Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([CH3:13])=[N:9]2)=[C:4]([F:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.[CH3:24][N:25](C=O)C>O.[Cl-].[Na+].O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[N:11][C:10]([CH3:13])=[N:9]1)[C:24]#[N:25]
Reactant: Cc1ncn(-c2ccc(Br)cc2F)n1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCO
Product: Cc1ncn(-c2ccc(C#N)cc2F)n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a mixture of 1-(4-bromo-2-fluorophenyl)-3-methyl-1H-1,2,4-triazole (1.02 g), potassium carbonate (0.55 g) and potassium hexacyanoferrate(II) trihydrate (0.68 g) in DMF (4 mL)/ethanol (0.20 mL) was added palladium acetate (45 mg) at room temperature, and the mixture was stirred at 120° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and diluted with water and saturated brine, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.51 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][NH:29][CH:30]([CH3:32])[CH3:31])=[O:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[OH:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=1)[C:26]([NH:28][N:29]([C:19](=[O:20])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:9]=1)[CH:30]([CH3:32])[CH3:31])=[O:27]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(NC(=O)c1cccc(O)c1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (200 mg, 0.696 mmol), 3-hydroxy-N′-isopropylbenzohydrazide (202.81 mg, 1.04 mmol) and HATU (397.02 mg, 1.04 mmol) dissolved in DMF (7.0 ml), N,N-diisopropylethylamine (DIPEA) (0.1819 ml, 1.04 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (28% EtOAc) and dried so that ivory (E)-tert-butyl 3-(3-(2-(3-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (54 mg, 16.7%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[C:3]([N:12]([CH2:19][CH3:20])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCN(CC1CCCC1)c1nc2ccccc2nc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC1CCCC1)c1nc2ccccc2nc1CBr

Procedure:
A mixture of N-(3-methylquinoxalin-2-yl)-N-(cyclopentylmethyl)ethylamine (160 mg, 0.59 mmol), N-bromosuccinimide (130 mg, 0.73 mmol), and 2,2′-azobisisobtyronitrile (10 mg) in CCl4 is stirred and refluxed for 1 hour. The reaction mixture is purified by silica gel column chromatography to give N-[3-(bromomethyl)quinoxalin-2-yl]-N-(cyclopentylmethyl)ethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1Cl)([O-:3])=[O:2].[CH3:18][NH2:19].C(O)C>O>[CH3:18][NH:19][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Two and six-tenths grams (.01 mole) of 2,6-dinitro-4-t-butylchlorobenzene was reacted with 3.1 grams of 40% aqueous solution of methylamine in 50 ml. ethanol. The temperature was slowly increased as follows: 30° C for 1 hour; 40° C for 1 hour; 50° C for 1 hour, then 80° C for 5 hours. When the reaction was complete about 100 ml. H2O was added, precipitating the product. This was filtered, washed with portions of H2O and upon recrystallization from ethanol yielded 2.5 grams of N-methyl-2,6-dinitro-4-t-butylaniline as orange needles melting at 129°-130° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:15]2[S:19][C:18]([C@@:20]3([OH:32])[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([CH3:31])([CH3:30])[CH2:21]3)=[N:17][CH:16]=2)[CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].O.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C.[Fe]>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:15]2[S:19][C:18]([C@@:20]3([OH:32])[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH3:29])=[O:27])[C:22]([CH3:31])([CH3:30])[CH2:21]3)=[N:17][CH:16]=2)[CH:9]=[C:10]([NH2:12])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COC(C)=O)cc([N+](=O)[O-])c3)s2)CC1(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(N)cc(COC(C)=O)c3)s2)CC1(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the product of Step 5 (200 mg, 0.43 mmol) dissolved in ethanol (3.7 mL) and water (0.57 mL) was added iron (72.4 mg, 1.29 mmol). Saturated aqueous ammonium chloride (0.57 mL) was added and heated the mixture to 70° C. The reaction was stirred for 8 h at 70° C., then cooled to room temperature, diluted with ethyl acetate, and filtered. The filter cake was washed with 1:1 ethanol:ethyl acetate, and then the filtrate was washed with 1:1 water:saturated aqueous sodium bicarbonate. The filtrate was extracted with ethyl acetate (3×) and the combined organic layers were washed with brine, and then dried over sodium sulfate, filtered, and concentrated to give methyl (1S,4R)-4-(5-{3-[(acetyloxy)methyl]-5-aminophenyl}-1,3-thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (186.5 mg, 0.43 mmol, 100% yield) as a yellow foam. MS ESI: [M+H]+ m/z 433.2.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].C(O)C[OH:14]>C1(C)C=CC=CC=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>[O:3]1[CH2:1][CH2:2][O:14][CH:4]1[CH2:5][C:6](=[O:11])[C:7]([F:9])([F:10])[F:8]
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CC1OCCO1)C(F)(F)F
Yield: 67.3 %

Procedure:
4-Methylbenzenesulfonic acid monohydrate (500.1 mg, 467.4 μL, 2.629 mmol) was added to a solution of 4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (200.97 g, 1.195 mol) and ethylene glycol (77.27 g, 69.42 mL, 1.245 mol) in toluene (502.5 mL). The reaction mixture was heated to reflux for 90 min (oil bath). Then, the reflux was continued with simultaneous distillation of ethanol/toluene. The Dean-Stark was removed and the flask was connected to a distillation apparatus. 3-(1,3-Dioxolan-2-yl)-1,1,1-trifluoro-propan-2-one was distilled using a KNF pump (Bp 81° C.) as a light yellow oil (148 g, 67% yield). 1H NMR (500 MHz, CDCl3) δ 5.38-5.40 (t, 1H), 4.02-4.05 (m, 2H), 3.93-3.95 (m, 2H), 3.10 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:56])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:22][CH:21]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:15]3)[CH:8]=[CH:9][CH:10]=2)[N:5](COCC[Si](C)(C)C)[C:4](=[O:55])[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][C:2]1([CH3:56])[C:11]2[C:6](=[C:7]([CH2:12][O:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[O:38][CH3:39])=[CH:22][CH:21]=4)[CH2:18][CH2:17][N:16]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:15]3)[CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:55])[CH2:3]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)CC3(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2NC(=O)CC3(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 0.225 g of tert-butyl 3-[4,4-dimethyl-2-oxo-1-(2-trimethylsilanylethoxymethyl)-1,2,3,4-tetrahydroquinolin-8-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 2.5 ml of tetrahydrofuran is admixed with 2.5 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at reflux over 6.5 hours. The reaction mixture is cooled to room temperature, poured onto water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.40 (1:1 EtOAc-heptane); Rt=5.97.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([CH:20]=[CH2:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:27]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([CH:20]=[CH2:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Reactant: C=O
Solvent: O=CO
Product: C=CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1C

Procedure:
A mixture of 200 mg of 1-cyclopropyl-7-(3-ethenyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin is heated for 2 hours, then evaporated. The residue is diluted with water, neutralized to pH 7 with 1N sodium hydroxide, the solid collected, and washed with water, ether and dried in vacuo, giving 150 mg of the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:18][C:19]1([F:65])[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[CH:33]([O:35]CC4C=CC(OC)=CC=4)[CH2:32][C:31]([CH3:46])([CH3:45])[CH2:30][C:29]=3[N:28]=[C:27]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:26]=2[CH:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:21][CH2:20]1>>[F:65][C:19]1([F:18])[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[CH:33]([OH:35])[CH2:32][C:31]([CH3:45])([CH3:46])[CH2:30][C:29]=3[N:28]=[C:27]([CH:47]3[CH2:52][CH2:51][N:50]([C:2]4[N:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][N:3]=4)[CH2:49][CH2:48]3)[C:26]=2[CH:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:56][CH:55]=2)[CH2:21][CH2:20]1
Reactant: CSc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Clc1ncc(Br)cn1
Product: CSc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloro-5-methylthiopyrimidine, which was prepared by a method similar to that of Reference Example 36, instead of 5-bromo-2-chloropyrimidine, and from 60 mg (89 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 50 mg of the title compound was obtained as a white solid (yield: 84%).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[C:3]3[N:4]([CH:8]=[C:9]([CH3:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: Fc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn2cccc(OCc3ccc(F)cc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension under nitrogen of 15.0 g 8-hydroxy-2-methyl-imidazo[1,2-a]pyridine (from Step A) in 150 ml dimethylformamide maintained at 0°-5° C., was added 5.15 g 50% sodium hydride-oil dispersion in portions over 10 minutes. The mixturewas stirred in the cold 1/2 hr. and a brown solution resulted. 15.3 g 4-Fluorobenzyl chloride was added, and the solution was heated on a steam bath for 1/2 hr. The solution was poured into an ice bath and after 1/2 hour it became a brown solution. The solution was poured into 1.5 liters ice/water with vigorous stirring and the precipitate was separated by suction filtration, washed, and dried to give 8-(4-fluorobenzyloxy)-2-methylimidazo[1,2-a]pyridine (m.p. 137° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[C:11]([C:17]([O:19]CC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[NH:9][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:19]
Reactant: CCOC(=O)C(=CNc1ccc(OC)cc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2ccc(OC)cc2c1=O
Reaction time: 1.17 h
Yield: 44.7 %

Procedure:
Diethyl (4-methoxyphenylaminomethylene)malonate (5.18 g, 17.9 mmol) is added to phenyl ether (22 mL) preheated to 250° C. Heating is continued for 70 minutes. The reaction mixture is allowed to cool, diethyl ether is added, and the precipitate is collected, rinsed with diethyl ether and dried to afford 1.98 g of ethyl 6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylate.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[O:20][CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:4]=1.Cl[C:22]1[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[N:23]=1.C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[O:20][CH2:19][CH2:18][N:17]([C:22]4[N:27]([CH3:28])[C:26](=[O:29])[CH:25]=[C:24]([C:30]5[CH:35]=[CH:34][N:33]=[CH:32][N:31]=5)[N:23]=4)[CH2:16][CH2:15]3)=[CH:12][CH:13]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc(C3CCNCCO3)cc2)no1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1nc(-c2ccc(C3CCN(c4nc(-c5ccncn5)cc(=O)n4C)CCO3)cc2)no1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a slurry of optically active 7-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-[1,4]oxazepane hydrochloride (0.12 g, 0.41 mmol) and 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.09 g, 0.38 mmol) was added triethylamine (0.21 mL, 1.5 mmol) at room temperature. The mixture was stirred for 20 hours and poured into water. Extractive workup with chloroform was performed and the organic phase was dried over sodium sulfate. Concentration followed by purification of the residue by flash column chromatography on silica gel (chloroform/methanol=100/0 to 90/10 as eluants) yielded (+)-2-{7-[4-(5-methyl-[1,2,4]-oxadiazole-3-yl)phenyl]-[1,4]-oxazepane-4-yl}-3-methyl-6-pyrimidin-4-yl-3H-pyrimidin-4-one (A100) (0.09 g, 0.19 mmol, 50%) as yellowish solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1CCc2cc([N+](=O)[O-])ccc21)OCc1ccccc1
Temperature: 65 °C
Yield: 41.1 %

Procedure:
To a solution of 5-nitroindoline (1 g, 6.09 mmol) in dry DMF (20 ml), K2CO3 (1.094 g, 7.92 mmol) and benzyl 2-bromoacetate (1.242 ml, 7.92 mmol) were added, and the resulting suspension was heated at 65° C. for 2 hours. The mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was removed. The residue was purified by flash chromatography on silica gel column (DCM:petroleum ether=60:40) affording benzyl 2-(5-nitroindolin-1-yl)acetate (0.782 g, 2.504 mmol, 41% yield). MS/ESI+ 312.9 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([OH:21])=O)[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([Cl:25])=[O:21])[CH:15]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc2cc(OCc3ccccc3)ccc2c1
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2cc(OCc3ccccc3)ccc2c1

Procedure:
Heated for refluxing were 2-benzyloxy-6-naphthoic acid of 27.8 g and oxalyl chloride of 15.2 g in toluene of 200 g for 3 hours, and then excess oxalyl chloride and toluene were distilled off under reduced pressure to obtain 2-benzyloxy-6-naphthoyl chloride. This acid chloride was dissolved in toluene of 120 g, and pyridine of 9.5 g and 2-propanol of 6.6 g were added thereto, followed by stirring the solution at 80° C. for 3 hours. Then, after filtering off deposited pyridine hydrochloride, an organic layer was washed with 1N-hydrochloric acid and further washed with water to neutral. The organic layer was separated, and toluene was distilled off under reduced pressure to obtain a crude product. The product was recrystallized from ethanol, whereby 1'-methylethyl 2-benzyloxy-6-naphthoate of 27.2 g was obtained in the form of colorless crystal.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)[CH:13]([CH3:15])[CH3:14].C(OCC)C>C(O)C>[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:13]([CH3:15])[CH3:14]
Reactant: Sc1nc2ncccc2[nH]1
Reactant: CC(C)CNc1ccccc1CCl
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Yield: 49.7 %

Procedure:
To a dispersion of 0.96 g of 2-mercaptoimidazo[4,5-b]pyridine in 30 ml of ethanol was added at once 1.5 g of 2-(isobutylamino)benzyl chloride hydrochloride at room temperature under stirring. The resulting mixture was further stirred for one hour. To the mixture was added 30 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with a mixture of ethanol and diethyl ether (1/1 in volume). The obtained powdery product was added portionwise to a mixture of 30 ml of chloroform and 30 ml of a saturated NaHCO3 solution for neutralization. The organic phase was separated, washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was crystallized by addition of diethyl ether and hexane. The crystalline product was collected by filtration, washed with a mixture of diethyl ether and hexane (1/1 in volume) and dried to give 985 mg (yield: 49.3%) of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine as a white crystalline powder.
Reaction SMILES: [Mg].[CH3:2][Si:3]([CH3:6])(Cl)[Cl:4].[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1>C(OCC)C>[Cl:4][Si:3]([CH3:6])([CH3:2])[CH2:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1
Reactant: COc1ccc(CCl)cc1
Reactant: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C[Si](C)(C)Cl)cc1
Reaction time: 1 h
Yield: 64 %

Procedure:
In a 2-liter three-neck flask equipped with a stirrer, reflux condenser, dropping funnel, and thermometer were placed 31.0 g (1.28 mol) of magnesium powder, 129 g (1 mol) of dimethyldichlorosilane, and 500 ml of diethyl ether. With the flask cooled below 10° C., a mixture of 100 g (0.639 mol) of p-methoxybenzyl chloride and 250 ml of diethyl ether was added dropwise from the dropping funnel over 4 hours. After aging at room temperature for 1 hour, excess magnesium and magnesium chloride were removed by suction filtration. The filtrate was distilled to give 87.8 g (0.409 mol) of the desired product in a 64.0% yield.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][O:5][CH2:6][CH2:7]OCCO.[H-].[Na+].[F:18][C:19]([F:24])([F:23])CCO.BrC1C=CC=CC=1CBr>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:18][C:19]([F:24])([F:23])[CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[Br:1]
Reactant: OCCC(F)(F)F
Reactant: OCCOCCOCc1ccccc1Br
Agent: BrCc1ccccc1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Solvent: C1CCOC1
Product: FC(F)(F)CCOCc1ccccc1Br

Procedure:
The reaction and work up was conducted as described in the preparation of compound 415. Starting materials were NaH (60% in oil, 0.08 g, 2 mmol) in dry THF (10 mL), 3,3,3-trifluoropropan-1-ol (0.23 g, 2 mmol), 2-bromo-benzylbromide (0.50 g, 2 mmol) and tetrabutylammonium iodide (0.74 g, 0.2 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether 1 : 35 as the eluent to afford the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1[CH2:2][O:3][C:4](=[O:11])[C:5]2[C:6]=1[S:7][C:8](=O)[CH:9]=2.[CH2:12]1[C@@H:15](C(O)=O)[NH:14][CH2:13]1>CN(C)C=O.C(O)(=O)C>[S:7]1[C:6]2[NH:1][C:2](=[O:3])[C@@H:13]3[CH2:12][CH2:15][N:14]3[C:4](=[O:11])[C:5]=2[CH:9]=[CH:8]1
Reactant: O=C1C=C2C(=O)OCN=C2S1
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1Nc2sccc2C(=O)N2CC[C@@H]12
Yield: 72.6 %

Procedure:
A solution of 7.23 g (42.75 mmol) of 6H-thieno[2,3-d]-[1,3]oxazine-4,6(7H)-dione (J. chem. Res. (M), 1986, 1459) and 1.99 g (24.75 mmol) of L-azetidine-2-carboxylic acid in 30 ml of dimethylformamide and 6 ml of acetic acid was stirred at 120° for 16 hours. The brown solution was evaporated and the brown residue obtained was crystallized from ethanol. There were obtained 3.74 g (42%) of (S)-7,7a-dihydroazeto[1,2-a]thieno[2,3-e][1,4]diazepine-4,8(6H,9H)-dione as colourless needles of m.p. 272°-274°.