Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1.O>CN(C)C=O>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[NH:7][C:8]1[C:17]2[O:16][C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:14]([CH3:24])[C:13](=[O:25])[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C=NCCCl
Reactant: Cc1c(-c2ccccc2)oc2c(N)cccc2c1=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)oc2c(NC(=O)NCCCl)cccc2c1=O
Reaction time: 5 h

Procedure:
4 ml of 2-chloroethylisocyanate were added, under stirring at ambient temperature, to a solution of 3.9 g of 8-amino-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran in 52 ml of anhydrous dimethylformamide. Stirring was continued at 70° C. for 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic phase was evaporated to dryness in vacuo. The residue was suspended in diethyl ether under stirring. The title product was then filtered off and recrystallized from methanol. Yield 3.74 g, m.p. 213°-214° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]([F:36])([F:35])[C:12]1[CH:34]=[CH:33][CH:32]=[CH:31][C:13]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[N:26][C:25]([C:28](O)=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:28]([C:25]3[N:26]=[N:27][C:22]([N:19]4[CH2:18][CH2:17][N:16]([C:14]([C:13]5[CH:31]=[CH:32][CH:33]=[CH:34][C:12]=5[C:11]([F:36])([F:10])[F:35])=[O:15])[CH2:21][CH2:20]4)=[CH:23][CH:24]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: Nc1cc(Br)cnc1N
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4cc(Br)cnc4[nH]3)nn2)CC1
Temperature: 12.5 °C
Yield: 74 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (0.188 g, 1.000 mmol) and 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.380 g, 1.000 mmol) in POCl3 (7 mL) was heated to reflux for 24 hours. The solvent was evaporated in vacuo, and the dark residue was neutralized with ice-cold NaOH solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and filtered through the short pad of silica gel. The filtrate was concentrated, ether was added. After cooling to 10-15° C. the white precipitation started to form. This was filtered off and dried in vacuo to yield {4-[6-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyridazin-3-yl]piperazin-1-yl}-(2-trifluoromethylphenyl)methanone in 74% yield (0.394 g, 0.810 mmol). 1H NMR (300 MHz, CDCl3) δ 13.64 (br., s, 1H), 8.40 (s, 1H), 8.17 (d, J=9.6 Hz, 1H), 8.03 (br, s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.4 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.43 (d, J=9.6 Hz, 1H), 3.90-3.20 (m, 8H13C NMR (75 MHz, CDCl3) δ 166.8, 159.9, 152.8, 144.9, 143.5, 135.0, 133.4, 130.1, 128.0, 127.1, 127.0, 126.9, 126.0, 125.9, 125.6, 122.4, 113.8, 46.4, 44.5, 44.3, 41.2. MS (ES+) m/z 532, 534 (M+1).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][F:11])/[CH:4]=[CH:5]/[C:6]([O:8]C)=[O:7]>Cl>[NH2:2][C@H:3]([CH2:10][F:11])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C=C/[C@H](N)CF
Agent: Cl
Product: N[C@@H](/C=C/C(=O)O)CF

Procedure:
410 mg of 26C was stirred in 25 ml of 5N hydrochloric acid for 48 hours at room temperature, then the solvent was evaporated at a temperature below 40° C. and the residue was dried over phosphorus pentoxide for 24 hours. The resulting product was recrystallized from acetic acid/ethyl acetate to give 26, as powdery white flakes, m.p.: 169°-170° C.
Reaction SMILES: [CH2:1]([C:3](=[CH:7][CH2:8][O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:11]1)[C:4]([OH:6])=[O:5])[CH3:2].[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([CH:3]([CH2:7][CH2:8][O:9][C@@H:10]1[CH2:15][CH2:14][CH2:13][C@H:12]([O:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])[CH2:11]1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CCC(=CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CCO[C@@H]1CCC[C@H](OCc2nc(-c3ccc(F)cc3)oc2C)C1)C(=O)O

Procedure:
0.3 g of the 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}but-2-enoic acid is dissolved in a solvent mixture of 2 ml of ethyl acetate and 1 ml of methanol, and 0.05 g of palladium (10% on carbon) is added. The mixture is then hydrogenated at a hydrogen pressure of 1 bar for 3 h. After removal of the palladium by filtration, the solvent mixture is removed under reduced pressure and the residue is recrystallized from acetonitrile. This gives 0.25 g of 2-ethyl-4-{(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyloxy}butanoic acid as a white solid. C23H30FNO5 (419.49), MS (ESI): 420 (M+H+)
Reaction SMILES: C(OC)(OC)OC.[CH2:8]([C@H:11]([NH2:15])[C:12]([OH:14])=[O:13])[CH2:9][NH2:10].Cl.[C:17](#N)[CH3:18]>CO>[CH3:17][C:18]1[NH:10][CH2:9][CH2:8][C@@H:11]([C:12]([OH:14])=[O:13])[N:15]=1
Reactant: NCC[C@H](N)C(=O)O
Reactant: CC#N
Agent: Cl
Solvent: CO
Solvent: COC(OC)OC
Product: CC1=N[C@H](C(=O)O)CCN1

Procedure:
60 ml of trimethyl orthoformate are dissolved in 400 ml of methanol, and reacted with 30 g of L-diaminobutyric acid×2 HCl at 55° C. with constant stirring. After a reaction time of 2 hours, the solvent is evaporated under reduced pressure, the crude product which remains is dissolved in 50 ml of demineralized water, and the solution is neutralized using NaOH. The compound is subsequently purified on an ion retardation column type BIORAD® AG11A8 (Bio-Rad Laboratories GmbH, Munich, Germany) using demineralized water as the eluent, and the product is dried and recrystallized from methanol. The compound obtained can be identified by means of high-pressure liquid chromatography (HPLC); (for example E. Merck, Darmstadt, Germany, LiChroCART® 125-NH2 5μ, eluent: 80% acetonitrile), and is characterized by the following 13C-NMR data:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@@H:25]([OH:28])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[CH2:12]([O:19][C:20]([C:22]1[C@H:23]2[CH2:31][CH:30]=[C:29]([CH3:32])[C@@H:24]2[C@H:25]([O:28][C:10](=[O:11])[NH:9][CH3:8])[O:26][CH:27]=1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN=C=O
Reactant: CC1=CC[C@@H]2C(C(=O)OCc3ccccc3)=CO[C@H](O)[C@@H]12
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2CC=C(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
9.2 ml of triethylamine and 2.4 ml of methylisocyanate were added to an acetonitrile solution containing 4.98 g of (1S,4aS,7aR)-1-hydroxy-7-methyl-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless oil from the hexane-ethyl acetate eluate in the form of (1S,4aS,7aR)-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c]-pyrane-4-carboxylic acid benzyl ester of 5.10 g (yield: 86%). The physicochemical properties of this compound are shown below.
Reaction SMILES: [CH3:1][CH2:2][C:3]12[CH2:21][C:20](O)([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([C:13]5[C:18]3=[CH:17][CH:16]=[CH:15][CH:14]=5)[CH2:11][CH2:12][N:7]([CH:8]14)[CH2:6][CH2:5][CH2:4]2>C(O)=O>[CH3:1][CH2:2][C@:3]12[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[N:19]3[C:9]4=[C:10]([CH2:11][CH2:12][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=13
Reactant: CCC12CCCN3CCc4c(n(c5ccccc45)C(O)(C(=O)OC)C1)C32
Solvent: O=CO
Product: CC[C@@]12C=C(C(=O)OC)n3c4c(c5ccccc53)CCN(CCC1)[C@H]42
Yield: 80.3 %

Procedure:
A solution of 3.54 g (0.01 mol) of 16-epivincamine in 50 ml of formic acid is heated under reflux for 10 hours, under nitrogen. The formic acid is evaporated on a water bath in vacuo, the residue is dissolved in methylene chloride, and the latter solution is washed with a saturated solution of sodium bicarbonate and with water. The solution is dried over sodium sulphate and filtered, and the methylene chloride is evaporated from the filtrate. 2.7g (yield = 80%) of apovincamine are thus collected.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[CH:5]=[CH:4][C:3]=1[CH2:18][C:19]1[C:27]2[CH:26]=[N:25][CH:24]=[N:23][C:22]=2[NH:21][CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:18][C:19]1[C:27]2[CH:26]=[N:25][CH:24]=[N:23][C:22]=2[NH:21][CH:20]=1
Reactant: COc1ccc(CNc2ccc(Cc3c[nH]c4ncncc34)c(F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Cc2c[nH]c3ncncc23)c(F)n1
Yield: 93 %

Procedure:
To [6-fluoro-5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-pyridin-2-yl]-(4-methoxy-benzyl)-amine (P-0105, 4.5 g, 12.38 mmol) in 100 mL of dichloromethane, trifluoroacetic acid (95 mL, 1.238 mol) was added. The reaction was stirred at reflux for several hours, then concentrated under vacuum. The resulting material was taken up in ethyl acetate and poured into aqueous potassium carbonate. The resulting solid was filtered, washed with water, azeotroped from toluene and triturated with dichloromethane. The solid was isolated by filtration to provide the desired compound as a white solid (68, 2.8 g, 11.51 mmol, 93% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:4][CH:3]=1.CN(C)[CH:25]=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:25]=[O:26])=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:4][CH:3]=1
Reactant: Cc1cc(C#Cc2cn(-c3ccc(F)cc3)c(C)n2)ccn1
Reactant: CN(C)C=O
Product: Cc1cc(C#Cc2nc(C)n(-c3ccc(F)cc3)c2C=O)ccn1

Procedure:
3-(4-Fluoro-phenyl)-2-methyl-5-(2-methyl-pyridin-4-ylethynyl)-3H-imidazole-4-carbaldehyde (89) [MS: m/e=320.4 (M+)] was prepared in analogy to the method as above from 4-[1-(4-Fluoro-phenyl)-2-methyl-1H-imidazol-4-ylethynyl]-2-methyl-pyridine (1) and N,N-dimethyl-formamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CN1CCCC1=O>[CH3:22][C:4]1[CH:3]=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(Cl)c2ccc(COc3ccc(C#N)cc3)cc2n1
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCN(C)CC2)c2ccc(COc3ccc(C#N)cc3)cc2n1
Yield: 67.1 %

Procedure:
A solution of 4-(4-chloro-2-methyl-quinolin-7-ylmethoxy)-benzonitrile (100 mg, 0.32 mmol) and 1-methylpiperazine (81 mg, 0.81 mmol) in 1-methylpyrrolidin-2-one (1.5 mL) was stirred at 100° C. for 24 h. After cooling the reaciton mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (80 mg, 66%). Light yellow oil, ISP-MS: m/e=373.5 ([M+H]+).
Reaction SMILES: Cl[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[OH-].[NH4+:16]>O>[NH2:16][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [NH4+]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Temperature: 120 °C
Reaction time: 7 h

Procedure:
2-Chloro-3-nitrobenzoic acid (20.6 g, 0.24 mol) was dissolved in ammonium hydroxide solution (120 mL) and the reaction mixture stirred at 120° C. in a sealed vessel for 7 hours. The reaction mixture was diluted with water (250 mL) and acidified to pH 2 with hydrochloric acid. The precipitate formed was filtered off and dried in vacuo to yield the title product, 15.0 g (80%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)(C)CO)c1OC
Temperature: 80 °C
Yield: 19.4 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (110 mg, 0.80 mmol) and 3-bromo-2,2-dimethylpropan-1-ol (133 mg, 0.80 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[Cl:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:11](=[O:10])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cnc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)c(Cl)c1
Temperature: 40 °C

Procedure:
To a solution of 5,6-dichloropyridin-3-amine (commercially available) in THF (0.2 M) stirred at 0° C. was added (BOC)2O (1.2 eq). The reaction mixture was heated at 40° C. until full conversion as monitored by TLC. The reaction mixture was then concentrated. Flash chromatography (silica gel, 20-50% EtOAc in hexanes) of the crude afforded tert-butyl 5,6-dichloropyridin-3-ylcarbamate.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:22][C@H:21]1[CH2:23][OH:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C1COCC1>O>[CH3:25][S:26]([O:24][CH2:23][C@@H:21]1[CH2:22][C@H:20]1[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:28])=[O:27]
Reactant: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CO)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1COS(C)(=O)=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
TEA (0.450 mL, 3.23 mmol) was added to a mixture of trans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (1 g, 2.94 mmol), methanesulfonyl chloride (0.250 mL, 3.23 mmol) and THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give trans-(2-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)methyl methanesulfonate (1.230 g, 2.94 mmol, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:24]I.Cl>CN(C)C=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH3:24])[C:7](=[O:12])[N:6]3[CH2:13][CH2:14][O:15][C:5]3([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2(c3ccccc3)OCCN12
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N2CCOC2(c2ccccc2)c2cc(Cl)ccc21
Yield: 76.4 %

Procedure:
To a solution of 1.5 g of 9-chloro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one in 20 ml of dimethylformamide was added 0.21 g of 62.5% sodium hydride. The resultant mixture was stirred with heating at 50° - 55°C for 1 hour, and 1.42 g of methyl iodide was added thereto at room temperature. Then, the mixture was heated at 55° - 60°C for 3 hours. After cooling, the reaction mixture was poured into 100 ml of water and acidified with hydrochloric acid. The resulting mixture was extracted with 50 ml of chloroform and the chloroform layer was washed successively with dilute hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 1.2 g of 9-chloro-2,3,6,10b-tetrahydro-6-methyl-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one, having a melting point of 124° - 125°C. Recrystallization from ethanol gave colorless prisms, having a melting point of 136° - 137°C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[N:5][N:4]1[C:26](=[O:29])[NH:27][CH3:28].O.NN>C(O)C.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][CH:3]([CH2:2][OH:1])[N:4]([C:26](=[O:29])[NH:27][CH3:28])[N:5]=2)=[CH:18][CH:19]=1
Reactant: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1CO)OCO3
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CNC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1CO)OCO3
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A suspension of 1.02 g (2.56 mmol) of 8-hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (stage C) in 40 ml of ethanol is mixed with 0.45 ml (9 mmol) of 98% hydrazine hydrate and RaNi catalyst while being stirred. After 30 minutes, the catalyst is filtered off, and the solution is concentrated by evaporation. The residue is recrystallized in ethanol, and 0.83 g (88%) of product with a melting point of 136-138° C. is obtained.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[C:17]([F:18])=[C:16](F)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1.Cl.[OH:35][NH:36][CH:37]1[CH2:40][NH:39][CH2:38]1.CN1CCCC1>C(OCC)C>[NH2:7][C:8]1[C:17]([F:18])=[C:16]([N:39]2[CH2:40][CH:37]([NH:36][OH:35])[CH2:38]2)[C:15]([Cl:20])=[C:14]2[C:9]=1[C:10](=[O:33])[C:11]([C:30]([OH:32])=[O:31])=[CH:12][N:13]2[C:21]1[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([NH2:29])[N:22]=1
Reactant: ONC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3c(N)c(F)c(N4CC(NO)C4)c(Cl)c32)c(F)cc1F
Temperature: 100 °C
Reaction time: 0.05 h
Yield: 45.6 %

Procedure:
To 300 mg of pyridine were added 120 mg of 5-amino-1- (6-amino-3, 5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-hydroxyaminoazetidine hydrochloride, and 250 mg of N-methylpyrrolidine, and the mixture was stirred at 100° C. for 3 minutes. After adding 5 ml of diethylether, the mixture was allowed to stand for 1 hour and decanted. 2 ml of ethanol was added and the mixture was stirred. The precipitate was collected by filtration and washed with ethanol and diethylether successively to obtain 64 mg of the title compound as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH2:10]SC)=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5].O>C(O)C.[Ni]>[NH2:1][C:2]1[C:9]([CH3:10])=[C:8]([F:13])[C:7]([F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CSCc1c(N)c(C#N)cc(F)c1F
Agent: [Ni]
Solvent: CCO
Solvent: O
Product: Cc1c(N)c(C#N)cc(F)c1F
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of 2-amino-4,5-difluoro-3-methylthiomethylbenzonitrile (4.0 g) in ethanol (80 ml) are added Raney nickel (40 ml) with ethanol (80 ml). The mixture is stirred at 40°-50° C. for 30 minutes, and then filterd. To the filtrate is added water, the reaction mixture is extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. The product is recrystallized from n-hexane to give 2-amino-4,5-difluoro-3-methylbenzonitrile (2.4 g), as a white crystal, m.p. 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCBr
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: CCOC(=O)CCN1CCC(c2ccc(F)cc2)CC1
Yield: 111.2 %

Procedure:
A mixture of 4-(4-fluorophenyl)-piperidine (15 g), ethyl 3-bromopropionate (20 g), and potassium carbonate (14 g) in methyl isobutyl ketone was refluxed for 16 h. Filtration and removal of solvent in vacuo gave 26 g of crude ethyl 3-(4-(4-fluorophenyl)-1-piperidyl)propionate as an oil which was used directly in the next step.
Reaction SMILES: [C:1]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:18]([SH:22])[CH2:19][CH2:20][SH:21].Cl>C(Cl)(Cl)Cl>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[S:22][CH2:18][CH2:19][CH2:20][S:21]2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: SCCCS
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2(CCC(=O)O)SCCCS2)cc1OC
Reaction time: 3 h

Procedure:
50 g of 3-veratroylpropionic acid in 400 ml of chloroform and 22.7 g of 1,3-propanedithiol are treated with hydrogen chloride up to saturation while stirring. After 3 hours at room temperature, the solution is evaporated to 50 ml and diluted with ether. The resulting solution is extracted three times with 5% sodium carbonate. The basic phases are combined and made acidic with concentrated hydrochloric acid. The precipitated product is extracted with ether/methylene chloride (1:3). The organic extracts are dried and evaporated. The residue is recrystallized from ethanol, there being obtained 2-(3,4-dimethoxyphenyl)-m-dithiane-2-propionic acid of melting point 134°-135° C.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Al](C)C.[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][CH:18]2[CH:16]1[O:17]2.[F-].[Na+]>ClCCl>[F:14][C:15]1([F:22])[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[C@@H:16]1[OH:17]
Reactant: FC1(F)CCCC2OC21
Reactant: C[C@@H](N)c1ccccc1
Agent: C[Al](C)C
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (1R)-1-phenylethanamine (72 mL, 0.57 mol) in dichloromethane (200 mL) was cooled to 0° C. and treated with trimethylaluminum (260 mL, 0.52 mol) and the resulting solution was stirred for 1 hour at 0° C. To this solution was added a solution of 2,2-difluoro-7-oxabicyclo[4.1.0]heptane (66 g, 0.49 mol) in dichloromethane (200 mL) and the resulting mixture stirred at 0° C. for 3 hours. The reaction was then warmed to ambient temperature for 16 hours. The reaction was cooled to 0° C., treated with 103 g of sodium fluoride and then quenched with water (90 mL, slow addition). The reaction was warmed to ambient temperature, the solids filtered and the solution evaporated in vacuo. Purification by flash chromatography afforded the title compound as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.32 (s, 5H); 3.90 (q, 1H); 3.39 (ddd, 1H); 2.70 (m, 1H); 2.11 (m, 1H); 1.80 (m, 1H); 1.62 (m, 2H); 1.43 (m, 1H); 1.36 (d, 3H); 0.96 (m, 1H).