Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].C=O.[CH3:14]N(C)C.CCCCCCC>O>[CH2:14]=[N:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: CN(C)C
Agent: C=O
Solvent: O
Solvent: CCCCCCC
Product: C=Nc1c(CC)cccc1CC

Procedure:
2,6-Diethylaniline (149.2 grams; 1.0 mole), paraformaldehyde (40 grams), a 25% solution of trimethylamine (1.7 grams) and heptane were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser connected to a Dean-Stark trap. The reaction mixture was heated and the water formed removed by azeotropic distillation. When no more water could be removed, the reaction mixture was stripped of solvent and distilled to yield the desired product N-methylene-2,6-diethylaniline as a colorless oil having a boiling point of 65°C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(CCNC(=O)c2ccc(Br)cc2)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(c1)CCN=C2c1ccc(Br)cc1
Temperature: 80 °C
Yield: 98.1 %

Procedure:
50 g of 4-bromo-N-[2-(3-methoxy-phenyl)-ethyl]-benzamide are dissolved in 750 ml of acetonitrile and treated under argon with 55 ml of phosphorus oxychloride. After heating to 80° C. the majority of the solvent is removed and the residue is adjusted to pH >12 with concentrated ammonia solution and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried and concentrated. There are obtained 46.4 g of 1-(4-bromo-phenyl)-6-methoxy-3,4-dihydro-isoquinoline, MS: m/e 314 (M+, 1 Br).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](Cl)[CH:5]=[C:4]([CH3:10])[C:3]=1[OH:11].[N+]([O-])(O)=[O:13]>C(O)(=O)C>[CH3:1][C:2]1[C:3](=[O:11])[C:4]([CH3:10])=[CH:5][C:6](=[O:13])[C:7]=1[CH3:8]
Reactant: Cc1cc(Cl)c(C)c(C)c1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
17.0 g (0.1 mole) of 2,3,6-trimethyl-4-chlorophenol obtained in Example 1 (A) was dissolved in 100 g of acetic acid, and 10 g of concentrated nitric acid was added dropwise thereto in 30 minutes under stirring. The reaction proceeded immediately. After stirring for another 30 minutes, the reaction solution was subjected to steam distillation. The same treatment as in Example 1 was conducted to obtain 13.8 g of 2,3,6-trimethyl-p-benzoquinone (92.0 percent in yield).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:25])[NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([CH2:15][NH:14][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[O:25])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc2c(c1)OCO2)C1CCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.8 %

Procedure:
2-[(Benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (278 mg, 0.80 mmol) was dissolved in DCM:TFA (1:1, 6 mL) and stirred at room temperature for 3 hours. After this period, the solution was concentrated down under vacuum. The crude material was diluted in DCM (50 mL) and washed with 1M NaOH (aq) (50 mL) to afford the crude residue. The crude product was purified by Flash chromatography (0-10% methanol/DCM gradient) to afford 85.1 mg (43%) of pyrrolidine-2-carboxylic acid (benzo[1,3]dioxol-5-ylmethyl)-amide. [M+H]+ 249.08.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].S(=O)(=O)(O)O.O.[CH3:21]O>>[OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:21])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: CO
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)/C=C/c1ccc(O)c(OC)c1
Yield: 97 %

Procedure:
To a solution of (E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid (3.0 g, 15 mmol) in methanol (30 mL) was added sulfuric acid (0.5 mL), and the mixture was heated under reflux for 12 hours. After the reaction solution was returned to room temperature, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure to give the title compound (3.1 g, yield 97%) as an oily matter. The obtained compound was used in the next reaction without purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7]C(=O)C)=[C:5]([C:11]#[C:12][Si](C)(C)C)[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.C([OH:25])C.[OH-].[Na+]>C(OCC)(=O)C.O>[NH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:11](=[O:25])[CH3:12]
Reactant: CC(=O)Nc1c(C#C[Si](C)(C)C)c(-c2ccccc2)nn1C
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1c(-c2ccccc2)nn(C)c1N
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A mixture of N-(1-methyl-3-phenyl-4-((trimethylsilyl)ethynyl)-1H-pyrazol-5-yl)acetamide (2.3 g, 7.4 mmol), ethanol (20 mL) and 25% aq. NaOH solution (20 mL) was heated with stirring at 90° C. for 6 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. The residue was purified using chromatography (silica gel, gradient 0 to 40% ethyl acetate/CH2Cl2), followed by trituration in diethyl ether to provide the title compound as a white solid (724 mg).
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=O)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([NH:34][S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=2)(=[O:32])=[O:33])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NS(=O)(=O)c2ccc(C)cc2)o1

Procedure:
The title compound was prepared as described in Example 1 starting from 0.228 g (0.7 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid and 0.361 g (2.1 mmol) of 4-methylbenzenesulfonamide. MS (m/z, ES−): 476.63 (M−1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[CH:19][NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4=[C:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[NH:20][CH:21]=[C:15]4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2c[nH]cc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: c1nnn[nH]1
Product: CC1c2c[nH]c(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 52, (6-bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-2,4,6,7-tetrahydro-pyrrolo[3,4-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[C:9](=[S:11])=[S:10].[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:9](=[S:10])[SH:11])=[N:3][CH:4]=1
Reactant: S=C=S
Reactant: Cc1ccc(N)nc1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=S)S)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
2-Amino-5-methylpyridine (21.6 g., 0.2 mol.) was suspended in triethylamine (60 ml.) and carbon disulphide (30 ml.) was added. The mixture was shaken at room temperature for 3 hours. The pale yellow solid precipitate was filtered off and washed with ether to give 5-methyl-2-pyridyldithiocarbamic acid triethylamine salt (37.7 g., 66%). This material was suspended in ethanol (100 ml.) and stirred at room temperature. Benzyl chloride (16.5 g., 15 ml.) was added dropwise. After 2 hours, a clear solution was obtained. Water was added and the precipitated benzyl ester collected. After washing with water and petrol ether (40°-60° C.), the product weighed 33.8 g. (m.pt. 141° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([Si:20]([C:41]2[CH:46]=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:44]([O:51][Si](C)(C)C)=[C:43]([C:56]([CH3:59])([CH3:58])[CH3:57])[CH:42]=2)([C:22]2[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:25]([O:32][Si](C)(C)C)=[C:24]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:23]=2)[OH:21])[CH:8]=[C:9]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[O:11][Si](C)(C)C)([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:37]([C:24]1[CH:23]=[C:22]([Si:20]([C:41]2[CH:42]=[C:43]([C:56]([CH3:59])([CH3:58])[CH3:57])[C:44]([OH:51])=[C:45]([C:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=2)([C:7]2[CH:8]=[C:9]([C:16]([CH3:17])([CH3:18])[CH3:19])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[OH:21])[CH:27]=[C:26]([C:28]([CH3:31])([CH3:29])[CH3:30])[C:25]=1[OH:32])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)c1cc([Si](O)(c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc([Si](O)(c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a stirred solution of 0.40 g (0.45 mmol) of tris-(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)hydroxysilane in 3 ml of tetrahydrofuran at 0° C. is added dropwise a solution of 0.43 g (1.37 mmol) of tetrabutylammonium fluoride trihydrate in 3 ml of tetrahydrofuran. The reaction mixture is stirred for 5 minutes at 0° C. and to it is added dropwise a solution of 0.19 g of concentrated hydrochloric acid in 1 ml of tetrahydrofuran. The solvent is removed in vacuo and the residue is dissolved in 30 ml of diethylether. The solution is extracted (3×25 ml) with water. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to give 0.29 g of a white amorphous solid. The crude product is purified by preparative thin layer chromatography (silica gel, 7:3, heptane:ethyl acetate eluent) followed by crystallization from a heptane/toluene solvent mixture to give 0.14 g (46%) of product as a white solid; mp. 257°-258 ° C.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[C:19]([Cl:21])[C:18]([O:22][CH2:23][CH3:24])=[C:17]([Cl:25])[CH:16]=1)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:21][C:19]1[CH:20]=[C:15]([NH2:14])[CH:16]=[C:17]([Cl:25])[C:18]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1c(Cl)cc(NC(=O)OC(C)(C)C)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOc1c(Cl)cc(N)cc1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Trifluoroacetic acid (5 mL) is added to solid (3,5-dichloro-4-ethoxy-phenyl)-carbamic acid tert-butyl ester (0.97 g) and the mixture is stirred for approximately 45 minutes at room temperature. Water is then added, and the mixture is cooled in an ice bath and basified with solid potassium carbonate. The solution is extracted three times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium chloride then dried over anhydrous sodium sulfate. Concentration under reduced pressure and recrystallization from hexanes provides the desired product as a pale yellow crystalline solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[CH3:2].F[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1.CCOCC>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:13]=[CH:12][C:11]2[C:10]([CH3:15])([CH3:14])[CH2:9][CH:8]=[C:7]([CH2:16][CH3:17])[C:6]=2[CH:5]=1)[C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][N:20]=1)[CH3:2]
Reactant: O=C(O)c1ccc(F)nc1
Reactant: CCNc1ccc2c(c1)C(CC)=CCC2(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1=CCC(C)(C)c2ccc(N(CC)c3ccc(C(=O)O)cn3)cc21
Temperature: 125 °C
Yield: 4.2 %

Procedure:
To a mixture of 0.35 g (1.5 mmol) ethyl-(8-ethyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-amine (Compound 167 and 0.32 g (2.2 mmol) of 6-fluoro-nicotinic acid was added a small amount of ether and toluene to help stirring. The resulting mixture was heated at 100-150° C. for 1 h. The mixture was cooled. The product was purified by flash chromatography (silica, 50% ethyl acetate in hexanes) followed by recrystallization using ethyl acetate:hexane (1:1) to give the title compound as white crystals (22 mg).
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21](O)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=2[CH:36]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:1]1([S:6]([C:9]2[CH:10]=[C:11]([C:15]3[N:23]4[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]5[CH:27]=[CH:28][C:29]6[N:33]=[C:32]([CH2:34][OH:35])[NH:31][C:30]=6[CH:36]=5)=[N:22]4)=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1)N1CCCC1

Procedure:
(6-{7-[3-(Pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-1H-benzoimidazol-2-yl)-methanol was prepared from 7-[3-(pyrrolidine-1-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow foam (57 mg, 40%). LCMS (m/e) 490 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.23-12.01 (m, 1H), 9.47-9.35 (m, 1H), 9.05-8.99 (m, 1H), 8.77-8.61 (m, 1H), 8.35-8.26 (m, 1H), 7.91-7.70 (m, 3H), 7.62-7.37 (m, 2H), 7.32-7.24 (m, 1H), 7.01-6.94 (m, 1H), 5.67-5.58 (m, 1H), 4.70-4.62 (m, 2H), 3.22-3.12 (m, 4H), 1.69-1.60 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]2[C:9](=[O:30])/[C:10](=[CH:12]/[C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15](COCC[Si](C)(C)C)[N:14]=3)/[O:11][C:7]=2[C:6]=1[CH2:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[NH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](/[CH:12]=[C:10]2\[O:11][C:7]3[C:6]([CH2:33][N:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:36][CH2:35]4)=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:32]=[CH:31][C:8]=3[C:9]\2=[O:30])=[N:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
A solution of tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.100 g, 0.154 mmol) obtained in Step 3 in THF (1 mL) was added with a 1 M solution of tetrabutylammonium fluoride in THF (1.54 mL, 1.54 mmol), and the mixture was refluxed for 3 hours by heating. The reaction mixture was cooled to room temperature, and then added with water (20 mL), the mixture was extracted three times with ethyl acetate, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-(2-hydroxyethoxy)-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0440 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7](Cl)(=[O:9])[CH3:8]>C1(C)C=CC=CC=1>[C:7]([N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)(=[O:9])[CH3:8]
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)n1cnc(C)c1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of 50 g (609 mmol) of 4-methylimidazole in 250 ml of toluene was stirred at room temperature under nitrogen and 239 g (304 mmol) of acetyl chloride was added. The mixture was stirred at room temperature for 5 hours, filtered to remove insolubles and the filtrate concentrated giving 19 g (50%) of 1-acetyl-4-methyl-imidazole as a yellow oil which crystallizes on standing. nmr (CDCl3) (δ): 8.06 (s, 1H); 7.17 (s, 1H); 2.57 (s, 3H); 2.23 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5](/[CH:7]=[CH:8]/[C:9]2[C:10]([O:20]COC)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[N:6]=1.[ClH:24]>CO>[ClH:24].[CH3:1][C:2]1[S:3][CH:4]=[C:5](/[CH:7]=[CH:8]/[C:9]2[C:10]([OH:20])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[N:6]=1
Reactant: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C)n1
Agent: Cl
Solvent: CO
Product: Cc1nc(/C=C/c2cn(-c3ccccc3)nc2O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-methyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole (2.72 g) in methanol (30 mL) was added concentrated hydrochloric acid (1.00 mL) at room temperature, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was evaporated under reduced pressure, and the residue was washed with ethyl acetate-methanol to give 4-[(E)-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol.hydrochloride (2.30 g, yield 90%) as pale-yellow crystals. melting point: 211-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[F:11].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(Br)c(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (3.00 g, 12.6 mmol) and anisole (1.65 mL, 1.65 g, 15.2 mmol, 1.20 eq) in DCM (30 mL) at −5° C. was added, portion-wise, over 5 minutes, AlCl3 (2.54 g, 19.0 mmol, 1.50 eq) as a powder. The reaction was stirred at −5° C. for 2 h. The reaction was poured onto a mixture of 1 N HCl (100 mL) and ice (200 g) and stirred for 1 h. The DCM layer washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL) then dried (MgSO4) and concentrated. The resulting white solid was triturated with ˜100 mL hexanes, filtered and air-dried overnight to afford 3.26 g (83%) of compound 185. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3 H), 7.11 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 1 H), 7.78 (d, J=8.9 Hz, 2H), 7.91 (t, J=7.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH3:18][C:19]1[N:20]=CNC=1CSCCN>C(O)C>[C:1]([NH:3][C:4]([NH:20][CH2:19][CH3:18])=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])#[N:2]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Solvent: CCO
Product: CCNC(=NCCSCc1[nH]cnc1C)NC#N

Procedure:
Anhydrous ethylamino (9.0 g) was added to a solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (5.0 g), prepared from 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole by the procedure of Example 97, in ethanol. The solution was heated under reflux for 8 hours and concentrated under reduced pressure. The residue was dissolved in isopropyl alcohol, filtered, and diluted with water. The white solid obtained was recrystallised from isopropyl alcohol-ether to yield N-cyano-N'-ethyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine, m.p. 118°-120°. (Found: C, 49.6; H, 6.8; N, 31.2; S, 11.7. C11H18N6S requires: C, 49.6; H, 6.8; N, 31.6; S, 12.0).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([O:11][C:12](=[O:18])[C:13](OCC)=[O:14])[CH3:10].CC[O-].[Na+]>>[CH2:9]([O:11][C:12](=[O:18])[C:13](=[O:14])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:1]1=[O:8])[CH3:10]
Reactant: O=C1CCCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)C1CCCCCC1=O
Temperature: 25 °C
Yield: 52.3 %

Procedure:
Cycloheptanone (1.9998 g, 17.8 mmol) and diethyloxalate (2.42 mL, 17.8 mmol) were mixed together, and then added to a solution of NaOEt (˜3 M, 5.94 mL) stirring in an ice bath under N2. After stirring for 15 minutes, the reaction was warmed to room temperature and stirred overnight. The reaction was quenched at 0° C. with 1N HCl and extracted 2× with CH2Cl2. The combined organics were washed with H2O, dried with Na2SO4, filtered, and concentrated to yield crude 13. The crude material was purified with 1:1 Hexanes:CH2Cl2 to obtain 1.9775 g (52.3%) of 13. Note: The product was still not completely pure at this point, but was carried on to the next step. 1H (CDCl3, 400 MHz): δ 4.31 (2H, q, J=7.3 Hz), 2.66-2.58 (2H, m), 2.48-2.43 (2H, m), 1.77-1.59 (6H, m), 1.34 (3H, t, J=7.3H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1.[F:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24](F)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:24]3[CH:23]=[N:22][CH:21]=[C:20]([F:19])[CH:25]=3)=[CH:15][CH:14]=[C:13]([CH3:18])[N:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)cn2)n1
Reactant: Fc1cncc(F)c1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2ccc(F)cn2)n1

Procedure:
The title compound, light yellow solid, MS (ISP): m/e=342.1 (M+H+), was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-pyridin-2-yl)-amide and 3,5-Difluoropyridine in accordance with the general method of example 7.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:38]=3)[CH:33]=[C:32]2C(OCC)=O)([CH2:21][NH:22][C:23]([O:25]C(C)(C)C)=O)[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[O:25]=[C:23]1[C:32]2=[CH:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][C:39]=3[N:31]2[CH2:30][C:18]2([CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)[CH2:21][NH:22]1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC3(CNC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCNCC1)CNC3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.6 %

Procedure:
Trifluoroacetic acid (13.4 mL, 173.8 mmol) is added dropwise to the solution of diethyl 1-{[1-(tert-butoxycarbonyl)-4-{[(tert-butoxycarbonyl)amino]methyl}piperidin-4-yl]methyl}-1H-indole-2,6-dicarboxylate (17 g, 29.0 mmol) in CH2Cl2 (200 mL) at 0° C. The reaction mixture is stirred for 3 h at room temperature and then is basified with aqueous K2CO3 solution until the pH is 8. The aqueous layer is separated and extracted with CH2Cl2 (2×250 mL). The organic layers are combined, washed with brine, dried (Na2SO4) and concentrated. The crude material is recrystallized using diethyl ether to afford the title compound (6 g, 61%) as a white solid.