Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3noc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3noc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a suspension of benzhydryl 7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (2.4 g) in methylene chloride (15 ml) and anisole (1.8 g) was added trifluoroacetic acid (4.9 g), and the mixture was stirred at ambient temperature for an hour. To the reaction mixture was added diisopropyl ether (150 ml), and the precipitated material was collected by filtration, followed by suspension in a mixture of ethyl acetate and water, and adjusting to pH 7 with 10% aqueous sodium hydroxide. To the separated aqueous solution was added ethyl acetate and saturated with sodium chloride. After adjusting to pH 1.5 with 10% hydrochloric acid, the ethyl acetate solution was separated, washed with a saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain 7-[2-(5-amino-1,2,4-oxadiazol-3-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.6 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9](O)=[O:10].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH2:9][OH:10]
Reactant: O=C(O)CC1CC2CCC1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCC1CC2CCC1C2
Reaction time: 72 h
Yield: 96.3 %

Procedure:
2-Norbornane acetic acid (15 g, 97 mmol) was dissolved in anhydrous tetrahydrofuran (150 mL) and treated dropwise with lithium aluminum hydride (195 mL, 1 M in tetrahydrofuran) at 0° C. The reaction was stirred for three days then quenched by dropwise addition of water (50 mL). The reaction was diluted with diethyl ether (300 mL) and washed with water (3×200 mL). The combined organic phases were dried (MgSO4), filtered, and concentrated to yield an oil. The product was passed through a pad of silica gel to yield 2-bicyclo[2.2.1]hept-2-yl-ethanol as a colorless oil (13.1 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C([BH3-])#N.[Na+]>>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)c1sccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Product: COC(=O)c1sccc1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
3-Amino-2-methoxycarbonylthiophene is reductively alkylated with 1-tert-butyloxycarbonylpiperidin-4-one and sodium cyanoborohydride to give 3-(1-tert-butyloxycarbonylpiperidin-4-ylamino)-2-methoxycarbonylthiophene.
Reaction SMILES: [Br-].[C:2]1([C:8]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11][O:10][C:9]2=[N+:13]([CH3:15])[CH3:14])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C@H:24]1[C@@H:29]([NH:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:31]([NH:30][C@H:29]1[CH2:28][CH2:27][N:26]([CH2:11][CH2:12][C:8]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]([N:13]([CH3:15])[CH3:14])=[O:10])[CH2:25][C@H:24]1[O:23][CH3:22])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)c1ccccc1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CO[C@@H]1CN(CCC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC[C@@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 35 %

Procedure:
A mixture of 7.6 parts of N-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide, 4.7 parts of cis-N-(3-methoxy-4-piperidinyl)benzamide, 3.8 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone was stirred and refluxed for 18 hours using a water-separator. The reaction mixture was cooled to room temperature and washed with water. The organic phase was separated, dried, filtered and evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 3.5 parts (35%) of cis-4-(benzoylamino)-3-methoxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide; mp. 146.6° C. (compound 122).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5](Cl)[C:6]=1[C:7]#[N:8].[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+].Cl>O>[NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([S:12]([O-:15])(=[O:14])=[O:13])[C:6]=1[C:7]#[N:8].[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#Cc1c(N)sc(C=O)c1S(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
93.3 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene, 126 parts of sodium sulfite and 300 parts of water are heated at the boil for 2 hours, after which 200 parts of concentrated hydrochloric acid are added to the ice-cooled mixture, and the mixture is left to stand overnight. Thereafter, the mixture is filtered under suction, and the residue is washed with a little ice water and dried. 85 parts (67% of theory) of sodium 2-amino-3-cyano-5-formylthien-4-ylsulfonate are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:13].[OH2:14].C1(C)C=C(C)C=C(C)C=1S(O)(=O)=O.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O
Reactant: C1=CCN(Cc2ccccc2)C1
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 85.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of l-benzyl-3-pyrroline, 56.7 g (0.24 mol) of 2-mesitylenesulfonic acid dihydrate (produced by Aldrich Chemical Co., Inc.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at 40° C. without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 85.9%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)[CH:22]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:34][CH2:35][S:36]([CH3:39])(=[O:38])=[O:37]>>[CH3:39][S:36]([CH2:35][CH2:34][N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[CH:22]=[C:21]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)[CH:26]=[CH:25][CH:24]=2)[CH2:28][CH2:29]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(C5CCNCC5)c4)nc23)cc1
Reactant: CS(=O)(=O)CCCl
Product: CS(=O)(=O)CCN1CCC(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1

Procedure:
{3-[1-(2-Methanesulfonyl-ethyl)-piperidin-4-yl]-phenyl}-[8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from [8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-piperidin-4-yl-phenyl)-amine and 1-chloro-2-methanesulfonyl-ethane (75.0 mg, 0.526 mmol) in a manner analogous to Example 183. Product isolated as a pale yellow solid (0.164 g, 65%). MP=217-219° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.5 Hz, 1H), 8.27 (d, J=7.7 Hz, 2H), 8.09 (d, J=7.5 Hz, 2H), 7.68 (d, J=7.0 Hz, 1H), 7.63 (s, 1H), 7.36-7.27 (m, 2H), 7.04 (t, J=6.5 Hz, 1H), 6.90-6.85 (m, 2H), 3.24 (t, J=6.5 Hz, 2H), 3.12-3.05 (m, 8H), 2.94 (t, J=6.7 Hz, 2H), 2.62-2.52 (m, 1H), 2.25-2.16 (m, 2H), 1.98-1.90 (m, 2H), 1.85-1.72 (m, 2H). MS=554 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]([CH3:18])=[CH:8][C:3]=1[C:4]([O:6]C)=O.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26](C1C=CC=CC=1Cl)[CH:27]=N>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:4](=[O:6])[C:3]2[C:2](=[C:11]([CH3:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH3:18])[CH:8]=2)[N:1]=[CH:27]1
Reactant: N=CN(c1ccccc1Cl)c1ccccc1Cl
Reactant: CCOC(=O)c1c(C)cc(C(=O)OC)c(N)c1C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)cc2c(=O)n(-c3ccccc3Cl)cnc2c1C
Temperature: 200 °C
Yield: 54.2 %

Procedure:
A mixture consisting of 500 mg of methyl 2-amino-4-ethoxycarbonyl-3,5-dimethylbenzoate and 640 mg of N,N-bis-(o-chlorophenyl)-formamidine was heated to 200° C. with occasional swirling in an open flask. The temperature of the mixture was maintained at around 200° C. for 1.5 hours. After cooling, the mixture was taken up in ethyl acetate, and then, the organic extract was washed with dilute hydrochloric acid, and with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated. The resulting residue was chromatographed on silica gel to give 385 mg (54% of theory) of 3-(2-chlorophenyl)-7-ethoxycarbonyl-6,8-dimethyl-4(3H)-quinazolinone melting at 151°-152° C. (recryst. from ethanol). 1H NMR: δ(CDCl3) 1.49 (t, 3H), 2.46 (s, 3H), 2.62 (s, 3H), 4.48 (q, 2H), 7.30-7.70 (m, 4H), 7.93 (s, 1H), 8.06 (s, 1H).
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].P(=O)(O)(O)O.C1C(O)=CC=C(C)C=1.[C:18]([C:22]1[C:27]([OH:28])=[CH:26][CH:25]=[C:24]([CH3:29])[CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:2]([C:26]1[C:27]([OH:28])=[C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])[CH:23]=[C:24]([CH3:29])[CH:25]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: C=C(C)C
Agent: Cc1ccc(O)cc1
Agent: O=P(O)(O)O
Product: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
Approximately 1000 grams of the above described steam distilled reaction mixture was realkylated in a suitable reactor, by the addition of about 270 grams of isobutylene in the presence of a small amount of phosphoric acid and at a temperature of around 60°C, whereby practically all of the p-cresol in said mixture and around 90% of the mono-tert-butyl-p-cresol were realkylated to form additional 2,6-di-tert-butyl-p-cresol, thus producing a reacted mixture showing the following analysis:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[CH:35]=[N:36][C:37]([Cl:40])=[N:38][CH:39]=1.C(=O)([O-])O.[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[CH:35]=[N:36][C:37]([Cl:40])=[N:38][CH:39]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2cnc(Cl)nc2)cc1
Reaction time: 1 h
Yield: 61.4 %

Procedure:
N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 4.0 g, 9.12 mmol), 5-bromo-2-chloropyrimidine (1.76 g, 9.12 mmol), tetrakis(triphenylphosphine) palladium (527 mg, 0.46 mmol), 1,2-dimethoxyethane (40 ml) and a saturated aqueous solution of sodium hydrogen carbonate (40 ml) were stirred at 80° C. under an atmosphere of argon for 18 hours. The cooled mixture was concentrated under reduced pressure. The residue was then stirred with ethyl acetate for 1 hour and the resultant solid collected by suction filtration and dried to give the title compound (2.38 g; 61%); NMR Spectrum: (DMSO-d6) 1.47 (s, 9H), 7.20 (m, 2H), 7.58 (d, 2H), 8.02 (d, 2H), 8.11 (d, 2H), 8.66 (s, 1H), 9.23 (s, 2H), 10.93 (s, 1H); Mass Spectrum: M+H+-+Bu 369.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>C(Cl)Cl.CCN(CC)CC>[N:22]1([C:20]([C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[O:12])=[CH:19][CH:18]=2)=[O:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Nc1ccc(C(=O)N2CCCCC2)cc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCCCC2)cc1)c1n[nH]c2ccccc12
Reaction time: 16 h

Procedure:
To a solution of 100 mg 1H-indazole-3-carboxylic acid in 2 mL DCM and 0.3 mL NEt3, 125 mg (4-Amino-phenyl)-piperidin-1-yl-methanone and 157 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:23][CH2:22][C:17]4([CH2:20][CH:19]([NH2:21])[CH2:18]4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:24](=O)([O:36]C1C=CC([N+]([O-])=O)=CC=1)[O:25][CH2:26][C:27]1[O:31][N:30]=[C:29]([C:32](=[O:35])[NH:33][CH3:34])[CH:28]=1.C(N(CC)C(C)C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:23][CH2:22][C:17]4([CH2:18][CH:19]([NH:21][C:24](=[O:36])[O:25][CH2:26][C:27]5[O:31][N:30]=[C:29]([C:32](=[O:35])[NH:33][CH3:34])[CH:28]=5)[CH2:20]4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NC1CC2(CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)C1
Reactant: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)CC3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 1, step 1.1. Starting with 1.08 g (3.47 mmol) of 7-[5-(4-fluorophenyl)pyridin-2-yl]-7-azaspiro[3.5]non-2-ylamine, described in the preceding step (step 10.5.), 1.34 g (4.16 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained in step 4.1., 1.12 g (8.67 mmol) of N,N-diisopropylethylamine and 0.212 g (1.73 mmol) of N,N-dimethylaminopyridine, and after purification by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.847 g of pure product is thus obtained in the form of a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:31][CH2:30][C:29]4[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=4[NH:27][C:26]3=[O:36])[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[N:37]1[CH:42]=[CH:41][C:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[CH:39][CH:38]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH2:11][CH:12]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:31][CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=3[NH:27][C:26]2=[O:36])[CH2:21][CH2:20]1)=[O:18])[C:13](=[O:14])[N:46]1[CH2:45][CH2:44][N:43]([C:40]2[CH:41]=[CH:42][N:37]=[CH:38][CH:39]=2)[CH2:48][CH2:47]1)[CH3:2]
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(CC(NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(c3ccncc3)CC2)cc1CC

Procedure:
Prepared analogously to Example 3f) from 3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid and 1-pyridin-4-yl-piperazine.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[OH-].[Na+]>O.[Zn]>[CH3:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N)c(N)c1C
Reaction time: 0.5 h

Procedure:
To a 125 mL round bottom flask 2.20 g of 2,3-dimethyl-6-nitro-aniline (13.2 mmol) was added. Then 15 mL of ethanol was added to the flask followed by the addition of 4 mL of 20 wt % NaOH in water. Then 2.0 g of zinc dust was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After about 0.5 hours the mixture became very pale-brown. After refluxing for 18 hours the mixture was filtered hot to give a pale filtrate which quickly became dark red. C8H12N2, fw=136.19. Yield 1.78 g, 98.7%. Mp: 60° C. (melt). 1H NMR (300 MHz, CDCl3): δ 6.54 (s, 2H), 3.46 (br s, 2H), 3.21 (br s, 2H), 2.22 (s, 3H), 2.11 (s, 3H). Rf=0.68 (ethyl acetate/silica).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([O:16]CC)=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[OH-].[K+].Cl.O>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]3[CH2:10][CH2:11][CH:12]([C:14]([OH:16])=[O:15])[CH2:13][C:7]=3[C:6]=2[CH:19]=1
Reactant: CCOC(=O)C1CCc2sc3ccc(F)cc3c2C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2sc3ccc(F)cc3c2C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 8-fluoro-1,2,3,4-tetrahydrodibenzo[b,d]thiophene-2-carboxylate (2.5 g, 9 mmol) in EtOH (60 mL) was added KOH (0.81 g, 15 mmol). The reaction was stirred at 40° C. overnight. After cooling in an ice-water bath, the mixture was acidified to pH 2-3 with 1 N HCl. Water was added and the resulting white solid precipitate was collected and dried to afford 2.15 g (96%) of the title compound: mp 245° C. (dec.), MS (−) 249 (M−H)−.
Reaction SMILES: [C:1]1([SH:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[CH3:9]C1CCCO1.COS(OC)(=O)=O.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:9][S:7][C:3]1[CH:2]=[C:1]([SH:8])[CH:6]=[CH:5][CH:4]=1
Reactant: CC1CCCO1
Reactant: Sc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: COS(=O)(=O)OC
Product: CSc1cccc(S)c1
Temperature: 50 °C
Yield: 78 %

Procedure:
A solution of benzene-1,3-dithiol (50 g, 0.351 mmol) in 2-methyltetrahydrofuran (375 mL, 0.351 mmol) was treated with dimethylsulfate (33.3 mL, 0.351 mol) followed by 2-methyltetrahydrofuran (25 mL, used as line wash). The resulting solution was cooled to between 0° C. and 5° C. and sodium hydroxide (2M aqueous solution, 210.6 mL) was added drop wise maintaining the temperature of the reaction mixture below 15° C. followed by 2-methyltetrahydrofuran (25 mL, used as line wash) and heated under nitrogen to 50° C. for 4 hours. After cooling to ambient temperature the resulting solution was treated with tert-butylmethylether (500 mL) and the phases were separated. The organic phase was extracted with sodium hydroxide (2 M aqueous solution, 250 mL) and the combined aqueous phases were cooled to 10° C. and hydrochloric acid (6M aqueous solution, 500 mL) was added whilst maintaining the temperature of the mixture below 25° C. The resulting solution was extracted with tert-butylmethylether (2-fold 250 mL) and the combined organic phases were washed with water (500 mL) and concentrated in vacuo to give the title compound as a yellow oil, 78% yield, 42.9 g.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2([C:46](=[O:54])[CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:44][CH2:43]2)[CH:38]=[CH:39][C:40]=1[Cl:41]>O1CCCC1>[Br:1][CH:47]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:46]([C:42]1([C:37]2[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=2)[CH2:45][CH2:44][CH2:43]1)=[O:54]
Reactant: [Br-]
Reactant: O=C(Cc1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: O=C(C(Br)c1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 153.9 %

Procedure:
Phenyltrimethylammonium tribromide (4.02 g) was added in portions at −10° C. to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone (3.41 g) in tetrahydrofuran (100 ml). The mixture was stirred at ambient temperature for 4 hours, then it was filtered, and the solvent removed in vacuo. The residue was purified via flash chromatography over silica using a 3:97 mixture of ethyl acetate and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined, and the solvents removed in vacuo to give 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone as a colourless oil (3.8 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:20])[CH2:14][C:15](OCC)=[O:16])[CH:8]=1>O1CCCC1>[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]([CH3:20])[CH2:14][CH2:15][OH:16])[CH:8]=1
Reactant: CCOC(=O)CC(C)c1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(CCO)c1cccnc1
Yield: 50.6 %

Procedure:
According to Step 3 of Reference Example 8-65, by use of lithium aluminum hydride (75 mg, 2.0 mmol), tetrahydrofuran (10 mL) and a solution prepared by dissolving, in tetrahydrofuran (5 mL), ethyl 3-(pyridin-3-yl)butanoate (339 mg, 2.0 mmol) obtained in Step 2 of Reference Example 8-66, the mixture was stirred and reacted under cooling in an ice bath for 1 hour. Thus, 3-(pyridin-3-yl)butan-1-ol (Compound EN) (153 mg, yield: 99%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:9])=[CH:5][C:6](=[O:8])[CH:7]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CCOCC>[OH:10][C:3]1[C:4]([CH3:9])=[CH:5][C:6]([OH:8])=[CH:7][C:2]=1[CH3:1]
Reactant: CC1=CC(=O)C=C(C)C1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(O)cc(C)c1O

Procedure:
A solution of 2,6-dimethyl-1,4-benzoquinone (Xa) (5.66g, 42 mmol, Aldrich) in Et2O (200 mL) was shaken vigorously in a separatory funnel with two 200 mL portions of aqueous sodium hydrosulfite solution (sodium dithionite, Na2S2O4, 14.5 g, 83.3 mmol) until the Et2O layer turned bright yellow. The ether layer was washed with brine (200 mL×2), dried (MgSO4) and concentrated in vacuo to obtain 4.865g (35.3 mmol, Y: 83.9%) of the title compound as a white solid: mp, 148°-150° C. (acetone-hexane) [mp reported by L. A. Carpino, S. A. Triolo, and R. A. Berglund in J. Org. Chem., 54, 3303 (1989): 145°-148° C.]; Rf 0.47 (10% EtOAc in CH2Cl2); IR(KBr) 3312 cm-1 (OH); 1H-NMR (300 MHz, acetone-d6) δ ppm: 2.15 (6H, s, Me), 6.45 (2H, s, Ar-H), 6.58 (1H, s, OH), 7.47 (1H, s, OH); 13C-NMR (75 MHz, acetone-d6) δ ppm: 16.84, 116.00, 126.45, 147.46, 151.54; MS (isobutane-DCI) m/e 139 (MH+).