Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1[CH:41]=[CH:40][C:17]([CH2:18][N:19]([CH2:30][C:31]2[NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[N:32]=2)[CH:20]2[C:29]3[N:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CCN(CC)CC>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[CH2:30][N:19]([CH2:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:41][CH:40]=1)[CH:20]1[C:29]2[N:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccnc(C)c1C(=O)NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 2,4-dimethyl-nicotinic acid (54 mg, 0.35 mmol) in SOCl2 (˜2 mL, excess) was heated to 80° C. for 4 hours. The condenser was removed and the mixture was flushed with N2 at 80° C. for ˜5 minutes and then dried in vacuo for 10 minutes. The resulting syrup was dissolved in CH2Cl2 (2.4 mL) and added to a stirring mixture of (4-aminomethyl-benzyl)-(1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (187 mg, 0.47 mmol), Et3N (0.33 mL, 2.35 mmol) and a catalytic amount of DMAP. The reaction mixture was stirred overnight at room temperature. Purification of the crude yellow foam (240 mg) by radial chromatography on silica gel (2 mm plate, CH2Cl2/MeOH/NH4OH, 100:2:1) followed by radial chromatography on silica gel (1 mm plate, EtOAc/MeOH/NH4OH, 400:3:3) afforded the desired amide (61 mg, 33%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([OH:31])=O)=[O:8].[NH2:36][CH2:37][CH2:38][OH:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:15][CH:16]=2)[N:11]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]=1[C:29]([NH:36][CH2:37][CH2:38][OH:39])=[O:31])=[O:8]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)O)n(Cc3ccccn3)c2c1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(=O)NCCO)n(Cc3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3,4-difluorobenzylcarbamoyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-2-carboxylic acid (Compound 102, 73 mg, 0.12 mmol) in DMF (2 ml) was added 2-aminoethanol (11 μl, 0.17 mmol), BOP (64 mg, 0.14 mmol), and i-Pr2NEt 30 μl, 0.17 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound as a yellow syrup.
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].Cl.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:19]=[C:20]([C:28](=[O:35])[NH:29][CH2:30][CH2:31][N:32]([CH3:34])[CH3:33])[CH:21]=[C:22]([CH:27]=1)[C:23](OC)=[O:24]>CN(C)C=O.C(OCC)(=O)C.O1CCCC1.O>[ClH:10].[ClH:1].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[C:18]1[CH:19]=[C:20]([C:28](=[O:35])[NH:29][CH2:30][CH2:31][N:32]([CH3:33])[CH3:34])[CH:21]=[C:22]([CH:27]=1)[C:23]([NH:4][C:3]([NH2:5])=[NH:2])=[O:24]
Reactant: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)ccc2Cl)c1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1cc(C(=O)NC(=N)N)cc(-c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of guanidine.hydrochloride (0.4 g) in N,N-dimethylformamide (7.2 ml) was added sodium methoxide (0.76 ml, 28% in methanol) under nitrogen atmosphere. After being stirred for 15 minutes at room temperature, to the reaction mixture was added methyl 5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.hydrochloride (0.36 g). After being stirred for 4 hours at room temperature, the residue was dissolved in a mixture of ethyl acetate (40 ml), tetrahydrofuran (20 ml) and water (40 ml). The aqueous layer was further extracted with a mixture of ethyl acetate (40 ml) and tetrahydrofuran (20 ml). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in ethanol (8 ml) and added slightly excess 4N hydrochloride in dioxane to afford [5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoyl]guanidine.dihydrochloride.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:19]=[CH:20]/[CH:21]=C/C(O)=O)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16]>[Cl-]>[CH3:18][O:17][C:13]1[CH:12]=[C:11](/[CH:19]=[CH:20]/[CH:21]=[CH:1]/[C:2]([Cl:4])=[O:3])[CH:10]=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(/C=C/C=C/C(=O)O)cc(OC)c1OC
Agent: [Cl-]
Product: COc1cc(/C=C/C=C/C(=O)Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After oxalyl chloride (0.055 ml; 0.63 mmol) was added to a solution of (E,E)-5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoic acid (116 mg; 0.44 mmol) in dimethylformamidemethylene chloride (0.1ml-5 ml) under ice cooling. The ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain crude crystals of (E,E)-5-(3,4,5-trimethoxyphenyl)-2,4-pentadienoyl chloride.
Reaction SMILES: Br.[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[OH-].[Na+].[C:23](Cl)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CN(C)C=O>[OH:2][C:3]1[C:19]([OH:20])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Oc1cc2c(cc1O)C(c1ccccc1)CNCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2cc(O)c(O)cc2C(c2ccccc2)C1
Temperature: 25 °C

Procedure:
A solution of 7.10 g. (18.6 mole) of 7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide in 120 ml. of aqueous dimethyl-formamide at 0° under an argon atmosphere is basified to pH 10.0 with 10% sodium hydroxide solution. To this cold mixture is added 13.0 g. (76 mole) of carbobenzyloxy chloride in small portions over 15 minutes with concomitant addition of 10% alkali so as to maintain a pH of 10 to 10.5. The reaction is allowed to warm to room temperature after stirring at 0° for one and one-half hours. The mixture is diluted with saturated salt and extracted with three portions of ethyl acetate. The combined organic extract is backwashed twice with saturated salt. The dried extract is concentrated in vacuo and heated at 75°/0.1 mm Hg to remove any benzyl alcohol to yield 7,8-dihydroxy-N-carbobenzyloxy-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[NH2:31][C@H:32]1[CH2:41][C:40]2[C:39]([N:42]3[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]3)=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:34][CH2:33]1>CN(C)C=O>[C:51]([O:50][C:48]([N:45]1[CH2:46][CH2:47][N:42]([C:39]2[CH:38]=[CH:37][CH:36]=[C:35]3[C:40]=2[CH2:41][C@H:32]([NH:31][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[CH:15][CH:14]=2)[CH2:33][CH2:34]3)[CH2:43][CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCOCC4)cc2)CC3)CC1
Temperature: 75 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
To a solution of 4-morpholinobenzoic acid (0.59 g, 2.8 mmol; described in: Degutis, J.; Rasteikiene, L.; Degutiene, A. Zh. Org. Khim. 1978, 14(10), 2060-2064) in anhydrous N,N-dimethylformamide (30 mL) was added 1,1′-carbonyldiimidazole (0.48 g, 3.0 mmol) and the reaction was heated at 75° C. When the carbon dioxide evolution had ceased (after 30 min), the reaction was cooled to room temperature and a solution of tert-butyl (R)-4-(7-amino-5,6,7,8-tetrahydro-1-naphthyl)piperazine-1-carboxylate (0.90 g, 2.7 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added. The reaction was allowed to stir at ambient temperature for 24 h and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform/ethanol saturated with NH3 (100:2) as the eluent gave 1.5 g (84% yield) of the title compound as a dark-red viscous oil: [α]21D −45° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 520 (5, M+).
Reaction SMILES: [C:1]([NH:18][C:19]([NH2:21])=[S:20])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].Br[CH2:23][C:24](=O)[C:25]([OH:27])=[O:26]>O1CCOCC1>[C:1]([N:18]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][S:20][CH:19]1[NH2:21])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2]
Reactant: O=C(O)C(=O)CBr
Reactant: NC(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Product: NC1SC=C(C(=O)O)N1C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 96.4 %

Procedure:
A solution of N-Fmoc-thiourea (5.96 g, 20 mmol) in dioxane (40 mL) was treated with bromopyruvic acid (3.34 g, 20 mmol). The reaction mixture was refluxed for 1 h, then the precipitated solids were recovered by filtration and washed with diethyl ether (3×20 mL) to afford N-Fmoc-2-aminothiazole-4-carboxylic acid (7.1 g, 97%) as a white solid: EI-HRMS m/e calcd for C19H14N2O4S (M+) 366.0674, found 366.0679.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[C:9]([N+:14]([O-])=O)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>[Fe].CCO.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([NH2:14])[C:8]=2[CH:7]=[N:6]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2Cc1ccc(F)cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1cnn2Cc1ccc(F)cc1F
Yield: 0.1 %

Procedure:
A solution of 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole (0.142 g, 0.491 mmol), ammonium chloride (0.013 g, 0.245 mmol) in 4:1 v/v EtOH/water (5 mL) was treated with iron (0.274 g, 4.91 mmol) and refluxed for 2 hours. The mixture was concentrated and the residue taken in EtOAc/water, filtered through glass fiber filter paper and concentrated again to provide 1-(2,4-difluorobenzyl)-1H-indazol-4-amine (0.096 mg, 75% yield) as an amber oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH2:11])=[N:7][C:6]=2[CH:12]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)#[N:14].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>CCCCCC>[CH:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:18]3[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)=[CH:12][C:6]=2[N:7]=1)=[CH2:11]
Reactant: C=Cc1nc2cc(Br)ccc2o1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1nc2cc(-c3ccc(C#N)cc3)ccc2o1
Temperature: 23 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
A mixture of 224 mg (1 mmol) of 5-bromo-2-vinyl-benzooxazole, 191 mg (1.3 mmol) of 4-cyanophenylboronic acid, 55 mg (0.03 mmol) of tris-(dibenzylidineacetone)dipalladium (0) (CAS #52409-22-0), 0.2 mL (0.06 mmol) of a 10% solution of tri-tert-butylphosphine in hexane, and 1.5 mL of tetrahydrofuran was stirred at 23° C. for 24 hours. It was then heated at 65° C. for 0.5 hour, then cooled. The mixture was suction filtered to remove particulates, then partitioned between 80 mL of water and a mixture of 30 mL of ethyl acetate and 10 mL of hexane. The organic phase was collected, dried over Na2SO4, and purified by flash chromatography on silica gel (eluting with 1:1 hexane: dichloromethane) to give 4-(2-vinyl-benzooxazol-5-yl)-benzonitrile (192 mg, 78%) as a white solid: mp 143-144° C.;
Reaction SMILES: [OH:1][C:2]1([CH3:26])[CH:8](Br)[CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1.C([SnH](CCCC)CCCC)CCC>O1CCCC1>[OH:1][C:2]1([CH3:26])[CH2:8][CH:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1Br
Agent: CCCC[SnH](CCCC)CCCC
Solvent: C1CCOC1
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Yield: 88.7 %

Procedure:
The product obtained by reducing 2.0 g of 3-hydroxy-3-methyl-4-bromo-7-(p-benzyloxyphenyl)-5-heptanolide with 5.59 g of tri-n-butyltin hydride in 50 ml of anhydrous tetrahydrofuran according to the method described in Example 2 (a), was recrystallized from a mixture of n-hexane and ethyl ether (5:1) to give 1.44 g of the desired compound melting at 82°-85° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[S:8])(=[O:3])[CH3:2].CCN(CC)CC.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[C:35]([C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=2)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=1>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:6]=1[C:7]([NH:33][C:34]1[C:35]([C:40]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=2)=[O:41])=[N:36][CH:37]=[CH:38][CH:39]=1)=[S:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C)ccc1C(O)=S
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1cc(C)ccc1C(=S)Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 1 h

Procedure:
To a 0° C. mixture of 2-acetoxy-4-methylthiobenzoic acid (5 g, 22.1 mmol), dichloromethane (75 mL), NEt3 (3.1 mL, 22.1 mmol) and DMF (17 μL, 0.221 mmol) was added oxalyl chloride (1.92 mL, 22.1 mL) at a rate to give gentle bubbling. The mixture was stirred for 1 h and then was concentrated in vacuo. The resulting residue was dissolved in dichloromethane (75 mL). To this solution was added 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide (5.5 g, 22.1 mmol) followed by NEt3 (3.1 mL, 22.1 mmol). The reaction mixture was stirred for 18 h, concentrated to a slurry in dichloromethane and chromatographed (75 g silica gel; 100% dichloromethane to 100% EtOAc) to give the title compound as an impure solid (8.5 g).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]2[C:6]=1[CH:7]1[CH:12]([C:13]2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1>N1C=CC=CC=1>[CH3:4][C:5]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]2[C:6]=1[CH:7]1[CH:12]([C:13]2=[N:2][OH:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NO
Reactant: Cc1cc(C)c2c(c1O)C(=O)C1CCCCC21
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(c1O)C(=NO)C1CCCCC21

Procedure:
7.99 Grams of hydroxylamine hydrochloride was added to a solution prepared by dissolving 17.22 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of pyridine and the mixture was refluxed under heating for 2 hours. Pyridine was distilled off under reduced pressure and the resulting residue was extracted with 300 ml of chloroform. The extract was washed with water 1% hydrochloric acid and then with saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. After the solvent was distilled off, the product was recrystallized from ethanol to obtain 11.56 g of 5,7-dimethyl-8-hydroxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone oxime as a mixture of syn-isomer and anti-isomer.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@H:14]2[C@@H:13]([C:21]([NH:23][CH2:24][CH:25]([OH:27])[CH3:26])=[O:22])[O:12]1.C(O)(=O)C.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@H:14]2[C@@H:13]([C:21]([NH:23][CH2:24][C:25](=[O:27])[CH3:26])=[O:22])[O:12]1
Reactant: CC(O)CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)CNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70.1 %

Procedure:
To a mixture of (3aR,4S,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-N-(2-hydroxypropyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (6.60 g) and powdered 4 Å molecular sieves (10 g) in dichloromethane (165 ml) at 0° C., was added acetic acid (3.0 ml) followed by the portionwise addition of pyridinium dichromate (9.36 g). The mixture was stirred at 0° C. for 15 min and then at 20° C. for 2 hours. Isopropanol (10 ml) was added and the mixture stirred for 15 min. Silica gel (Merck 9385, 9.9 g) and ethyl acetate (165 ml) were added and the reaction stirred for a further 15 min. The mixture was filtered through celite and the filter cake washed with ethyl acetate (300 ml). The filtrate was evaporated in vacuo to give a brown solid. Purification by flash chromatography on silica gel, eluting with dichloromethane:methanol (100:3) gave a light brown foam. Further purification by chromatography on silica gel (Merck 9385), eluting with ethyl acetate followed by ethyl acetate:methanol (100:2) gave the title compound as a white foam (4.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[N:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([OH:18])[CH2:14][CH2:13]1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:24][C:25](=[O:28])[CH2:26]Br)(C)(C)C.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:8][C:9]([N:10]([CH3:11])[C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][CH2:26][C:25]([OH:28])=[O:24])[CH2:14][CH2:13]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](O)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Product: CN(C(=O)OCc1ccccc1)[C@H]1CC[C@H](OCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 15.0 g (57 mmol) of trans-(4-hydroxy-cyclohexyl)-methyl-carbamic acid benzyl ester in 230 mL of toluene were added 16.8 mL (114 mmol, 2 eq) of bromo-acetic acid tert-butyl ester and 1.93 g (5.7 mmol, 0.1 eq) of tetra-n-butylammonium hydrogensulfate and 400 mL of 50% aqueous NaOH. The mixture was stirred at RT for 4 h, additional 1.93 g (5.7 mmol, 0.1 eq) of tetra-n-butyl-ammoniumhydrogensulfate and 4.2 mL of bromo-acetic acid tert-butyl ester were added, and stirring was continued over night. The solution was concentated and acidified by adding 400 mL of 37% HCl. The solution was extracted with EtOAc, the organic phase was washed with brine and dried over Na2SO4. The solvent was removed to yield 18.2 g (quantitative) trans-[4-(benzyloxycarbonyl-methyl-amino)-cyclohexyloxy]-acetic acid as white solid, MS: 320 (M−H)−.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][OH:10])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13]>C(Cl)Cl.O>[CH3:11][S:12]([O:10][CH2:9][CH2:8][C:3]1([CH2:1][CH3:2])[O:7][CH2:6][CH2:5][O:4]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CCO)OCCO1
Solvent: ClCCl
Solvent: O
Product: CCC1(CCOS(C)(=O)=O)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 140.2 %

Procedure:
To a solution of 2-(2-ethyl-1,3-dioxolan-2-yl)ethanol (233 mg, 1.59 mmol) and TEA (327 mg, 3.2 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.23 ml, 2.92 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 2-(2-ethyl-1,3-dioxolan-2-yl)ethyl methanesulfonate (500 mg, 100%) as yellow oil that was used without purification. Product tlc [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.6]
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:12]([NH:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=1)[C:11]2=[O:35])(C)(C)C>Cl.C(O)(=O)C>[NH2:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])[N:12]([NH:23][C:24](=[O:34])[CH2:25][C:26]1[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=1)[C:11]2=[O:35]
Reactant: CCN(CC)c1nc2ccc(NC(=O)OC(C)(C)C)cc2c(=O)n1NC(=O)Cc1cc(F)cc(F)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCN(CC)c1nc2ccc(N)cc2c(=O)n1NC(=O)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
{2-Diethylamino-3-[2-(3,5-difluoro-phenyl)-acetylamino]-4-oxo-3,4-dihydro-quinazolin-6-yl}-carbamic acid tert-butyl ester was dissolved in 1 M HCl in acetic acid. The mixture was stirred at RT for 1 h. The mixture was evaporated to near dryness, followed by addition of diethyl ether. The formed precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a hydrochloride salt (0.40 g, 77%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26])[CH:7]=2)#[N:2].C(O)(C(F)(F)F)=O>>[O:26]=[C:14]1[CH2:15][NH:16][CH2:17][CH2:18][N:13]1[C:8]1[CH:7]=[C:6]2[C:11]([CH:12]=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C#N)cnc3c2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc2cc(N3CCNCC3=O)ccc2c1

Procedure:
tert-Butyl 4-(3-cyanoquinolin-7-yl)-3-oxopiperazine-1-carboxylate was treated with TFA (2 mL) for 20 minutes at RT. The TFA was removed under vacuum, and the residue was dissolved in aqueous sodium carbonate, extracted with DCM, dried over sodium sulfate, and concentrated to deliver the free base of 7-(2-oxopiperazin-1-yl)quinoline-3-carbonitrile. LC-MS (IE, m/z): 253 [M+1]+.
Reaction SMILES: [C:1](=[S:12])([S-:11])[S:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[K+].Cl[CH2:15][C:16]#[N:17]>O1CCCC1>[C:1](=[S:11])([S:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[S:12][CH2:15][C:16]#[N:17]
Reactant: S=C([S-])SCCc1ccccc1
Reactant: N#CCCl
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCSC(=S)SCCc1ccccc1
Reaction time: 1 h
Yield: 95.7 %

Procedure:
To a solution containing 10.1 g (40 mmol) of potassium phenethyl trithiocarbonate in 100 ml of tetrahydrofuran is added 2.6 ml (40 mmol) of chloroacetonitrile while maintaining the temperature of the reaction mixture at 20°-25° C. The mixture is stirred for 1 hour and concentrated in vacuo. The residue is then taken up in ether, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo. The residue is crystallized from an ether-hexane mixture to give 9.7 g of a yellow solid, cyanomethyl phenethyl trithiocarbonate, melting point 72°-73° C.