Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(C)=CC=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][C:26]3[CH:33]=[CH:32][C:29]([CH3:30])=[CH:28][CH:27]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: Cc1ccc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Product: Cc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc1
Yield: 1.7 %

Procedure:
The title compound (0.013 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C, 0.74 g) using 4-methylbenzyl chloride (0.45 g) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(4-methyl-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H22ClN3, 351.15. found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.36 (m, 2H), 7.34-7.31 (m, 2H), 7.03 (d, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 2H), 5.21 (s, 2H), 2.83-2.67 (m, 4H), 2.75-2.72 (m, 2H), 2.69-2.67 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[CH:15][C:14]([CH:17](O)[CH2:18][CH2:19][CH3:20])=[C:13]([O:22][CH2:23][CH3:24])[CH:12]=1)[CH3:2].O=S(Cl)[Cl:27]>C(Cl)Cl>[Cl:27][CH:17]([C:14]1[C:13]([O:22][CH2:23][CH3:24])=[CH:12][C:11]([C:4]2[C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:9][CH3:10])=[N:16][CH:15]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(O)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCC(Cl)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 1 h

Procedure:
A mixture of 1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butan-1-ol (29 mg) and SOCl2 (0.2 mL) in CH2Cl2 (1 ml) is stirred at room-temperature for one hour. The volatile materials are removed in vacuo to give 5-(1-chlorobutyl)-2-(2,6-diethyl-phenyl)-4-ethoxy-pyridine.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Br[C:11](=[CH2:19])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13].C([O-])(=O)C=C.Cl[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>C(O)CCC>[F:33][C:32]([F:35])([F:34])[C:29]1[CH:30]=[CH:31][C:26]([O:3][C:2]2[CH:9]=[CH:8][C:6]([O:7][CH:11]([CH3:19])[C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])=[CH:5][CH:4]=2)=[N:27][CH:28]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Oc1ccc(O)cc1
Reactant: C=C(Br)C(=O)OCCCC
Agent: C=CC(=O)[O-]
Agent: [Na]
Solvent: CCCCO
Product: CCCCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium (6.9 g, 0.3 mol) was added to n-butanol (200 ml) under nitrogen. When the sodium had reacted, the solution was cooled to room temperature and hydroquinone (16.5 g, 0.15 mol) was added. The temperature was raised to 45° and n-butyl 2-bromoacrylate (26 g, 0.125 mol) was added dropwise. When the acrylate had all been added, the mixture was stirred for 20 hours and then 2-chloro-5-trifluoromethylpyridine (27.2 g, 0.15 mol) was added. The resulting mixture was heated for 30 hours at 65°, allowed to cool, treated with carbon and filtered through Celite. The resulting solution was made up to 500 ml with n-butanol and a hydrogenation catalyst (10% palladium on carbon; 0.5 g) was added. The crude product was hydrogenated at ambient temperature and pressure until hydrogen uptake ceased to give n-butyl 2-[4-(5-trifluoromethylpyridin-2-yloxy)phenoxy]propionate.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH2:18])(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([NH:36][C:37](OC2C=CC=CC=2)=[O:38])[C:23](=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:15]([NH:18][C:37]([NH:36][C:22]2[CH:21]=[C:20]([Cl:19])[CH:35]=[CH:34][C:23]=2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:38])(=[O:16])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)ccc1O
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)ccc1O
Yield: 93.1 %

Procedure:
320 mg (1.17 mmol) of 3-t-butoxycarbonyl-4-hydroxybenzenesulfonamide and 447 mg (1.17 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 611 mg (yield 93%) of benzyl 2-{[(3-t-butoxycarbonyl-4-hydroxybenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.62 (9H, s), 5.35 (2H, s), 7.01-7.05 (2H, m), 7.37-7.41 (5H, m), 7.96 (1H, d), 8.10 (1H, dd), 8.46-8.48 (2H, m), 10.99 (1H, s), 11.66 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([OH:20])[C:3]=1/[C:4](=[N:12]\[OH:13])/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:13]/[N:12]=[C:4](\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])/[C:3]1[C:14]([OH:20])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:2]=1[Cl:1])(=[O:23])[CH3:22]
Reactant: COc1cc(O)c(/C(=N\O)c2ccccc2F)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: COc1cc(O)c(/C(=N/OC(C)=O)c2ccccc2F)c(Cl)c1

Procedure:
The Z-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone oxime may be reacted with acetic anhydride as described in Example 30c to form E-2-chloro-2'-fluoro-6-hydroxy-4-methoxybenzophenone O-acetyl oxime.
Reaction SMILES: N1CC[CH2:4][CH2:3][CH2:2]1.[C:7]([NH:24][CH2:25][C:26]([OH:28])=[O:27])([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56](C)[CH:55]=1>CN(C=O)C>[NH:24]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:25][C:26]([OH:28])=[O:27].[CH2:56]1[C:55]2[C:54](=[CH:53][CH:2]=[CH:3][CH:4]=2)[CH2:59][CH:58]([CH2:60][C:7]([OH:9])=[O:8])[NH:57]1
Reactant: C1CCNCC1
Reactant: Cc1cc(C)nc(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: O=C(O)CC1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
0.072 mmol of A is washed with DMF (1×2 ml). The compound is subsequently deprotected twice using 20% of piperidine in DMF (2×2 ml), firstly for 5 minutes and then for 15 minutes, and washed with DMF (6×2 ml). An approximately 0.1M solution of 2.5 equivalents (based on the resin loading, 0.18 mmol) of Fmoc-glycine, 2.4 equivalents (0.17 mmol) of HATU and 30 equivalents (2.16 mmol) of sym-collidine in dry DMF is added to the resin-bound free amine, and the mixture is shaken at room temperature for 90 minutes. The reaction is terminated by washing in DMF (6×2 ml).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[C:9]1(=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[O:10]1>CCO>[OH:8][CH:5]1[CH2:6][CH2:7][CH:2]([N:1]2[C:9](=[O:10])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:18])[CH2:3][CH2:4]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1CCC(O)CC1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Yield: 60 %

Procedure:
A mixture of 4-aminocyclohexanol (3.9 g, 34 mmol) and isobenzofuran-1,3-dione (4.9 g, 34 mmol, 1.0 eq) in 100 mL of EtOH was heated at reflux for 2 days. EtOH was removed and the residue was purified by column chromatography on silica gel (eluent with DCM) to give 2-(4-hydroxycyclohexyl)isoindoline-1,3-dione as white solid (5.0 g, 59%). MS: m/z 246.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[S:5][C:4](=[O:16])[CH:3]=1.Cl[C:18]([O:20][CH3:21])=[O:19].CN(C1C=CC=CN=1)C.CCN(CC)CC>CCOC(C)=O>[CH3:21][O:20][C:18]([C:3]1[C:4](=[O:16])[S:5][C:6]([CH3:15])([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]=1[OH:1])=[O:19]
Reactant: COC(=O)Cl
Reactant: CCCCCCCCC1(C)SC(=O)C=C1O
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCC1(C)SC(=O)C(C(=O)OC)=C1O
Yield: 59.4 %

Procedure:
To 32 (91 mg, 0.37 mmol), methyl chloroformate (63 μL, 0.81 mmol), dimethylaminopyridine (DMAP) (23 mg, 0.18 mmol) and NEt3 (108 μL, 0.77 mmol) following General Procedure L was obtained 70 (66 mg, 59%, 79% based on recovered starting material) after flash chromatography (30% EtOAc/2% AcOH/Hexanes-10% THF/2% AcOH/EtOAc). 1H NMR (300 MHz, MeOD) δ 0.86 (t, J=6.9 Hz, 3H), 1.20 (bs, 12H), 1.35 (s, 3H), 1.55 (m, 1H), 1.71-1.75 (m, 1H), 3.59 (s, 3H); 13C NMR (75 MHz, MeOD) δ 13.3, 21.8, 24.4, 27.0, 28.5, 28.6, 29.0, 30.2, 31.0, 50.4, 58.3, 124.6, 168.1, 187.7, 196.7. HRMS (EI) m/z calculated for C15H24O4S+) 300.1389 obsd. 300.1375.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([NH2:23])=[O:22].[Cl:24][C:25]1[CH:26]=[C:27]([CH2:32]C(Cl)=O)[CH:28]=[CH:29][C:30]=1[Cl:31].[CH2:36]1CCCCC1.C(OCC)(=O)C>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:32][N:23]1[C:21](=[O:22])[C:3]2[C:4]([CH3:20])=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=[CH:36]1
Reactant: Cc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C(N)=O
Reactant: C1CCCCC1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Solvent: CCOC(C)=O
Product: Cc1nn(C(CCCc2ccccc2)C(C)O)c2ncn(Cc3ccc(Cl)c(Cl)c3)c(=O)c12

Procedure:
Starting from 805 mg (2.55 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-3-methyl-1H-pyrazole-4-carboxamide and 1.41 g (6.59 mmol) of 3,4-dichlorophenylacetyl chloride, are employed analogously to the protocol of Example 32 and 33. This gives 217 mg (18%) of the diastereomer which elutes more rapidly, Rf=0.2 (cyclohexane/ethyl acetate=2:1) and 186 mg (15%) of the diastereomer which elutes more slowly, M.p.: 160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.O>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNCC4)c(F)cc3cc2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A suspension of 2 g of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 30 cm3 of dimethyl sulphoxide and 5 g of piperazine is heated at a temperature close to 100° C., with stirring, for 2 hours. The solution obtained at about 100° C. is poured, with stirring, into a mixture of 150 cm3 of water and 50 g of ice. The solution is extracted with 3 times 40 cm3 of trichloromethane. The combined organic phases are extracted with twice 50 cm3 of 0.1 N methanesulphonic acid. 10 g of potassium carbonate are added to the combined aqueous phases. The mixture is extracted with 3 times 40 cm3 of trichloromethane. The combined organic extracts are washed with twice 50 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue obtained is recrystallized from 25 cm3 of ethanol. 0.8 g of 3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo-8-(1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid melting at 221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=O)NC2=[N:6][CH:7]=1.[H-].[Na+].I[CH3:15].[CH3:16][N:17]([CH:19]=[O:20])[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:9])([CH3:15])[C:19](=[O:20])[N:17]([CH3:18])[C:16]2=[N:6][CH:7]=1
Reactant: O=C1Cc2cc(Br)cnc2N1
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CN1C(=O)C(C)(C)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Aldrich, Buchs, Switzerland, 1.394 min) in DMF (7 ml) cooled with an ice-bath was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 30 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 30 min at rt. The RM was cooled with an ice-bath and was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 15 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 30 min at rt. The RM was cooled with an ice-bath and was added 55% NaH in oil (1.6 mmol) and the RM was stirred for 15 min at rt, then was added iodomethane (0.1 ml) and the RM was stirred for 1.5 h at rt. The RM was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine (3×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as an off-white solid. (HPLC: tR 2.99 min (Method A); M+H=255, 257 MS-ES)
Reaction SMILES: C1(O)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[S:16][CH:17]1[CH2:22][CH2:21][N:20](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:19][CH2:18]1.[OH-].[Na+]>Br>[ClH:8].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[S:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Sc3cc(Cl)ccc3Cl)CC2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: Cl
Product: Clc1ccc(Cl)c(SC2CCNCC2)c1
Temperature: 0 °C

Procedure:
A mixture of 200 g (2.13 mole) of phenol, 200 ml of 48% hydrobromic acid and 21.86 g (0.053 mole) of 4-[(2,5-dichlorophenyl)thio]-1-[(4-methylphenyl)sulfonyl]piperidine were heated at reflux for 1.5 hr. The reaction mixture was diluted to 2 liters volume with ice water and made alkaline with 50% sodium hydroxide. The aqueous layer was extracted with diethyl ether. The ether phase was extracted with 1N sulfuric acid. The resulting aqueous acidic phase was extracted with methylene chloride. The methylene chloride phase was dried, filtered and evaporated to remove solvent to give a brown oil, the free base of the title compound. The free base was converted to 9.36 g (59.1%) of a white crystalline hydrochlorid esalt as in Intermediate 33, m.p. 198°-200° C.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[OH-].[NH4+:35]>O1CCOCC1>[NH2:35][CH2:19][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:7]3[O:6][C:5]([CH3:26])([CH3:25])[N:4]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:3]3[CH2:2][F:1])=[CH:13][CH:12]=2)[O:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Temperature: 35 °C
Reaction time: 12 h

Procedure:
To a dioxane (10 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl) -2,2-dimethyl-5-(4-(3-((methylsulfonyloxy)methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (1.0 g, 2.1 mmol) is added 30% aqueous ammonium hydroxide solution (5 ml). The mixture is stirred at 35° C. for 12 hours. The product is partitioned between water (50 ml) and methylene chloride (25 ml). The organic phase is dried (sodium sulfate) and concentrated to give the title compound (685 mg): m/z (Cl) 406 ([M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6](=[O:14])[NH:5][C:4]=2[O:3][CH:2]=1.[Cl-:15].[CH3:16][N+:17](=[CH2:19])[CH3:18]>CN(C)C=O.C(#N)C>[ClH:15].[CH3:16][N:17]([CH2:19][C:2]1[O:3][C:4]2[NH:5][C:6](=[O:14])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[CH:1]=1)[CH3:18]
Reactant: C=[N+](C)C
Reactant: [Cl-]
Reactant: O=c1[nH]c2occc2c2ccccc12
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)Cc1cc2c([nH]c(=O)c3ccccc32)o1
Product: Cl
Yield: 65 %

Procedure:
Furo[2,3-c]isoquinolin-5(4H)-one (55 mg, 0.27 mmol) was dissolved in a mixture of dry dimethylformamide (1 ml) and dry acetonitrile (2 ml) and treated with N,N-dimethyl(methylene)ammonium chloride (1 mmol) prepared according to known procedure (Kinast G. et al. Angew. Chem. Int. Ed. Engl. 1976, 15(4), 239-240; Bohme H. et al. Chem. Ber. 1960, 93, 1305). The reaction mixture was refluxed overnight, and the resulting precipitate was filtered and washed with dry diethyl ether to give the title compound. Yield: 65%.
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:15][NH:16][C:17]1[CH:18]=[C:19]([CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=1)[CH:20](O)CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([CH2:20][C:19]1[CH:27]=[C:28]([NH:30][CH3:31])[CH:29]=[C:17]([NH:16][CH3:15])[CH:18]=1)[C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CCCNc1ccccc1
Reactant: CNc1cc(NC)cc(C(O)CS(C)(=O)=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(NC)c1

Procedure:
A mixture of 8.6 g. of sodium methylate, 12.4 g. of β-anilinopropionitrile and 20.4 g. of 3,5-bis(methylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol in 100 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50° C. and then treated with 1 liter of water. The precipitated product was extracted with 3 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 1 kg. of silica gel with methylene chloride/ethyl acetate (3:1), there being obtained α-(anilinomethylene)-3,5-bis(methylamino)hydrocinnamonitrile as a brownish-colored oil.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.[CH2:8]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1)[CH2:9][CH2:10][CH3:11].[OH-].[Na+]>C(Cl)Cl>[CH3:11][CH2:10][CH2:9][CH2:8][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([C:8]2[C:7]3[CH2:16][C:15]4[CH:14]=[CH:13][CH:21]=[CH:20][C:5]=4[CH2:4][NH:3][C:6]=3[CH:11]=[CH:10][CH:9]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)c2cccc3c2Cc2ccccc2CN3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6,11-dihydro-5H-dihydro-5H-dibenz[b,e]azepine (0.12 g, 0.6 mmol) in methylene chloride (2 ml) is added triethylamine (0.12 g, 1.2 mmol), followed by 4-butoxybenzoyl chloride ((0.15 g, 0.72 mmol). The resulting mixture is stirred at room temperature for 2 hours, and then treated with 4 ml of 1N NaOH. The mixture is extracted with ethyl acetate (10 ml), and the extract is washed with 1N sodium hydroxide and brine (5 ml), dried over anhydrous sodium sulfate, and filtered through hydrous magnesium silicate. The filtrate is evaporated, and the crude material is triturated with isoctane to give 0.24 g of white solid; Mass spectrum (CI), 372(MH+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N+:9]([O-])=O)[C:5]([Cl:12])=[C:4]([Cl:13])[N:3]=1.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C@H:27]([CH2:30]N)[C@H:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN1CCOCC1>C1COCC1>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH:9][C:6]2[C:7]([Cl:8])=[C:2]([Cl:1])[N:3]=[C:4]([Cl:13])[C:5]=2[Cl:12])[CH:26]([OH:32])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)nc(Cl)c1Cl
Reactant: NC[C@H]1CCN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CNc2c(Cl)c(Cl)nc(Cl)c2Cl)C(O)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,3,5,6-tetrachloro-4-nitropyridine (S. M. Roberts et al., J. Chem. Soc. C, 2844–2848(1968)) (1.7 g, 6.5 mmol) was added to a solution of (cis)-4-aminomethyl-3-hydroxy-piperidine-1-carboxylic acid benzyl ester (1.71 g, 6.49 mmol) and N-methylmorpholine (0.785 mL, 7.15 mmol) in THF (50 mL) at room temperature. The resulting reaction mixture was stirred for 18 h at room temperature then partitioned between EtOAc and water. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and the solvent evaporated to give crude product purified by flash column chromatography (20–80% EtOAc hexane) to give 3-hydroxy-4-[(2,3,5,6-tetrachloro-pyridin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester compound. M.S (M+1): 478.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]=[O:20])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][O:24][CH2:25][Mg]Cl.[Cl-].[NH4+].Cl.C(OC(C)C)(C)C>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]([OH:20])[CH2:25][O:24][CH2:23][CH2:22][Cl:21])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCOC[Mg]Cl
Reactant: O=Cc1ccc2cc(OCc3ccccc3)ccc2c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: OC(COCCCl)c1ccc2cc(OCc3ccccc3)ccc2c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
6.0 g of 6-benzyloxy-2-naphthaldehyde was dissolved in 60 ml of tetrahydrofuran. The solution was cooled to -30° C. Thereto was dropwise added, in 10 minutes, 30 ml of a tetrahydrofuran solution containing 1.6M of 2-chloroethoxymethylmagnesium chloride. The resulting mixture was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 100 ml of ice water, 100 ml of ethyl acetate and 3.6 g of ammonium chloride. The mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium chloride. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=20/1) to obtain a solid. To the solid was added 10 ml of diisopropyl ether. The resulting mixture was stirred at room temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 4.7 g of 1-(6-benzyloxy-2-naphthyl)-2-(2-chloroethoxy)ethanol.
Reaction SMILES: B(Cl)(Cl)Cl.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CO.ClC(Cl)(Cl)[C:22]#[N:23]>C(Cl)Cl>[C:22](#[N:23])[C:7]1[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Nc1ccccc1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccccc1N
Yield: 46 %

Procedure:
To 2 ml of a solution of 2M of boron trichloride in methylene chloride were added a solution of 0.93 g of aniline in 10 ml of methylene chloride, 1.2 ml of trichloroacetonitrile and 1.2 ml of stannic chloride under ice-cooling. The mixture was refluxed on an oil bath for 24 hr. and poured into a mixture of 16 g of potassium carbonate and 32 ml of methanol under ice-cooling. The mixture was refluxed on an oil bath for 1 hr., filtered to remove the insoluble material and evaporated under reduced pressure. The residue was mixed with water and extracted with ether. The ether layer was washed with dilute HCl, dried over anhydrous magnesium sulfate and evaporated. The residue was purified on a Lobar column. The eluate with 5% ethyl acetate-methylene chloride was evaporated and the residue was recrystallized from ether-petroleum ether to give 0.538 g of anthranilonitrile as crystals melting at 48°-50° C.