Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:32]([O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:7]2)(=[O:24])=[O:23])=[CH:30][CH:29]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CCCOc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-Butoxy-benzenesulfonyl)-1-(3-phenoxy-propyl)-piperidine-4-carboxylic acid ethyl ester (4.0 g, 7.9 mmol) dissolved in THF:Methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.0 g (79%); off white powder; mp 191° C.; MS: 476.5 (M+H)+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1.[OH:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>COCCOC>[NH:15]1[CH2:16][CH2:17][CH:12]([O:11][C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=2)[CH2:13][CH2:14]1
Reactant: Clc1ccc(Cl)nc1
Reactant: OC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(OC2CCNCC2)nc1
Temperature: 82 °C
Reaction time: 0.5 h

Procedure:
NaH (2.88 g, 66 mmol, 55% dispersion in mineral oil) was stirred in dry DME (200 ml), under Argon. A mixture of 2,5-dichloropyridine (8.87 g, 60 mmol) and 4-hydroxypiperidine (6.67 g, 66 mmol) dissolved in dry DME (200 ml) was added to the NaH suspension dropwise, over a period of 30 minutes. After complete addition the reaction is heated to 82° C. for 48 hrs, maintaining the Argon blanket. The reaction was slowly quenched with water before removing most of the THF. Extracted the aqueous with DCM (×3). The organic layers were dried with Na2SO4 and evaporated in vacuo to afford 2-(4-piperidinyloxy)-5-chloropyridine as a yellow oil (12.7 g, quantitative). 1H NMR (DMSO): 8.17 (d, 1H), 7.76 (dd, 1H), 6.81 (d, 1H), 4.96 (m, 1H), 2.93 (m, 2H), 2.53 (m, 2H), 1.91 (m, 2H), 1.46 (m, 2H); MS (ES+): 213.3 (MH+), 225.3 (MNa+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.OC(C(F)(F)F)=O.[NH2:20][CH:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:30][CH:29]([NH:31][C:32]([CH2:34][NH:35][C:36](=[O:47])[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=3)=[O:33])[CH2:28]2)[CH2:23][CH2:22]1>C(Cl)Cl>[F:46][C:43]([F:44])([F:45])[C:39]1[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=1)[C:36]([NH:35][CH2:34][C:32]([NH:31][CH:29]1[CH2:28][N:27]([CH:24]2[CH2:23][CH2:22][CH:21]([NH:20][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[O:11])[CH2:26][CH2:25]2)[CH2:30]1)=[O:33])=[O:47]
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Reactant: NC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(NC(=O)c3ccc4c(c3)OCO4)CC2)C1
Reaction time: 2 h

Procedure:
Benzo[1,3]dioxole-5-carbonyl chloride (Aldrich, 74 mg, 0.404 mmol) was added into a solution of N-{[1-(4-amino-cyclohexyl)-azetidin-3-ylcarbamoyl]-methyl}-3-trifluoromethyl-benzamide TFA salt (as prepared in the previous step 200 mg, 0.404 mmol) and TEA (170 μL, 1.21 mmol) in DCM (5 mL) at 0° C. The reaction was stirred for an additional 2 hours and quenched with saturated sodium bicarbonate. The reaction was then partitioned between DCM and water. The organic layer was separated and the aqueous layer was extracted 3 times with a chloroform/IPA “cocktail” (˜3:1, v/v). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[CH2:14]([NH2:16])[CH3:15]>C(#N)C>[CH2:14]([NH:16][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)[CH3:15]
Reactant: CCN
Reactant: N#Cc1ccc(OCC2CO2)cc1
Solvent: CC#N
Product: CCNCC(O)COc1ccc(C#N)cc1

Procedure:
86.0 g of 4-(oxiranylmethoxy) benzonitrile was dissolved in 250 ml acetonitrile and mixed with 29.7 g ethylamine in an autoclave. The mixture was heated in a boiling water-bath over night, evaporated and the residue was dissolved in 2-M hydrochloric acid. This acidic waterlayer was washed twice with ether, alkalized with 10-M sodium hydroxide and extracted with three portions of dichloromethane.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[C:31](=[O:34])([O-])O.[Na+]>COCCOC.O.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:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:31]=[O:34])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCNC(=O)OC(C)(C)C)c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)n(CCNC(=O)OC(C)(C)C)c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 171.5 %

Procedure:
To a suspension of methyl 2-bromo-1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (500 mg, 1.04 mmol), 2-formylphenylbononic acid (187 mg, 1.24 mmol) and sodium hydrogen carbonate (345 mg, 4.15 mmol) in 1,2-dimethoxyethane (5 ml) and water (2.5 ml) was added tetrakis(triphenylphosphine)palladium (60.0 mg, 0.05 mmol), and the mixture was stirred at 90° C. for 2 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1-3:1) to give methyl 1-(2-tert-butoxycarbonylaminoethyl)-3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (450 mg, yield 85%).
Reaction SMILES: [C:1]([N:3]=[C:4](OC1C=CC=CC=1)[NH:5][C:6]1[C:7]([N:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:2].[C:22]1([C:28]2([NH2:32])[CH2:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>O1CCOCC1>[CH3:14][N:12]([CH3:13])[C:7]1[C:6]([NH:5][C:4]([NH:32][C:28]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30][CH2:31]2)=[N:3][C:1]#[N:2])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CN(C)c1ncccc1NC(=NC#N)Oc1ccccc1
Reactant: NC1(c2ccccc2)CCC1
Solvent: CN1CCOCC1
Solvent: C1COCCO1
Product: CN(C)c1ncccc1NC(=NC#N)NC1(c2ccccc2)CCC1
Yield: 44.2 %

Procedure:
A stirred mixture of the product from Step 1 (3.23 g, 0.0115 mol), 1-phenylcyclobutylamine (1.73 g, 0.0126 mol) (A. Kalir and Z. Pelah, Israel J. Chem. 5:223 (1967)), N-methylmorpholine (2.74 ml, 0.0249 mol) and dioxane (40 ml) was refluxed, under nitrogen for 18 hours and concentrated in vacuo. The residue was mixed with EtOAc and concentrated to give a solid which was recrystallized from EtOAc-hexane to give 1.7 g, mp 204°-205° C. of the titled product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:22]3[CH2:23][CH:24]([C:26]4([OH:29])[CH2:28][CH2:27]4)[CH2:25][CH:14]2[CH2:15][C:16]2([CH2:21]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.I[CH3:31]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH:14]3[CH2:25][CH:24]([C:26]4([O:29][CH3:31])[CH2:28][CH2:27]4)[CH2:23][CH:22]2[CH2:21][C:16]2([CH2:15]3)[O:20][CH2:19][CH2:18][O:17]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N1C2CC(C3(O)CC3)CC1CC1(C2)OCCO1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC1(C2CC3CC4(CC(C2)N3S(=O)(=O)c2ccc(Cl)cc2)OCCO4)CC1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 46 mg, 1.16 mol) was added to a solution of 1-{9-[(4-chlorophenyl)sulfonyl]spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolan]-7-yl}cyclopropanol (55) (321 mg, 0.775 mmol) in THF (2 mL). The resulting solution was stirred for 10 minutes, after which iodomethane (72 μL, 1.16 mmol) was added. The reaction mixture was stirred at room temperature for 18 h and was subsequently diluted with EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, and concentrated to give 9-[(4-chlorophenyl)sulfonyl]-7-(1-methoxycyclopropyl)spiro[9-azabicyclo[3.3.1]nonane-3,2′-[1,3]dioxolane] (56). MS (ESI) 428.1 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(O)cc2c1O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(O)cc2c1O
Temperature: 180 °C
Yield: 52.8 %

Procedure:
A mixture of 4-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 250° C. for 45 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. The solid is suspended in 250 mL MeOH and brought to a boil. The insoluble material is filtered and the filtrate is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2 then with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.644 g of ethyl 4,6-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.372 g of the desired product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][Br:12].[C:13]([Li])#[C:14][CH2:15][CH2:16][CH2:17][CH3:18]>C1COCC1.CN(P(N(C)C)N(C)C)C>[C:11]([Br:12])#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: [Li]C#CCCCC
Reactant: BrCCCCCCCCCCBr
Agent: CN(C)P(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC#CBr
Reaction time: 8 h
Yield: 34.5 %

Procedure:
A 3 liter, 2-necked round bottom flask was equipped with a magnetic stir bar, an inlet valve and a septum. After being purged with an argon atmosphere, the flask was charged with 615 g (2.1 mol) of 1,10-dibromodecane in 350 mL of THF and 125 mL of hexamethylphosphorus triamide. A solution containing about 1 mol of hexynyllithium, prepared as described above, was then added to the solution of dibromide via the septum. The reaction mixture was allowed to stir overnight, then quenched by pouring over about 1 L of water. The reaction mixture was diluted with about 500 mL of hexane, phases separated and the organic layer washed twice with 500 mL aliquots of water. The organic layer was then dried over MgSO4, filtered, solvent stripped on the rotary evaporator, then vacuum distilled through a 2 foot column packed with 1/4" glass helices. About 104 g (35 mol % yield) of hexadecynyl bromide was obtained with a boiling point of 135° C. @ 0.3 mm Hg.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C@H:12]1[CH2:15][C@H:14]([OH:16])[CH2:13]1.F[C:18]1[C:23]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:22][CH:21]=[CH:20][N:19]=1.C(OCC)(=O)C>CN(C=O)C>[O:27]1[CH2:28][CH2:29][CH:24]([C:23]2[C:18]([O:16][C@H:14]3[CH2:13][C@H:12]([C:4]4[NH:5][C:6]5[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=5[N:3]=4)[CH2:15]3)=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1
Reactant: O[C@H]1C[C@H](c2nc3ccccc3[nH]2)C1
Reactant: Fc1ncccc1C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnc(O[C@H]2C[C@H](c3nc4ccccc4[nH]3)C2)c(C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% dispersion, 0.049 g, 1.2 mmol) was added to a solution of trans-3-(1H-benzo[d]imidazol-2-yl)cyclobutanol (0.11 g, 0.58 mmol) in DMF (1.5 mL) under argon and the mixture was stirred for 45 min at RT. 2-Fluoro-3-(tetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.58 mmol) was added and the mixture was stirred for 16 h at 110° C. Ethyl acetate was added and the mixture was washed with water (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 2-(trans-3-(3-(Tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)cyclobutyl)-1H-benzo[d]imidazole (37 mg, 0.11 mmol, 18% yield) as a white solid. [M+1]: 350.3. IC50 (uM) 0.01041.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:26][CH:27]=1
Reactant: CCSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
152 mg (2.33 mmol) of potassium cyanide were added to 510 mg (1.16 mmol) of the compound from Example 53A in 7 ml of DMF. The mixture was stirred at 80° C. for 2 h and, after cooling, water was added, the mixture was extracted with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). 222 mg (52% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][CH2:15][O:16][C:17]([C:19]([CH2:21]Br)=O)=[O:18]>CCO.CCOC(C)=O>[CH2:15]([O:16][C:17]([C:19]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N+:11]([O-:13])=[O:12])[S:7][CH:21]=1)=[O:18])[CH3:14]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccc(C(N)=S)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1csc(-c2ccc(C)cc2[N+](=O)[O-])n1
Temperature: 70 °C

Procedure:
4-Methyl-2-nitro-thio benzamide (60 mgs, 0.30 mmol, prepared as described in compound 5, Step 2, was stirred in 1 mL absolute EtOH at room temperature under N2. Ethyl bromo pyruvate (65 mgs, 0.33 mmol) was added, and the resulting solution was heated to 70° C. for 3 h. The reaction was diluted to 30 mL with EtOAc and washed with saturated NaHCO3, and saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to a yellow oil, which was used as is in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1.N1CCCCC1>C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH:19][C:15]3[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1CCCc2ccc(Br)cc21
Reactant: O=Cc1cccnc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C1C(=Cc2cccnc2)CCc2ccc(Br)cc21
Reaction time: 18 h
Yield: 81.6 %

Procedure:
A mixture of 7-bromo-1-tetralone (11.25 g), pyridin-3-carboxaldehyde (5.35 g), acetic acid (5 ml) and piperidine (6 ml) was heated on a stream bath for 6 hours and then allowed to stand for 18 hours. The volatile material was evaporated and the residue was dissolved in ethyl acetate. The solution was extracted several times with dilute hydrochloric acid and the combined extracts were made just alkaline with dilute sodium hydroxide solution. The solid was filtered off, washed with water and crystallised from methanol to give 7-bromo-2-(3-pyridylmethylene)-1-tetralone (12.8 g), m.p. 124°-125°.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].N1C=CC=CC=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>CN(C=O)C>[C:18]([O:11][CH2:10][CH:7]1[CH2:8][CH2:9][CH:4]([CH2:1][C:2]#[CH:3])[CH2:5][CH2:6]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCC1CCC(CO)CC1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C#CCC1CCC(COC(C)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a solution of 960 mg (6.31 mmol) of 86 in 6 mL DMF was added 0.62 mL (7.57 mmol) pyridine and 0.78 mL (8.27 mmol) acetic anhydride. The reaction was allowed to stir overnight at room temperature. After 16 hours, starting material still remained. The reaction mixture was heated at 75° C. for 3 hours. The solvent was removed under reduced pressure to yield a yellow oil which was purified by flash chromatography, on silica gel, eluting with 1:3 ether/petroleum ether to yield 1.12 g (91%) of 87 as an oil. 1H NMR (CDCl3) δ3.87 (d, J=6.2 Hz, 2H), 2.06 (d, J=4.3 Hz, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 1H), 1.92-1.83 (m, 2H), 1.83-1.74 (m, 2H), 1.63-1.36 (m, 2H), 1.12-0.90 (m, 4H); 13C NMR (CDCl3) δ 171.7, 83.7, 69.9, 69.6, 37.4, 37.3, 32.1, 29.7, 26.5, 21.4; APCI m/z (rel intensity) 195 (M+, 30), 153 (M+, 70), 135 (M+, 100).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[O:19][C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)[CH2:16]2)[CH2:10][CH:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=O)(C)(C)C.C(C1C=CC(N2CC(CBr)OC2=O)=CC=1)#N.C(OC(N1CCNCC1C(OCC)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:16][CH:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH:9]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10]3)[O:19][C:18]2=[O:20])=[CH:22][CH:23]=1)#[N:28]
Reactant: CCOC(=O)C1CN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)C1CNCCN1C(=O)OC(C)(C)C
Agent: N#Cc1ccc(N2CC(CBr)OC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CCN1
Reaction time: 1 h

Procedure:
A solution of 1 g of ethyl 1-tert-butoxycarbonyl-4-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperazine-2-carboxylate (obtainable by reacting 3-(4-cyanophenyl)-5-bromomethyl-2-oxazolidinone with ethyl 1-tert-butoxycarbonylpiperazine-2-carboxylate in accordance with the method described in Example 3) in 12 ml of dichloromethane and 12 ml of trifluoroacetic acid is left to stand at 20° for 1 h. and then concentrated by evaporation. Ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)piperazine-3-carboxylate is obtained, FAB 359.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][CH:14]([C:18]([OH:20])=[O:19])[CH2:13][C:12]=3[CH:21]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)CC(C(=O)O)CCO3)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
Into a suspension of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (280 mg) in methanol (20 ml)/ethyl acetate (10 ml) was added 10% palladium on charcoal (50% water content, 70 mg). Hydrogen gas was introduced, and the resulting mixture was stirred at room temperature for 17 hours and at 50° C. for 3 hours, and was then filtered to remove the catalyst. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate/hexane to obtain 7-(4-methylphenyl)-2,3,4,5-tetrahydro-1-benzooxepine-4-carboxylic acid (187 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:30])=[N:6][C:7]2[N:8]([N:27]=[CH:28][CH:29]=2)[C:9]=1[N:10]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:2]=[CH2:3].CSC.B.[OH-:35].[Na+].OO>O1CCCC1>[C:13]([O:12][C:11](=[O:17])[N:10]([C:9]1[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=[C:5]([Cl:30])[C:4]=1[CH2:1][CH2:2][CH2:3][OH:35])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=1)([CH3:15])([CH3:14])[CH3:16]
Reactant: [OH-]
Reactant: C=CCc1c(Cl)nc2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCCO)c(Cl)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a tetrahydrofuran (23 mL) solution containing tert-butyl (6-allyl-5-chloropyrazolo[1,5-a]pyrimidin-7-yl)(4-ethoxyphenyl)carbamate (3.0 g, 7.0 mmol), borane-dimethyl sulfide complex (2 mol/L tetrahydrofuran solution, 5.6 mL, 23 mmol) was added over 30 min with ice-cooling. This mixture was stirred at room temperature for 2 hr and then again cooled on ice. Here, 1 mol/L aqueous sodium hydroxide (11.2 mL, 11.2 mmol) was added over 20 min, and hydrogen peroxide (30% aqueous solution, 0.81 mL, 8.4 mmol) was added. The resultant mixture was stirred for 1 hr. After the reaction, the reaction mixture was extracted with ethyl acetate. The combined ethyl acetate layer was washed with brine and dried over sodium sulfate. After the sodium sulfate was filtered off, the solvent was distilled off and the residue was purified with column chromatography (20% ethyl acetate-hexane) to obtain the title compound (2.02 g, yield 65%).
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][CH3:9]>CO>[CH2:7]([N:6]([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:8][CH3:9]
Reactant: CCCN
Reactant: C=CC(N)=O
Solvent: CO
Product: CCCN(CCC(N)=O)CCC(N)=O
Temperature: 80 °C
Yield: 97590.4 %

Procedure:
A mixture of 118.6 g (1.67 mol) of acrylamide and 49.3 g (0.83 mmol) of 1-aminopropane in 250 ml of methanol was heated at 80° C. for 1 hour. The solvent was evaporated and the solid crystallized from ethanol. There was obtained 162.3 g (0.81 mol, 97%) of 3,3'-(propylimino)bispropanamide as a white solid mp 101°-101.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[C:7]([Cl:15])[CH:6]=1.[CH2:16]([NH2:19])[CH2:17][CH3:18].Cl>C(O)C>[Cl:15][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=1)[O:4][CH2:3][CH2:2][NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CS(=O)(=O)c1cc(Cl)cc(OCCBr)c1
Reactant: CCCN
Agent: Cl
Solvent: CCO
Product: CCCNCCOc1cc(Cl)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.5 g, 1.59 mmol) and propane-1-amine (1.04 ml, 12.76 mmol) in ethanol (5 ml). Yield: 368 mg (79.1%). The amine was converted to the hydrochloric acid salt and re-crystallized from ethanol/diethyl ether: M.p. 195-197° C. MS m/z (relative intensity, 70 eV) 291 (M+, 1), 264 (8), 262 (22), 73 (9), 72 (bp).