Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:7].O[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Cl:7][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: Oc1ncnc2ccccc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2ccccc12
Reaction time: 0.33 h
Yield: 93.3 %

Procedure:
Phosphorus oxychloride (64 mL, 687 mmol) and phosphorus pentachloride (14.89 g, 71.50 mmol) were added to 4-hydroxyquinazoline (7.94 g, 52.3 mmol), and the solution was stirred for 20 minutes under reflux. The reaction mixture was evaporated in vacuo, and the residue was dissolved in chloroform. The chloroform solution was poured on an ice bath, concentrated aqueous ammonia was added to adjust the pH to 10, then, the solution was partitioned. The aqueous layer was extracted with chloroform, and the combined chloroform layers were washed with water. The organic layer was dried over anhydrous magnesium sulfate, then, evaporated in vacuo, and the title compound (8.03 g,48.8 mmol, 93%) was obtained. This was used in the next reaction without purification.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1)#[N:2].N.[H][H]>CO.O>[NH2:2][CH2:1][CH2:3][C@H:4]1[O:9][C:8]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[O:7][C@@H:6]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:5]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CC#N)OC2(CCCCC2)O1
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reaction time: 22 h
Yield: 97.9 %

Procedure:
A solution of 1.19 g of (±)-cis-1,1-dimethylethyl 4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetate in 30 mL of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaker at 50 pounds per square inch gage (psig) and 40° C. After 22 hours, thin layer chromatography indicates no starting nitrile present. The suspension is cooled, filtered through filter aid, and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to give 1.18 g of (±)-cis-1,1-dimethylethyl 4-(2-aminoethyl)- 1,5-dioxaspiro[5.5]undecane-2-acetate as a clear oil which solidifies upon standing.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.O=[C:22]([CH2:26][CH3:27])[C:23]([OH:25])=[O:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:22]([C:23]([OH:25])=[O:24])[CH2:26][CH3:27])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CCC(=O)C(=O)O
Product: CCC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(=O)O

Procedure:
In the manner given in Example 3, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine was stirred with α-oxobutyric acid at room temperature to give 7-chloro-2-[(1-carboxypropylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([OH:34])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:13]=[C:14]([O:18][CH3:19])[C:15]=1[O:16][CH3:17]>N1C=CC=CC=1>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C@H:20]2[C@H:29]3[C:30]([O:32][CH2:33][C@@H:28]3[C@@H:27]([O:34][C:1]([CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:7])[C:26]3[CH:25]=[C:24]4[O:35][CH2:36][O:37][C:23]4=[CH:22][C:21]2=3)=[O:31])[CH:11]=[C:10]([O:9][CH3:8])[C:15]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)O1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc([C@@H]2c3cc4c(cc3[C@H](OC(=O)CCC(=O)O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
Succinic anhydride (0.9 g) was added to a solution of podophyllotoxin (207.2 mg, 0.5 mmol) in pyridine (12 mL). The resultant reaction mixture was stirred for 16 h at 25° C. Removal of solvent in vacuo afforded a residue. The crude residue was purified using a silica gel gravity column chromatography (35:7:1 CHCl3:MeOH:NH4OH) to give succinylpodophyllotoxin as white solid (198.5 mg, 80%) 1H NMR (500 MHz, DMSO-d6) δ 2.10 (d, J=5.4 Hz, 1H, H-4), 2.32 (dd, J=12.6, 4.8 Hz, 1H, H-2), 2.53 (m, 1H, H-3), 3.52 (s, 3H, OMe H-4′), 3.65 (dd, J=10.5, 7.5 Hz, 2H, H-11), 3.82 (s, 6H, two OMe groups, H-3′ and H-5′), 4.15 (t, J=7.9 Hz, 2H, CH2), 4.26 (t, J=7.9 Hz, 2H, CH2), 4.51 (d, J=5.4 Hz, 1H, H-1), 5.89 (s, 2H, OCH2O), 6.00 (s, 2H, H-2′, H-6′), 6.67 (s, 1H, H-8), 6.94 (s, 1H, H-5), 12.15 (s, 1H, CO2H). Mass (ESI) (M−1) calcd for C26H26N2O11 513.15. found 512.93.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]2[C:20](=[O:35])[N:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=1.CC1(C)C(C)(C)OB([C:45]2[CH:46]=[N:47][NH:48][CH:49]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH:47]1[CH:46]=[C:45]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:49]=[N:48]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccncc2-c2cn[nH]c2)cc1F
Temperature: 85 °C
Yield: 57 %

Procedure:
In a sealed tube, N-(4-(3-bromopyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.124 g, 0.221 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.064 g, 0.332 mmol), potassium carbonate (0.092 g, 0.664 mmol), and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were suspended in dioxane (6 mL) and water (1.5 mL). The mixture was degassed with Ar and heated at 85° C. overnight. Additional 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg) and tetrakistriphenylphosphine palladium (0) (0.026 g, 0.022 mmol) were added. The reaction mixture was degassed with Ar and heated at 85° C. for 2 days. The mixture was diluted with EtOAc and extracted with sat. NaHCO3 (aq). The organic extract was washed with brine, dried and evaporated. The crude product was purified by silica gel chromatography (25 g) eluting with CH2Cl2/MeOH to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (69 mg, 56.9% yield). The hydrochloride salt was formed by suspending N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.069 g, 0.126 mmol) in acetonitrile (2 ml) and adding 0.1N HCl (1.51 mL, 0.151 mmol). The mixture was sonicated for 10 min. The solution was diluted with water (2 mL), frozen and lyophilized. The crude lyophilate was dried at 80° C. for 4 h under vacuum to yield N-(4-(3-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (0.069 g, 87% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.32 (s, 1H); 9.15 (s, 1H); 8.49 (d, J=6.5 Hz, 1H); 8.43 (dd, J=12.5, 7.0 Hz, 1H); 8.33 (s, 2H); 7.93 (d, J=7.8 Hz, 1H); 7.69 (dd, J=10.8, 7.3 Hz, 1H); 7.48 (dd, J=8.8, 4.9 Hz, 2H); 7.37 (t, J=8.8 Hz, 2H); 7.25 (d, J=6.5 Hz, 1H); 6.56 (d, J=7.9 Hz, 1H); 4.28 (q, J=7.0 Hz, 2H); 1.34 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 508.2 (M+H+).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].[CH2:12]([O:19][N:20]1[C:26](=[O:27])[N:25]2[CH2:28][C@H:21]1[CH2:22][CH2:23][C@H:24]2[C:29](Cl)=[N:30][OH:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOC(C)=O>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:1][C:2]1[O:31][N:30]=[C:29]([C@@H:24]2[CH2:23][CH2:22][C@@H:21]3[CH2:28][N:25]2[C:26](=[O:27])[N:20]3[O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: O=C1N2C[C@@H](CC[C@H]2C(Cl)=NO)N1OCc1ccccc1
Reactant: C#CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
tert-Butyl prop-2-yn-1-ylcarbamate (0.37 g, 2.4 mmol) was added to the solution of (2S,5R)-6-(benzyloxy)-N-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbimidoyl chloride (˜2.0 mmol) in dry DCM (20 mL), followed by the addition of TEA (0.31 mL, 2.2 mmol) in dry DCM (2.0 mL) over a period of 30 minutes. The reaction mixture was stirred at rt overnight, then the mixture was diluted with EtOAc, washed with water and saturated sodium chloride. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (1:2 petroleum ether/EtOAc) to afford tert-butyl((3-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)isoxazol-5-yl)methyl)carbamate (180 mg, 21% for two steps) as a white solid. ESI-MS (EI+, m/z): 429.1 [M+H]+. 1H NMR (500 MHz, CDCl3): δ 7.45-7.35 (m, 5H), 6.24 (s, 1H), 5.09 (d, J=11.5 Hz, 1H), 4.93 (d, J=11.5 Hz, 1H), 4.58 (d, J=7.5 Hz, 1H), 4.43 (m, 2H), 3.32 (s, 1H), 2.86-2.84 (m, 1H), 2.68 (d, J=11.5 Hz, 1H), 2.34-2.30 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.04 (m, 1H), 1.82-1.78 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[N:36]1([C:40]2[N:45]=[CH:44][C:43](Br)=[CH:42][N:41]=2)[CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:40]2[N:45]=[CH:44][C:43]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)=[CH:42][N:41]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1cnc(N2CCC2)nc1
Product: C[C@@H](c1ccc(-c2cnc(N3CCC3)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared following a procedure analogous to Example 31 using (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 2-(azetidin-1-yl)-5-bromopyrimidine. LC (method 5): tR=1.48 min; Mass spectrum (ESI+): m/z=487 [M+H]+; 1H NMR (CD3OD) δ 0.95 (s, 3H), 1.23 (s, 3H), 1.55 (d, 3H), 2.14 (s, 2H), 2.20 (m, 1H), 2.40-2.60 (m, 4H), 3.04 (m, 1H), 4.33 (m, 4H), 5.57 (q, 1H), 7.08 (d, 2H), 7.25-7.40 (m, 7H), 8.62 (s, 2H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Br)[CH:15]=[CH2:16].O>CN(C)C=O>[CH2:16]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH:15]=[CH2:14]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC1CCC2(CC1)OCCO2
Temperature: 20 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
23.7 g (150 mmole) 1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 120 ml absolute dimethylformamide under a nitrogen atmosphere. After adding 7.9 g of 50% sodium hydride in mineral oil (165 mmole), the mixture was stirred for 1 hour at 20° C. After adding 14.3 ml allyl bromide (165 mmole), the mixture was heated to 70° C. and stirred for 1 hour. Thereafter it was treated with 160 ml water and was extracted at 10° C.-15° C., three times with ether, once with water and once with saturated sodium chloride solution. After removing the solvent by distillation, 24 g of crude product (81% theoretical) were obtained.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]2[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=2[O:9]1>C(OCC)C>[Cl:1][S:2]([C:18]1[CH:19]=[CH:20][C:10]2[O:9][CH:8]([C:7]([F:22])([F:21])[F:6])[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[CH:17]=1)(=[O:5])=[O:3]
Reactant: O=C(O)C1=Cc2ccccc2OC1C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: CCOCC
Product: O=C(O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To chlorosulfonic acid (50.0 mL) chilled to −15° C. was added 2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (Example 10) (4.0 g, 16.7 mmol). After stirring at −15° C. for 1 hour, the solution was warmed to room temperature and stirred for 16 hours. The resulting solution was added dropwise over ice (100 mL) with two diethyl ether(2×75 mL) extractions. The diethyl ether layers were combined, washed with water (2×75 mL), and brine (2×75 mL, dried over sodium sulfate and concentrated in vacuo. The resulting solids were triturated with hexane-ethyl acetate (9:1, 100 mL). The 6-chlorosulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid was isolated as a white solid: mp 169–174. 1H NMR (CD3OD/300 MHz) 8.18 (d, 1H, J=2.7 Hz), 8.06 (dd, 1H, J=8.7, 2.7 Hz), 7.93 (s, 1H), 7.28 (d, 1H, J=8.7 Hz), 6.00 (q, 1H, J=6.6 Hz). EIHRMS m/z 324.9977 (M+, Calcd 324.9994).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12]SC)=[CH:7][CH:6]=1)[CH3:3].[N+:16]([CH:19]=[C:20]([NH2:29])[NH:21][CH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)([O-:18])=[O:17]>>[CH3:1][N:2]([CH2:4][C:5]1[O:15][C:8]([CH2:9][S:10][CH2:11][CH2:12][NH:29][C:20]([NH:21][CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:19][N+:16]([O-:18])=[O:17])=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSCCSCc1ccc(CN(C)C)o1
Reactant: NC(=C[N+](=O)[O-])NC1CCCCCC1
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])NC2CCCCCC2)o1

Procedure:
24.54 grams of 2-[[5-[(dimethylamino)methyl]furfuryl]thio]ethylmethyl sulphide are reacted with 40 grams of 2-nitro-N-cycloheptyl-1,1-ethenediamine at 80° C. for 3 hours. The mixture is cooled and the procedure described in Example 1 is followed. The product melts at 91°-94° C. Spectrophotometric analyses confirm its structure.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:23]1[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)[CH2:21][OH:22].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:19][C@@H:20]([C:23]4[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[CH2:21][OH:22])[C:3]=3[CH2:11]2)=[N:13][CH:14]=1
Reactant: COc1ccc([C@H](N)CO)cn1
Reactant: Clc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc([C@@H](CO)Nc2ncnc3c2CN(c2ccc(Cl)cn2)CC3)cn1

Procedure:
A reaction mixture of 4-chloro-6-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (55 mg, 0.20 mmol) and (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (33 mg, 0.20 mmol) in acetonitrile (2 mL) and N,N-diisopropylethylamine (68 μL, 0.39 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC (100×20.2 mm, C18 column; 25-50% CH3CN-water [10 mM Et2NH]) to give an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:10]([CH3:12])[N:11]=2)[N:8]=1)[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)[N:20]=1.C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([O:18][CH3:17])[N:20]=[C:21]([NH:27][C:28]([NH:16][S:13]([C:9]2[N:7]3[N:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]3=[N:11][C:10]=2[CH3:12])(=[O:14])=[O:15])=[O:29])[N:22]=1
Reactant: CCc1ccc2nc(C)c(S(N)(=O)=O)n2n1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc2nc(C)c(S(=O)(=O)NC(=O)Nc3nc(OC)cc(OC)n3)n2n1
Temperature: 25 °C

Procedure:
As shown in the above reaction scheme, 6-ethyl-2-methylimidazo[1,2-b]pyridazin-3-ylsulfonamide (0.60 g, 2.50 mmol) and phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate (0.76 g, 2.76 mmol) were suspended in acetonitrile (10 ml) and stirred under ice-cooling, during which DBU (0.46 g, 3.02 mmol) was added thereto. The temperature of the reaction solution was increased to room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction solution was poured into ice-water (150 ml) and adjusted to pH 3 with conc. hydrochloric acid. The reaction mixture was stirred at room temperature for 5 minutes, and the precipitated crystals were washed with water, acetonitrile and diethyl ether in this order, and collected by filtration. The crystals were dried under reduced pressure to give the title compound as colorless crystals. The yield was 0.55 g (52%), and the melting point was 172 to 174° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1.[C:9]1([C:15](Cl)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>N1C=CC=CC=1.CN(C=O)C>[C:15]([N:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[N:3]=[CH:2]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
To a RT solution of 1H-imidazole-4-carboxylic acid (1.12 g, 9.99 mmol) in pyridine (15 mL) and DMF (30 mL) was added triphenylmethyl chloride (3.06 g, 11.0 mmol). The reaction mixture was stirred at RT overnight, then was partitioned between EtOAc (500 mL) and H2O (50 mL). The organic phase was washed with H2O (20 mL), 10% citric acid (20 mL) and brine (5 mL), dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc to afford 1-trityl-1H-imidazole-4-carboxylic acid (2.78 g, 79% yield) as a white solid. LCMS Method A (ESI, positive ion spectrum): (M+H)/z=not observed, tR=3.27 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:46][S:47]([NH2:50])(=[O:49])=[O:48].C1CCN2C(=NCCC2)CC1.Cl>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:24])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:50][S:47]([CH3:46])(=[O:49])=[O:48])=[O:19])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C(=O)O)c2)c2cccc(Cl)c2C)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2cccc(C(=O)NS(C)(=O)=O)c2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
182 mg of 3-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid was dissolved in 0.50 mL of DMF, and 75 mg of 1,1′-carbonyldiimidazole was added thereto, followed by stirring at room temperature for 1 hour. To the reaction liquid were added 40 mg of methane sulfonamide and 66 mg of DBU, followed by stirring at 50° C. for 8 hours. The reaction liquid was acidified by addition of 2.50 mL of 1 M hydrochloric acid, and then extracted with a mixed solvent of chloroform/methanol (5/1), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 95:5) to obtain 207 mg of 3-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]-N-(methylsulfonyl)benzamide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC.CC1C=CC=C(C)C=1CN1C2C(=CC=C(C(O)=O)C=2)C=C1>>[CH:18]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1)=[CH2:19]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Agent: Cc1cccc(C)c1Cn1ccc2ccc(C(=O)O)cc21
Product: C=Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)CC2

Procedure:
The titled compound (207 mg) as a white solid was prepared from tert-butyl 6-bromo-2,3-dihydro-1H-indole-1-carboxylate obtained by the method described in the document (WO 1998/43956 A) and tributyl(vinyl)tin according to the method of the process (2) of Example 66.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([OH:12])=O.S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([C:8]#[N:9])[NH:4][C:3]=1[C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Product: N#Cc1[nH]c(C(=O)Cl)c(Cl)c1Cl

Procedure:
3,4-Dichloro-5-cyano-1H-pyrrole-2-carboxylic acid (Intermediate 131, 0.9 g, 0.2 mmol) was dissolved in excess thionyl chloride (5 ml) and heated to reflux for 30 minutes. The reaction mixture was concentrated and the residue was dissolved in THF and concentrated (×2). The solid (0.82 g, 89%) was pumped to dryness and stored under argon.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].Cl.[O:37]1CCOCC1.O>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH3:26])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:13]=[C:12]([OH:37])[N:11]=1)=[O:9]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(S(C)(=O)=O)ncc1-c1ccccc1
Reactant: C1COCCO1
Agent: Cl
Solvent: O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1nc(O)ncc1-c1ccccc1
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 0.3 g (0.58 mmol) 2-methanesulfonyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide in 10 ml dioxan/H2O 5 ml 2N NaOH solution was added. The reaction mixture was stirred for 3 hrs. The pH of the reaction solution was than adjusted to 4 with 25% HCl. The aqueous layer was extracted three times with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/methanol 9:1) to give 0.20 g (75%) 2-hydroxy-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a off-white solid, m.p. 218.5-219.5°.