Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:43]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:43][C:17]([C:19]4[S:20][C:21]([CH:24]5[CH2:28][O:27][C:26]([CH3:29])([CH3:30])[O:25]5)=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:32][CH:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: CC1(C)OCC(c2cnc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)O1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)OCC(c2cnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)s2)O1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (730 mg) in acetic acid (15 mL) was added ammonium acetate (1.60 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (470 mg, yield 67%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 543 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([NH2:23])[CH:10]=[CH:11][C:12]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:5][CH:4]=[N:3]1.Cl[C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CC(N(C)C)=O.CS(C)=O>[CH:28]([O:27][C:25](=[O:26])[NH:23][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)([CH3:30])[CH3:29]
Reactant: CC(C)OC(=O)Cl
Reactant: Cn1nccc1-c1cc(N)ccc1OCCN1CCCOCC1
Solvent: CC(=O)N(C)C
Solvent: CS(C)=O
Product: CC(C)OC(=O)Nc1ccc(OCCN2CCCOCC2)c(-c2ccnn2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of 3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenylamine (0.08 g, 0.253 mmol) in 2.0 mL of DMA was added isopropyl chloroformate (0.034 g, 0.278 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted to 5.0 mL with DMSO and was subjected to purification on RP-HPLC. The proper fractions were collected and lyophilized to afford [3-(2-methyl-2H-pyrazol-3-yl)-4-(2-[1,4]oxazepan-4-yl-ethoxy)-phenyl]-carbamic acid isopropyl ester as an off-white semisolid in 80% yield. LCMS m/z (%)=403 (M+H, 100). 1H NMR (400 MH, Acetone-d6) δ: 8.35 (bs. 1H), 7.45 (dd, J=8.4 and 2.6 Hz, 1H), 7.33 (s, 1H), 7.23 (d, J=1.8 Hz, 1H), 6.94 (d, J=8.95 Hz, 1H), 6.05 (d, J=1.82 Hz, 1H), 4.69-4.76, (m, 1H), 4.31 (t, J=4.36 Hz, 2H), 3.52 (s, 3H), 3.41 (t, J=4.93 Hz, 2H), 3.10-3.30 (m, 4H), 2.71-2.80 (m, 4H), 1.05 (d, J=6.12 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:9]([CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[N+:24]([O-])=O)[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Ni]>[NH2:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[O:16][CH:13]([CH2:14][CH3:15])[CH:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]([OH:12])=[O:11]
Reactant: CCC(Oc1ccc(F)cc1[N+](=O)[O-])C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Agent: [Ni]
Solvent: CO
Product: CCC(Oc1ccc(F)cc1N)C(C(=O)O)N(Cc1ccccc1)Cc1ccccc1

Procedure:
4.30 g (9.50 mmol) racemic (2S,3R and 2R,3S)-2-dibenzylamino-3-(4-fluoro-2-nitro-phenoxy)-pentanoic acid in 30 ml methanol were hydrogenated with 1.12 g Raney-Nickel. Filtration and removal of the solvent by distillation yielded 3.95 g (98%) (2S,3R and 2R,3S)-3-(2-amino-4-fluoro-phenoxy)-2-dibenzylamino-pentanoic acid as foam, MS m/e (%): 423.1 (M+H+, 100).
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:5]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[N:26]=[C:25]([C:33](O)=O)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[N:26]=[C:25]([C:33]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[C:6]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=4)[N:14]=3)[N:24]=2)[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(O)c1nc(-c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)n2)c1

Procedure:
The title compound was prepared from N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (0.16 g, 0.74 mmol) and 4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.6) (0.17 g, 0.50 mmol) according to the general procedure V. Obtained as a light yellow solid (0.055 g, 21%). MS (ISP) 516.1 [(M+H)+]; mp 258° C.
Reaction SMILES: C([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[O:19][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][CH:16]=2)[CH2:11][CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[K+]>CO.O>[CH2:20]([C:18]1[O:19][C:15]([CH:12]2[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]2)=[CH:16][N:17]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(c1ccccc1)N1CCC(c2cnc(Cc3ccccc3)o2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: c1ccc(Cc2ncc(C3CCNCC3)o2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To 40 mg of 1-benzoyl-4-(2-benzyloxazol-5-yl)piperidine (step F) in 4.5 mL methanol and 0.5 mL water was added 260 mg of potassium hydroxide. The reaction was stirred at 80° C. overnight, 20 mL of water was added and the mixture was extracted with 3×20 mL ethyl acetate. The combined organic layers were dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 22 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F-:11].[K+].[F-].[Cs+].C1S(=O)(=O)CCC1>>[F:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: [F-]
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccccc1F
Temperature: 110 °C
Yield: 85.5 %

Procedure:
1,300 parts of o-chloronitrobenzene, 960 parts of potassium fluoride and 25 parts of cesium fluoride are stirred in 1,300 parts of tetramethylenesulfone under nitrogen for 16 hours at 225° C. The solution is cooled to 110° C. and filtered, the solid residue is washed with 500 parts of methylene chloride and the filtrates are combined and distilled. 991 parts (85.5% of theory) of o-fluoronitrobenzene of boiling point 55° to 57° C/1.2 mm Hg are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1.[OH-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:26])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:15]=1)[CH:30]=[CH2:29]
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)cc(C)n(C)c2=O)c1
Reactant: C=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C)n(C)c(=O)c1C(=O)C=Cc1cccc(OCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.71 g of 4-hydroxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 5 ml of dimethylformamide was added 0.09 g of sodium hydroxide (60% oily), and this was stirred at room temperature for 1 hour. 0.26 ml of allyl bromide was added, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, 5 ml of tetrahydrofuran was added, insolubles were filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 4-allyloxy-3-[3-[3-(methoxycarbonylmethoxy)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (1b)] as a pale yellow crystal.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2](/[CH:27]=[CH:26]/[C:25]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C

Procedure:
A mixture of 0.194 g (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.180 mL (2.00 mmol) of methyl acrylate, 22.4 mg (0.0999 mmol) of palladium acetate, 122 mg (0.400 mmol) of tri-o-tolylphosphine and 0.278 mL, (2.00 mmol) of triethylamine in 4.0 ml of N,N-Dimethylformamide was heated at 100° C. for 6 hours. The mixture was concentrated in vacuum and partitioned between ethyl acetate and water. The organic extracts were washed with dilute aqueous HCl, water, brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified on 4 g silica column eluting with heptane-ethyl acetate gradient to give (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate. Yield 0.11 g. M/z 394.2, calc. 393.18
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH2:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24])[CH3:20]>>[CH2:19]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:3][CH:4]2[CH2:8]1)=[O:24])[CH3:20]
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: CCc1ccccc1C(=O)O
Product: CCc1ccccc1C(=O)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 2-ethylbenzoic acid. MS (ESI) mass calcd. for C23H24N4O, 372.46; m/z found, 373.2 [M+H]+.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:22][CH3:23])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.40 g (1.13 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at RT for 2 hrs. The reaction solution was evaporated in a high vacuum and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/AcOEt 7:1) and crystallization from EtOH yielded 0.25 g (66%) of (3-benzenesulphonyl-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-yl)amine as colorless crystals, m.p. >230°.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:7])[CH3:6])=[O:3].[N+:8]([O-:22])([O:10][C@@H:11]([C@H:13]([O:18][N+:19]([O-:21])=[O:20])[CH2:14][CH2:15][CH2:16][OH:17])[CH3:12])=[O:9].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][CH:5]([Cl:7])[CH3:6])[O:17][CH2:16][CH2:15][CH2:14][C@@H:13]([O:18][N+:19]([O-:21])=[O:20])[C@H:11]([O:10][N+:8]([O-:22])=[O:9])[CH3:12]
Reactant: CC(Cl)OC(=O)Cl
Reactant: C[C@@H](O[N+](=O)[O-])[C@@H](CCCO)O[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OCCC[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reaction time: 16 h

Procedure:
1-Chloroethyl chloroformate (1.55 mL, 14.2 mmol) was added dropwise to a stirred dichloromethane (50 mL) solution of (2R,3R)-6-hydroxyhexane-2,3-diyl dinitrate (intermediate 1, 2.60 g, 11.6 mmol), followed by pyridine (1.20 mL, 14.8 mmol). After 16 hours, the reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel, eluting with 5-25% ethyl acetate/hexanes to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 6.41 (q, J=5.7 Hz, 1H), 5.18-5.28 (m, 2H), 4.18-4.32 (m, 2H), 1.83 (d, J=5.7 Hz, 3H), 1.68-1.90 (m, 4H), 1.42 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:33])[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[CH2:35]([O:37][C:38](=[O:42])[C@H:39]([CH3:41])[NH2:40])[CH3:36]>>[CH2:35]([O:37][C:38](=[O:42])[C@@H:39]([NH:40][C:30]([C:27]1[CH:26]=[CH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([C@@H:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:17])[CH2:9][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[O:33])=[CH:23][CH:22]=2)=[CH:29][CH:28]=1)=[O:31])[CH3:41])[CH3:36]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccccc2C)ccn1
Agent: Cl
Product: CCOC(=O)[C@H](C)NC(=O)c1ccc(-c2ccc([C@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1

Procedure:
In analogy to example 89, step 2, from 4′-[(S)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid and L-alanine ethyl ester hydrochloride was prepared the title compound as a light yellow oil, MS (ESI+): m/z=535.3 ([M+H]+).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH2:7]1)(=O)=O.[Br:24][C:25]1[CH:39]=[CH:38][CH:37]=[CH:36][C:26]=1[CH2:27][O:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:19]1([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][N:8]3[CH2:9][CH2:10][C@@H:6]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=4[O:28][CH2:27][C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[Br:24])[CH2:7]3)=[CH:14][CH:15]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reactant: Nc1ccccc1OCc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1ccccc1COc1ccccc1N[C@@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1

Procedure:
(S)-3-Methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine (0.30 g, 0.89 mmol) was added to 2-(2-bromobenzyloxy)aniline (1.15 g, 4.13 mmol) in argon stream. The obtained mixture was dissolved in acetonitrile (50 ml). Potassium carbonate (1.62 g, 11.7 mmol) was added to the obtained solution, and they were refluxed for 85 hours. Acetonitrile (15 ml) was added to the reaction mixture, and they were refluxed for additional 48 hours. The reaction mixture was filtered through Celite to obtain the filtrate. The solvent was evaporated under reduced pressure to obtain the title compound in the form of a brown oily mixture (1.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]([CH3:10])[C:8]3=[N:11][C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:13]([CH2:14][C:15](O)=[O:16])[N:7]3[C:6]=2[CH:24]=1.[CH3:25][NH2:26].Cl>O1CCCC1>[CH3:25][NH:26][C:15](=[O:16])[CH2:14][C:13]1[N:7]2[C:8]([N:9]([CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:24][C:6]=32)=[N:11][C:12]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc2c(c1)n1c(CC(=O)O)c(-c3ccccc3)nc1n2C
Reactant: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNC(=O)Cc1c(-c2ccccc2)nc2n(C)c3ccc(C)cc3n12
Reaction time: 2 h

Procedure:
A suspension of 1.5 g (0.0047 mol) of 6,9-dimethyl-2-phenyl-9H-imidazo[1,2-a]benzimidazole-3-acetic acid is prepared in 50 ml of dry tetrahydrofuran, 1.22 g (0.0075 mol) of N,N'-carbonyldiimidazole are added thereto and the mixture is stirred for 2 h. The solution obtained is treated with an excess of dry gaseous methylamine and stirred for several hours. The solvent is evaporated under reduced pressure. The residue is taken up in water and the solid residue is isolated by filtration. After drying, the product is purified by silica gel column chromatography, eluting with a dichloromethane/methanol 95/5 mixture. The product obtained is then treated with a hydrochloric acid solution. The precipitate is collected by filtration and treated with an excess of ammonium hydroxide up to a pH of 9 to 10. A solid is isolated which is washed with water and dried. 0.79 g of product is obtained. Melting point: 251°-253° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:20]([CH2:22][C:23](O)=[O:24])#[N:21].CCN=C=NCCCN(C)C.Cl>O.CN(C=O)C>[C:20]([CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:6][CH:7]=1)=[O:24])#[N:21]
Reactant: N#CCC(=O)O
Reactant: COC(=O)c1ccc(CCc2ccc(N)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
To a mixture of 43.9 g of methyl 4-[2-(4-aminophenyl)ethyl]benzoate, 22.3 g of cyanoacetic acid, and 150 mL of DMF was added 49.5 g of WSC.hydrochloride under ice cooling. After the reaction mixture was stirred for 24 hours at room temperature, 450 mL of water was added thereto at room temperature, followed by stirring for 30 minutes at room temperature. Thereafter, the precipitate was collected by filtration, thereby obtaining 54.2 g of methyl 4-(2-{4-[(cyanoacetyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:32])[CH2:13][C:14]1[C:15](=[O:31])[NH:16][CH2:17][CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29]C)[CH:25]=3)[C:20]=12)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH:1]([N:4]([CH:12]([CH3:32])[CH2:13][C:14]1[C:15](=[O:31])[NH:16][CH2:17][CH2:18][CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([OH:29])[CH:25]=3)[C:20]=12)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:2])[CH3:3]
Reactant: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(OC)cc3CCC2CCNC1=O
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCN(C(C)C)C(C)CC1=C2c3ccc(O)cc3CCC2CCNC1=O

Procedure:
The solution of 2.2 g of 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-methoxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2-one, RR racemate in 18 ml of methylene chloride, precooled in a dry ice-acetone bath, is added to 31.3 ml of a similarly cooled 10% solution of boron tribromide in methylene chloride. The mixture is allowed to reach room temperature and is stirred at said temperature overnight. It is cooled in an ice bath, neutralized to pH=9 with 75 ml of saturated aqueous sodium carbonate and stirred at room temperature for 3.5 hours. The methylene chloride layer is separated, washed with water, dried and evaporated. The residue is suspended in diethyl ether, the crystallized material is collected and recrystallized from ethyl acetate to give the 1-[2-(N-isopropyl-N-heptylamino)propyl]-9-hydroxy-3,4,5,5a,6,7-hexahydro-2H-naphth[1,2-d]azepin-2one, RR racemate melting at 144°-146°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=O)[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.COC1C=CC([SH:32]2(=S)PP(=S)(C3C=CC(OC)=CC=3)S2)=CC=1.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:12][C:11](=[S:32])[CH2:10][CH2:9][S:8](=[O:15])(=[O:14])[CH:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: O=C1CCS(=O)(=O)C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: COc1ccc(P2(=S)P[SH](=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: O=S1(=O)CCC(=S)Nc2ccc(Cl)cc2C1c1ccccc1F
Temperature: 25 °C

Procedure:
A solution of 13.4 g of 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-oxo-2H-5,1-benzothiazocine 5,5-dioxide in 380 ml of hexamethylphosphoric acid triamide is treated with 7.7 g of 2,4-bis-(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane-2,4-disulphide, the mixture is heated to 100° for 2 hours, again cooled to room temperature and then poured into 8.3 l of water. The mixture is extracted twice with ethyl acetate and the organic extracts are washed with water and with saturated sodium chloride solution. The ethyl acetate solutions are evaporated and the residue is chromatographed on 500 g of silica gel. By elution with chloroform which contains 0.5% ethanol and crystallization from ether there is obtained 8-chloro-6-(2-fluorophenyl)-1,3,4,6-tetrahydro-2-thiono-2H-5,1-benzothiazocine 5,5-dioxide of melting point 226°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([SH:18])[NH:10][C:11]=2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]([F:24])=[C:21]([F:23])[F:22]>>[C:1]1([C:7]2[N:8]=[C:9]([S:18][C:21]([F:23])([F:22])[CH:20]([F:24])[F:19])[NH:10][C:11]=2[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1nc(-c2ccccc2)c(-c2cccnc2)[nH]1
Reactant: FC(F)=C(F)F
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2cccnc2)[nH]1

Procedure:
4-Phenyl-5-(3-pyridyl)-1H-2-imidazolethiol (2.0 g; 7.9 mmoles) was reacted with 5.0 g (50 mmoles) of tetrafluoroethylene and the crude product purified by chromatography on Silicar CCNo. 7 with chloroform to afford 800 mg of 4-phenyl 5-(3-pyridyl)-2-(1,1,2,2-tetrafluoroethylthio)-1H-imidazole, m.p. 153°-154° (recrystallized from toluene).
Reaction SMILES: O[C:2]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][C:4](=[O:9])[CH:5]=[CH:6][O:7]C.C(O)(C(F)(F)F)=O>C1C=CC=CC=1>[C:10]([C:2]1[O:7][CH:6]=[CH:5][C:4](=[O:9])[CH:3]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: COC=CC(=O)C=C(O)C(C)(C)C
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(=O)cco1
Temperature: 25 °C
Reaction time: 14 h
Yield: 102.2 %

Procedure:
A mixture of 5-hydroxy-1-methoxy-6,6-dimethyl-hepta-1,4-dien-3-one (Step 1.7) (6.8 g, 36.9 mmol) and TFA (5.65 mL, 74 mmol, 2 eq) in benzene (250 mL) is stirred for 14 h at rt and concentrated. Purification of the residue by silica gel column chromatography (Hex/EtOAc, 1:0→75:25) provides 5.74 g of the title compound as a yellow oil: ESI-MS: 153.1 [M+H]+; tR=3.21 min (System 1); TLC: Rf=0.22 (Hex/EtOAc, 1:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([NH2:11])=[C:9]([N+:12]([O-])=O)[CH:8]=[N:7][CH:6]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[C:10]([NH2:11])=[C:9]([NH2:12])[CH:8]=[N:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cncc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cncc(N)c1N
Yield: 77.7 %

Procedure:
A mixture containing 4-amino-5-nitro-nicotinic acid ethyl ester (78; 15 g, 0.071 mol) and 10% Pd/C (500 mg) in MeOH (500 mL) was stirred under 1 atm of hydrogen at room temperature for 18 h. The reaction mixture filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to afford 4,5-diamino-nicotinic acid ethyl ester 79 (10 g, 80%).