Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:32][CH2:33][NH:34]C(=O)OC(C)(C)C)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[C:9]([F:31])[CH:8]=2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[NH2:34][CH2:33][CH2:32][N:6]1[C:7]2[C:12](=[CH:11][C:10]([NH:14][C:15]([C:17]3([C:20]4[CH:30]=[CH:29][C:23]5[O:24][C:25]([F:28])([F:27])[O:26][C:22]=5[CH:21]=4)[CH2:18][CH2:19]3)=[O:16])=[C:9]([F:31])[CH:8]=2)[CH:13]=[C:5]1[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCn1c(C(C)(C)C)cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
To a solution of tert-butyl 2-(2-tert-butyl-5-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6-fluoro-1H-indol-1-yl)ethylcarbamate (137.5 mg, 0.24 mmol) in dichloromethane (1.8 mL) was added trifluoroacetic acid (444 μL, 5.8 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with dichloromethane and washed with saturated aqueous NaHCO3 solution (3 mL) and brine (3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-10% methanol in dichloromethane) to yield N-(1-(2-aminoethyl)-2-tert-butyl-6-fluoro-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide as a white solid (93.7 mg, 82%). ESI-MS m/z calc. 473.19. found 474.5 (M+1)+. Retention time 1.61 minutes.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Brc1cnn(-c2ccccc2)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccccc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-phenylpyrazole.
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[N:2]([CH3:1])[N:3]=[C:6]([S:5][CH3:4])[CH:7]=1
Reactant: CNN
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n(C)n1
Yield: 33.9 %

Procedure:
Methylhydrazine (1.9 g) was added dropwise to a solution of 5.0 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (22) in 50 ml of ethanol at room temperature, followed by refluxing for 3 hours. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel, giving 1.6 g of the desired compound in the form of a brown oil (yield 28.5%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:24][CH:25]=1>CN(C)C=O>[F:37][C:34]([F:35])([F:36])[C:30]1[CH:29]=[C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)[N:22]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1cccc(C=Cc2nc(CCl)co2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)c1
Reaction time: 0.5 h
Yield: 41 %

Procedure:
26 mg (1.0 mmol) of 95% sodium hydride were given at 0° C. to a solution of 217 mg (1.00 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 6.0 ml N,N-dimethylformamide and stirred for 30 min. 288 mg (1.00 mmol) 4-Chloromethyl-2-[2-(3-trifluoromethyl-phenyl)-vinyl]-oxazole dissolved in 1.0 ml N,N-dimethylformamide were added at 0° C., stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched by 30 ml water, stirred for 1 h and the precipitate isolated by filtration. After washing with water, three times with cold ether and drying at 40° C. in vacuo, 192 mg (41%) 1-[4-(4-{2-[2-(E)-(3-Trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-1H-[1,2,3]triazole were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[OH-:36].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:36][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CC(CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of ester 38 (0.065 g, 0.107 mmol) in methanol (1.5 ml) and THF (1.5 ml) was stirred in presence of NaOH 1M (1 ml) for 2 h at 80° C. After cooling to rt, the solution remaining was concentrated in vacuo. HCl 1M (1.5 ml) was added and the formed white solid was filtered, washed with water (10 ml) and dried. The pure acid 40 was obtained without further need for purification (0.050 g, 0.088 mmol, 83%), mp 119-121° C. 1H NMR (400 MHz, CD3OD) δ 2.61 (1H, dd, J 8.4, 14.8 Hz, H—CHCO), 2.82 (1H, dd, J 6.0, 14.8 Hz, H—CHCO), 3.09 (1H, dd, J 7.8, 13.4 Hz, H—CHNH), 3.16 (1H, dd, J 6.4, 13.2 Hz, H—CHNH), 6.99 (2H, d, J 9.2 Hz), 7.06-7.08 (2H, m), 7.17-7.24 (5H, m), 7.47.44 (2H, m), 7.54 (2H, d, J 9.2 Hz), 7.72 (2H, d, J 8.8 Hz), 7.91 (2H, d, J 9.2 Hz). 13C NMR (400 MHz, CD3OD) δ. νmax (pure sample)/(cm−1) 3359 (st) (OH), 1686 (st) (C═O), 1595 (st) (C═O), 1530 (st), 1487 (st), 1410 (md), 1318 (md), 1246 (st), 1150 (st) 1092 (md). MS (API-ES): m/z 563 [M+H]+ (100%), HRMS (API-ES) m/z found 563.10436 [M−H]−.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:22]2[CH:23]=[N:24][C:19]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=4)[CH2:18][CH2:17]3)=[N:20][C:21]2=[O:25])=[CH:29][CH:28]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 52.7 %

Procedure:
To an N,N-dimethylformamide solution (170 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (8.48 g, 30.8 mmol) synthesized in Reference Synthesis Example 3, 4-chlorobenzyl bromide (6.32 g, 30.9 mmol) and potassium carbonate (5.11 g, 37.0 mmol) were added and the resultant mixture was stirred at 50° C. for 1 hour and at 70° C. for 3 hours. To the reaction solution, 4-chlorobenzyl bromide (1.90 g, 9.25 mmol) and potassium carbonate (2.13 g, 15.4 mmol) were added and the resultant reaction solution was stirred at 70° C. further for 2 hours. After the completion of the reaction, water was added to the reaction solution and a resultant solid was filtered and was dried under reduced pressure. The resultant solid was suspended in ethyl acetate and the suspension was stirred at room temperature for 10 minutes. The solid was filtered and was dried under reduced pressure. These operations from suspending of the solid to the second drying of the solid were performed twice to obtain the title compound (6.49 g, yield: 53%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][NH:40][C:39](=O)[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCOCC1>[CH2:28]([N:35]1[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Br:1])[C:38]=2[CH:37]=[CH:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]ccc2c1ccn2Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Brc1nccc2c1ccn2Cc1ccccc1
Reaction time: 1 h

Procedure:
35 g of N-bromosuccinimide are added to a solution of 52 g of triphenylphosphine in 1.5 l of dioxane. After stirring the mixture for 1 hour, 9 g of 1-benzyl-1,5-dihydro-pyrrolo[3,2-c]pyridin-4-one in 200 ml of dioxane are added and the mixture is heated at reflux for 15 hours. After removal of the dioxane under reduced pressure, 100 ml of triethylamine are added to the residue and the whole is then concentrated in vacuo. Chromatography on silica gel (cyclohexane/ethyl acetate: 50/50) enables the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[N:3]=2)=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: N#Cc1ccc(Cl)nc1OC1CCCC1
Reactant: O=Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Br)c(C=O)c2)nc1OC1CCCC1
Temperature: 69 °C
Yield: 100.3 %

Procedure:
To a mixture of 6-chloro-2-cyclopentyloxy-nicotinonitrile (1.32 g, 5.92 mmol) and 2-bromo-5-hydroxy-benzaldehyde (1.43 g, 7.10 mmol) in DMF (10 mL) was added potassium carbonate (1.22 g, 8.88 mmol). The resulting mixture was heated at 69° C. overnight. DMF was removed under reduced pressure, the residue was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to give white solid, which was purified by flash chromatography on silica gel using 10-25% EtOAc/hexanes as eluent to yield the title compound (2.30 g, quantitative) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1 H), 8.24 (d, J=8.2 Hz, 1 H), 7.88 (d, J=8.6 Hz, 1 H), 7.70 (s, 1 H), 7.60-7.46 (m, 1 H), 6.79 (d, J=8.2 Hz, 1 H), 4.95 (br. s., 1 H), 1.87-1.50 (m, 6 H), 1.52-1.30 (m, 2 H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][O:10]CC1C=CC=CC=1)[CH3:6])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][CH:5]([CH2:7][CH2:8][CH2:9][OH:10])[CH3:6])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC(C)CCCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC(C)CCCO
Yield: 98.8 %

Procedure:
10% palladium-active carbon (48 mg) was added to a mixed solution of 5-benzyloxypent-2-yl acetate (419 mg, 1.78 mmol) in methanol (1.86 mL) in an ice bath in an argon atmosphere, followed by stirring at room temperature in a hydrogen atmosphere. After completion of the reaction, filtration was carried out and the filtrate was concentrated under reduced pressure. 257 mg of the title compound (yield: 87%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4](Cl)[C:3]=1[C:13]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[N:19]=[C:18]([NH:25][C:26]3[C:31]([N+:32]([O-])=O)=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:35])[N:17]=[CH:16][C:15]=2[N:14]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:35])[C:26]=1[NH:25][C:18]1[N:17]=[CH:16][C:15]2[N:14]=[C:13]([C:3]3[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[CH:2]=3)[C:22](=[O:23])[N:21]([CH3:24])[C:20]=2[N:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2nc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)cc(-c2nc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1
Yield: 44 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(2-methyl-6-nitrophenylamino)pteridin-7(8H)-one (200 mg, 0.38 mmol) in ethanol (50 mL) and water (2 mL) was added iron powder (210 mg, 3.8 mmol) and ammonium chloride (450 mg, 8 mmol). The mixture was refluxed for 2 h. The solvents were evaporated, and the residue was diluted with brine and dichloromethane. The solid was filtered off, and the filtrate was extracted with dichloromethane (50 mL*6). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (70 mg, 38%). MS (ES+) C22H20Cl2N6O3 requires: 486, 488. Found: 487, 489 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 8.83 (s, 1H), 7.09 (t, 1H, J=8.0 Hz), 6.74-6.71 (m, 2H), 6.65 (s, 1H), 3.94 (s, 6H), 3.85 (br. s., 2H), 3.63-3.59 (br, 3H), 2.25 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].C(N(CC)CC)C>>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:23]
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2Cl)CC1
Yield: 86 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 126, Step 3) was stirred at room temperature with 2-chlorobenzoyl chloride (129 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-2% methanol/DCM gradient to afford 2-[1-(2-chloro-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a white solid. (225 mg; 86% yield).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][C:16]=2[CH3:17])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[S:13][CH:14]=[CH:15][C:16]=3[CH3:17])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: Cc1ccsc1-c1nn(N)c(=O)c2ccccc12
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: Cc1ccsc1-c1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12

Procedure:
The product from Example 14B and 2-(3,5-difluorophenyl)acetic acid was processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (s, 1H), 8.39-8.42 (m, 1H), 7.90-8.05 (m, 2H), 7.73 (d, J=5.1 Hz, 1H), 7.62-7.65 (m, 1H), 7.08-7.22 (m, 4H), 3.77 (s, 2H), 2.10 (s, 3H); MS (APCI) M/Z 412 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]([CH3:22])[CH2:24][CH2:25][OH:26])[N:11]=2)=[CH:15][CH:16]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNCCO
Product: COc1ccc(N(C)c2nc(N(C)CCO)nc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), 2-methylamino-ethanol 1.0 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.31-7.40 (m, 2H), 7.08-7.11 (m, 2H), 6.87-6.90 (m, 2H), 6.81-6.84 (m, 1H), 6.61-6.65 (m, 1H), 3.94-3.96 (m, 2H), 3.84-3.86 (m, 2H), 3.82 (s, 3H), 3.51 (s, 3H), 3.34 (s, 3H); HRMS (ES) m/z calcd for C19H22N4O2 (M+H) 339.1815, found 339.1830.
Reaction SMILES: CN1CCCC1.[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:9]=1.CN(C1C=CC=CN=1)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-]>O>[Cl:14][C:12]1[N:11]=[C:10]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[N:9]=[C:8]([NH:7][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccc(Nc2nc(N)cc(Cl)n2)cc1
Agent: CN(C)c1ccccn1
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Solvent: O
Product: N#Cc1ccc(Nc2nc(Cl)cc(NC(=O)c3ccccc3)n2)cc1
Temperature: 82.5 °C
Reaction time: 0.5 h

Procedure:
1400 ml of N-methylpyrrolidine and 140 g of 4-(4-Amino-6-chloropyrimidin-2-ylamino)benzonitrile was charged into a reaction vessel. To this were added 85.49 g of dimethylamino pyridine and 87.21 g of diazabicyclo undecene and stirred for 30 mins. To the reaction mixture was added 27.36 g of benzoyl chloride and stirred at RT for 30 mins. and heated to 80-85° C. and maintained the same for 4 hrs. After completion of the reaction, the reaction mass was cooled to RT and 1400 ml of water was added, followed by 1400 ml of 50% carbonate solution. The reaction mass was extracted with 1400 ml of dichloromethane and the dichloromethane layer was washed with 700 ml of water. The organic layers were separated and dried over anhydrous sodium sulfate and filtered; distilled off dichloromethane and the solid was isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]([N:12]([CH2:17][CH3:18])[S:13]([CH3:16])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:19])[CH:8]=2)[O:3]1.[H-].[Na+].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32]Cl)[CH:27]=1>CC(N(C)C)=O>[CH2:17]([N:12]([CH:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:19][CH2:32][C:28]3[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=[CH:30][N:29]=3)[CH:8]=2)[O:3][C:2]([CH3:1])([CH3:20])[CH2:11]1)[S:13]([CH3:16])(=[O:15])=[O:14])[CH3:18]
Reactant: CCN(C1CC(C)(C)Oc2ccc(O)cc21)S(C)(=O)=O
Reactant: COc1ccnc(CCl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(C1CC(C)(C)Oc2ccc(OCc3cc(OC)ccn3)cc21)S(C)(=O)=O
Temperature: 75 °C

Procedure:
0.58 g (1.9 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-ethyl-methanesulfonamide (Example 1g) was stirred at 50° C. for 30 min with 0.15 g (5 mmol) of NaH (80%) in 40 ml of DMA. A solution of 0.4 g (2 mmol) of 4-methoxy-2-chloromethylpyridine hydrochloride in 5 ml of DMA was then added dropwise and the mixture was heated to 75° C. for 2 h. After reaction was complete, it was concentrated in vac., the residue was treated with ice water, the mixture was extracted with EA, the extract was dried and concentrated, and the residue was crystallized using diisopropyl ether. 0.5 g was obtained, m.p. 87-89° C.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12]([CH2:18][C:19]#[N:20])(=O)[C:13]([CH3:16])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[NH2:20][C:19]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[C:12]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:18]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2ccc(C(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
To a suspension of 2.4 g (16 mmol) 4-hydrazino-benzoic acid in 12 mL toluene, 2.0 g of pivaloyl acetonitrile are added at rt. The suspension is heated to and kept under reflux for 12 h. After completion, the resulting reaction mixture is allowed to cool to rt. The precipitated product is isolated by filtration, washed with cold toluene and dried under high vacuum. [M+1]+=260.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C@@:9]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:14][C:13](=[O:15])[C@@H:12]2[C@H:10]1[C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](N)(C(=O)OCC)[C@@H]21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1[C@@H]2C(=O)C[C@@](NC(C)=O)(C(=O)OCC)[C@@H]21
Reaction time: 2 h

Procedure:
Add acetic acid anhydride (5 mL, 50.8 mmol) to a stirred solution of diethyl (1S,2S,5R,6R)-2-amino-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (7.2 g, 28.2 mmol) and triethylamine (7.9 mL, 56.4 mmol) in dry dichloromethane (72 mL) at room temperature. After 2 hours, quench with water (100 mL) and stir vigorously for 20 minutes. Separate the dichloromethane layer via a hydrophobic frit and evaporate to a light brown oil (9.6 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (70:30 to 90:10) to give the title compound as a pale yellow glass foaming on drying (6.53 g, 22 mmol). MS (m/z): 298 (M+1), 320 (M+23), 617 (2M+23).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][CH2:13][CH2:14][OH:15]>CN(C=O)C>[C:1]([O:9][CH2:12][CH2:13][CH2:14][OH:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCCl
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCCCO)c1ccccc1
Temperature: 135 °C
Yield: 70.9 %

Procedure:
Sodium benzoate (96.32 g) in DMF (690 ml) was heated to 80° C., and 1-chloro-3-hydroxypropane (63.06 g) was added over 15 minutes. The temperature increased to 135° C., and the reaction mixture was heated at 135°-175° C. for 3 hours. Filtration removed 38 g of sodium chloride (97% of theory). The filtration was partially evaporated at reduced pressure at <40° C. The concentrated filtrate was poured into ice water and extracted well with ether. The combined ether extracts were washed with water, dried over anhydrous sodium sulfate, and evaporated. The residual oil was distilled through a Vigreux column to give 3-benzoyloxy-1-propanol (85.2 g), b.p. 124°-132° C. at 0.055 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([OH:14])=[C:12]([C:15](=O)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:19][O:20][C:21]([C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([NH:28][NH2:29])=[O:27])=[O:22]>>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12](=[C:15]([NH:29][NH:28][C:26](=[O:27])[C:25]3[CH:30]=[CH:31][CH:32]=[C:23]([C:21]([O:20][CH3:19])=[O:22])[CH:24]=3)[CH3:16])[C:11]([CH3:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1cccc(C(=O)NN)c1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Product: COC(=O)c1cccc(C(=O)NNC(C)=C2C(=O)N(c3ccc(C)c(C)c3)N=C2C)c1

Procedure:
From 1-(1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl)-ethanone and 3-methoxycarbonylbenzhydrazide, 27.4 mg of the desired product was obtained in the same manner as in Synthetic Example 4 as a pale yellow solid (yield 35%).