Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@:3]12[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@H:4]1[N:5]([C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:6][CH2:7]2.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C@:3]12[CH2:19][NH:18][CH2:17][C@H:4]1[N:5]([C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:6][CH2:7]2
Reactant: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 5-tert-butyl 1-[(2S)-1,1,1-trifluoropropan-2-yl] (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1,5-dicarboxylate (15 mg) in CHCl3 (0.5 mL) was added TFA (0.5 mL). After stirring for 1 hour at room temperature, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated to give (2S)-1,1,1-trifluoropropan-2-yl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate as a pale yellow foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2cc(NCCc3ccc(S(N)(=O)=O)cc3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[H-].[Na+].Cl[CH2:19][CH2:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>CN(C)C=O>[C:24]1([NH:23][C:21]([CH2:20][CH2:19][N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([CH2:6][C:2]3[NH:3][CH:4]=[CH:5][N:1]=3)=[CH:8]2)=[O:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCCl)Nc1ccccc1
Reactant: c1ccc2c(Cc3ncc[nH]3)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCn1cc(Cc2ncc[nH]2)c2ccccc21)Nc1ccccc1
Reaction time: 18 h
Yield: 35 %

Procedure:
3-(1-Imidazolylmethyl)indole (1.97 g) was dissolved in dry N,N-dimethylformamide (50 ml) and the solution was cooled to °C. Sodium hydride (0.55 g of 50% dispersion in oil) was added portionwise with stirring and the mixture was stirred at 0° C. for 30 minutes. A solution of 3-chloropropionanilide (1.83 g) in dry N,N-dimethylformamide was added dropwise with stirring and the resulting mixture was stirred at 0° C. for 2 hours followed by 18 hours at room temperature. The mixture was evaporated and water was added to the residue. The solid product was filtered off, washed with chloroform to remove impurity and crystallised from methanol to give 1-[2-(N-phenylcarbamoyl)ethyl]-3-(1-imidazolylmethyl)indole (1.20 g), m.p. 254°-255° C. Found: C, 73.14; H, 5.82; N, 15.88. C21H20N4O requires: C, 73.23; H, 5.85; N, 16.27%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19].[BH4-].[Na+]>CO.C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:19][CH2:18][CH2:17][O:16][CH3:15])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 16 h

Procedure:
Amine preparation: 1-BOC-4-piperidone (500 mg) and 2-methoxyethylamine (218 μL) were stirred in MeOH at room temperature. After 16 h, sodium borohydride was added (190 mg) carefully. After a further 3 h, the reaction mixture was diluted with DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (560 mg).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:27]1[CH2:31][CH:30]=[CH:29][CH2:28]1>>[N:27]1([CH:2]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]4[CH2:19][CH2:20][C:21]5[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=54)=[CH:15][N:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH2:31][CH:30]=[CH:29][CH2:28]1
Reactant: C1=CCNC1
Reactant: CC(C)CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Product: CC(C)CC(c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1)N1CC=CC1
Temperature: 60 °C

Procedure:
This compound was prepared from intermediate 229a and 6 equivalents of 3-pyrroline according to the procedure described in Example 171, with the exception of heating to 60° C. Received 83.3 mg (30%)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.Cl[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)[CH2:6][CH2:7]1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCC1CCN(c2nccnc2C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCN(c2nccnc2C2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of [1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give {1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol (142 mg, 0.35 mmol, yield 70.47%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:37]=[C:36]([F:38])[C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:39])[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:25]1[CH:37]=[C:36]([F:38])[C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:27]([F:39])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(Br)cc(F)c1OC1CCOCC1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cc(F)c(OC2CCOCC2)c(F)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-bromo-2,6-difluoro-phenoxy)-tetrahydro-pyran (Intermediate 18) in analogy to Example 1a): MS (ISP): 516.1 and 518.1 (M+H)+, 416.2 and 418.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1)[CH3:16].ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH2:15][CH3:16])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc(N)n(-c2cccc3ncccc23)n1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n(-c2cccc3ncccc23)n1
Temperature: 80 °C
Yield: 57.1 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.064 g, 0.27 mmol) and 3-ethyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.21 mmol) in pyridine (0.5 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol). The reaction mixture was stirred at room temperature for 1 h and the solvent was removed in vacuo. The resulting residue was partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL) and the phases were separated. The aqueous layer was extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.053 g, 0.12 mmol, 58%). 1H NMR (400 MHz, CDCl3) δ 9.00 (d, J=3.6 Hz, 1H), 8.23 (d, J=8.8 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 7.79 (dd, J=8.0, 8.4 Hz, 1H), 7.69-7.65 (m, 2H), 7.59 (dd, J=4.4, 8.8 Hz, 1H), 7.51-7.47 (m, 3H), 6.05 (s, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.37 (s, 9H), 1.29 (t, J=7.6 Hz, 3H); MS: (ES) m/z calculated for C24H27N4O2S [M+H]+ 435.2. found 435.2.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:17](OC)=[O:18].Cl>O1CCCC1.COCCOC>[F:13][C:14]1[CH:15]=[C:16]([C:17](=[O:18])[CH2:3][S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH:21]=[CH:22][C:23]=1[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)cc1F
Reactant: CS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)CS(=O)(=O)c2ccccc2)cc1F

Procedure:
A solution of 864 mg. of sodium hydride and 5.3 g. of methylphenylsulfone in 20 ml. of 1,2-dimethoxyethane is stirred at 60° C. for one hour under an atmosphere of argon. To this solution is then added a solution of 5.0 g. of methyl 3-fluoro-4-(hexadecylamino)benzoate and 50 ml. of tetrahydrofuran and the reaction mixture is stirred at 60° C. for 1.5 hours. The mixture is cooled, poured onto ice, acidified with dilute hydrochloric acid to pH 3 and then extracted with chloroform. The organic layer is separated, washed three times with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated to dryness. The crude solid is chromatographed on silica gel, eluting with methylene chloride to yield 3'-fluoro-4'-(hexadecylamino)-2-(phenylsulfonyl)acetophenone.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:13][CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Reactant: Nc1ccccc1
Product: Clc1cnc2nc(-c3ccc(OCCN4CCOCC4)cc3)[nH]c2c1Nc1ccccc1
Yield: 44 %

Procedure:
By a procedure similar to that of Example 219 but using 6,7-dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) and aniline, the title compound was obtained in 44% yield.
Reaction SMILES: [O-2].[Cd+2:2].[CH2:3]([C:17]([OH:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cd+2:2].[CH2:3]([C:17]([O-:19])=[O:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC(=O)O
Agent: [Cd+2]
Agent: [O-2]
Product: CCCCCCCCCCCCCCC(=O)[O-]
Temperature: 90 °C

Procedure:
Cadmium oxide (0.127 g, 1 mmol) and tetradecylcarboxylic acid (0.500 g) were reacted at 220° C. for 10 min, cooled to 90° C., then a cadmium tetradecylcarboxylate (precursor) was formed. Into said system, toluene (10 ml), trioctylphosphine oxide (3.866 g) and trioctylphosphine (3.7 g) were added. Then a 0.05M aqueous solution of sodium hydrogen telluride (10 ml) was added. After the system was reacted at 90° C. for 3 h, a clear red sol containing CdTe nanoparticle was obtained. Said sol has a typical exciton absorption peak of the CdTe nanoparticles, can result in a quantum size effect and emit a fairly strong red light under the irradiation of a UV lamp.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH2:29][CH2:30][CH2:31][CH3:32])[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:10]=1[C:11]#[N:12])(=[O:5])[CH3:4].Cl>C(O)(C)C.C(O)C>[CH2:29]([C:8]1[N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([OH:28])=[O:27])=[CH:16][CH:15]=2)[C:10]([C:11]#[N:12])=[C:6]([CH:3]([OH:5])[CH3:4])[N:7]=1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCCc1nc(C(C)=O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Product: CCCCc1nc(C(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
68 mg of sodium borohydride were added to a solution of 718 mg of 4-acetyl-2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-5-cyanoimidazole [prepared as described in step (b) above] in a mixture of 20 ml of isopropanol and 10 ml of ethanol, and the resulting mixture was stirred at room temperature for 3 hours. At the end of this time, the pH of the reaction mixture was adjusted to a value of 3 by the addition of 1N aqueous hydrochloric acid, after which the solvent was distilled off under reduced pressure. The resulting residue was mixed with methylene chloride and water, and the methylene chloride layer was separated. The aqueous layer was extracted three times with methylene chloride, and the combined extracts were dried and concentrated by evaporation under reduced pressure. The resulting residue was dissolved in 10 ml of ethyl acetate and allowed to stand at room temperature. The solid which then deposited was collected by filtration and dried, to give 398 mg of the title compound as a colorless powder, melting at 200°-201° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:10]([CH2:20][C:21]2[N:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2.[N:30]#[C:31][NH2:32].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[C:31]([NH:32][C:27]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:20][N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)[CH:17]=[C:9]2[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:26]=1)=[O:29])#[N:30]
Reactant: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(=O)O)n1
Reactant: N#CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)cc(-c1cc(F)ccc1F)n2Cc1cccc(C(=O)NC#N)n1
Temperature: 25 °C
Reaction time: 35 h
Yield: 74.1 %

Procedure:
To a solution of 6-[2-(2,5-difluorophenyl)-5-methoxyindol-1-ylmethyl]pyridine-2-carboxylic acid (70 mg) in dichloromethane (1.8 mL) were successively added cyanamide (8.2 mg), 4-dimethylaminopyridine (48 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg). This mixture was stirred for 35 hours at room temperature. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-methanol) to obtain the title compound (55 mg). 1H-NMR (DMSO-d6) δ ppm: 3.77 (3H, s), 5.37 (2H, s), 6.45 (1H, d, J=7.4 Hz), 6.66 (1H, s), 6.79 (1H, dd, J=2.4, 8.9 Hz), 7.10-7.45 (4H, m), 7.50-7.85 (3H, m). ESI-MS (m/z): 419 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.N#N>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Reactant: O=C([O-])[O-]
Agent: N#N
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1nnc(-c2ccc(F)cc2)n1
Temperature: 82 °C
Yield: 70.9 %

Procedure:
A mixture of 5-(4-fluorophenyl)-2H-tetrazole (6.61 g, 40.3 mmol), K2CO3 (6.68 g, 48.3 mmol), and iodomethane (3.02 mL, 48.3 mmol) in acetonitrile (115 mL) was heated to reflux (ca. 82° C.) for one hour. After cooling, the mixture was concentrated to dryness and the residue was partitioned between water (75 mL) and EtOAc (100 mL). The layers were separated, the aqueous layer was back-extracted with EtOAc (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL). The organic layer was dried over anh. MgSO4, filtered and concentrated to give 9.5 g as a colorless oil that solidified upon standing. The residue was purified by flash chromatography to give 2 main products: Intermediate 35B as the N2 isomer: 5-(4-fluorophenyl)-2-methyl-2H-tetrazole (5.09 g, 70.9% yield) as a white solid: No NOE observed between the methyl group at 4.42 ppm and the aromatic protons; 1H NMR (400 MHz, DMSO-d6) δ ppm 4.42 (s, 3H) 7.33-7.45 (m, 2H) 8.03-8.14 (m, 2H); MS m/z 179.2 (M+H)+; HPLC >99.5%, RT=1.75 minutes.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12](Cl)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1.C(#N)C.[CH2:18]([SH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][N+:7]1[C:12]([S:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]([NH2:14])=[CH:9][N:8]=1
Reactant: SCc1ccccc1
Reactant: C[n+]1ncc(N)cc1Cl
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[n+]1ncc(N)cc1SCc1ccccc1

Procedure:
24.4 parts of 1-methyl-4-amino-6-chloropyridazinium perchlorate in 200 parts of acetonitrile is stirred with 12.4 parts of benzylmercaptan and 20 parts of triethylamine for three hours at 80° C. The solvent is then distilled off at subatmospheric pressure, the residue is treated with about 300 parts of water and the sparingly soluble reaction product is suction filtered. 29.5 parts (89.2% of theory) of 1-methyl-4-amino-6-benzylmercaptopyridazinium perchlorate is obtained; C12H14O4N3SCl, melting point 139° to 141° C.
Reaction SMILES: Cl.[CH2:2]([NH:6][CH2:7][CH2:8][CH2:9]Cl)[CH:3]([CH3:5])[CH3:4].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[N:6]([CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:7][CH2:8][CH2:9][S:23]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)CNCCCCl
Agent: Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCCCN1CC(C)C

Procedure:
3-Aminopropanol was reacted with butyraldehyde according to Method B9a, Step 1 to afford 2-isopropyltetrahydro,1,3-oxazine. The oxazine was reduced according to Method B9a, Step 2 to give N-isobutyl-3-hydroxypropylamine. The 3-hydroxypropylamine was reacted with SOCl2 according to Method B9a, Step 3 to give N-isobutyl-3-chloropropylamine HCl salt. The 3-chloropropylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C1a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyltetrahydro-1,3-thiazine.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[C:18]([O:17][C:13]1[CH2:14][CH2:15][CH2:16][C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCCCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Reaction time: 16 h

Procedure:
A stirred solution of 100 g. of 2-(6-carbethoxyhexyl)cyclopentan-1-one (Example 9) in 250 ml. of acetic anhydride containing 0.940 g. of p-toluenesulfonic acid monohydrate is heated to boiling under partial reflux allowing distillate at 118° C. or less (i.e., acetic acid) to escape through a Vigreaux column equipped with a condenser to collect the distillate. After 16 hours, during which period acetic anhydride is added in portions in order to keep the solvent level at at least 100 ml., the solution is cooled and poured cautiously into a stirred cold mixture of saturated sodium bicarbonate solution (400 ml.) and nexane (250 ml.). The resulting mixture is stirred for an additional 30 minutes during which period solid sodium bicarbonate is added periodically to insure a basic solution. The hexane layer is separated and washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation of the residual oil gives 102 g. (87%) of pale yellow oil, b.p. 118° C. (0.07 mm.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:2].CC1C=CC(S(O[CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:10]([C:5]1[CH:6]=[C:7]([O:9][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[O:19])[CH:13]=1)[CH3:11]
Reactant: CCc1cc(O)cc(CC)c1-c1cccc(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCCCS(C)(=O)=O)cc(CC)c1-c1cccc(C=O)c1
Temperature: 90 °C
Reaction time: 70 h
Yield: 79.6 %

Procedure:
To a solution of 2′,6′-diethyl-4′-hydroxybiphenyl-3-carbaldehyde (2.44 g, 9.59 mmol) and 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (3.36 g, 11.5 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.73 g, 12.5 mmol), and the mixture was stirred at 90° C. for 70 hr under nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (2.86 g, yield 80%) as a pale-yellow oil.