Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][C:7]2[C:12]3[C:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)=[N:14][O:15][C:11]=3[C:10]([OH:24])=[C:9]([C:25](OCC)=[O:26])[N:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+]>>[OH:24][C:10]1[C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:12]=2[C:7]([CH2:6][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:8][C:9]=1[C:25]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:26]
Reactant: CCOC(=O)c1nc(Cn2cccn2)c2c(-c3ccc(OC)cc3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2noc3c(O)c(C(=O)NCC(=O)O)nc(Cn4cccn4)c23)cc1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
Ethyl 4-((1H-pyrazol-1-yl)methyl)-7-hydroxy-3-(4-methoxyphenyl)isoxazolo[4,5-c]pyridine-6-carboxylate (19 mg, 0.048 mmol) and glycine (181 mg, 2.41 mmol) were added to sodium methoxide solution (3.6 mL, 1.81 mmol, 0.5 M in MeOH) and the mixture was refluxed for 3 days. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was dissolved in 10 mL of water, and washed with EtOAc. The aqueous layer was acidified to pH 3 with 4M hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 14 mg of the title compound. MS: (+) m/z 424.31 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH:21]([CH:24]1[NH:29][C:28](=[O:30])[CH2:27][NH:26][CH2:25]1)([CH3:23])[CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:26]3[CH2:25][CH:24]([CH:21]([CH3:23])[CH3:22])[NH:29][C:28](=[O:30])[CH2:27]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC(C)C1CNCC(=O)N1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)C1CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC(=O)N1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.6 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (184 mg, 0.62 mmol) in DCE (15 mL) was added 6-isopropylpiperazin-2-one (106 mg, 0.75 mmol) and powdered 4 Å molecular sieves. The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (364 mg, 1.72 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (93 mg, 35%). LCMS (Method H): RT=3.44 min, [M+H]+ 422.4
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:12][CH2:11][C:10](=O)[NH:9][CH2:8]2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(Cl)(Cl)Cl.CO.N>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[N:6]=1
Reactant: Cc1nc(C2CNC(=O)CO2)cs1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nc(C2CNCCO2)cs1

Procedure:
Prepared analogously to Example O by reduction of 2-(2-methyl-thiazol-4-yl)morpholin-5-one with lithium aluminium hydride and purification of the base on a silica gel column with chloroform/methanol/ammonia=93:7:0.7 as eluant.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[CH2:11][CH2:12][CH2:13][Cl:14]>>[CH3:1][C:2]1[CH:3]=[C:4]([S:9][CH2:11][CH2:12][CH2:13][Cl:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(S)cc1C
Reactant: ClCCCBr
Product: Cc1ccc(SCCCCl)cc1C

Procedure:
Prepared by Procedure R and Scheme Z using 3,4-dimethylbenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccc(F)c(OCc2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(F)c(OCc2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a solution of methyl 4-fluoro-3-[(4-fluorophenyl)methoxy]benzoate (571 mg, 2.05 mmol) in THF (6 mL) cooled to −50° C., was added LiAlH4 solution (4.6 mL, 4.11 mmol, 1.0 M in THF) drop wise. Thereto, the mixture was stirred at this temperature for 1 h. Added water (0.2 mL) slowly, followed by NaOH (aq, 10%, 0.2 mL) and water (0.6 mL), the resulting mixture was filtered and washed with THF, the filtrate was concentrated to give 444 mg of the title compound (86%). 1H NMR (400 MHz, CDCl3): δ 1.67 (1H, t, J=6.0 Hz), 4.62 (2H, d, J=6.0 Hz), 5.10 2H, s), 6.87-6.91 (1H, m), 7.04-7.09 (4H, m), 7.40-7.43 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[C:4]([C:12]2[N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:3]1.[CH3:31][C:32](C)([O-])[CH3:33].[K+].C(Br)C=C.O>CN(C)C=O>[CH2:33]([O:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:12]1[N:20]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1)[CH:32]=[CH2:31]
Reactant: CC(C)(C)[O-]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3cccnc32)cc1
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.1 %

Procedure:
A solution of 1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indol-5-ol [2.1 g, Reference Example 14(a)] in dry dimethylformamide (50 mL) was treated with potassium tert-butoxide (620 mg) at 0° C. under nitrogen. After stirring for 10 minutes the mixture was treated with allyl bromide (480 μl) and then allowed to warm slowly to ambient temperature. Stirring was continued for a further 6 hours after which time the mixture was poured carefully into water and the aqueous phase extracted exhaustively with ethyl acetate. The combined organic extracts were washed twice with brine (100 mL), then dried over sodium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:1, v/v) to give the title compound (1.2 g) as a yellow foam, m.p. 257–259° C. MS: 458(MH+).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[S:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCC>[S:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][N:17]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=3)[N:3]=2)[CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CNCCS2
Reactant: Cc1ccc2nc(Cl)nc(N)c2c1
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(N)c2c1
Temperature: 150 °C
Yield: 100 %

Procedure:
To a solution of 2-chloro-6-methylquinazolin-4-amine (454 mg, 2.345 mmol) in n-butanol (5 mL) was added 2,3,4,5-tetrahydro-1,4-benzothiazepine (388 mg, 2.345 mmol). After being heated at 150° C. for 1.5 hours under microwave irradiation, the reaction mixture was filtered and the collected solid was washed with ether to afford 756 mg of the product as a white solid. MS obsd. (ESI+) [(M+H)+] 323, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (s, 1 H), 7.83-7.81 (d, J=8.0 Hz, 1 H), 7.62-7.60 (d, J=8.0 Hz, 1 H), 7.53-7.49 (m, 2 H), 7.29-7.25 (m, 1 H), 7.22-7.19 (m, 1 H), 4.98 (s, 2 H), 4.25 (s, 2 H), 2.98 (s, 2 H), 2.35 (s, 3 H).
Reaction SMILES: [CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)=[O:23])=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(O)cc3)cc2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccc(O)cc3)cc2)cc1)C(=O)O
Yield: 93.8 %

Procedure:
In a similar manner to that described in Example 2, ethyl 2-butyl-3-[4-[2-(4′-hydroxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionate (260 mg), which is the product of Example 25, was reacted with aqueous sodium hydroxide solution (1N, 2.20 ml) and the reaction mixture was treated to give the title compound (230 mg) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11]([O:13][CH2:14]C)=[O:12].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[CH:10]([CH3:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(C)cc1OC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(C)cc1OC
Reaction time: 1 h

Procedure:
The resulting ethyl 2-methoxy-4-methylphenylacetate was dissolved in tetrahydrofuran (50 ml), and to the solution was added dropwise a 1.0 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (19 ml) at −70° C., the mixture was stirred at the same temperature for 1 hour, then methyl iodide (3.1 ml) was added dropwise to the mixture, and the mixture was further stirred at −30° C. for 1 hour. The reaction mixture was quenched with 2 M aqueous hydrochloric acid (15 ml), and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/1) to give methyl 2-(2-methoxy-4-methylphenyl)propionate (2.65 g).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:18])[C@H:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]1[CH2:25][S:22](=[O:24])(=[O:23])[O:21][CH2:20]1>O1CCCC1>[CH2:11]([C@H:9]([NH:10][CH2:20][CH2:19][CH2:25][S:22]([OH:24])(=[O:23])=[O:21])[C:8]([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S1(=O)CCCO1
Reactant: N[C@@H](Cc1ccccc1)C(=O)NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)[C@H](Cc1ccccc1)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of L-Phenylalanine cyclohexylamide (2.5 g, 10.1 mmol) in tetrahydrofuran (25 mL) was added 1,3-propanesultone (1.17 g, 9.7 mmol). The solution was stirred at reflux for 2 hours. It was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in the vacuum oven (50° C.), affording the title compound (1.39 g, 39%). 1H NMR (D2O, 500 MHz) δ ppm 7.21 (m, 3H), 7.08 (m, 2H), 4.42 (m, 0.5H), 3.83 (m, 1H). 3.29 (m, 1H), 3.15 (m, 1H), 3.02 (m, 2H), 2.86 (m, 3H), 2.49 (m, 0.5H), 2.01 (m, 2H), 1.54 (m, 1H), 1.45 (m, 1H), 1.33 (m, 2H), 1.02 (m, 4H), 0.55 (m, 1H). 13C (D2O, 125 MHz) δ ppm 133.71, 129.54, 129.18, 128.03, 62.08, 49.25, 47.97, 45.41, 36.29, 31.73, 31.46, 24.86, 24.28, 24.20, 21.39. [α]D=+36.4° (c=0.0019 in water), ES-MS 369 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:8]=[CH2:9])[CH2:3][C:4]([O:6]C)=[O:5].[OH-].[K+]>C(O)C>[CH3:1][C:2]([CH3:10])([CH:8]=[CH2:9])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: C=CC(C)(C)CC(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(C)(C)CC(=O)O
Temperature: 25 °C
Yield: 77 %

Procedure:
To a solution of methyl 3,3-dimethylpent-4-enoate (0.5 mole) in 500 ml of ethanol (95% grade) was added potassium hydroxide (1 mole). The solution was refluxed for 1.5 hours. After cooling down to room temperature, the solution was concentrated to 200 ml on a rotary evaporator, and acidified by the addition of 5N H2SO4 solution. The product was isolated by extraction with diethyl ether (3×200 mls). After removal of the solvent, the crude product was distilled under reduced pressure to yield the pure acid (77%) b.p. 78°-80° C. (1.5 mmHg). 1H NMR (CDCl3) δ10.60 (1H, broad s), 5.90 (1H, dd, J 10.3, 17.6 Hz), 5.00 (1H, dd, J 17.6 Hz, J 1.3 Hz), 4.97 (1H, dd, J 10.3 Hz, J 1.3 Hz), 2.35 (2H, s), and 1.20 (6H, s).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(=O)(O)[O-].[Na+].C(=O)=O.[CH3:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>CO.CN(C)C=O>[C:1]([O:5][CH2:21][CH2:20][CH2:19][CH2:18][O:17][C:16]1[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=1[CH3:14])(=[O:4])[C:2]#[CH:3]
Reactant: Cc1ccccc1OCCCCBr
Reactant: C#CC(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: C#CC(=O)OCCCCOc1ccccc1C
Temperature: 40 °C
Yield: 37.2 %

Procedure:
A mixture of 10 g of propiolic acid, 12 g of anhydrous sodium bicarbonate in 150 ml of anhydrous methanol was heated to 40° C. with stirring. When evolution of carbon dioxide ceased, the reaction mixture was cooled to a temperature 10° C. or less. The resultant precipitate was collected and dried under reduced pressure for two days. A mixture of 1 g of the sodium propiolate thus obtained and 2.64 g of 4-(2-methylphenoxy)butyl bromide in 30 ml of anhydrous N,N-dimethylformamide was heated at 110° C. under nitrogen atmosphere for four hours with stirring. After the reaction was completed, the reaction solution was poured into ice-water, and extracted twice with toluene. The combined toluene layer was washed successively with a saturated aqueous ammonium chloride solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.937 g of 4-(2-methylphenoxy)butyl propiolate (compound 10).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[S:11][C:12]=2[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18](O)=O>COC(OC)OC>[C:1]1([N:7]2[C:8]3[C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[S:11][C:12]=3[N:13]=[CH:18]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CO
Reactant: Nc1sc2ccccc2c1Nc1ccccc1
Solvent: COC(OC)OC
Product: c1ccc(-n2cnc3sc4ccccc4c32)cc1
Temperature: 120 °C
Yield: 85 %

Procedure:
Into a solution of N3-phenylbenzo[b]thiophene-2,3-diamine (16 g, 66.7 mmol) in trimethoxymethane (200 ml) was added formic acid (1.5 ml, 42.3 mmol) at room temperature. The reaction mixture was subsequently heated at 120° C. for 6 h. After cooling to room temperature, it was quenched with aqueous NaHCO3 solution and extracted with ethyl acetate. Upon evaporation off the solvent, the residue was purified by chromatography on silica gel with hexane/EtOAc (95/5, v/v) as eluent to yield 1-phenyl-1H-benzo[4,5]thieno[2,3-d]imidazole (9.0 g, 54%) as a solid.
Reaction SMILES: [CH2:1]([C:5]1([CH2:22][CH2:23][CH2:24][CH:25]=C)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:11]=2)[C:6]1([C:19]([CH3:21])=[CH2:20])[OH:18])[CH2:2][CH2:3]C>ClCCl.[Ru+2](Cl)Cl>[CH2:22]([C:5]12[CH2:1][CH2:2][CH2:3][CH:21]=[C:19]([CH3:20])[C:6]1([OH:18])[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:15][O:16][CH3:17])=[CH:11][C:12]=1[CH2:13]2)[CH2:23][CH2:24][CH3:25]
Reactant: C=CCCCC1(CCCC)Cc2cc(OCOC)ccc2C1(O)C(=C)C
Agent: Cl[Ru+2]Cl
Solvent: ClCCl
Product: CCCCC12CCCC=C(C)C1(O)c1ccc(OCOC)cc1C2
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A solution of 2-butyl-1-isopropenyl-5-(methoxymethoxy)-2-(4-pentenyl)-1-indanol (200 mg, 0.56 mmol) in dichloromethane (22 mL) was treated with tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine]ruthenium(IV) dichloride (47 mg, 0.056 mmol). After stirring at 45° C. overnight, the mixture was treated with additional tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydro-imidazol-2-ylidene]benzylidine]ruthenium (IV) dichloride (47 mg, 0.056 mmol) and stirred at 45° C. for another 24 hours. The mixture was concentrated and the residue purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates (Analtech, Newark, Del.), developing with 10% EtOAc in hexane. The UV visible product band was eluted with EtOAc and the eluant was evaporated under vacuum to provide 9a-butyl-2-(methoxymethoxy)-5-methyl-8,9,9a,10-tetrahydrobenzo[a]azulen-4b(7H)-ol as an oil.
Reaction SMILES: [C:1](/[C:3](=[C:7](/OCC)\[CH3:8])/[C:4]([NH2:6])=[S:5])#[N:2].C(O)C.[NH3:15].C(OCC)(=O)C>C1(C)C=CC=CC=1>[NH2:15]/[C:7](/[CH3:8])=[C:3](/[C:1]#[N:2])\[C:4]([NH2:6])=[S:5]
Reactant: CCO/C(C)=C(/C#N)C(N)=S
Reactant: N
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C/C(N)=C(\C#N)C(N)=S
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 3 liter multi-neck flask was equipped with air stirrer, gas inlet, thermometer and condenser. To the flask was charged 2-cyano-3-ethoxythiocrotonamide (68 g, 0.4 mole) and 74 OP ethanol (2 liters). The mixture was then stirred at room temperature. Very little of the solid appeared to dissolve. Ammonia was then bubbled through the reaction mixture. After approximately 15 minutes it became apparent that the starting material was reacting, evidenced by the increased solubility, and after 30 minutes a homogeneous solution resulted. Passage of ammonia through the solution was continued until no more gas was taken up. TLC showed the reaction to be complete, as evidenced by the disappearance of the starting material (silica, eluent 30% ethyl acetate in toluene, Rf product: 0.5, Rf starting material: 0.1).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.[C:22]([C:24]([NH:27][C:28](=[O:35])[CH:29]([NH2:34])[CH2:30][CH:31]([CH3:33])[CH3:32])([CH3:26])[CH3:25])#[N:23]>CN(C)C=O>[C:22]([C:24]([NH:27][C:28]([CH:29]([NH:34][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][Br:1])=[CH:11][CH:10]=1)[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:35])([CH3:26])[CH3:25])#[N:23]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CC(C)CC(N)C(=O)NC(C)(C)C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)c1ccc(CBr)cc1)C(=O)NC(C)(C)C#N
Reaction time: 0.17 h

Procedure:
4-Bromomethylbenzoic acid (4.1 mmol), HOBt (4.1 mmol) and WSCD.HCI (4.1 mmol) are dissolved in dimethylformamide (7 ml) and stirred for 10 min. 2-Amino-4-methyl-pentanoic acid (cyano-dimethyl-methyl)-amide (4.1 mmol) is added in DMF (3 ml) and the reaction mixture is stirred at RT overnight. After evaporation of the solvent, the residue is extracted with ethyl acetate. The extract is washed with water, 10% citric acid, brine, sodium bicarbonate, brine and dried over magnesium sulfate and evaporated. The crude product is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 185-187° C., Rf=0.43 (n-hexane:ethyl acetate=1:1) is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCCCCl
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ClCCCOCc1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
In a 2 l flask, a mixture of 3-chloropropanol (56.7 g), benzyl bromide (102.6 g) and dry THF (600 ml) is stirred and cooled with ice/salt mixture. Potassium tert-butoxide (70 g) is added in portions (5-10 g), maintaining the internal temperature at about 0° C. After the mixture is stirred for 3 more hours at room temperature, the solvent is evaporated. Addition of 1 N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum to give the title compound, (108.4 g), bp0.01 60°-80° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([C:12]1[S:20][C:19]2[C:14](=[N:15][CH:16]=[CH:17][C:18]=2[Cl:21])[CH:13]=1)=[O:11].[CH2:22](I)[CH3:23]>CN(C=O)C>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:6]3[CH2:7][CH2:8][CH2:9][C@@H:5]3[CH2:4][O:3][CH2:22][CH3:23])=[O:11])[S:20][C:19]=12
Reactant: CCI
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC[C@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
NaH (80 mg, 2 mmol) was added to a solution of (2R)-(2-hydroxymethyl-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone (297 mg, 1 mmol) in DMF (5 mL), at 0° C. The reaction mixture was allowed to stir for 20 min, and EtI (234 mg, 1.5 mmol) was added dropwise. After 3 h the reaction was quenched with saturated aqueous KCN (10 mL). The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), and the solvent was removed. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 94:6) afforded the title compound as a white solid (145 mg, 50%). MS: 326 (MH+); HPLC Rf: 5.11 min; HPLC purity: 97%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:41][C:42]1[N:47]=[C:46](Cl)[CH:45]=[CH:44][N:43]=1.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([C:44]4[CH:45]=[CH:46][N:47]=[C:42]([Cl:41])[N:43]=4)[CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2ccnc(Cl)n2)CC1
Yield: 71.4 %

Procedure:
To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (295 mg) in ethanol (5 ml) were added triethylamine (0.15 ml) and 2,4-dichloropyrimidine (150 mg), and the mixture was stirred under reflux for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) and dried under reduced pressure to give the title compound (263 mg).
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.ClC1N=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (250 mg, 1.1 mmol) and 6-chloro-3-pyridinesulfonyl chloride (233 mg, 1.1 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-30%) of MeOH/EtOAc, to give benzamide I-2 (279 mg, 63%) as a white powder: mp (MeOH/EtOAc) 226-228° C.; 1H NMR δ 10.36 (s, 1H, NHCO), 8.93 (d, J=2.2 Hz, 1H, H-2′), 8.75 (dd, J=2.6, 0.6 Hz, 1H, H-2″), 8.61 (br s, 1H, NHSO2), 8.32 (dd, J=4.6, 1.5 Hz, 1H, H-6′), 8.10-8.20 (m, 2H, H-4′, H-6″), 7.90 (br d, J=8.3 Hz, 2H, H-2, H-6), 7.72 (dd, J=8.4, 0.6 Hz, 1H, H-5″), 7.36-7.42 (m, 3H, H-3, H-5, H-5′), 4.19 (s, 2H, CH2N); 13C NMR δ 165.4, 153.6, 147.7, 144.6, 142.0, 141.2, 137.9, 136.6, 135.8, 133.1, 127.8 (2), 127.6 (2), 127.3, 125.0, 123.5, 45.7; MS m/z 404.0 (MH+, 100%), 406.0 (MH+, 60%). Anal. calcd for C18H15ClN4O3S: C, 53.67; H, 3.75; N, 13.91. Found: C, 53.37; H, 3.81; N, 14.03%.