Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCO[CH:2]1[C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][N:7]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>C(O)C.O.Cl>[NH2:12][C:11]1[C:6]([CH:2]=[N:13][NH:14][C:15]([NH2:17])=[S:16])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNC(N)=S
Reactant: Nc1cccnc1C1OCCO1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NC(=S)NN=Cc1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(1,3-dioxolanyl)-3-aminopyridine (0.80 g, 4.8 mmol) in 10 mL of ethanol, 8 mL of water and 2 mL of concentrated hydrochloric acid was added 0.48 g (5.3 mmol) of thiosemicarbazide. The mixture was stirred at room temperature overnight and refluxed for 1 h, cooled and filtered. The crude yellow hydrochloride salt was dissolved in 50 mL of hot water and filtered. To the hot filtrate was added 10 mL of 5% sodium bicarbonate solution. The mixture was stirred at room temperature for 1 h, filtered and washed with water, followed by ethanol to yield 3-amino-2-formylpyridine thiosemicarbazone. Yield: 0.72 g (77%); mp 240°-241° C. dec; MS m/e 194 (M+); 1H NMR (90 MHz, DMSO-d6) δ 6.48 (br s, 2H, 3-NH2, D2O exchangeable), 7.12 (m, 2H, 4-H and 6-H), 7.83 (dd, 1H, 5-H), 8.10 (br s, 2H, CSNH2, D2O exchangeable), 8.10 (s, 1H, 2-CH), 10.95 (s, 1H, NNH, D2O exchangeable). Anal. (C7H9N5S) C, H, N.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:4][OH:5].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:8]([O:7][C:3](=[O:6])[CH2:4][O:5][CH2:14][CH2:13][CH2:12][CH2:11][Br:10])[CH3:9]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCCCCBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of sodium hydride in 40 mL DMF stirred at 0° C. was slowly added ethyl glycolate (5 g, 48 mmol). After 1 hour, 1,4-dibromobutane (8.6 mL, 72 mmol) was added, and the mixture was stirred for an additional 2 hours. The reaction was allowed to warm to room temperature for an additional 3 hours. A sodium bicarbonate solution was added, and the organic layer was dried over anhydrous sodium sulfate, concentrated and the residue was purified by chromatography to afford a colorless oil.
Reaction SMILES: [CH2:1]([C@H:8]([NH:26]C(=O)OC(C)(C)C)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:34]>ClCCl.O1CCOCC1>[ClH:34].[NH2:26][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([OH:25])[CH2:10][NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)[CH2:14][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)[C@H](O)CNC1(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 0.5 h

Procedure:
6.8 g of tert-butyl [(1S,2R)-1-benzyl-2-hydroxy-3-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)propyl]carbamate are then dissolved in 250 cm3 of dichloromethane at a temperature close to 20° C. 36.6 cm3 of a 4M solution of hydrochloric acid in dioxane are added. The reaction mixture is kept stirring for 1 h 30 min at a temperature close to 20° C. The reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). The beige solid obtained is triturated in diisopropyl ether then filtered. 5.4 g of (2R,3S)-3-amino-4-phenyl-1-({1-[3-(trifluoromethyl)phenyl]cyclopropyl}amino)butan-2-ol hydrochloride (2:1) are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18].[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][C:29]#[N:30])=[CH:27][C:22]=2[O:21][CH2:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][C:26](/[C:28](=[CH:13]/[C:12]3[CH:15]=[CH:16][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:10]([O:17][CH3:18])[CH:11]=3)/[C:29]#[N:30])=[CH:27][C:22]=2[O:21][CH2:20]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: COc1cc(C=O)ccc1OCCCCCCO
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCO
Yield: 85 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(6-hydroxyhexyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared from 4-[(6-hydroxyhexyl)oxy]-3-methoxybenzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 85% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1[C:14]([O:16]C)=[O:15].O.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[C:6]2[C:7]([F:13])=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=2[S:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: COC(=O)c1sc2c(OC)ccc(F)c2c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c2c(Cl)c(C(=O)O)sc12
Temperature: 40 °C
Yield: 57.4 %

Procedure:
Methyl 3-chloro-4-fluoro-7-methoxy-1-benzothiophene-2-carboxylate (2.00 g, 7.29 mmol) was suspended in THF:H2O[10:1] and lithium hydroxide (260 mg) added, the resulting suspension was heated to 40° C. for 1 h. After cooling to room temperature the mixture was extracted with diethyl ether (50 mL) and the aqueous phase acidified to pH 2 and the solid collected by filtration and vacuum dried to give a white solid (1.09 g, 58%); δH (300 M , DMSO) 7.32-7.20 (1H, m, Ar), 7.15-7.05 (1H, dd, Ar), 3.98 (3H, s, OCH3).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26](Br)[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:37][N:38](C)C=O.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH:31]([CH3:34])[CH2:32][CH3:33])=[C:26]([C:37]#[N:38])[CH:25]=3)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(Br)c3)cc2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)c3ccc(CC(C)CC)c(C#N)c3)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of this 3-bromo-4-(2'-methylbutyl)benzoic acid 4-octyloxy-4'-biphenylyl ester (5.5 g, 0.01 mol), cuprous cyanide (1.1 g, 0.06 mol) and dimethylformamide (20 ml) was heated to 145°-147° C., following by agitating it for 6 hours, adding a mixture of ferric chloride (4 g), hydrochloric acid (1 ml) and water (7 ml), keeping the mixture at 60°-70° C. for 15 minutes, feeding it into ice water, adding toluene, sufficiently agitating the mixture, transferring it into a separating funnel, several times washing the resulting organic layer with water, drying it over anhydrous MgSO4, distilling off toluene and recrystallizing the residue from ethanol (50 ml) to obtain the objective 3-cyano-4-(2'-methylbutyl)benzoic acid 4'-octyloxy-4-biphenylyl ester (1.7 g). The phase transition points of this product were as follows: ##STR46##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=[CH:11][C:12]([OH:14])=[O:13])[CH:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cc(Br)ccn1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(Br)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
4-Bromo-pyridin-2-carbaldehyde (10.0 g, 53.5 mmol), malonic acid (12.5 g, 120.5 mmol), and piperidine (4.4 mL, 44.4 mmol) were added to pyridine (32.5 mL). The reaction mixture was stirred at 100° C. for 1 hour, concentrated under reduced pressure, and then distilled water was added thereto. The mixture was filtered and then the resulting solid was dried under reduced pressure to give 6.3 g of the titled compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:19])/[CH:16]=[CH:17]/[CH3:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[CH3:21][S+](C)(C)=O.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH:16]2[CH2:18][CH:17]2[CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[S+](C)(C)=O
Reactant: C/C=C/C(=O)c1cccc(OCc2ccccc2)c1
Agent: [I-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CC1C(=O)c1cccc(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of 93.C (5.33 g, 21.1 mmol) in ACN (200 mL) were added trimethylsulfoxonium iodide (available from Aldrich) (5.58 g, 25.3 mmol) and DBU (4.11 mL, 27.5 mmol). The mixture was stirred overnight at 60° C. under N2, cooled to room temperature, and concentrated. The crude product was purified by silica gel flash chromatography (0-10% EtOAc/hexane) to afford 93.D (2.04 g, 36% yield) as a colorless oil.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]=O)=[C:29]([C:36]([F:39])([F:38])[F:37])[CH:28]=2)=[O:25])=[CH:19][CH:18]=1)(C)(C)C.C(O)(=O)C.[CH3:46][NH:47][CH3:48].C([BH3-])#N.[Na+]>C(O)C>[CH3:46][N:47]([CH3:48])[CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([N:12]3[CH:11]=[N:10][C:9]4[C:13]3=[N:14][CH:15]=[N:16][C:8]=4[NH:7][CH3:6])=[CH:22][CH:21]=2)=[O:25])=[CH:28][C:29]=1[C:36]([F:38])([F:37])[F:39]
Reactant: CNC
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CC=O)c(C(F)(F)F)c2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(CCN(C)C)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
In 1 mL of ethanol, 25 mg (0.04 mmol) of methyl-[9-(4-{3-[4-(2-oxoethyl)-3-(trifluoromethyl)phenyl]ureido}-phenyl)-9H-purin-6-yl]-carbamic acid tert-butyl ester was dissolved, and 10 μL of acetic acid and 0.1 mL (0.20 mmol) of 2N dimethylamine were added thereto and the mixture solution was stirred at room temperature for 30 minutes. Furthermore, 7 mg (0.11 mmol) of sodium cyanoborohydride was added to the obtained solution and the mixture solution was stirred at room temperature for one hour. The reaction solution was concentrated and to the residue, 0.5 mL of trifluoroacetic acid was added and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated, and a target product was obtained by a reversed phase HPLC (a product of Wako Pure Chemical, Combi ODS, 28 mm×50 mm, 0.05% acetonitrile-water, 30 mL/min). The fraction containing the target product was concentrated, and then dissolved in methanol and neutralized by addition of amino silica gel R 66030 B (a product of Silicycle), and then a solid was removed by filtration and the filtrate was concentrated to obtain 15 mg (52%) of a title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[CH2:13]O.P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>ClCCl>[Br:16][CH2:13][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[C:7]([O:8][CH3:9])[C:2]=1[Cl:1]
Reactant: COc1c([N+](=O)[O-])ccc(CO)c1Cl
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c([N+](=O)[O-])ccc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
To a solution of (2-Chloro-3-methoxy-4-nitrophenyl)methanol (Compound 54H, 1.1 g, 5.06 mmol) in dichloromethane (10 mL) at 0° C. was added phosphorous tribromide (684 mg, 2.53 mmol). After the addition was over, the reaction mixture was allowed to stir at RT overnight. The reaction mixture was neutralized with NaHCO3, extracted with ethyl acetate (30 mL) and the solvent was removed under reduced pressure to get the compound 900 mg (64%). 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 1H), 4.58 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].Cl.N1C=CC=CC=1.Cl[N:22]1[CH:27]=[C:26]([C:28]#[N:29])[CH:25]=[C:24]2[S:30][CH:31]([I:33])[CH:32]=[C:23]12.C(=O)(O)[O-].[Na+]>C(OCCO)C>[I:33][C:31]1[S:30][C:24]2[C:23](=[N:22][CH:27]=[C:26]([C:28]#[N:29])[C:25]=2[NH:6][C:5]2[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:32]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: N#CC1=CN(Cl)C2=CC(I)SC2=C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)cc(OC)c1OC
Yield: 85.7 %

Procedure:
A mixture of 3,4,5-trimethoxyaniline (964 mg, 5.26 mmol), pyridine hydrochloride (100 mg, 0.76 mmol) and 4-chloro-2-iodothieno[3,2-b]pyridine-6-carbonitrile (937 mg, 2.92 mmol) in 50 mL of 2-ethoxyethanol is heated at reflux overnight. The solution is poured into saturated aqueous sodium bicarbonate and the resulting solid is collected by filtration, washed with water and dried under reduced pressure. The resultant solid is purified by flash column chromatography eluting with 2% methanol in dichloromethane. The fractions containing product are combined and concentrated to provide 1.17 g of 2-iodo-7-[(3,4,5-trimethoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 254-256° C.; 1H NMR (DMSO-d6) δ 3.70-3.78 (m, 9H), 6.66 (s, 2H), 7.72 (s, 1H), 8.53 (s, 1H), 9.56 (s, 1H); MS 468.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)N)=[CH:4][CH:3]=1.[C:18]([OH:21])(=[O:20])[CH3:19]>C1CCCCC1>[C:10]([N:8]1[C:3]2[CH2:4][CH:19]([C:18]([OH:21])=[O:20])[CH2:6][CH2:7][C:2]=2[C:6]2[C:5]1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NN(C(=O)c1ccccc1)c1ccc(Cl)cc1
Reactant: CC(=O)O
Solvent: C1CCCCC1
Product: O=C(O)C1CCc2c(n(C(=O)c3ccccc3)c3ccc(Cl)cc23)C1
Reaction time: 3 h

Procedure:
A stirred mixture of 2.0 g. of N1 -p-chlorophenyl-N1 -benzoylhydrazine, 1.1 g. of cyclohexanone-3-carboxylic acid, 5 ml. of glacial acetic acid and 7 ml. of cyclohexane were heated under an atmosphere of nitrogen. After 3 hours of stirring at reflux, the reaction mixture was concentrated under reduced pressure and 10 ml. of ethanol was added to the residue. After standing overnight in the refrigerator, the insoluble portion was removed by filtration, washed with a small amount of cold ethanol and dried, yielding 0.4 g. of product, m.p. 196°-197° . Following a recrystallization from ethanol, 0.2 g. of 9-benzoyl-6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid was obtained, m.p. 207°-208°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]([O:21][CH3:22])=[C:6]([CH:20]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[C:27]([O-:30])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:23]([C:4]1[C:5]([O:21][CH3:22])=[C:6]([CH:20]=[C:2]([C:9]2[C:27](=[O:30])[NH:15][CH:12]=[CH:11][CH:10]=2)[CH:3]=1)[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(Br)cc1C(C)(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1c(COc2ccc(NS(C)(=O)=O)cc2)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
step 5—A mixture of 120 (0.20 g, 0.46 mmol), 112 (0.095 g, 0.69 mmol), Pd(PPh3)4 (0.053 g, 0.046 mmol) and Na2CO3 (0.15 g, 1.4 mmol) in DCM/MeOH (3:1, 8 mL) was irradiated in microwave synthesizer at 115° C. for 35 min. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified by SiO2 chromatography eluting with DCM/MeOH/NH4OH and the recovered product triturated with ether to afford I-71 as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH3:16])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: CCBr
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cc2c(cc1C)OCO2
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 2.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in 15 ml of anhydrous tetrahydrofuran was dropwise added at a room temperature to a Grignard reagent prepared from 0.32 g of magnesium ribbon, 20 ml of anhydrous tetrahydrofuran and 1.4 g of bromoethane, followed by stirring for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the obtained mixture was distilled to remove the solvent. The residue was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.27 g of the title compound as a colorless crystal.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2](=[N:18][O:16][CH3:17])[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:13][C@H:14]([C:16]1[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=1)[CH3:15]>CO.C(Cl)(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:13][C@H:14]([C:16]2[O:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][N:20]=2)[CH3:15])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CCOC(=O)C1CN=C([C@H](C)N)O1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CN=C([C@H](C)NC(=O)Cc2cc(F)cc(F)c2)O1

Procedure:
Following General Procedure A and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-(1-aminoethyl)-5(R,S)-ethoxycarbonyl-2-oxazoline (Example F), the title compound was prepared as a semisolid. The reaction was monitored by tlc (Rf=0.3 in 5% MeOH/CHCl3) and the product was purified by silica gel chromatography using 5% MeOH/CHCl3 as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([N:13]([OH:26])[C:14](=[O:25])[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH3:24])[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)=[O:4].[O:27]1[CH:31]=[CH:30][CH2:29][CH2:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][O:2][C:3]([C:5]1([N:13]([O:26][CH:28]2[CH2:29][CH2:30][CH2:31][O:27]2)[C:14](=[O:25])[CH2:15][C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: C1=COCC1
Reactant: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1(N(OC2CCCO2)C(=O)Cc2c(C)cc(C)cc2C)CCN(OC)CC1

Procedure:
To a solution of 4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.3 obtained in analogy to preparation example 11, step 4) (70 g, 192.1 mmol) in dichloromethane (1500 ml) under argon atmosphere was added 2,3-dihydro-furan (29.1 ml, 26.9 g, 384.1 mmol) and a catalytic amount of p-toluenesulfonic acid monohydrate (1.94 g, 19.2 mmol). The reaction mixture was stirred at reflux for 7 hours, filtered and concentrated. The residue was triturated with hexane, filtered and the solid dried in vacuo. Yield: 70.0 g of 1-methoxy-4-{(tetrahydro-furan-2-yloxy)-[2-(2,4,6-trimethyl-phenyl)acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (compound P3ii.6) as a solid, mp 107-109° C. This material was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccccc1C1N(CC(=O)NC2CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 30.9 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in example 34a was reacted with cyclopropylamine (0.1 g, 1.8 mmol) (Aldrich), N-methylmorpholine (48 mg, 0.47 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(cyclopropylamino)-carbonyl-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.039 g, 30%).
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](F)(F)F)[CH:22]=3)[CH2:17][CH2:16]2)[C:11](=[O:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].[CH3:32]C1C(C)=CC=CC=1N1CCNCC1>>[CH3:32][C:22]1[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:12]2[C:11](=[O:31])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]2[CH2:1][CH3:2])[CH2:16][CH2:17]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: CCc1nc2ccccc2c(=O)n1CCN1CCN(c2cccc(C)c2C)CC1

Procedure:
This compound was prepared in compliance with the procedure described in 7d, using 1-(2,3-dimethylphenyl)piperazine instead of 1-(3-(trifluoromethyl)phenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[CH3:12].[Br:13]N1C(=O)CCC1=O.O>ClC1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(CBr)cc1F
Yield: 109.4 %

Procedure:
1-Chloro-4-fluoro-2-methyl-5-nitrobenzene (1 g) was dissolved in chlorobenzene (6 mL) and N-bromosuccinimide (1.408 g) was added followed by benzoyl peroxide (0.183 mg). The reaction mixture was stirred at reflux for 4 hours. The reaction mixture was cooled and water was added. The mixture was extracted with dichloromethane (3×) and concentrated under reduced pressure. The crude oil obtained was triturated with diethyl ether, filtered and the filtrate concentrated under reduced pressure (3×) to yield the title compound (1.55 g).