Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:21])[O:4][C:5]2[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:1][C:2]2[C:3](=[O:21])[O:4][C:5]3[CH:18]=[C:17]([CH3:19])[C:16]([CH3:20])=[CH:15][C:6]=3[C:7]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1cc2oc(=O)c(N)c(-c3ccccc3C)c2cc1C
Solvent: C1CCOC1
Product: Cc1cc2oc(=O)c(NC(=O)Nc3ccc(Cl)cc3)c(-c3ccccc3C)c2cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 88.3 %

Procedure:
To a solution of 3-amino-6,7-dimethyl-4-(2-methylphenyl)-2H-1-benzopyran-2- one (279 mg) in tetrahydrofuran (4 ml) was added 4-chlorophenylisocyanate (184 mg). The mixture was stirred for 3 days at room temperature and distilled to remove the solvent. Ethyl ether was added to the residue to obtain crystals of N-(4-chlorophenyl)-N'-[6,7-dimethyl-4-(2-methylphenyl)-2-oxo-2-H-1-benzopyran-3-yl] urea (382 mg, 88.2%). Recrystallization from acetone gave colorless needles.
Reaction SMILES: C([NH:9][C:10]([NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:15][CH:14]=1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[NH2:9][C:10]([NH:12][C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)=[CH:15][CH:14]=1)=[S:11]
Reactant: CN1CCN(c2cccc3ccc(NC(=S)NC(=O)c4ccccc4)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1CCN(c2cccc3ccc(NC(N)=S)cc23)CC1
Yield: 48.1 %

Procedure:
The title product of example 22 (1.09 g, 2.7 mmol) was slurried in ethanol (10 mL) and a solution of 1.4 g NaOH in water (14 mL) was added. The mixture was refluxed 3 hours; then the ethanol was removed with a stream of nitrogen. The aqueous residue was extracted with methylene chloride. The organic phase was washed with brine, dried over calcium sulfate, and concentrated to leave 0.39 g (48%) of the title product. A sample was recrystallized from acetonitrile for analysis: mp 194°-195° C. Analysis calculated for C16H20N4S·CH3CN·0.5 H2O; C, 62.96; H, 6.67; N, 19.32. Found: C, 62.86; H, 6.71; N, 19.69.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[CH:15])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[O:25]1[C:2]([CH3:16])([CH3:1])[CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]#[CH:15])=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCOc1ccc(OCC=C(C)C)cc1
Solvent: ClCCl
Product: C#CCOc1ccc(OCC2OC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
6.4 g of 1-[(3-methyl-2-butenyl)oxy]-4-propargyloxy-benzene is dissolved in 80 ml of methylenechloride and cooled to 0° C. (ice-bath cooling). 7.15 g of 80% by weight m-chloroperbenzoic acid is added portionwise to this mixture and the solution is thereafter stirred at 0° C. for 2 hours. The mixture is worked up as follows: diluted with 350 ml of methylene chloride; washed with ice-cold 1-N caustic soda; washed with saturated aqueous sodium chloride solution; dried over sodium sulfate; and evaporated. By chromatography on Kieselgel, there is obtained 1-[(2,3-epoxy-3-methylbutyl)oxy]-4-propargyloxy-benzene; M.P. 72°-73° C.
Reaction SMILES: Cl.CN.[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:33][CH:34]=1.O[N:40]1[C:44]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[F:4][C:5]1[C:13]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:12]2[C:8]([CH:9]=[C:10]([C:19]3[S:20][CH:21]([CH2:24][C:25]([NH:40][CH3:44])=[O:27])[CH2:22][N:23]=3)[NH:11]2)=[CH:7][C:6]=1[O:28][C:29]1[CH:30]=[N:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=1
Reactant: COCCOc1c(F)c(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)c(F)c(OCCOC)c3[nH]2)S1
Temperature: 0 °C
Yield: 78.8 %

Procedure:
To an ice-cooled and stirred mixture of methylamine hydrochloride (35 mg) and triethylamine (0.072 mL) in N,N-dimethylformamide (7 mL) were added {2-[6-fluoro-7-(2-methoxyethoxy)-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetic acid (135 mg), 1-hydroxybenzotriazole (70 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (100 mg). After stirring at 4° C. to room temperature for 15 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution and brine, dried (MgSO4), filtered, and concentrated to give colorless crystals, which were recrystallized from tetrahydrofuran-ethyl acetate to give the title compound (109 mg, 79%) as colorless crystals. MS 537 (MH+). mp 151-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[Cl:13][C:14]1[CH:20]=[C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:15]=1[NH2:16].C1(C)C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([NH:10][C:11]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([O:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:14]=1[Cl:13])=[S:12])=[O:9]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Commercially available 2-chloro-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[NH2:19][C:20]1[C:25]([NH2:26])=[C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[C:30]([F:41])[CH:29]=2)[CH:23]=[CH:22][N:21]=1>C1COCC1>[O:4]=[C:2]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[C:30]([F:41])[CH:29]=3)=[C:25]2[NH:26]1
Reactant: Nc1nccc(Oc2ccc(NC(=O)C(F)(F)F)c(F)c2)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)[nH]c23)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 48 h
Yield: 49 %

Procedure:
Method E3 (with triphosgene and Pyridine). N-(4-(2,3-Diaminopyridin-4-yl-oxy)-2-fluorophenyl)-2,2,2-trifluoroacetamide (500 mg, 1.5 mmol) was dissolved in dry THF (20 mL), pyridine (1 mL) was added and the solution was cooled at 0° C. Triphosgene (445 mg, 1.5 mmol) in dry THF (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 48 hours. The solvent was evaporated and the residue washed with water. The precipitate was recovered by filtration to afford the title compound (260 mg, 49%). 1H-NMR (δ, ppm, DMSO-d6): 6.57 (d, 1H, HPy,5), 6.98 (d, 1H, Harom,Ph), 7.36 (d, 1H, Harom,Ph), 7.50 (d, 1H, Harom,Ph), 7.75 (d, 1H, HPy,6), 11.26 (s, 1H, NHPy3), 11.30 (s, 1H, NHCOCF3), 11.48 (s, 1H, NHPy2). LC-MS (m/z): 356 (M, 100).
Reaction SMILES: [CH:1]1([NH:7][S:8](=[O:11])(=O)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1(C)C=CC=CC=1>[CH:1]1([NH:7][S:8]([Cl:13])(=[O:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 82.5 %

Procedure:
Under a nitrogen atmosphere, a solution of N-cyclohexylsulfamic acid (50 g, 279 mmol) and PCl5 (58.1 g, 279 mmol) in 150 mL of toluene is very gently warmed up to 100° C. and maintained at that temperature for 1 hour. Distillation of the solution yields N-cyclohexylsulfamoyl chloride as a colorless solid (45.5 g, 82%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[N:4][CH:5]=1)#[CH:10]
Reactant: CNc1ccc(C#C[Si](C)(C)C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP3 starting from 1.5 g (7.3 mmol) methyl-(5-trimethylsilanylethynyl-pyridin-2-yl)-amine and 507 mg (3.7 mmol) K2CO3 in 10 mL MeOH. Yield: 698 mg (56%) after chromatography on silica gel.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])[CH:26]=[CH:27][CH:28]=1>>[F:22][C:23]1[CH:24]=[C:25]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(3-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.C([Li])(C)(C)C.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH:18]=[O:19])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: Brc1ccc(C2CC2)cc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc(C2CC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromostylene (1.83 g) in dichloromethane (5 mL) was added diethylzinc (1 mol/L, 30 mL) under an argon atmosphere at 0° C., and the mixture was stirred at the same temperature for 10 minutes. Chloroiodomethane (4.3 mL) was added to the mixture, and the mixture was warmed to room temperature and stirred for 9 days. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 4-cyclopropylbromobenzene. The obtained 4-cyclopropylbromobenzene was dissolved in tetrahydrofuran (25 mL) and cooled to −78° C. To the solution was added dropwise tert-butyl lithium (1.45 mol/L pentane solution, 9.4 mL) under an argon atmosphere, and the mixture was stirred at −78° C. for 30 minutes. To the reaction mixture was added a solution of N,N-dimethylformamide (1.2 mL) in tetrahydrofuran (16 mL), and the mixture was warmed to 0° C. and stirred for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=12/1) to give 4-cyclopropylbenzaldehyde (0.72 g).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][NH:20][CH:21]([CH3:23])[CH3:22]>C(#N)C>[CH:21]([N:20]([CH3:19])[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:23])[CH3:22]
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CNC(C)C
Solvent: CC#N
Product: COc1ccc(-c2c(N(C)C(C)C)c(=O)c2=O)cc1
Yield: 63.3 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and methyl-isopropylamine (0.07 mL, 0.670 mmol) in acetonitrile (3 mL) were converted to the title compound (0.10 g, 63%) m.p.: 109-115° C.; 1H NMR (DMSO-d6) δ 7.60(m,2H), 7.07(m,2H), 4.91(m,1H), 3.81(s,3H), 1.23(br d,6H); MS (m/z) 259 [M+].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:37]1([NH2:44])[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1>CN1C(=O)CCC1.CO>[NH2:43][C@H:40]1[CH2:41][CH2:42][C@H:37]([NH:44][C:2]2[CH:3]=[C:4]([N:21]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[F:20])=[O:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:38][CH2:39]1
Reactant: COc1ccc(CN(c2ccccn2)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(CN(c2ccccn2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reaction time: 0.33 h

Procedure:
A suspension of 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide 5B (0.500 g, 0.992 mmol) and (trans)-cyclohexane-1,4-diamine (1.360 g, 11.91 mmol) in NMP (2.5 mL) was subjected to 110° C. in a 300 W CEM Discover microwave for 20 min. The mixture was diluted with MeOH and purified via preparatory HPLC using a YMC ODS C-18 column (30×250 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 60 min, flow rate 25 mL/min. Rt=42 min. 6-((trans)-4-aminocyclohexylamino)-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (0.500 g, 54.6% yield) was obtained as a light yellow solid. LC/MS, m/z 582.1 (M+1). HPLC Rt=3.211 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (1H, d, J=1.76 Hz), 8.69 (1H, d, J=2.77 Hz), 8.46-8.53 (1H, m), 8.41-8.47 (1H, m), 8.28 (1H, dd, J=4.78, 1.26 Hz), 8.01 (1H, s), 7.89 (2H, d, J=4.28 Hz), 7.57-7.72 (1H, m), 7.26 (2H, d, J=8.81 Hz), 7.18 (1H, d, J=7.81 Hz), 7.11 (1H, d, J=8.31 Hz), 7.03 (1H, dd, J=6.55, 5.04 Hz), 6.83 (2H, d, J=8.81 Hz), 6.52 (1H, s), 5.43 (2H, s), 3.72-3.84 (1H, m), 3.64-3.72 (3H, s), 3.06 (1H, d, J=4.78 Hz), 2.03-2.15 (2H, m), 1.95 (2H, d, J=10.07 Hz), 1.34-1.49 (2H, m), 1.26 (2H, d, J=12.34 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]([C:17]3[CH2:21][C:20]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>O.C(O)C>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([C:17]3[CH2:21][C:20]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)([C:22]([F:25])([F:23])[F:24])[O:19][N:18]=3)=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nn1-c1ncccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.9 g of methyl 1-(3-chloropyridin-2-yl)-3-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-1H-pyrazole-5-carboxylate were dissolved in a mixture of 10 ml of water and 20 ml of ethanol, 0.2 g of sodium hydroxide were added and the mixture was stirred at RT for 3 h. The reaction was acidified with 2N hydrochloric acid, extracted three times with methyl tert-butyl ether and dried over magnesium sulphate. The product was obtained after distillative removal of the solvent.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25](O)=[O:26])[CH:6]=1)[CH2:3][OH:4].[NH2:28][C@@H:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][C@@H:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:28][CH:29]([CH2:33][C:34]([NH2:36])=[O:35])[C:30]([NH2:32])=[O:31])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: NC(=O)C[C@H](N)C(N)=O
Reactant: O=C(O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CC(NC(=O)c1cc([C@H](O)CO)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(N)=O
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of (S)-4-(1,2-dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinic acid (assume 0.44 mmol) in DMF (5 mL) was added (S)-2-aminosuccinamide (0.076 g, 0.45 mmol), DIEA (0.20 mL, 1.1 mmol) and HBTU (0.203 g, 0.54 mmol). The reaction was stirred overnight then partitioned between 50 mL EtOAc and 50 mL brine. The aqueous layer was extracted once more with 25 mL EtOAc and combined. The organics were dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from 4 mL warm acetone, the solid filtered off, rinsed with additional acetone and dried under vacuum at 50° C. to yield the product S)-2-(4-((S)-1,2-Dihydroxyethyl)-6-(4-(4-fluorophenoxy)phenyl)picolinamido)succinamide as a light tan powder (0.125 g, 0.26 mmol, 59% yield, LC/MS: m/z=483.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6): δ 9.29 (d, J=8.4 Hz, 1H), 8.25 (d, J=8.8 Hz, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 7.32-7.25 (m, 2H), 7.21-7.15 (m, 2H), 7.14-7.07 (m, 3H), 6.99 (s, 1H), 5.64 (d, J=4.8 Hz, 1H), 4.85 (t, J=6.0 Hz, 1H), 4.75-4.64 (m, 2H), 3.62-3.49 (m, 2H), 2.79-2.70 (m, 1H), 2.61-2.53 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C1C(=O)N([Br:19])C(=O)C1>C(O)(=O)C.O.[Zn]>[Br:19][C:7]1[CH:6]=[C:5]([NH2:8])[C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(N)c(N)cc1Br
Reaction time: 2.5 h
Yield: 83.2 %

Procedure:
To the solution of 4-methyl-2-nitro-phenylamine (1 g, 1 eq.) in 15 mL of acetic acid was added NBS (1.4 g, 1.2 eq.). The reaction was allowed to stir for 2.5 hours. Reaction was then diluted with 15 mL of water and Zn dust (1.29 g, 3 eq.) was added. Reaction was stirred for 1 hour, filtered and then pH was adjusted to ˜7 with ammonia. The aqueous layer was extracted with CH2Cl2 twice, dried over Na2SO4, concentrated and adsorbed on silica. Purification by flash column chromatography (60:40 hexanes/EtOAc) afforded 1.1 g (83 %) of product as off-white solid. MS (electrospray): mass calculated for C7H9BrN2, 201.06; m/z found 202.2, [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].C(N(C(C)C)CC)(C)C.[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:11][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10]
Reactant: O=C(O)c1cccc(CCCCO)c1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1cccc(CCCCO)c1
Reaction time: 65 h

Procedure:
A solution of 3-(4-hydroxybutyl)benzoic acid (100 mg) in dry DMF (10 ml) was treated with diisopropylethylamine (0.134 ml) and benzyl bromide (106 mg) and the reaction mixture was stirred for 65 h. The reaction mixture was partitioned between EtOAc and water. The organic phase was washed with sat. NH4Cl(aq), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (SPE, gradient Cyclohexane to cyclohexane-EtOAc 1:1) to give the title compound LCMS RT=3.38 min.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:21]([CH3:22])=[CH:20][S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Product: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:32])[C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:41])C=1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:32])[C:23]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)=[CH:24][C:18]=3[N:17]=2)=[O:41])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(N3CCN(C)CC3)c(F)cc2[nH]1
Yield: 51.5 %

Procedure:
The title compound (0.15 g, 51%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(4-methylpiperazin-1-yl)-1H-benzimidazole (0.28 g, 0.6 mmol) (obtained in example 20), m-chloroperbenzoic acid (50%, 0.25 g, 0.72 mmol) and chloroform (20 mL). mp 73-74° C.; IR (KBr) 3470, 1080 cm- 1; 1H NMR (CD3OD) δ 2.20 (s, 3H, CH3), 2.50 (s, 3H, CH3), 2.88 (t,J=4.6 Hz, 4H, N(CH2)2), 3.18 (t,J=4.8 Hz, 4H, N(CH2)2), 4.68 (q,J=8.2 Hz, 2H, OCH2CF3), 4.80 (s, 2H, SOCH2), 7.00 (d,J=5.8Hz, 1H), 7.24 (d,J=7.6Hz, 1H), 7.32 (d,J=12.2Hz, 1H), 8.18 (d,J=5.7Hz, 1H); Mass (m/z) 486 (M+ 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S@:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([S:11]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)=[O:12])[NH:8][C:7]=2[CH:24]=1
Reactant: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Solvent: CO
Product: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Reaction time: 96 h

Procedure:
Approximately 850 mL of methanol was placed in a 1 liter glass bottle with a screw cap. The solution was saturated by dissolving approximately 10.5 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole, and the resulting solution was stirred. Once the solution was saturated, an additional 17 g of (5)6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole was added to the saturated solution to create a suspension. The cap was sealed and the saturated suspension was allowed to stir and equilibrate for about four days.