Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:9](OC)=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1.C(Cl)Cl.O>[NH2:2][CH2:1][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(C#N)CCCCC1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: NCC1(CO)CCCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a stirred solution of methyl 1-cyanocyclohexanecarboxylate (2 g, 11.96 mmol) in anhydrous THF (40 mL) at rt was added portionwise LiAlH4 (1.36 g, 35.88 mmol). The reaction vessel was sealed and the mixture was heated at 80° C. for 5 h. The mixture was cooled to 0° C. and water (1 mL), 1M aq NaOH (1 mL), and water (3 mL) were added sequentially. To the resulting mixture were added DCM and saturated aq sodium potassium tartrate, and the mixture was stirred for 3 h. The organic layer was separated and further washed with brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to afford (1-(aminomethyl)cyclohexyl)methanol (1 g) which was not purified further. LCMS (ESI) m/z 144 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][OH:41]>CC(C)=O>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([CH2:39][CH2:40][OH:41])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: OCCBr
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCN1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 324 (50 mg, 0.118 mmol) in acetone was added potassium carbonate (32 mg, 0.236 mmol) and 2-bromo ethanol (17.7 mg, 0.141 mmol), and stirred for 12 h at 60° C. The reaction was filtered through celite bed and washed with ethyl acetate. The organic layer was concentrated to get the crude, which was purified by neutral alumina and the compound was eluted at 2% methanol in chloroform as half white coloured solid 2-(4-(4-(3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)piperidin-1-yl)ethanol 348. 1HNMR (400 MHz, DMSO) δ: 11.93 (s, 1H), 8.54 (d, 1H), 8.38 (m, 2H), 7.99 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.43 (d, 1H), 4.39 (m, 1H), 4.11 (m, 1H, 3.50 (m, 2H), 2.97 (d, 2H), 2.43 (m, 2H), 2.14 (m, 2H), 1.96 (m, 4H) and MS ES+468.0.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[NH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:23])[CH2:18][CH2:17]1>>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[CH3:10]
Reactant: NCCC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: CCOc1c(OCC)c(=O)c1=O
Product: CCOc1c(NCCC2CCN(C(=O)OCc3cc(Cl)cc(Cl)c3)CC2)c(=O)c1=O

Procedure:
The title compound was prepared from 3,4-diethoxycyclobut-3-ene-1,2-dione and 3,5-dichlorobenzyl 4-(2-aminoethyl)piperidine-1-carboxylate (step 1) analogously to Example 2;
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]1[C:11]([O:13]C)=O>C(N)CCC>[CH2:3]([NH:4][C:11]([CH:3]1[CH:2]([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1)=[O:13])[CH2:2][CH2:10][CH3:9]
Reactant: COC(=O)C1Nc2ccccc2C1C
Solvent: CCCCN
Product: CCCCNC(=O)C1Nc2ccccc2C1C

Procedure:
Methyl 3-(R/S)-methylindoline-2(R/S)-carboxylate (3.60 g, 18.8 mmol) was dissolved in butylamine (100 ml) under nitrogen and the solution was then stirred at reflux for 3 hours. After cooling the mixture, the remaining butylamine was removed under vacuum. The crude product was purified by chromatography on a column of silica gel, using a 7/3 and then a 5/5 petroleum ether/ethyl acetate mixture as eluent. Two main fractions were collected. The first was a white solid which is the trans isomer.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][CH:14]=1)=[O:12].[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[CH3:21][C:22]1[S:23][C:24]([C:30]2[CH:31]=[C:32]([CH3:36])[CH:33]=[CH:34][CH:35]=2)=[C:25]([C:27]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][CH:14]=2)=[O:12])=[O:28])[N:26]=1
Reactant: O=C(NC[C@H]1NC[C@@H]2CCC[C@@H]21)c1cnc2sccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2cnc3sccn23)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: OB(O)c1cccnc1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(-c2cccnc2)nc(N2CCOCC2)n1
Yield: 63.5 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol), 3-pyridylboronic acid (92 mg, 0.75 mmol), PdCl2(dppf) (28 mg), and aq. Na2CO3 (2M, 4 mL) in dioxane (20 mL) was heated under reflux under nitrogen for 1 hr. After cooling, the mixture was diluted with water, extracted with CH2Cl2, and dried. Chromatography on alumina, eluting with CH2Cl2, gave 0.13 g (64% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(3-pyridinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp (MeOH) 199-201° C.; 1H NMR (DMSO-d6) δ 9.59 (d, J=1.6 Hz, 1H), 8.85 (dd, J=4.8, 1.7 Hz, 1H), 8.75 (td, J=8.0, 1.9 Hz, 1H), 8.50 (d, J=8.2 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.86 (t, JHF=52.6 Hz, 1H), 7.65 (ddd, J=8.0, 4.8, 0.7 Hz, 1H), 7.59 (dt, J=7.8, 1.1 Hz, 1H), 7.49 (dt, J=7.6, 1.1 Hz, 1H), 4.09 (m, 2H), 3.94 (m, 2H), 3.79 (m, 4H); Anal. Calcd. for C20H17F2N7O: C, 58.7; H, 4.2; N, 23.95. Found: C, 58.45; H, 4.1; N, 24.2%.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)cc1C(F)(F)F
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)cc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-2-trifluoromethylphenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C17H10ClF3N4, 364. Found, 363, 365.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([O:21]CC)=[O:20])[CH:16]=[N:15]3)=[CH:12][C:3]1=2>CO.[OH-].[Na+]>[CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[N:15]3)=[CH:12][C:3]1=2
Reactant: CCOC(=O)c1cnn(Cc2ccc3c(c2)N(C)C(=O)CO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)COc2ccc(Cn3cc(C(=O)O)cn3)cc21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Ethyl 1-((4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-1H-pyrazole-4-carboxylate (780 mg, 0.618 mmol) was dissolved in a mixture of MeOH (5 ml) and 1N NaOH (5.00 ml). The reaction mixture was stirred for 2 hr at 20° C. and the MeOH was removed by evaporation under reduced pressure. The aqeuous phase was washed with AcOEt, then acidified with HCl and extracted with AcOEt. The organic layer was concentrated under reduced pressure to afford the title compound. HPLC (Method H) Rt=2.636 min; MS (Method A) [M−H]−=286.1
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH:15]=O)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.C(O)(=O)C>CO.CN1C(=O)N(C)CCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:14]=[C:13]([CH2:15][NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[NH:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=Cc1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: COc1ccc(CN)cc1
Agent: [Ni]
Solvent: CN1CCCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCc2cc3c(Nc4cccc(Cl)c4)ncnc3[nH]2)cc1

Procedure:
273 mg (1.00 mmol) of 4-(3-chloroanilino)-6-formyl-7H-pyrrolo[2,3-d]pyrimidine (stage 1.6) and 156 ml (1.2 mmol) of 4-methoxybenzylamine in 10 ml of methanol, DMPU and 126 μl (2.2 mmol) of acetic acid are stirred at RT for 1 h. 0.1 g of Raney nickel is then added and the mixture is hydrogenated at RT and finally at 50° C. The catalyst is filtered off, the filtrate is evaporated and the residue is dissolved in ethyl acetate and satd Na2CO3 solution. The aqueous phase separated off is extracted twice with ethyl acetate; the organic phases are washed with satd NaHCO3 solution, and twice with water and brine, dried (MgSO4) and evaporated. Stirring the residue in diethyl ether yields 4-(3-chloroanilino)-6-[(4-methoxybenzylamino)-methyl]-7H-pyrrolo[2,3-d]pyrimidine; HPLC: tRet(Grad20)=9.5; TLC-Rf=0.17 (CH2Cl2/methanol=10:1); FAB-MS: (M+H)+=394.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36][SH:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[C:8]([S:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:33][CH:34]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(CS)cc1
Reactant: CC(C)(C)n1ncc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 2-tert-butyl-4-tert-butyldimethylsilyloxymethyl-5-chloro 3(2H)-pyridazinone (1.5 g, 4.54 mmol) in DMF (10 ml) is added anhydrous cesium carbonate (2.9 g, 9.09 mmol) and 4-tert-butybenzyl mercaptan (1.02 g, 4.54 mmol). The mixture is stirred for 2 hours at 70° C. and then cooled to room temperature and ethyl acetate is added to it. The solution is then washed with water, dried and concentrated and the residue subjected to purification by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH2:21])[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[N:12]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:41])([F:40])[C:24]([C:26]1[S:30][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[CH:28][CH:27]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]3([CH2:20][NH:21][C:34](=[O:35])[C:33]4[CH:37]=[CH:38][CH:39]=[C:31]([C:29]5[S:30][C:26]([C:24](=[O:25])[C:23]([F:22])([F:40])[F:41])=[CH:27][CH:28]=5)[CH:32]=4)[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: CN1CCC(CN)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc(C(=O)C(F)(F)F)s3)c2)(c2csc(-c3ccc(Cl)cc3)n2)CC1
Yield: 4 %

Procedure:
This compound was synthesized from (4-(2-(4-chlorophenyl)thiazol-4-yl)-1-methylpiperidin-4-yl)methanamine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 8 step 6 (8.5 mg, yield 4%). 1H NMR (400 MHz, DMSO-d6) δ 8.54 (m, 1H), 8.14-8.13 (m, 2H), 8.00-7.86 (m, 4H), 7.82-7.77 (m, 1H), 7.70 (m, 1H), 7.60-7.56 (m, 1H), 7.48-7.46 (m, 2H), 3.50 (m, 2H), 3.39-3.17 (m, 4H), 2.57 (m, 3H), 2.43 (m, 2H), 2.08 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
33.0 g (0.1 mol) of benzyl 4'-acetyl-4-biphenylcarboxylate, 200 ml of tetrahydrofuran and 50 ml of ethanol were supplied into the same flask as used in Example 9. Then 3.8 g (0.1 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. After standing at the same temperature for 2 hours, the reaction solution was poured into ice-water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and concentrated under reduced pressure to obtain 32.9 g (99% yield) of benzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-15).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:22]=[CH:21][C:11]([C:12]([NH:14][C@H:15]3[C@H:19]([OH:20])[CH2:18][NH:17][CH2:16]3)=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([N:17]1[CH2:18][C@@H:19]([OH:20])[C@H:15]([NH:14][C:12](=[O:13])[C:11]2[CH:21]=[CH:22][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)[CH2:16]1)=[O:37]
Reactant: O=C(N[C@@H]1CNC[C@H]1O)c1ccc(-c2cccc(F)c2)nc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)N1C[C@@H](O)[C@H](NC(=O)c2ccc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of trans-6-(3-fluorophenyl)-N-[4-hydroxypyrrolidin-3-yl]nicotinamide (50 mg, 0.15 mmol) in DMF (1.0 mL) was added DIPEA (95 mg, 0.32 mmol) and pivaloyl chloride (66 mg, 0.24 mmol). After stirring at rt overnight the mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and the solvent removed to give an oil, which after chromatography (silica, 1% MeOH/EtOAc) gave the product (36 mg, 63%). HRMS (M+H)=386.1880 expected, 386.1914 observed.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(Cl)C(F)=S.Cl.[CH3:19][N:20]([S:24]SC1C=CC(Cl)=CC=1)[C:21]([F:23])=[O:22]>CCCCC>[CH3:19][N:20]([S:24][S:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[C:21]([F:23])=[O:22]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: CN(SSc1ccc(Cl)cc1)C(=O)F
Agent: CN(Cl)C(F)=S
Agent: Cl
Solvent: CCCCC
Product: CN(SSc1ccc(C(C)(C)C)cc1)C(=O)F

Procedure:
Prepared by reacting 0.5 g of 4-t-butylthiophenol in pentane with 0.44 g of N-methyl-N-chlorothiocarbamoyl fluoride. The reaction proceded with a vigorous exotherm and evolution of hydrochloric acid gas. The infrared and n.m.r. spectra of the product was identical to the material prepared by Method I.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)=[N:5][N:6]([CH3:12])[C:7]=1[N:8]=[CH:9]OC)#[N:2].[CH3:22][NH:23][NH2:24].C(C1C(C2N(C)C([N+]([O-])=O)=CN=2)=NN(C)C=1N=CO)#N>C(O)C>[CH3:22][NH:23][NH:24][CH:9]=[N:8][C:7]1[N:6]([CH3:12])[N:5]=[C:4]([C:13]2[N:14]([CH3:21])[C:15]([N+:18]([O-:20])=[O:19])=[CH:16][N:17]=2)[C:3]=1[C:1]#[N:2]
Reactant: CNN
Reactant: COC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C
Agent: Cn1nc(-c2ncc([N+](=O)[O-])n2C)c(C#N)c1N=CO
Solvent: CCO
Product: CNNC=Nc1c(C#N)c(-c2ncc([N+](=O)[O-])n2C)nn1C

Procedure:
A mixture of 1.0 g. of methyl N-[4-cyano-1-methyl-3-(1-methyl-5-nitro-2-imidazolyl)pyrazol-5-yl]formimidate, 1 ml. of methyl hydrazine, and 10 ml. of ethanol was stirred at ambient room temperature for about 1 hour. The reaction product mixture was filtered. The solid which was recovered was recrystallized from ethanol to yield product in the form of yellow needles having a melting point of about 232°-234° C. The product was identified by NMR spectrum and elemental analyses as N-[4-cyano-1-methyl-3-(1-methyl-5-nitroimidazol-2-yl)pyrazol-5-yl]formimidic acid, 2-methyl hydrazine.
Reaction SMILES: OC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.S(=O)(=O)(O)O.[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH:32]=[C:33]([C@@H:35]([C@H:37]([C@@H:39]([C@@H:41]([CH2:43][OH:44])[OH:42])[OH:40])[OH:38])[OH:36])[OH:34]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=[C:43]([OH:44])[C@@H:41]([OH:42])[C@@H:39]([OH:40])[C@H:37]([OH:38])[C@@H:35]([OH:36])[C:33](=[CH:32][C:31]1[CH:45]=[CH:46][C:47]([Cl:48])=[C:29]([Cl:28])[CH:30]=1)[OH:34]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC(=Cc1ccc(Cl)c(Cl)c1)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccc(Cl)c(Cl)c1
Temperature: 21 °C
Reaction time: 6 h
Yield: 0.5 %

Procedure:
A 500 ml four-necked flask was charged with a 70 wt % aqueous solution of 52 g (0.20 mole) of D-sorbitol, 35.0 g (0.20 mole) of 3,4-dichlorobenzaldehyde and 6 g of 50 wt % sulfuric acid. The air inside the system was replaced with nitrogen gas. The contents of the flask were stirred at a temperature of 21° C. for 6 hours. The obtained reaction mixture was analyzed by GC. It was found that mono(3,4-dichlorobenzylidene)-D-sorbitol was produced in a yield of 70% and 0.5% or less of bis(3,4-dichlorobenzylidene)-D-sorbitol was also produced. After standing for 24 hours, the reaction mixture was neutralized for 2 hours using 8.6 g of potassium hydroxide, and filtered to obtain cake. The cake was dispersed in 150 ml of toluene and was filtered again. After drying at 100° C. under a pressure ranging from normal pressure to 5 mmHg for 7 hours, 19.7 g of 2,4-O-(3,4-dichlorobenzylidene)-D-sorbitol was obtained with a purity of 99.2% as measured by GC (yield 29.2%). The product had a melting point of 202 to 205° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[C:21]#[N:22])=[O:15])[C@H:12]2[CH2:23][C@@H:9]1[C@H:10]([O:24][CH2:25][C:26](O)=[O:27])[CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31].N12CCCN=C1CCCCC2>CN(C)C=O>[C:21]([C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14]([C@@H:13]1[C@H:12]2[CH2:23][C@H:9]([C@H:10]([O:24][CH2:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:27])[CH2:11]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:15])#[N:22]
Reactant: CS(N)(=O)=O
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)O)[C@H]1C(=O)N1CCC[C@H]1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC(=O)NS(C)(=O)=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [((1R,3S,4S,6R)-2-(tert-butoxycarbonyl)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-2-azabicyclo[2.2.1]hept-6-yl)oxy]acetic acid obtained in Example 15-2 (195 mg) in dimethylformamide (2.5 mL), was added 1,1′-carbonyldiimodazole (165 mg). The mixture was stirred at room temperature. After 30 minutes, methanesulfonamide (66 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene (106 mg) were added, and the resulting mixture was stirred at room temperature for 12 hrs.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[N:7]=[C:8]([CH3:10])[S:9][C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:18])C(=O)C1>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:10][C:8]1[S:9][C:5]2[S:4][CH:3]=[C:2]([Cl:1])[C:6]=2[N:7]=1
Reactant: Cc1nc2c(Cl)csc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: Clc1csc2sc(CBr)nc12
Temperature: 75 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To a solution of 310 mg(1.62 mmol) of 6-chloro-2-methylthieno[3,2-d]thiazole (from Step 2) and 10 mg of benzoyl peroxide in 15 ml of CC14 was added 306 mg(1.72 mmol) of NBS at r.t. The mixture was stirred at 75° C. under radiation from a sunlamp for 30 min. The solid was filtered, the solution was evaporated to dryness and the residue purified on silica gel with hexane/EtOAc=8:1 to give 300 mg (69%) of the title product. 1H NMR (CDCl3) 7.35(s, 1H), 4.80(s,2H).
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.C(OC([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.[Na]>C(Cl)Cl>[N:30]1([CH:11]2[CH2:12][CH2:13][CH2:14][NH:9][CH2:10]2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: O=C1CCCN(Cc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CNCC(N2CCNCC2)C1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.3 %

Procedure:
1-Benzyl-3-piperidone hydrochloride (700 mg, 2.7 mmol), triethylamine (270 mg, 2.7 mmol) and 1-(tert-butoxycarbonyl)-piperizine (500 mg, 2.7 mmol) in DCM, was stirred at rt for 1 h, then heated to 50° C. for 40 min. Sodium triacetoxyborahydride (1.12 g, 5.3 mmol) was added and the reaction mixture allowed to cool, with stirring, over 12 h then concentrated to dryness in vacuo. The residue was partioned between DCM/water, the organics dried (MgSO4) and concentrated to dryness in vacuo. The resulting residue in EtOH (10 ml) was hydrogenated with 10% w/w palladium on carbon (200 mg) under hydrogen at rt for 18 h. The reaction was filtered through celite and concentrated to dryness in vacuo to give 3-piperazine-1-yl-piperidine as a pale yellow gum (700 mg, 2.6 mmol, 97%). 8H (CDCl3, 300K) 3.43-3.37 (4H, m br), 3.21 (1H, d br, J=11.6 Hz), 3.01 (1H, d br, J=12.2 Hz), 2.59-2.47 (6H, m br), 2.45-2.38 (1H, m), 1.99-1.92 (1H, m br), 1.82-1.75 (1H, m), 1.58-1.48 (1H, m), 1.45 (9H, s), 1.42-1.33 (1H, m). m/z (ES+, 70V) 270.3 (MH+).
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[C:4](=[O:7])[O:3][C:2]2=[O:8].[CH3:9][OH:10]>C(N(CC)CC)C>[CH3:9][O:10][C:4]([CH:5]1[CH2:6][CH:1]1[C:2]([OH:8])=[O:3])=[O:7]
Reactant: O=C1OC(=O)C2CC12
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1CC1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Oxabicyclo[3.1.0]hexane-2,4-dione (766 mg) was added to methanol (10 mL) at 0° C. After addition of triethylamine (0.953 mL), the mixture was stirred at room temperature for 1 hr. The solvent was evaporated. The residue was dissolved in ethyl acetate, washed with 1 N hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (460 mg) as a colorless oil.