Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2cccc(F)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 79.9 %

Procedure:
Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) (500 mg, 1.49 mmol), 3-fluorobenzyl bromide (280 mg, 2.98 mmol), and cesium carbonate (971 mg, 2.98 mmol) were placed in DMF (12 mL) and stirred at 90° C. for 4 hours. The solution was cooled to ambient temperature, diluted with H2O (200 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (10-20% ethyl acetate in hexane) to afford methyl 4-(N-(3-fluorobenzyl)-N-(4-methoxybenzyl) sulfamoyl)benzoate (528 mg, 80%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C@@H:3]([C@@H:9]([OH:12])[CH2:10][OH:11])[O:4]C(=O)C=1O.[OH:13]O>>[O:1]=[C:2]([OH:13])[C@@H:3]([C@H:9]([CH2:10][OH:11])[OH:12])[OH:4]
Reactant: OO
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H](O)[C@@H](O)CO

Procedure:
Under pH 6-10, preferably at pH 7-9, vitamin C was oxidized by oxidant, for example, by hydrogen peroxide solution to get a solution of L-threonic acid,
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]C)=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.B(Br)(Br)Br>ClC(Cl)C>[Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: COc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: Oc1cc2onc(-c3ccccc3F)c2cc1Cl

Procedure:
A solution of 5-chloro-3-(2-fluorophenyl)-6-methoxy-1,2-benzisoxazole (1 g) and boron tribromide (1.3 l ml) in dichloroethane (30 ml) is refluxed for about 24 hours. The reaction mixture is poured onto ice-water and extracted with dichloromethane to give a solid of 5-chloro-3-(2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 180°-182° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2O)[CH3:2].N.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:7]1[C:6]2[C:11](=[N:12][C:13]([CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O
Agent: N
Product: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.5 g) was added to phosphorus oxychloride (20 ml) with stirring at ambient temperature. The mixture was warmed to 40° C. and kept at this temperature for 1 hour then cooled to 10° C. The mixture was added to excess ice/water and the mixture basified with aqueous ammonia solution (specific gravity 0.88) while keeping the temperature below 5° C. The product was extracted into dichloromethane. The combined dichloromethane extracts were evaporated under reduced pressure at ambient temperature to give ethyl 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate, m.p. >250° C.
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1.Cl>O>[OH:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]([CH2:6][C:7]([OH:16])=[O:1])=[CH:4][O:8][C:9]=2[CH:10]=1
Reactant: O=c1cc(CCl)c2ccc(O)cc2o1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1coc2cc(O)ccc12
Temperature: 60 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
Sodium hydroxide (135 g) was dissolved in water (830 mL) to prepare a 14% aqueous sodium hydroxide solution. To a solution (623 mL) of 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (254 g) in water was added the above-mentioned 14% aqueous sodium hydroxide solution at 5° C., and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 4 hr. The concentrated hydrochloric acid (270 mL) was added at 35° C., a seed crystal was added, and the reaction mixture was stirred at 35° C. for 1 hr and at 5° C. for 1 hr. The precipitated crystals were collected by filtration, washed with water (123 mL), and dried at 60° C. under reduced pressure. To the crystals was added ethyl acetate (1.9 L), and the mixture was stirred at room temperature for 1 hr. After filtration, the insoluble material was washed with ethyl acetate (144 mL). To the filtrate was added activated carbon (16.5 g), and the mixture was stirred at 25° C. for 1 hr and filtered again. The filtrate was concentrated and dried under reduced pressure to give (6-hydroxy-1-benzofuran-3-yl)acetic acid (146 g). (6-Hydroxy-1-benzofuran-3-yl)acetic acid (130 g) was dissolved in methanol (270 mL), a solution of (1R)-1-phenylethylamine (82 g) in methanol (90 mL) was added at 60° C., and diisopropyl ether (3.6 L) was added at 55° C. After stirring at 25° C. for 2 hr, the precipitated solid was collected by filtration. The obtained solid was washed with a mixed solvent (445 mL) of methanol-diisopropyl ether (1:9), and dried at 50° C. under reduced pressure to give the title compound (198 g) as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:16]1([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:9]1([C:5]2[CH:4]=[C:3]([CH2:2][N:25]3[CH2:24][CH:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:27][CH2:26]3)[CH:8]=[CH:7][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: ClCc1cccc(-c2ccccc2)c1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C1=C(c2ccccc2)CCN(Cc2cccc(-c3ccccc3)c2)C1
Temperature: 25 °C

Procedure:
To a solution of 45 mg of 3-chloromethylbiphenyl in 5 mL of chloroform was added 50 mg of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 0.5 mL triethylamine. The reaction mixture was heated at reflux temperature overnight, cooled to room temperature, washed successively with 50 mL aliquots of dilute sodim hydroxide and brine. The chloroform was removed by evaporation under reduced pressure to yield 3-phenyl[(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl]benzene which was purified by chromatography on silica gel using 5% methanol in dichloromethane as eluent. Evaporation of the solvent yielded a solid which was treated with ethereal-HCl to give 15 mg of 3-[(4-1,2,3,6-tetrahydropyridin-1-yl)methyl]biphenyl hydrochloride (Compound 3), mp 236-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:17]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]([CH3:17])[S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)N(C)Cc1cncc(Br)c1
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a solution of ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11, 0.21 g, 0.752 mmol) in DMF (6 mL) cooled at 0° C. with an ice bath was added 60% NaH in mineral oil (0.039 g, 0.98 mmol) and the mixture was stirred for 15 min. Then, MeI (0.136 g, 0.96 mmol) was added and the reaction was stirred at 0° C. for another 15 min before being quenched with aq. ammonia (2 mL). The mixture was further diluted with brine and then extracted with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness to give the title compound (0.209 g, 85%) as a yellow oil which was used with no further purification. MS: 293.1 and 295.1 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12](Cl)=[O:13])=[CH:9][CH:8]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O>CC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:11][C:10]([C:12]([N:15]=[N+:16]=[N-:17])=[O:13])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(-c2ccccn2)s1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC(=O)c1ccc(-c2ccccn2)s1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 83 %

Procedure:
A solution of 5-(pyrid-2-yl)thiophene-2-carbonyl chloride (254 mg, Reference Example 43) in acetone (3 mL) was treated with a solution of sodium azide (128 mg) in a water and acetone mixture (3.5 mL, 1:6, v/v). After stirring at room temperature for a further 75 minutes the reaction mixture was treated with water (4 mL). The insoluble material was collected and washed with water to give the title compound (217 mg) as a white solid, which was used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[C:6]([C:16]2[NH:20][CH:19]=[N:18][N:17]=2)[S:5][C:4]=1[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=1)#[N:2].[Br:31]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(#N)C>>[Br:31][C:19]1[NH:20][C:16]([C:6]2[S:5][C:4]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28](=[O:30])[CH3:29])[CH:22]=3)=[C:3]([C:1]#[N:2])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[Cl:15])=[N:17][N:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1cc(-c2sc(-c3nnc[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Nc1cc(-c2sc(-c3nnc(Br)[nH]3)c(-c3ccc(Cl)cc3Cl)c2C#N)ccn1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A suspension of N-(4-(3-cyano-4-(2,4-dichlorophenyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)pyridin-2-yl)acetamide (0.0700 g, 0.154 mmol) and N-Bromosuccinimide (33.1 mg, 0.186 mmol) in Carbon tetrachloride (2.5 mL, 26 mmol) was heated to 85° C. in a capped vial for 2.5 hours. To the suspension was added dry Acetonitrile (6.0 mL, 110 mmol) and the mixture was heated at 85° C. (turned into a clear solution) for additional 2 hours. The mixture was cooled to r.t., evaporated in rotavapor. The residue was dry loaded in a silica column and eluted with MeOH/DCM (0/100 to 5/95) to give a solid product (66.0 mg, yield 80.4%). LCMS: (FA) ES+, 533, 535, 537 and ES− 531, 533, 535. 1H NMR (400 MHz, d1-chloroform) δ: 8.65 (s, 1H), 8.42 (d, J=5.02 Hz, 1H), 8.26 (s, 1H), 7.61 (d, J=2.01 Hz, 1H), 7.56 (dd, J=5.27, 1.76 Hz, 1H), 7.43-7.45 (dd, J=8.28, 2.01 Hz, 1H), 7.37-7.39 (d, J=8.28 Hz, 1H), 2.26 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=2)O1>>[F:15][C:14]([F:16])([F:17])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=3)[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)cc(-c3cccc(Br)c3)n2)cc1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Product: NS(=O)(=O)c1cccc(-c2cccc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.20) (0.223 g, 0.5 mmol) and commercially available 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzenesulfonamide [CAS-No. 486-422-08-6] (0.283 g, 1.0 mmol) according to the general procedure VI. Obtained as a light brown solid (0.125 g, 43%). MS (ISP) 523.3 [(M+H)+]; mp 176-179° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1.O>[C:16]1([S:22]([NH:1][C:2]2[S:6][C:5]3[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c(N)sc2c1CCCC2
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Yield: 41.5 %

Procedure:
Ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.113 g) was added to a solution of benzenesulphonyl chloride (0.097 g) in pyridine (5 ml) and the resultant solution was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with hydrochloric acid (1M), water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane (5%) to give ethyl 2-benzenesulphonylamino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.076 g) as a pale yellow solid.
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=O)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[CH:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cccc2c1CCc1ccccc1C2=CCCN(C)C
Temperature: 45 °C
Reaction time: 10 h

Procedure:
10 g. of Gilman alloy are covered with 30 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, 40 ml. of 1-chloro-3-dimethylaminopropane in 120 ml. of dry ether are added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is heated at 45° C. under reflux conditions for an additional 3 hours, then cooled with ice water and treated dropwise over a period of one hour with a solution of 21.8 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (J. Med. Pharm. Chem. 4, 335-49, 1961) in 400 ml. of dry ether. Subsequently, the mixture is stirred at 45° C. under reflux conditions for an additional 10 hours, then cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is removed by separation. The aqueous phase is shaken twice with 100 ml. portions of ether and the combined ether extracts are dried over sodium sulfate and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene has a melting point of 154°-155° C. after recrystallization from high-boiling petroleum ether.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:27])([CH3:26])[CH2:4][C@H:5]([NH:18]C(=O)OC(C)(C)C)[CH2:6][N:7]([CH3:17])[C:8]([O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOCC.C(O)C>[NH2:18][C@@H:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:27])[CH3:26])[CH2:6][N:7]([CH3:17])[C:8](=[O:9])[O:10][CH2:11][CH2:12][Si:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: COC(C)(C)C[C@@H](CN(C)C(=O)OCC[Si](C)(C)C)NC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CCO
Product: COC(C)(C)C[C@H](N)CN(C)C(=O)OCC[Si](C)(C)C
Temperature: 62.5 °C

Procedure:
To a solution of (S)-tert-butyl 4-methoxy-4-methyl-1-(N-methyl-N-(2-(trimethylsilyl)-ethoxycarbonyl)amino)pentan-2-ylcarbamate (0.17 g, 0.42 mmol) in ether (2.0 mL) was added a solution of p-toluenesulfonic acid (80.7 mg, 0.43 mmol) in ethanol (1.0 mL). Transfer of the p-toluenesulfonic acid was completed with the aid of additional ether (1.0 mL). The solution was placed on a rotary evaporator and the ether was removed at rt. Then, with continuing evacuation, the bath temperature was raised to 60-65° C. for 20 min, during which gas evolution was evident. After cooling down to rt, the solid residue (S)-2-(trimethylsilyl)ethyl 2-amino-4-methoxy-4-methylpentyl(methyl)-carbamate was used without further purification as a p-toluenesulfonic acid salt. MS m/z 291 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10]>>[Cl:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=Cc1ccc(Cl)s1
Reactant: O=[N+]([O-])O
Product: O=Cc1cc([N+](=O)[O-])c(Cl)s1
Temperature: -5 °C
Yield: 58 %

Procedure:
5-Chlorothiophene-2-carbaldehyde (2.0 g, 13.6 mmol) was added dropwise to a stirred fuming nitric acid (13 mL) cooled to −5° C. with an ice/methanol bath. When addition was complete the stirred reaction mixture was allowed to warm slowly to 5° C. over 1 hour, then it was poured into ice/water (200 mL). The precipitated solid was collected by filtration, dissolved in dichloromethane (100 mL), washed with water and the organic layer was separated and dried (MgSO4). After filtration the solvent was removed under reduced pressure and the residual brown solid was crystallised from hexane (insoluble brown material was removed by decantation of the supernatant solution), to afford title product as an off-white solid (1.51 g, 58%). 1H NMR (300 MHz, CDCl3) δ: 9.83 (1H, s), 8.20 (1H, s).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][C:8]1=[O:20])[CH2:4][CH2:5][CH3:6].[CH:21](OCC)=[O:22]>C(COC)OC>[CH:21]([CH:14]([CH2:13][C:10]1[CH:11]=[CH:12][N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:20])[CH:9]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:22]
Reactant: CCCCn1ccc(CCC(=O)OCC)cc1=O
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCn1ccc(CC(C=O)C(=O)OCC)cc1=O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a stirred suspension of 50% sodium hydride in oil (13.89 g) in dimethoxyethane (100 ml) at -2° C., was added dropwise over 90 minutes, a mixture of ethyl β-(N-n-butyl-2-oxo-4-pyridyl)propionate (58.19 g) and ethyl formate (25.73 g), the reaction temperature being maintained below 5° C. The reaction mixture was then allowed to warm to room temperature overnight, poured on to ice and extracted successively into petroleum ether (40°-60°) (150 ml) and diethyl ether (3×100 ml). The combined organic extracts were washed with water (40 ml); and the aqueous layer and aqueous washings were taken to pH 5 with glacial acetic acid. A brown oil came out of solution which was extracted into ethyl acetate (3×150 ml). The combined ethyl acetate extracts were washed with water (2×30 ml), dried over MgSO4 and evaporated under reduced pressure. The residue was washed with petroleum ether (40°-60°) and dried in vacuo to afford as a pale brown solid, ethyl α-formyl-β-(N-n-butyl-2-oxo-4-pyridyl)propionate (54.84 g).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: O=C(NCC1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (pyrrolidin-3-ylmethyl)-amide (example A146) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])=[O:4]
Reactant: NC1CCc2ccccc2C1=O
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC1CCc2ccccc2C1=O
Reaction time: 1 h
Yield: 39.4 %

Procedure:
Chloroacetyl chloride (14 g, 124 mmol) was added to a solution of 2-amino-3,4-dihydro-2H-naphthalen-1-one hydrochloride (16 g, 81 mmol) and triethylamine (41 g, 405 mmol) in tetrahydrofuran (600 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide (7.58 g, 31.9 mmol, 39%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]([CH3:19])=[CH2:18])[CH2:15][C:14](=[O:20])[CH2:13][CH:12]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N-:28]=[N+]=[N-].[Na+]>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@:6]3([C@@H:12]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=4)[CH2:13][C:14](=[O:20])[NH:28][CH2:15][C@H:16]3[C:17]([CH3:19])=[CH2:18])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=C(C)C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: C=C(C)[C@@H]1CNC(=O)C[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Yield: 20.8 %

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-iso-propenylspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (120 mg, 0.3 mmol) was reacted with NaN3 (39 mg, 0.6 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.3 mL) (Aldrich) in acetonitrile (10 mL) followed by chiral chromatography separation to give (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (25.9 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, Found: 415.0974; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl))-1,1′,2,2′,3,5,6,7-octahydro-3-(1-methylethenylspiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (28.8 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0975; (3S,4R,5R)-4′-chloro-3-(3-chlorophenyl))-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethenylspiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (20.7 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0974; and (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-5-(1-methylethenyl)-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (21.6 mg): HRMS (ES+) m/z Calcd for C22H20Cl2N2O2+H [(M+H)+]: 415.0975, found: 415.0974.