylamine-hydrochloride, 2.30 g (15.4 mmol) 4,6-dichloropyrimidine and 6.50 mL (47.0 mmol) TEA in 15 mL 1-butanol were stirred for 3 h at 100° C. After cooling to RT the reaction mixture was evaporated down, the residue was stirred in DCM and the precipitate formed was suction filtered and dried.