Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:34])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:22]=2)=[N:4][N:3]=[N:2]1.ClC1C=CC=C(C(OO)=[O:43])C=1>C(Cl)(Cl)Cl>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20](=[O:34])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:26]=2)=[O:43])=[N:1][N:2]=[N:3]1
Reactant: CCCCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCCCOc1ccc(C(=O)Nc2ccccc2S(=O)c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a solution of 2.5 g of N-[2-[2-(1H-tetrazol-5yl)phenylthio]phenyl]-4-hexyloxybenzamide in 30 ml of chloroform was added 1.5 g of 80% m-chloroperbenzoic acid, and the mixture was stirred at room temperature for 2 hours, at the end of which time the solvent was distilled off. Then, ethyl acetate-chloroform was added to the residue and the resulting crystals were collected by filtration and recrystallized from ethanol-chloroform to give 0.67 g of the title compound as white crystals, m.p. 206°-210° C. (decomp.)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:9][C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][N:11]=2)=[CH:7][CH:6]=1)=[O:4].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[H-].[Na+]>C1COCC1>[CH2:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]([C:8]2[O:9][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:11]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(-c2n[nH]c3ccccc23)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1

Procedure:
A solution of 3-(5-methoxycarbonyl-2-furyl)-1H-indazole (2.0 g, 8.3 mmol) and benzyl bromide (2.5 mL, 21.0 mmol) in THF (100 mL) was added dropwise via dropping funnel to a suspension of sodium hydride (60% dispersion in oil: 0.50 g, 12.5 mmol) in THF (200 mL). The resultant mixture was stirred at room temperature for 20 h. The mixture was poured onto brine and the layers separated. The aqueous layer was extracted three times with ether and then the combined organic material was washed with saturated aqueous NaHCO3 solution, dried (MgSO4) and concentrated under reduced pressure. The residue was chromatographed on silica (EtOAc:cyclohexane 1:4) and then the product was recrystallised (EtOAc/hexane) to give a yellow solid: mp 137–138° C.; MS (EI) M+ 332; 1H-NMR (CDCl3) 3.97 (s, 3H), 5.67 (s, 2H), 7.03 (d, 1H, J=3.7 Hz), 7.22–7.43 (m, 9H), 8.27 (d, 1H, J=8.1 Hz); Anal. (C20H16N2O3) C, calcd 72.28; found 71.92, H, calcd 4.85; found 4.75, N, calcd 8.43; found 8.39.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[N:9]2[CH:12]([CH3:17])[C:13](=[O:16])[NH:14][N:15]=3)=[CH:4][CH:3]=1.O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH3:17][CH:12]1[N:9]2[C:10]3[C:5]([CH2:6][CH2:7][C:8]2=[N:15][NH:14][C:13]1=[O:16])=[CH:4][CH:3]=[C:2]([NH:1][CH:19]1[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22]1)[CH:11]=3
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1C(=O)NN=C2CCc3ccc(N)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1C(=O)NN=C2CCc3ccc(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
A solution of 9-amino-1-methyl-5,6-dihydro-1H-[1,2,4]triazino[4,3-a]quinolin-2(3H)-one (0.035 g, 0.152 mmol) and tert-butyl 3-oxoazetidine-1-carboxylate (0.078 g, 0.45 mmol) in MeOH (5 mL) and AcOH (0.5 mL) was stirred for 1 h at rt. Sodium cyanoborohydride (0.028 g, 0.456 mmol) was added and the reaction mixture was stirred at ambient temperature overnight. The solution was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 3-(1-methyl-2-oxo-2,3,5,6-tetrahydro-1H-[1,2,4]triazino[4,3-a]quinolin-9-ylamino)azetidine-1-carboxylate (0.020 g, 34%). LC/MS (Table 1, Method 2) Rt=1.104 min; MS m/z: 386 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][NH:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.Cl[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22].O>C1COCC1>[CH3:3][O:4][C:5]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:6]=1[CH2:7][N:8]([C:9]1[S:10][CH:11]=[CH:12][N:13]=1)[S:21]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])(=[O:23])=[O:22]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2nccs2)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Sodium hydride (60% in mineral oil, 239 mg, 5.99 mmol, 1.5 eq) was added portionwise to a solution of N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 1 g, 3.995 mmol, 1 eq) in THF (10 ml) at 0° C. The mixture was stirred for 40 minutes before the addition of methyl 3-(chlorosulfonyl)benzoate (937, 3.995 mmol, 1 eq) and the reaction mixture stirred for a further 1 hour at 0° C. and 5 hours at room temperature. Water (2 ml) was added and the THF evaporated in vacuo. The residue was extracted from water (10 ml) into ethyl acetate (3×5 ml), washed with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to yield methyl 3-{[(2,4-dimethoxybenzyl)(1,3-thiazol-2-yl)amino]sulfonyl}benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:35][CH2:34][CH2:33][NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(NCCNc2ccccn2)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
A suspension of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylic acid (101 mg, 0.292 mmol), 2-(2-pyridylamino)ethylamine (60.2 mg, 0.436 mmol), and triethylamine (60.7 μL, 0.435 mmol) in DMSO (1.5 mL) was stirred at 100° C. for 3 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. Recrystallization of the filtered precipitates from CH2Cl2-EtOH gave 5-amino-6-fluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-7-[2-(2-pyridylamino)ethylamino]-3-quinolinecarboxylic acid (103 mg, 76%) as a pale brown powder.
Reaction SMILES: C(S[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:15])[C:7](=[O:16])[CH2:6][N:5]=1)C.[CH:17]([NH:19][NH2:20])=O>C(O)CCC>[CH3:15][N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4]2=[N:20][N:19]=[CH:17][N:5]2[CH2:6][C:7]1=[O:16]
Reactant: NNC=O
Reactant: CCSC1=NCC(=O)N(C)c2ccccc21
Solvent: CCCCO
Product: CN1C(=O)Cn2cnnc2-c2ccccc21
Reaction time: 16 h

Procedure:
A mixture of 1,3-dihydro-5-(ethylthio)-1-methyl-2H-1,4-benzodiazepin-2-one (1 eq.) and formic hydrazide (5.8 eq. Aldrich) in n-butanol (0.1 M in benzodiazepine) was stirred at reflux under N2 for 24 hours. An additional 1.67 eq. of formic hydrazide was added and refluxing continued an additional 16 hours. The yellow solution was evaporated in vacuo and the residue was purified via flash chromatography eluting with a gradient from 98:2® 96:4 CH2Cl2/MeOH. The product was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:4][O:5][C:6]=1[CH3:7].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>ClCCl.O>[C:8]([C:3]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][Cl:27])=[C:6]([CH3:7])[O:5][N:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1onc(C(=O)c2ccccc2)c1N
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1onc(C(=O)c2ccccc2)c1NC(=O)CCl
Reaction time: 1 h

Procedure:
To a chilled (5° C.) mixture of 6.5 g of (4-amino-5-methylisoxazol-3-yl)phenylmethanone, 65 ml of 2N sodium carbonate, 163 ml of a saturated solution of sodium bicarbonate, and 150 ml of dichloromethane was added, dropwise, 5.1 ml of chloroacetyl chloride. The resulting mixture was stirred for one hour, diluted with dichloromethane and water, and separated. The organic phase was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to an oil. Flash chromatography of the oil (20% ethyl acetate/hexane as the eluent) afforded 7.15 g of N-(3-benzoyl-5-methylisoxazol-4-yl)chloroacetamide, m.p. 86°-88° C.
Reaction SMILES: [C:1](=[O:13])([O:6][CH2:7][C:8]1[S:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[K+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[S:12][CH:11]=[CH:10][CH:9]=2)=[O:13])[CH3:4])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(Cl)OC(=O)OCc1cccs1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2cccs2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 96 h

Procedure:
1-Chloroethyl thenyl carbonate (2.43 g, 11 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 10 mmol) and potassium iodide (0.17 g, 1 mmol) in dry DMF. After stirring at 50° C. for 5 hours and at room temperature for 4 days the solvent was removed at reduced pressure. The residue was suspended in chloroform (100 ml) and washed three times with a saturated sodium hydrogen carbonate solution and finally twice with water. After drying with magnesium sulfate the solution was evaporated to dryness. Yield: 7.9 g. Purity by HPLC: 88%. 1H-NMR (DMSO-d6): delta=1.64 (CHCH3); 1.65 (N(CH3)COCH3); 2.05 (NCOCH3 ); 2.95 (NCH3); 5.41 (CH2); 7.00 (CHCH3); 7.05; 7.25; 7.61 (thiophene); 10.11 ppm (NH).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:20][CH2:19][CH2:18][C@@H:17]3[N:12]2[C:13](=[O:22])[CH:14](I)[CH2:15][CH2:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[P:23]([O:30]CC)([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[CH2:20][CH2:19][CH2:18][C@H:17]3[N:12]2[C:13](=[O:22])[CH:14]([P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH2:15][CH2:16]3)=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc([C@H]2CCC[C@H]3CCC(I)C(=O)N32)cc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccc(C(=O)OC)cc3)N2C1=O
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of (6R*,9aS*)-6-(4-carbomethoxyphenyl)-3-iodooctahydroquinolizin-4-one (180 mg) with triethyl phosphite (2 mL) was stirred at 120° C. for two hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 185 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCC.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15][Br:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol (0.88 g, 3.2 mmol) and CBr4 (1.3 g, 4.0 mmol) were dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over 0.5 h. The mixture was stirred at 0° C. for 10 min., then diluted with pentane (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was separated and washed with ethyl ether, and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (99:1 ethyl ether-hexane) to yield 0.8 g, (74%) of the 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[CH:19][C:18]4=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[C:26]([CH:30]=O)[CH:27]=[N:28][CH:29]=5)[N:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:32][S:33]([CH2:36][CH2:37][NH2:38])(=[O:35])=[O:34].Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:32][S:33]([CH2:36][CH2:37][NH:38][CH2:30][C:26]1[CH:25]=[C:24]([C:23]2[N:17]3[C:18]([CH:19]=[N:20][C:15]([NH:14][C:11]4[CH:10]=[CH:9][C:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:13][CH:12]=4)=[N:16]3)=[CH:21][CH:22]=2)[CH:29]=[N:28][CH:27]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)CCN
Reactant: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(C=O)c5)n4n3)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(c2ccc(Nc3ncc4ccc(-c5cncc(CNCCS(C)(=O)=O)c5)n4n3)cc2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
Into a 8-dram vial, 5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-pyridine-3-carbaldehyde (100.2 mg, 0.2424 mmol), 2-Methanesulfonyl-ethylamine; hydrochloride (0.2322 g, 1.454 mmol), 1,2-Dichloroethane (15.0 mL), and Acetic acid (100.0 uL, 1.759 mmol) were added and heated at 45° C. overnight. Sodium triacetoxyborohydride (0.1541 g, 0.7273 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The reaction was partitioned with saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (5 to 25% methanol). The collected fractions afforded (7-{5-[(2-Methanesulfonyl-ethylamino)-methyl]-pyridin-3-yl}-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (8 mg, 6%). LCMS (E/I+) 521.19 (M+H). NMR 1H (DMSO-d6)-9.27 (s, 1H), 9.19 (d, 1H, J=2.25 Hz), 8.97 (s, 1H), 8.57 (t, 1H, J=1.90 Hz), 8.52 (d, 1H, J=1.61 Hz), 7.56 (d, 2H, J=8.79 Hz), 7.27 (d, 1H, J=5.28 Hz), 6.95 (d, 1H, J=5.28 Hz), 6.92 (d, 1H, J=8.79 Hz), 3.84 (d, 2H, J=5.80 Hz), 3.25 (t, 2H, J=6.63 Hz), 3.08 (t, 4H, J=4.97 Hz), 3.00 (s, 3H), 2.94 (q, 2H, J=6.63 Hz), 2.46 (t, 4H, J=4.97 Hz), 2.24 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[Cl:21][C:22]1[CH:31]=[CH:30][C:25]2[C:26](=O)[CH2:27][O:28][C:24]=2[CH:23]=1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:26]3[C:25]4[CH:30]=[CH:31][C:22]([Cl:21])=[CH:23][C:24]=4[O:28][CH2:27]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=C1COc2cc(Cl)ccc21
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3COc4cc(Cl)ccc43)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 6-chloro-benzofuran-3-one using decaborane yielded a mixture of epimers of the title compound as a white foam. MS (ESI): m/z=431.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=2[N:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN1C(=O)CCC1>[CH3:17][S:16][C:13]1[N:14]=[CH:15][C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:18]([O:20][CH3:21])=[O:19])=[CH:5][C:4]=3[N:3]=[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:11]=2[N:12]=1
Reactant: COC(=O)c1ccc2c(c1)nc(Cl)c1nc(SC)ncc12
Reactant: Nc1ccccc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2c(c1)nc(Nc1ccccc1)c1nc(SC)ncc12
Temperature: 120 °C

Procedure:
methyl 5-chloro-3-(methylthio)pyrimido[4,5-c]quinoline-8-carboxylate (1.0 eq, 182 mg, 0.57 mmol) was mixed with aniline (0.5 ml) in NMP (1 ml). The mixture was heated under microwave for 10 minutes at 120° C. Water was added and the resulting solid was filtered and dried. The compound was triturated in EtOAc and hexanes and filtered to afford methyl 3-(methylthio)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate as a yellow solid. LCMS (ES): >95% pure, m/z 377 [M+1]+. This material was suspended in CH2Cl2 (4 ml) and meta-chloroperbenzoic acid (77% pure, 2.5 eq, 165 mg, 0.737 mmol) was added in small portions. After one hour, an additional amount (100 mg) of mcpba was added and the mixture stirred for 1.5 hours. After addition of more CH2Cl2, the organic phase was washed with water (4×), dried over Na2SO4 and the solution was filtered through a pad of silica gel, eluting with a MeOH/CH2Cl2 mixture. After evaporation of the solvents, methyl 3-(methylsulfonyl)-5-(phenylamino)pyrimido[4,5-c]quinoline-8-carboxylate was isolated as a yellow solid (166 mg, 72% yield). LCMS (ES): >95% pure, m/z 409 [M+1]+, 1H NMR (DMSO-d6, 400 MHz) δ 3.77 (s, 3H), 3.93 (s, 3H), 7.15 (t, J=7.2, 1H), 7.45 (t, J=7.6, 2H), 7.99 (dd, J=2.0, J=8.4, 1H), 8.16 (d, J=7.6, 2H), 8.28 (d, J=2.0, 1H), 8.89 (d, J=8.8, 1H), 9.76 (s, 1H), 10.61 (s, 1H) ppm.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]([C:27](=[O:30])[CH2:28]Cl)[CH2:24][CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:35])[C:12]2[O:18][C:17]3[C:19]([Cl:31])=[CH:20][C:21]([N:23]4[CH2:24][CH2:25][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:28][C:27]4=[O:30])=[CH:22][C:16]=3[CH2:15][S:14](=[O:33])(=[O:32])[C:13]=2[CH:34]=1)=[O:8]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Reactant: CC(C)N
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C(C)C)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Isopropylamine (2 mL, 48.72 mmol) was added to a solution of Example 57k (0.3 g, 0.59 mmol) in DMF (5 mL) and stirred at 80° C. for 3 h. The reaction mixture was concentrated, treated with water, and extracted with chloroform. The organic layer was washed with water, brine and concentrated to obtain the title compound which was purified using flash chromatography (silica gel, 2% methanol/chloroform). Yield: 0.16 g, (55.17%); 1H NMR (CDCl3): δ 1.10 (d, 6H, 2CH3), 2.7 (s, 3H, CH3), 2.8 (q, 1H, CH), 2.86 (t, 2H, CH2), 3.41 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.92 (s, 3H, OCH3), 4.71 (s, 2H, CH2), 7.38 (d, 1H, Ar), 7.46 (d, 1H, Ar), 8.1 (s, 1H, Ar), 8.46 (s, 1H, Ar); MS: m/e (ES+) 493 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19]O)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1.[CH3:22][C:23]1[N:24]=[N:25][NH:26][N:27]=1.CO>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][N:25]3[N:26]=[N:27][C:23]([CH3:22])=[N:24]3)[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]1
Reactant: Cc1nn[nH]n1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)nn1
Solvent: ClCCl
Solvent: CO
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4nnc(C)n4)OC3=O)cc2F)nn1
Yield: 44.1 %

Procedure:
This compound was prepared from (5R)-3-[3-Fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-(hydroxymethyl)oxazolidin-2-one (Intermediate 19) (1.054 g, 3.61 mmol) and 5-methyl-2H-tetrazole (0.608 g, 7.23 mmol), as described for Example 29. Chromatography on silica gel with 5% methanol in dichloromethane gave the crude product (0.72 g) which was purified further by trituration with dichloromethane and diethyl ether to afford the title product (0.571 g). The regioisomeric product (5R)-3-[3-fluoro-4-(4-methyl-1H-1,2,3-triazol-1-yl)phenyl]-5-[(5-methyl-1H-tetrazol-1-yl)methyl]-1,3-oxazolidin-2-one was also isolated (0.228 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[NH:8][N:7]=1)=[O:5])[CH3:2].[Cl-].[Li+].N1C=CC=CC=1.C1(C)C=CC(S([Cl:34])(=O)=O)=CC=1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1[Cl:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2c(c1=O)CCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Yield: 60.6 %

Procedure:
To a slurry of 4-oxo-1,4,5,6,7,8-hexahydrocinnoline-3-carboxylic acid ethyl ester (1 g), lithium chloride (0.19 g) and pyridine (0.36 ml) in dichloromethane (30 ml) was added p-toluenesulphonyl chloride (0.85 g). The reaction mixture was heated at reflux for 20 h. The solid was collected by filtration, and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography using a gradient elution: CH2Cl2 (500 ml), CH2Cl2/MeOH 99:1 (500 ml), CH2Cl2/MeOH 98:2 (1 liter). The appropriate fractions were combined and evaporated under reduced pressure to give a solid (0.65 g, 61%). δH (360 MHz; CDCl3) 1.44 (3H, t, J=7 Hz, CH3), 1.89 (4H, m, CH2), 2.85 (2H, t, J=5.7 Hz, CH2), 2.62 (2H, t, J=5.7 Hz, CH2), 4.51 (2H, t, J=7 Hz, CH2), m/z (ESP+) 241/243 (MH+).
Reaction SMILES: [C:1]([Cl:5])(=O)OC.[C:6]1([CH3:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH3:12][C:6]1[CH:11]=[CH:10][C:9]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:8][C:7]=1[CH2:1][Cl:5]
Reactant: Cc1ccccc1
Reactant: COC(=O)Cl
Product: Cc1ccc(-c2ccccc2)cc1CCl
Temperature: 25 °C
Reaction time: 7 h

Procedure:
315 mg (1.40 mmol) of N,N-dimethyl-(2-methyl-5-phenylbenzyl)amine (produced in the same manner as in Intermediate Production Example 12) was dissolved in 3 ml of toluene, and to this solution was added 370 mg (3.92 mmol) of methyl chlorocarbonate at room temperature. Directly after addition, the reaction mixture tuned to white suspension. This while suspension was stirred at room temperature for 7 hours, then, washed with 1 N hydrochloric acid, saturated sodium bicarbonate water, and saturated saline, sequentially, and dried over anhydrous magnesium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (eluant: hexane, then, hexane/ethyl acetate=10/1 (v/v)), to obtain 282 mg of 2-methyl-5-phenylbenzyl chloride.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][O:4]1.[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C)C=O.C1C=CC=CC=1>[F:1][C:2]([F:25])([F:24])[C:3]1([C:20]([F:23])([F:22])[F:21])[O:7][CH:6]([CH2:8][N:26]=[N+:27]=[N-:28])[CH2:5][O:4]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2COC(C(F)(F)F)(C(F)(F)F)O2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: [N-]=[N+]=NCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reaction time: 3.5 h

Procedure:
A sample of 14.00 grams of 2,2-bis(trifluoromethyl)-4-tosyloxymethyl-1,3-dioxolane (m.p. 58°-60° C.) is dissolved in 40 ml of dimethylformamide and 4.85 grams NaN3 is added. The mixture is stirred magnetically at 140°-149° C. for 3.5 hours. The product is diluted with benzene and filtered. The filtrate is washed thoroughly with water, vacuum-stripped and distilled. The product, 2,2-bis(trifluoromethyl)-4-azidomethyl-1,3-dioxolane, has a boiling point of 78° C./20 mm Hg and a refractive index of 1.37447 at 20° C.