Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:45][CH2:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([C:35]2[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=2)[CH:43]=1)=[O:7])[CH3:2]
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.7 %

Procedure:
Acid 4B (273.28 mg, 1 mmol) was dissolved in 10 ml of THF and at rt DEPC (1.1 equiv, 0.15 ml) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 equiv., 277.5 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 1/petroleum ether 1) afforded 100 mg of a white solid. Yield=19% 1HNMR (DMSO, 400 MHz) δ 1.09 (3H, t, J=7.2 Hz), 3.39 (2H, q, J=6.8 Hz), 4.48 (2H, d, J=6 Hz), 5.15 (1H, s), 6.14 (1H, s), 7.36 (1H, dd, J=4.8 Hz, J′=1.2 Hz), 7.47 (2H, t, J=8.8 Hz), 7.84 (4H, m), 8.01 (1H, s), 8.30 (2H, d, J=8 Hz), 8.64 (1H, dd, J=5.2 Hz, J′=0.8 Hz), 8.89 (1H, bt) [M+1] 508.7 (C24H21F4N3O3S requires 507.50).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[N:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[C:38]1([OH:44])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O1CCOCC1>CN(C=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([O:44][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=4)=[CH:22][CH:21]=3)[N:4]=[C:5]2[N:6]([CH2:14][C:15]([CH3:18])([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: Cn1c(=O)c2c(Cl)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(Oc3ccccc3)n(Cc3ccc(-c4ccncc4)cc3)nc2n(CC(C)(C)C)c1=O
Temperature: 150 °C
Yield: 67.3 %

Procedure:
3-chloro-5-methyl-7-neopentyl-2-(4-(pyridin-4-yl)benzyl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (30 mg, 0.069 mmol), potassium carbonate (29 mg, 0.2 mmol) and phenol (20 mg, 0.20 mmol) are placed in a Biotage microwave vial, and then 0.3 mL of dioxane is added. The vial is sealed, and then heated in a Biotage microwave instrument at 150° C. for 3 h. The reaction mixture is diluted with DMF, and then filtered. The filtrate is purified with a semi-preparative HPLC to give 23 mg of pure product as pale yellow solids. MS (ESI) m/z 496.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1C=C2OCOC2=C[C:20]=1[C:28](=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:38]=[CH:37]C(C)=CN=1.NC1C=C2OCOC2=CC=1C(=O)C>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[N:32]=[CH:33][C:38]([CH3:37])=[CH:28][CH:20]=1)=[O:17])(=[O:9])=[O:10]
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Reactant: Cc1ccc(N)nc1
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: Cc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)nc1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148), except that 2-amino-5-picoline was used in stead of 2'-amino-4',5'-(methylenedioxy)acetophenone, N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide was obtained, via HPLC purification of the crude reaction mixture, as a bright yellow powder (17% yield, m.p. 158-160° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][C:4]=1[F:31])[CH3:2].[NH:32]1[CH2:37][CH2:36][S:35][CH2:34][CH2:33]1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:32]3[CH2:37][CH2:36][S:35][CH2:34][CH2:33]3)=[O:17])[CH2:12][CH:11]([C:27]([O:29][CH3:30])=[O:28])[CH2:10]2)=[CH:5][C:4]=1[F:31])[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)Oc3ccc([N+](=O)[O-])cc3)C2)cc1F
Reactant: C1CSCCN1
Product: CCc1ccc(C2CC(C(=O)OC)CN(C(=O)N3CCSCC3)C2)cc1F

Procedure:
According to General Method 5A, 2.2 g (5.0 mmol) of 3-methyl 1-(4-nitrophenyl) 5-(4-ethyl-3-fluorophenyl)piperidine-1,3-dicarboxylate and 2.8 ml (3.1 g, 30.0 mmol) of thiomorpholine were reacted. Yield: 1.2 g (57% of theory)
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)=[CH:24][C:18]=2[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:11])[CH3:10].[Al].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[NH:22][C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH2:31])[N:26]=3)=[C:24]([I:1])[C:18]=2[C:17]1=[O:32])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)cc2C1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Al]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)c(I)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
N-iodo succinimide (0.75 g, 3.34 mml) was added to a solution of 2-(2-amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester [(1), Q=Boc] (1.0 g, 3.03 mmol) in dry DMF (15 mL) and the reaction mixture was stirred at room temperature overnight, in a flask surrounded by an aluminium sheet. After reaction completion, a solution of Na2S2O3 (10%, 0.100 ml) was added and the product was extracted with DCM (3×0.100 mL). The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to yield the crude 2-(2-amino-pyrimidin-4-yl)-3-iodo-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester as a yellow solid (1.240 g, 2.72 mmol, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([CH3:10])[C:7]=1[N:8]=[O:9].[OH:12]O>C(O)(=O)C.N.N.N.N.N.N.O.O.O.O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O[Mo](O)(=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O>[CH3:10][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:12])=[O:9]
Reactant: OO
Reactant: Cc1cc(O)cc(C)c1N=O
Agent: O=[Mo](=O)(O)O
Agent: O=[Mo](=O)=O
Agent: N
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 3,5-dimethyl-4-nitrosophenol (70.63 g) from above and (NH4)6Mo7O24.4H2O) (2.83 g) in 770 ml of glacial acetic acid was warmed to 100° C. 30% H2O2 (84 ml) was added to the mixture in 10 ml portions until an exothermic reaction was observed. The reaction mixture was then stirred and the remainder of the H2O2 solution added in small portions. The reaction mixture was heated and stirred until a clear dark red solution results. A yellow-orange solid precipitated from the solution after stirring for another 20-30 minutes. The reaction mixture was stirred overnight and filtered to give a small amount of a yellow solid and a clear dark red filtrate. The red filtrate was concentrated in vacuo and partitioned between water and ether. The aqueous layer was washed with ether and the combined ether extracts washed with 10% sodium carbonate until the aqueous layer becomes basic. The ether extract was dried over anhydrous sodium sulfate, filtered, concentrated and allowed to cool overnight. After cooling in an ice bath the mixture was filtered to give 49.5 g of 3,5-dimethyl-4-nitrophenol as a yellow-green solid. Mp. 106-108° C.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)[C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])=[CH:13][CH:12]=2)[CH2:29]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 1, (intermediate 74) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak IC column, 4.6 mm×25 cm, 25% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 4.33 retention time); 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.38 (br. s., 1H), 7.63-7.76 (m, 3H), 7.55 (d, J=7.8 Hz, 2H), 7.39-7.50 (m, 1H), 7.30-7.39 (m, 1H), 7.21-7.30 (m, 1H), 6.45-6.60 (m, 1H), 5.11-5.28 (m, 1H), 3.41 (dd, J=12.7, 7.1 Hz, 2H), 2.75-2.91 (m, 1H), 2.46 (t, J=7.1 Hz, 2H), 2.29 (s, 3H), 1.92-2.00 (m, 1H), 1.56-1.67 (m, 2H), 1.42-1.55 (m, 1H), 1.12 (s, 3H), 1.07 (s, 3H); MS (M+1): 464.3.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:34][CH2:33]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3].[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([O:30][CH2:31][CH:32]2[CH2:33][CH2:34]2)=[C:9]([C:11]2[C:12]3[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][N:27]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:26][CH2:25]4)=[O:22])[C:13]=3[N:14]=[CH:15][N:16]=2)[CH:10]=1)(=[O:4])[CH3:3]
Reactant: COCC(=O)Cl
Reactant: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C(C)=O)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[5-acetyl-2-(cyclopropylmethoxy)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f55) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [I-:1].[Na+].S(O[CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:11][CH2:10]1)(C)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CC(C)=O>[I:1][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([CH3:21])([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:11][CH2:10]1
Reactant: C=CCOC(=O)C1(C)CCC(COS(C)(=O)=O)CC1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCOC(=O)C1(C)CCC(CI)CC1
Yield: 49.6 %

Procedure:
5 g of sodium iodide was added to a solution of 2 g of allyl 4-mesyloxymethyl-1-methyl-1-cyclohexanecarboxylate (Example 45) in 50 ml of acetone. The solution was reacted for 4 hours, while it was refluxed. After reaction, 100 ml of an aqueous sodium thiosulfate solution was added to the reaction solution. The solution was extracted three times with 30 ml of ethyl acetate. The organic layer obtained was washed twice with an aqueous sodium thiosulfate solution and twice with an aqueous sodium chloride solution, and was dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 10 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 1.1 g of allyl 4-iodomethyl-1-methyl-1-cyclohexanecarboxylate as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:19]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([O:46]C(C)(C)C)=[O:45])[CH:39]=3)=[O:36])[C:18]2=[O:51])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([C:14]([CH2:16][N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:20][CH:19]([NH:34][C:35](=[O:36])[NH:37][C:38]3[CH:39]=[C:40]([CH:41]=[CH:42][CH:43]=3)[C:44]([OH:46])=[O:45])[C:18]2=[O:51])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccccc3N(CC(=O)C3CCCCC3)C2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(=O)O)c1)NC1CN(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of 1-(1-cyclohexylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-tert-butoxycarbonylphenyl)urea (560 mg) in methylene chloride (5 ml), the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, etanol was added to the residue for crystallization, collected by filtration, to thereby obtain 330 mg of the title compound.
Reaction SMILES: [S:1]1(=[O:12])(=[O:11])[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:13]([C:15](=[CH:21]OCC)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(OCC)(=O)C>C(O)C>[C:13]([C:15](=[CH:21][NH:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1](=[O:11])(=[O:12])[CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: Nc1ccc2c(c1)CCS2(=O)=O
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=CNc1ccc2c(c1)CCS2(=O)=O
Yield: 82.1 %

Procedure:
5 g (27.3 mmol) of 2,3-dihydro-1-benzothiophen-5-amine 1,1-dioxide were suspended in 50 ml of ethanol under argon, 4.62 g (1 eq, 27.3 mmol) of ethyl 2-cyano-3-ethoxyacrylate were added, and the mixture was heated under reflux overnight. For working up, ethyl acetate was added to the mixture, and the precipitate which formed was filtered off with suction on a frit. The solid was dried in vacuo at 50° C. for 1.5 h. 6.87 g (81%) of the target compound were isolated and were employed without further purification in the next stage.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CC(C)C(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 55.7 %

Procedure:
A suspension of 25.2 g (64.3 mmol) N-(2benzyloxy-4-bromo-6-nitro-phenyl)-isobutyramide, 6.3 g (38.5 mmol) iron(III) chloride and 15.7 g activated charcoal in 600 ml methanol was heated to 70° C. 31.3 ml (643 mmol). Hydrazine hydrate were added dropwise and the reaction mixture was refluxed for 90 min. After cooling to room temperature the reaction was filtered through celite, the filter cake washed with dichloromethane/methanol and the filtrate concentrated in vacuo. The residue was dried in vacuo at 40° C. to afford 13.0 g (56%) of the title compound as a white solid. m.p. 214°-215° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].CN(C)CC1C=CC=CC=1.[CH2:15]1[O:17][CH:16]1[CH2:18][OH:19]>CC(CC(C)=O)C>[OH:4][CH2:3][CH2:2][S:1][CH2:15][CH:16]([OH:17])[CH2:18][OH:19]
Reactant: OCCS
Reactant: OCC1CO1
Agent: CN(C)Cc1ccccc1
Solvent: CC(=O)CC(C)C
Product: OCCSCC(O)CO
Temperature: 50 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In a reaction vessel equipped with a stirrer, a cooling tube, a nitrogen introducing tube and a thermometer, 78.1 parts of 2-mercaptoethanol was charged, and 2-mercaptoethanol was diluted with 159.6 parts of MIBK. Then, 0.41 part of dimethylbenzylamine was added, and after heating to 50° C., 81.5 parts of glycidol was added dropwise with stirring over 3 hours in a dry nitrogen atmosphere. The reaction vessel was cooled and maintained at 50° C. 2 Hours after dropping, it was confirmed that an absorption of --SH (2540 cm-1) and an absorption of a glycidyl group (910 cm-1) are disappeared by the measurement of infrared spectra. Further, the reaction product had no mercapto-like odor. Thereafter, MIBK was removed under reduced pressure to give 1-(2-hydroxyethylthio)-2,3-propanediol as a viscous liquid. Yield was 90% of the charge weight.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])([F:14])[F:13])[N:8]=[C:7]([C:23]([OH:25])=O)[CH:6]=[CH:5]2.CCN=C=NCCCN(C)C.Cl.[NH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:18]([O:17][P:15]([C:12]([C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([C:23]([NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:25])=[N:8]2)=[CH:3][C:2]=1[Br:1])([F:13])[F:14])(=[O:16])[O:20][CH2:21][CH3:22])[CH3:19]
Reactant: Nc1ccccc1
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)Nc3ccccc3)ccc2cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the product of step 5 (109 mg) in 5 mL CH2Cl2 was added EDCl (96 mg), aniline (0.1 mL) and Hunig's base (0.1 mL). The solution was stirred at ambient temperature for 3 hours and after concentration and flash chromatography on silica with a gradient of 10-25% EtOAc/toluene the amide was obtained.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:40])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27]N2C=C(C)OC2C2C=CC=CC=2)=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6].O.Cl.[O:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CO>[CH3:40][C:4]([CH3:3])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:10]2[N:17]=[C:47]([C:46]3[CH:16]=[CH:11][CH:12]=[CH:44][CH:45]=3)[O:43][C:4]=2[CH3:3])=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)(C)/C(=N\OCc1ccc(OCN2C=C(C)OC2c2ccccc2)cc1)c1ccccc1
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/c2ccccc2)C(C)(C)C(=O)O)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Potassium hydroxide (1.83 g) was added to a solution of ethyl Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-3-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (265 mg) in tetrahydrofuran (3 ml)-water (3 ml)-methanol (6 ml), the mixture was heated to reflux for 3 days and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (130 mg, yield 52%) as pale-yellow crystals. m.p. 142-143° C. (decomposition).
Reaction SMILES: CC1N=C(N[C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])SC=1C1C=CN=CC=1.[CH3:21][C:22]1[N:23]=[C:24]([NH2:39])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1>>[CH3:21][C:22]1[N:23]=[C:24]([NH:39][C:14]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)=[O:15])[S:25][C:26]=1[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccncc1
Reactant: Cc1nc(N)sc1-c1ccnc(N2CCOCC2)n1
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(N2CCOCC2)n1

Procedure:
The titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (see example 16 for reference) with 4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-ylamine (25d).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1)[NH2:44].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:44][C:43]1[CH:45]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:47]=[C:41]([O:40][CH3:39])[CH:42]=1
Reactant: COc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Yield: 56.1 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (0.25 g, 0.42 mmol) was treated with 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.26 g, 1.05 mmol), sodium carbonate (0.11 g, 1.05 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.10 g, 0.13 mmol) and 10.6 ml 1,2-dimethoxyethane and 2.4 ml water as a solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 0.15 g (54% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18]C)=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH:7]=1.O>Br.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH:7]=1
Reactant: COc1ccc(Cl)cc1-n1c(=O)[nH]c2ccccc21
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2n1-c1cc(Cl)ccc1O
Yield: 52.7 %

Procedure:
1-(5-chloro-2-methoxyphenyl)-1,3-dihydro-2H-benzimidazol-2-one (0.3 g) was refluxed for 32 hours in 48% HBr (1 ml) in acetic acid (5 ml). The reaction mixture was then cooled and 25 ml water was added, whereby the crude product precipitated. To the mixture was added 5 ml diethylether whereafter it was filtered to give 150 mg of the title compound, M.p. 248°-250° C.