Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7]([OH:9])=[O:8])=[CH:5][CH:6]=1.S(=O)(=O)(O)O.O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:16][CH3:17])=[O:8])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(Br)s1

Procedure:
2-Bromo-5-thiophenecarboxylic acid (500 mg) was dissolved in ethanol (5 mL), conc. sulfuric acid (50 μL) was added and the mixture was heated under reflux for 4 hrs. Conc. sulfuric acid (50 μL) was further added and the mixture was heated under reflux for 5 hrs. Then, the mixture was allowed to return to room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent. The solvent was evaporated from the eluent to give the title compound (500 mg) as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[Cl:59][C:60]1[CH:61]=[CH:62][C:63]2[S:67][CH:66]=[C:65]([CH2:68]O)[C:64]=2[CH:70]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:68][C:65]2[C:64]3[CH:70]=[C:60]([Cl:59])[CH:61]=[CH:62][C:63]=3[S:67][CH:66]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OCc1csc2ccc(Cl)cc12
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1nc(C)n(Cc2csc3ccc(Cl)cc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (5-chloro-1-benzothien-3-yl)methanol (0.83 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 55%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC)=O)[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1.O>O1CCCC1>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 68.1 %

Procedure:
To a stirred suspension, under nitrogen, of 4.7 g of lithium aluminum hydride (50-55% oil dispersion) in 90 ml of tetrahydrofuran was added, dropwise, 8.9 g of 6-fluoro-3-(1-methoxycarbonyl-4-piperidinyl)-1H-indazole, dissolved in 50 ml of tetrahydrofuran. After the addition was complete, the reaction was heated under reflux for 2 hr. The reaction was cooled in an ice-salt bath and water was carefully added. The mixture was filtered and the filter cake was washed with tetrahydrofuran and twice with hot methanol. The filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to yield 5.1 g (68%) of product, mp 217°-220°. Recrystallization from ethanol (twice) provided the analytical sample, mp 218°-220° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=[O:9].O>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([CH:13]=[CH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)c1cnn2cccc2c1Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn2cccc2c1Cl
Temperature: 55 °C
Reaction time: 1 h

Procedure:
Dissolved ethyl 4-chloropyrrolo[1,2-b]pyridazine-3-carboxylate (Preparation 2 from Step 5B, 2 g, 8.90 mmol) in THF (12 mL) and added water (2 mL) followed by monohydrated lithium hydroxide (0.747 g, 17.81 mmol) and the resulting yellow mixture was sonicated to give a fine dispersion followed by heating to 55° C. and stirring vigorously for one hour. After removing the organics under vacuum, the resulting residue was dissolved in ˜50 mL of water and 6 N aqueous HCl added until acidic giving a yellow slurry of the product. The product was extracted with ethyl acetate, washed with brine, dried over Na2SO4, decanted and conc. in vacuo to afford 1.8 g (˜quant.) of a yellow solid as the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:32])([F:31])[F:30].[CH3:36][NH:37][CH3:38].CCOC(C)=O>C(Cl)Cl>[CH3:7][C@H:8]1[CH2:13][N:12]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23](=[O:24])[N:37]([CH3:38])[CH3:36])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[C@H:11]([CH3:26])[CH2:10][N:9]1[C:27](=[O:35])[C@:28]([OH:34])([CH3:33])[C:29]([F:30])([F:31])[F:32]
Reactant: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)[C@@](C)(O)C(F)(F)F)[C@@H](C)CN1S(=O)(=O)c1ccc(C(=O)N(C)C)cc1
Yield: 7.7 %

Procedure:
Oxalyl chloride (0.08 ml, 0.88 mmol) was added to a solution of (R)-[(2S,5R)-2-methyl-5-methyl-4-(4-carboxyphenylsulphonyl)-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropionyl)piperazine] (320 mg, 0.73 mmol) (Example 4) in DCM (25 ml). The resultant mixture was stirred at ambient temperature for 4 hours, evaporated to dryness, the residue treated with 40% aqueous dimethylamine (0.82 ml, 7.3 mmol) and the resultant mixture was stirred at ambient temperature overnight. The mixture was treated with EtOAc (25 ml), washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on silica with 50% EtOAc in DCM as eluent to give a solid which was recrystallized from EtOAc/hexane to give the title compound as a solid (26 mg, 0.056 mmol). Mp: 86-87° C.; NMR: 0.95 (d, 3H), 1.25 (dd, 3H), 1.65 (s, 3H), 2.95 (s, 3H), 3.1 (s, 3H), 3.25 (dd, 1H), 3.5 (dd, 1H), 4.2 (m, 2H), 4.5 (s, 1H), 4.8 (s, 1H), 7.5 (d, 2H), 7.85 (d, 2H); m/z: 464.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1.Cl>O1CCOCC1.CCOCC>[CH3:10][NH:9][C:8](=[O:11])[C:6]1[CH:5]=[CH:4][C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:2]([CH3:1])[CH:7]=1
Reactant: CNC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 4-(2-methyl-4-(methylcarbamoyl)phenyl)piperazine-1-carboxylate (1.90 g, 5.70 mmol) was added hydrochloric acid solution (17.10 mL, 68.4 mmol) in dioxane at 23° C. The reaction was stirred at 23° C. for 30 min. The resulting suspension was diluted with Et2O (20 mL), filtered, rinsed with Et2O (3×10 mL), and the resulting solid was dried in vacuo to provide the title compound as an off-white, hygroscopic solid (1.70 g, 5.55 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H) 2.72-2.79 (m, 3H) 3.05-3.14 (m, 4H) 3.17-3.28 (m, 4H) 7.06 (d, J=8.34 Hz, 1H) 7.64-7.68 (m, 1H) 7.68-7.70 (m, 1H) 8.29-8.39 (m, 1H) 9.36 (br. s., 2H). ESI-MS: m/z 234.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[O:14][CH3:15].[NH:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1.ClCCl.CO.N>>[CH3:15][O:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:17]1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCBr
Reactant: NC(=O)C1CCNCC1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 1.1.c. from 1 g (3.622 mmol) of 1-(2-bromoethoxy)-2-methoxy-4-nitrobenzene and 1.4 g (10.87 mmol) of piperidine-4-carboxylic acid amide. Yield: 1.05 g (90% of theory); C15H21N3O5 (M=323.34); calc.: molecular ion peak (M+H)+: 324; found: molecular ion peak (M+H)+: 324; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:16])[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[N:5]([CH3:17])[C:4]=1[C:18]([NH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:19].C(N(CC)CC)C.[C:34]([O:37][CH2:38][C:39](Cl)=[O:40])(=[O:36])[CH3:35]>C1COCC1.C(=O)([O-])O.[Na+]>[C:34]([O:37][CH2:38][C:39]([N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:18]([C:4]2[N:5]([CH3:17])[C:6]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8](=[O:16])[C:7]=3[C:3]=2[O:2][CH3:1])=[O:19])[CH2:22][CH2:23]1)=[O:40])(=[O:36])[CH3:35]
Reactant: COc1c(C(=O)NC2CCNCC2)n(C)c2c1c(=O)[nH]c1ccccc12
Reactant: CC(=O)OCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c(C(=O)NC2CCN(C(=O)COC(C)=O)CC2)n(C)c2c1c(=O)[nH]c1ccccc12
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of 3-methoxy-1-methyl-4-oxo-N-piperidin-4-yl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxamide (300 mg, 0.87 mmol) and triethylamine (88 mg, 0.87 mmol) in THF (30 mL) was added acetoxyacetyl chloride (119 mg, 0.87 mmol) under ice-cooling, and the mixture was stirred for 2 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The obtained solid was washed with diethyl ether-hexane to give the title compound (221 mg, 56%) as a white solid.
Reaction SMILES: C1C=CC2N(O)N=[N:7]C=2C=1.[CH3:11][N:12]([CH2:14][C:15]1[C:16]([O:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20]([OH:22])=O)[CH3:13]>C(Cl)Cl>[CH3:11][N:12]([CH2:14][C:15]1[C:16]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=2)=[N:17][CH:18]=[C:19]([CH:23]=1)[C:20]([NH2:7])=[O:22])[CH3:13]
Reactant: On1nnc2ccccc21
Reactant: CN(C)Cc1cc(C(=O)O)cnc1Oc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CN(C)Cc1cc(C(N)=O)cnc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
N-N-Diisopropylethylamine (44 μL, 0.25 mmol), HOBt (20 mg, 0.15 mmol) and WSCDI (23 mg, 0.12 mmol) were added to the acid from step (i) (35 mg, 0.10 mmol) in CH2Cl2 (2 mL) and stirred for 30 min. (NH4)2CO3 (19 mg, 0.20 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between water (10 mL) and CH2Cl2 (10 mL) and the organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography [SiO2; DCM/MeOH/880 NH3 (93:7:1)] and then triturated with Et2O to give the desired product (20 mg, 57%) as a white solid; δH (CDCl3, 400 MHz) 2.35 (6H, s), 3.62 (2H, s), 5.66 (1H, br), 6.00 (1H, br), 7.18 (2H, m), 7.26 (2H, m), 8.23 (1H, d), 8.50 (1H, d); MS m/z (TS+) 356 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][C:13]1[C:21]2[C:20]([OH:22])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[O:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:13]([CH3:12])=[N:14][NH:15]2
Reactant: Cc1n[nH]c2cccc(O)c12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
100 mg (0.63 mmol) of 3,4-difluoronitrobenzene, 93.1 mg (0.63 mmol) of 3-methyl-1H-indazol-4-ol (from example I) and 95.6 mg (0.69 mmol) of potassium carbonate are suspended in 5 ml of anhydrous dimethylformamide and stirred at 50° C. for five hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography. The mobile phase used is a mixture of cyclohexane and ethyl acetate (1:1).
Reaction SMILES: [C:1]12([O:14]CCO1)[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=1[CH2:3][CH2:2]2.[C:15](Cl)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[O:14]=[C:1]1[C:9]2[C:4](=[C:5]([NH:10][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2c1CCC21OCCO1
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of Example 25 (3.9 g, 20.6 mmol) in pyridine (40 mL) was slowly added acetyl chloride (1.6 mL, 22.6 mmol). The reaction was stirred at room temperature for about 15 minutes and then the solvent was removed under vacuum. The residue was dissolved in acetone (38 mL) and water (12 mL) and p-toluenesulfonic acid (3.9 g, 20.6 mmol) was added. The mixture was heated to reflux for about 1 hour, cooled, and concentrated under vacuum. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (1:1) as the mobile phase to provide the desired product. MS (ESI): m/z 188 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH3:9])[CH:3]=[CH:4][C:5](=[O:7])[CH3:6].[C:10]([Mg]Cl)#[CH:11]>O1CCCC1>[CH3:6][C:5]([OH:7])([CH:4]=[CH:3][CH:2]([CH3:1])[CH2:8][CH3:9])[C:10]#[CH:11]
Reactant: C#C[Mg]Cl
Reactant: CCC(C)C=CC(C)=O
Solvent: C1CCOC1
Product: C#CC(C)(O)C=CC(C)CC
Yield: 83 %

Procedure:
126 g (1 mole) of 5-methyl-hept-3-en-2-one are added in the course of 1 hour, with stirring, to 1 liter of a 1.1 molar solution of ethynyl-magnesium chloride in tetrahydrofuran, at 10° C. After allowing about a further hour for reaction, the mixture is worked up similarly to Example 1. 126 g of 3,6-dimethyl-oct-4-en-1-yn-3-ol, of boiling point 41° C./0.05 mbar and nD25 =1.4514, are obtained. This corresponds to a yield of 83% of theory. Scent: woody, herbal, fatty.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[CH3:30][S:31](C)=O>>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[S:31][CH3:30])[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Reactant: CS(C)=O
Product: CSc1cc(-n2ccccc2=O)ccc1-n1cnc(CNC(=O)c2ccc(Cl)s2)c1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 21 prepared in Example 11 (96 mg, 0.22 mmol) and NaSMe (68 mg, 0.97 mmol) in DMSO (2 mL) was heated at 80° C. for 1 h. The mixture was purified by HPLC to give 5-chloro-N-((1-(2-(methylthio)-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (16 mg). MS 457.0 and 459.0 (M+H, Cl pattern)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][OH:11])=[CH:2]1.[CH3:12]O>O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][O:11][CH3:12])=[CH:2]1
Reactant: CO
Reactant: OCc1c[nH]c2ccccc12
Solvent: O
Product: COCc1c[nH]c2ccccc12

Procedure:
Relatively pure 1H-indole-3-methanol (I3C™ from Designed Nutritional Products, Orem, Utah, U.S.) in a water solution was prepared for HPLC analysis. One sample was diluted with water and the other was diluted with methanol. By the time the methanol solution of 1H-indole-3-methanol could be injected into the HPLC, the reaction with methanol had taken place to form 1H-indol-3-yl methoxy methane, the methyl ether of 1H-indole-3-methanol and two peaks of about the same magnitude were observed. The water solution of 1H-indole-3-methanol showed only one peak.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:17]1([S:23][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC=C(C(=O)OC)c1ccccc1CSc1ccccc1
Yield: 97 %

Procedure:
2 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate, 0.65 g of thiophenol and 1.1 g of potassium carbonate are reacted similarly to Example 1. 1.8 g of white crystals of melting point 71° C. are obtained (compound No. 2).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][C:10]1[N:14]([CH3:15])[C:13]2[C:16]([NH:20][CH2:21][CH2:22][CH3:23])=[CH:17][CH:18]=[CH:19][C:12]=2[N:11]=1.[CH:25]1([CH:28]=O)[CH2:27][CH2:26]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH:25]1([CH2:28][N:20]([CH2:21][CH2:22][CH3:23])[C:16]2[C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:2]4[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=4[CH3:24])=[N:11][C:12]=3[CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1
Reactant: CCCNc1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CC1CC1)c1cccc2nc(Nc3c(C)cc(C)cc3C)n(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To 0.041 g (0.13 mmol) of N2-mesityl-1-methyl-N7-propyl-1H-benzimidazole-2,7-diamine in 2 mL of methanol was added 95 μL (1.3 mmol) of cyclopropane carboxaldehyde, 200 μL of glacial acetic acid and 0.032 g (0.51 mmol) of sodium cyanoborohydride. The mixture was stirred at room temperature for 24 h. The reaction mixture was cooled to room temperature and the volatiles were removed in vacuo. The crude solid was partitioned between saturated sodium bicarbonate and dichloromethane, the organic layer was separated, dried over sodium sulfate, filtered, concentrated and purified by reverse-phase HPLC to give 0.026 g (42%) of the title compound as a colorless sticky solid.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][CH3:23])[CH:12]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Br)[C:25]1[CH:30]=[CH:29]C=[CH:27][CH:26]=1>>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=4)[N:13]([CH2:22][C:23]4[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=4)[CH:12]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CCn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Reactant: BrCc1ccccc1
Product: N#Cc1ccc2c(c1)c(C1CCC3(CC1)OCCO3)cn2Cc1ccccc1
Yield: 57 %

Procedure:
This compound was prepared in the manner described above for intermediate 5b by replacing ethylbromide with benzylbromide (14.3 g, 84 mmol) to afford 6.04 g (57%) of the title compound as a white solid: mp 129-130° C.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12](Cl)[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.[CH3:18][NH2:19]>>[NH2:4][C:5]1[CH:13]=[C:12]([NH:19][CH3:18])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CN
Reactant: CC(=O)Nc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Product: CNc1cc(N)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture of 2-acetylamino-4-chloro-5-nitrobenzoic acid (10.0 g) and 40% aqueous methylamine solution (60 ml) is stirred at 80° C. for 10 hours and then evaporated under reduced pressure. To the residue is added 40% aqueous methylamine solution (100 ml), and the resulting solution is stirred at 80° C. for 20 hours. After cooling, the mixture is diluted with water (50 ml) and then adjusted to the pH of about 4 with acetic acid. The precipitate is collected and recrystallized from acetonitrile to give the title compound (7.6 g), mp 260°-272° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:35])[C:11](=[O:34])[CH2:12][N:13]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[CH3:27])[N:23](C1CCCCO1)[N:22]=[CH:21]2)[CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[CH2:41](O)[CH3:42]>>[CH2:41]([O:17][C:15](=[O:16])[CH2:14][N:13]([CH2:12][C:11]([N:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:35])=[O:34])[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[CH3:27])[NH:23][N:22]=[CH:21]2)[CH3:42]
Reactant: Cc1cc2c(cnn2C2CCCCO2)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Yield: 83 %

Procedure:
The compound (2.23 g, 4.67 mmol) of step A was dissolved in ethanol (60 ml), concentrated sulfuric acid (0.5 ml) was added at room temperature, and the mixture was heated under reflux for 80 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.64 g, yield 83%) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=1.[CH3:15][N:16]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:9][CH2:8][C:6]1[CH:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([C:15]#[N:16])[CH:7]=1
Reactant: COCc1cc(Cl)nc(C(F)(F)F)c1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COCc1cc(C#N)nc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
A solution of 2-chloro-4-(methoxymethyl)-6-(trifluoromethyl)pyridine (0.5 g, 2 mmol, from Step B) and zinc cyanide (1.56 g, 13.3 mmol) in N-methylpyrrolidinone (8 mL) was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) was added and the mixture was degassed similarly for 5 minutes. The reaction vial was sealed and heated in the microwave to 140° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous portion was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded purified product (0.36 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 4.60 (dd, J=0.9 Hz, 2H), 3.51 (s, 3H); 19F NMR (376 MHz, CDCl3) 5-68.55 (s); LCMS (M+H)+: 217.1.