Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(CC)CC.[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][NH:30][CH2:29][C:26]21[CH2:28][CH2:27]2)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:32][CH2:31][N:30]([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:29][C:26]21[CH2:27][CH2:28]2)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC12CC2
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 110 °C

Procedure:
To commercially available 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol) dissolved in DMF (5 ml) was added Et3N (1.3 ml, 9.8 mmol) followed by commercially available 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester (1.5 g, 7.2 mmol). The reaction mixture was heated for 16 hours at 110° C. After evaporation of the solvent in vacuo the crude mixture was treated with water (25 mL) and extracted with EtOAc (4×30 mL) the combined organic phases were washed with brine (2×20 mL), dried over Na2SO4, filtered and concentrated in vacuo to provide 1.5 g crude. The product was purified by flash chromatography on silica using EtOAc in heptane as eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([O:18]C)=[O:17])[CH2:8]2>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][CH:7]([C:16]([OH:18])=[O:17])[CH2:8]2
Reactant: COC(=O)C1CCc2c(OC)ccc([N+](=O)[O-])c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c2c1CCC(C(=O)O)C2
Yield: 95.3 %

Procedure:
A mixture of methyl 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.9 g, 7.1 mmol) in methanol (20 mL) and 2 M NaOH (10 mL) was refluxed for 1.5 h and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and acidified. The organic phase was separated and dried and evaporated in vacuo to afford 1.7 g (95% yield) of crystals: mp (after recrystallization in diisopropyl ether/ethanol) 189-190° C.; EIMS (70 eV) m/z (relative intensity) 251 (30, M+).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]=12.[NH2:12][CH:13]1[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)([OH:19])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClC(Cl)C>[N:1]1[S:5][N:4]=[C:3]2[CH:6]=[C:7]([CH2:10][NH:12][CH:13]3[CH2:18][CH2:17][C:16]([CH2:20][CH2:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]=[CH:24][N:23]=4)([OH:19])[CH2:15][CH2:14]3)[CH:8]=[CH:9][C:2]=12
Reactant: O=Cc1ccc2nsnc2c1
Reactant: COc1ccc2ncnc(CCC3(O)CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(Cl)Cl
Product: COc1ccc2ncnc(CCC3(O)CCC(NCc4ccc5nsnc5c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Molecular sieve, type 3A, (1 g) and benzo[1,2,5]thiadiazol-5-carbaldehyde (0.066 g, 0.4 mmol) were added to a solution of 4-amino-1-[2-(6-methoxy-quinazolin-4-yl)-ethyl]-cyclohexanol (0.116 g, 0.38 mmol) in methanol (1 ml) and dichloroethane (3 ml). The reaction mixture was stirred at room temperature for 20 hours and sodium triacetoxyborohydride (0.22 g, 1.04 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and then filtered over Hydromatrix (wetted with an NaHCO3 solution, 2 ml) and subsequently washed with dichloromethane. The filtrate was concentrated to dryness by rotary evaporation. The residue was purified by column chromatography on silica gel (dichloromethane/MeOH 9/1 1% NH4OH).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][C:14]=3[C:22]3[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>O1CCCC1>[C:1]12([CH2:11][O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH:19][S:33]([CH3:32])(=[O:35])=[O:34])=[O:18])=[CH:15][C:14]=3[C:22]3[C:23]([O:28][CH3:29])=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1-c1cc(C(N)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(=O)NS(C)(=O)=O)ccc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
To a solution of 4-(adamantan-1-ylmethoxy)-3-(2-methoxypyridin-3-yl)benzamide (0.39 g, 1.00 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (0.09 g, 2.25 mmol). The reaction mixture was stirred at ambient temperature for 2 h, methanesulfonyl chloride (0.12 mL, 1.54 mmol) was added; stirring was continued for 46 h at ambient temperature and quenched by addition of 5% hydrochloric acid (1.0 mL). Diluted with ethyl acetate (100 mL) and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography using 10% to 50% gradient ethyl acetate in hexanes to afford the title compound as a colorless solid (0.13 g, 27%): 1H NMR (300 MHz, CDCl3) δ 8.73 (br s, 1H), 8.21-8.17 (m, 1H), 7.88-7.83 (m, 1H), 7.78-7.65 (m, 1H), 7.55-7.50 (m, 1H), 7.00-6.93 (m, 2H), 3.88 (s, 3H), 3.53 (s, 2H), 3.40 (s, 3H), 1.90 (br s, 3H), 1.69-1.31 (m, 12H); MS (ES−) m/z: 469.1 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][C:26]([C:36]([O:38]C)=[O:37])([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]>O1CCCC1.[OH-].[Na+]>[C:36]([C:26]1([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]2=[O:35])[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:28][CH2:27]1)([OH:38])=[O:37]
Reactant: COC(=O)C1(N2CCCCC2=O)CCN(CC[C@H](CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C[C@@H](CCN1CCC(C(=O)O)(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Yield: 39.4 %

Procedure:
A solution of (S)-N-[2-(3,4-dichlorophenyl)-4-[4-methoxycarbonyl-4-(2-oxopiperidino)piperidino]butyl]-N-methylbenzamide (0.65 g) in tetrahydrofuran (15 mL) and 1.0N sodium hydroxide (15.5 mL) was heated at reflux overnight. After the tetrahydrofuran was distilled off, the resulting aqueous mixture was adjusted to a pH of 5.5-6.0 and extracted several times with dichloromethane. The organic extracts were dried and evaporated. The crude product was suspended in ether and filtered to give the title compound as a white solid (0.25 g); MS: m/z=560(M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[S:11]([OH:14])(=[O:13])=[O:12])([OH:3])=O.[NH2:15][C:16]1[N:17]=[CH:18][N:19]([CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([O:24]CC)=[O:23])[CH:20]=1.[N+](C1N=CN(C(CCCCCC)C(OCC)=O)C=1)([O-])=O.C(N(CC)CC)C>C(Cl)(=O)C(Cl)=O.CN(C=O)C.C(O)C.C1COCC1.[Pd].C(OCC)(=O)C>[OH:10][C:6]1[C:5]([S:11]([OH:14])(=[O:13])=[O:12])=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:1]([NH:15][C:16]1[N:17]=[CH:18][N:19]([CH:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:22]([OH:24])=[O:23])[CH:20]=1)=[O:3]
Reactant: CCCCCCC(C(=O)OCC)n1cnc(N)c1
Reactant: O=C(O)c1cccc(O)c1S(=O)(=O)O
Agent: [Pd]
Agent: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)O)n1cnc(NC(=O)c2cccc(O)c2S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Carboxy-6-hydroxybenzenesulfonic acid (1.8 mmole, 400 mg) was dissolved in 15 ml of oxalyl chloride. One drop of DMF was added. The reaction was stirred for 30 minutes at room temperature. The solvent was removed in vacuo, and 20 ml THF added. A solution of ethyl 2-(4-amino-1H-imidazol-1-yl)octanoate (prepared by the reduction of 1.8 mmoles of ethyl 2-(4-nitro-1H-imidazol-1-yl)octanoate in ethanol with 5% Pd/C) in 40 ml THF and 2.0 moles of triethylamine was added dropwise. The reaction was stirred at room temperature for 3 hours; ethyl acetate was added. The solution was washed with water, dried over sodium sulfate and concentrated. The intermediate was slurried in ether, filtered, chromatographed over silica gel eluted with 15% methanol in methylene chloride. The ester was hydrolyzed in 20 ml methanol and 45 ml of 2N NaOH at room temperature for 2 hours. The solvent was removed; water was added. The pH was adjusted to 2.0 using 5N HCL. The product was extracted into ethyl acetate, dried over sodium sulfate and concentrated to yield 2-[4-(3-Hydroxy-2-sulfobenzoyl)amino-1H-imidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: [OH-].[K+].CN(N=O)S([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=O)=O.[N+](=C)=[N-].[Cl:20][C:21]1[N:29]=[CH:28][CH:27]=[CH:26]C=1C(O)=O>CCOCC.CO.O.C(O)C>[Cl:20][C:21]1[C:14]([C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=2)=[CH:26][CH:27]=[CH:28][N:29]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CO
Product: Clc1ncccc1-c1ccccc1
Yield: 91.4 %

Procedure:
A stirred solution of potassium hydroxide (22.6 g, 0.4 mole), ethanol (45.3 mL), and water (36 mL) was treated with N-methyl N-nitroso-p-toluenesulfonamide (22.6 g, 0.1 mole; Diazald®-Aldrich) in ether (204 mL) at 65°. The rate of addition of the solution was regulated by the rate of distillation of the ether diazomethane solution. A diazomethane generation kit containing all polished glass surfaces was used to distill the ethanol diazomethane solution which was received in two collection vessels connected in tandem, the first cooled to 0° and the second to -78°. The combined diazomethane solutions were treated dropwise with the solution of 2-chloronicotinic acid (4.7 g, 0.03 mole) in methanol at -15°. The reaction mixture was maintained at -15° for 4 hr and then slowly allowed to equilibrate to room temperature. The solution was concentrated in vacuo to a yellow solid, partitioned between aqueous sodium carbonate and methylene chloride, and the organic layer was isolated, dried (MgSO4), and concentrated in vacuo to yield 5.2 g (approximately 100%) of methyl 2-chloronicotinate (VI) as a crude oil suitable for reaction with piperazine as given below.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>>[F:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][CH:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH2:11][CH2:10]2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: Cc1ncc(F)c(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(F)c(N2CCC(C3CCNCC3)CC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The tert-butyl 1′-(5-fluoro-2-methylpyrimidin-4-yl)-4,4′-bipiperidine-1-carboxylate (22 mg, 0.058 mmol) was mixed with 0.2 mL of TFA and stirred at r.t. for 5 min and was concentrated on rotavapor to yield title compound and was used directly for next step.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][NH:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[C:11]([O:13][CH3:14])=[O:12].[CH2:22]=O>ClC(Cl)C.O>[CH3:14][O:13][C:11](=[O:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[N:9]1[CH2:8][CH2:7][C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:22]1
Reactant: C=O
Reactant: COC(=O)C(NCCc1cccs1)c1ccccc1Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: COC(=O)C(c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 60 °C
Yield: 90.1 %

Procedure:
6 g (0.017 mol) of dextrorotatory methyl [2-(2-thienyl)ethylamino](2-chlorophenyl)acetate hydrochloride is suspended in 6.7 ml of 38% aqueous formaline solution and heated to 60° C. under stirring. The starting material dissolves at 60° C., the resulting solution is stirred at the temperature for 30 minutes, till the completion of the reaction. The reaction mixture is then diluted with 100 ml of 1.2 dichloroethane and 150 ml of water, and after shaking well, the phases are separated. The aqueous phase is extracted with 2×30 ml of 1,2-dichloroethane, the united organic phase is extracted with 100 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residual 6 g of material is dissolved in 30 ml of diethyl ether, and while cooling the reaction mixture, 0.6 g of dry hdyrogen chloride gas is introduced into the solution, at room temperature. The precipitated crystalline material is filtered off, washed with ether and dried. Weight: 5.5 g. Mp.: 130-132° C., [α]22D=+60°. Yield: 90.1%. Optical purity: 99% (by HPLC investigation).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]([NH:18][C:19]([C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=O)[CH3:17])=[CH:14][N:15]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:17][C:16]1[N:18]=[C:19]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)[N:12]2[C:13]=1[CH:14]=[N:15][C:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N:11]2
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccsc3)nn2)cc1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(Nc2ncc3c(C)nc(-c4ccsc4)n3n2)cc1
Yield: 49.4 %

Procedure:
Applying the Cyclization Procedure 1, using N-[1-(3-{[4-(methyloxy)phenyl]amino}-1,2,4-triazin-6-yl)ethyl]-3-thiophenecarboxamide (Intermediate 57) (95 mg, 0.27 mmol), 1,2-dichloroethane (5 mL) and phosphorus oxychloride (0.20 mL, 2.14 mmol), to afford 5-methyl-N-[4-(methyloxy)phenyl]-7-(3-thienyl)imidazo[5,1-f][1,2,4]triazin-2-amine (45 mg) as a yellow solid. MS m/z 338 (M+1).
Reaction SMILES: [Br:1]C1C(OC)=C(C(CSC2C=CC=CC=2)=CC=1)C(OCC)=O.[I:23][C:24]1[C:25]([O:38][CH3:39])=[C:26]([C:32]([CH3:37])=[CH:33][C:34]=1[O:35][CH3:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Br:1][CH2:37][C:32]1[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]([O:38][CH3:39])[C:24]([I:23])=[C:34]([O:35][CH3:36])[CH:33]=1
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(C)cc(OC)c(I)c1OC
Product: CCOC(=O)c1c(CBr)cc(OC)c(I)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 87, starting from ethyl 3-iodo-2,4-dimethoxy-6-methylbenzoate (Intermediate 203).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][NH:21]C(OC(C)(C)C)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].O1CCOCC1>C(Cl)Cl>[ClH:30].[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][NH2:21])[CH:18]=2)[NH:13][C:12]=1[CH3:29])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(CNC(=O)OC(C)(C)C)cc2c1C(=O)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CN)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 5-(tert-butoxycarbonylamino-methyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.8 g, 4.6 mmol) in methylene chloride (10 μL) was added 4 M hydrogen chloride in dioxane (1.2 mL, 4.8 mmol). The mixture was stirred at room temperature for 1 hour and the formed solid was then filtered. The product was further purified by recrystallization (ethanol and methylene chloride) to give 950 mg (63%) of titled product as a beige solid: mp 260-261° C.; MS(APCI−): m/z 293.1 (M−H); Anal. Calcd for C18H18N2O2.1.06HCl: C, 64.92; H, 5.77; N, 8.41; Cl, 11.29. Found: C, 64.58; H, 5.79; N, 8.31; Cl, 11.38.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:14]1[CH2:18][CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:16]2[CH2:17][CH2:18][O:14][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C2CCOC2)CC1

Procedure:
To tetrahydro-furan-3-ol (1.0 g, 11.4 mmol) in anhydrous dichloromethane (15 mL) with triethylamine (2.37 mL, 17.03 mmol), was added methane sulfonyl chloride (12.5 mmol) at 0° C. The reaction mixture was stirred at RT for 3.5 hours, diluted with dichloromethane (50 mL) and washed with water. The organic phase was dried (MgSO4) and evaporated in-vacuo to give methanesulfonic acid tetrahydro-furan-3-yl ester as light orange oil (1.68 g, 89%). A mixture of piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 5.38 mmol), methanesulfonic acid tetrahydrofuran-3-yl ester (1.07 g, 6.45 mmol) and K2CO3 (2.96 g, 21.5 mmol) was stirred in anhydrous acetonitrile (50 mL) under reflux conditions for 12 hours. The reaction mixture was cooled and poured onto water and extracted with dichloromethane to give after silica chromatography, 4-(tetrahydro-furan-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, as a colourless oil (0.57 g, 41%).
Reaction SMILES: [CH2:1]([NH:5][C:6](SC)=[C:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]([CH3:4])[CH3:3].[NH2:17][CH2:18][CH:19]1[O:24][CH2:23][CH2:22][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:20]1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:21]2[CH2:22][CH2:23][O:24][CH:19]([CH2:18][NH:17][C:6]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[C:7]([C:13]#[N:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20]2)=[CH:27][CH:28]=1
Reactant: NCC1CN(Cc2ccc(F)cc2)CCO1
Reactant: CCOC(=O)C(C#N)=C(NCC(C)C)SC
Product: CCOC(=O)C(C#N)=C(NCC(C)C)NCC1CN(Cc2ccc(F)cc2)CCO1
Yield: 22 %

Procedure:
This compound was synthesized as a yellow oily substance from ethyl 3-isobutylamino-3-methylthio-2-cyanoacrylate and 2-aminomethyl-4-(p-fluorobenzyl)morpholine according to the same procedure as in Example 8. Yield=22%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][N:13]([CH3:30])[C:14](=[O:29])/[CH:15]=[CH:16]/[C:17]1[CH:18]=[N:19][C:20]([NH:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:21][CH:22]=1.COC(CNC1N=CC(/C=C/C(N(C)CC2C3C(=CC=CC=3)NC=2C)=O)=CC=1)=O>>[C:25]([CH2:24][NH:23][C:20]1[N:19]=[CH:18][C:17](/[CH:16]=[CH:15]/[C:14]([N:13]([CH2:12][C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH3:11])[CH:8]=2)[CH3:30])=[O:29])=[CH:22][CH:21]=1)([OH:27])=[O:26]
Reactant: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2cn(C)c3c(Cl)cccc23)cn1
Agent: COC(=O)CNc1ccc(/C=C/C(=O)N(C)Cc2c(C)[nH]c3ccccc23)cn1
Product: CN(Cc1cn(C)c2c(Cl)cccc12)C(=O)/C=C/c1ccc(NCC(=O)O)nc1
Yield: 100.4 %

Procedure:
According to the procedure of Example 20, except substituting (E)-N-(7-chloro-1-methyl-1H-indol-3-ylmethyl)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methylacrylamide (0.75 g, 1.8 mmole) for the (E)-3-[6-[N-(methoxycarbonylmethyl)amino]pyridin-3-yl]-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)acrylamide, the title compound (0.746 g, 100%) was prepared as a white solid: MS (ES) m/e 413.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23])[CH:11]=[CH2:12].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.CCOCC.O>[CH3:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH:12]=[CH:11][CH2:10][N:13]1[C:17](=[O:18])[C:16]2[C:15](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]1=[O:23]
Reactant: C=CCN1C(=O)c2ccccc2C1=O
Reactant: Cc1cccc(C)c1Br
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cccc(C)c1C=CCN1C(=O)c2ccccc2C1=O
Temperature: 100 °C

Procedure:
A mixture 9.3 g (50 mmole) of 2-bromo-m-xylene, 15.0 g (80 mmole) of N-allylphthalimide, 0.56 (2.5 mmole) of paladium acetate and 1.44 (5.5 mmole) of triphenylphosphine were dissolved in 111 ml of triethylamine. The solution was placed in a sealed container and heated at 100° C. for 24 hours. The reaction was then diluted with 800 ml of ether and 200 ml of water. The aqueous layer was separated and the organic washed twice with 100 ml portions of 2N HCl. After filtering the organic phase, washing with saturated KHCO3 and brine, and drying over MgSO4, it was concentrated on the steam bath. The resulting solid product was purified by flash chromotography and used in subsequent reactions.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[CH2:27]([O:34][CH2:35][C:36](Cl)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][CH2:35][C:36]([N:21]1[CH2:20][CH2:19][C:16]2([C:15](=[O:24])[N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=3)[CH2:18][CH2:17]2)[CH2:23][CH2:22]1)=[O:37])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Solvent: CC(=O)O
Product: O=C(COCc1ccccc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and benzyloxy-acetyl chloride. Off-white solid. MS (ESI): 463.3 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].Cl[C:8]1([F:23])[C:12](Cl)([F:13])[O:11][C:10]([C:19]([F:22])([F:21])[F:20])([C:15]([F:18])([F:17])[F:16])[O:9]1.Cl.O1C=CCO1>O1CCCC1>[F:13][CH:12]1[CH:8]([F:23])[O:9][C:10]([C:15]([F:18])([F:16])[F:17])([C:19]([F:20])([F:21])[F:22])[O:11]1
Reactant: FC(F)(F)C1(C(F)(F)F)OC(F)(Cl)C(F)(Cl)O1
Agent: C1=COOC1
Agent: Cl
Agent: [Al+3]
Solvent: C1CCOC1
Product: FC1OC(C(F)(F)F)(C(F)(F)F)OC1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In a round-bottomed flask was charged lithium aluminum hydride (3.8 g, 0.1 mole) in tetrahydrofuran (75 mL) and the contents was cooled in an ice-water bath at 0° to 5° C. 4,5-Dichloro-4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxolane (31.5 g, 0.1 mole) was added slowly. After the addition was complete, the reaction mixture was stirred at room temperature for 30 minutes. The resulting mixture was neutralized with 4.8N HCl (50 mL), then poured into 300 mL of ice-water. The bottom layer was separated and washed twice with cold water (200 mL). Distillation gave the saturated product 4,5-difluoro-2,2-bis(trifluoromethyl)-1,3-dioxolane (17 g, 69% yield) instead of the unsaturated dioxole product.
Reaction SMILES: C([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[N:25]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:24]=[C:23]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[ClH:41]>C(OCC)(=O)C>[ClH:41].[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[N:25]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[N:24]=[C:23]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH2:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-{3-[4-(N-BOC-amino)-piperidin-1-yl]-phenyl}-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (110.0 mg, 6.6 mmol) prepared in Example 98 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 100.0 mg of the titled compound as a brown liquid.
Reaction SMILES: S([Cl:5])(C)(=O)=O.[F:6][C:7]1[C:8]([O:15][CH3:16])=[C:9]([CH2:13]O)[CH:10]=[CH:11][CH:12]=1>>[Cl:5][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=1[O:15][CH3:16]
Reactant: COc1c(F)cccc1CO
Reactant: CS(=O)(=O)Cl
Product: COc1c(F)cccc1CCl

Procedure:
In an analogous manner to that described in (γ) (3-fluoro-2-methoxy-phenyl)-methanol was treated with mesylchloride to obtain 1-chloromethyl-3-fluoro-2-methoxy-benzene as a colorless liquid; MS: 174 (M)+.