Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27](I)=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[N:25]([CH3:33])[N:24]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:27]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:26]([NH:29][C:30](=[O:32])[CH3:31])[N:25]([CH3:33])[N:24]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1c(I)c(-c2ccccc2Cl)nn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C#Cc2ccccc2)c(-c2ccccc2Cl)nn1C
Temperature: 85 °C
Yield: 47 %

Procedure:
To a degassed solution of phenylacetylene (157 μl, 1.43 mmol) and Et3N (3.3 mL) in DMF (1.2 mL) were added N-(3-(2-chlorophenyl)-4-iodo-1-methyl-1H-pyrazol-5-yl)acetamide (413 mg, 1.1 mmol), CuI (42 mg, 0.22 mmol) and PdCl2(PPh3)2 (77 mg, 0.11 mmol). The mixture was flushed with N2 and then heated to 85° C. for 3 h. The reaction mixture was concentrated in metro and the residue was purified by column chromatography (silica gel, gradient 0 to 100% ethyl acetate/isohexane) yielding N-(3-(2-chlorophenyl)-1-methyl-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide as a solid (181 mg).
Reaction SMILES: [ClH:1].[I:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9]N.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>C(O)C(F)(F)F>[ClH:1].[I:2][C:3]1[C:4]2[NH:9][C:16]3[CH2:17][CH2:18][NH:13][CH2:14][C:15]=3[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1ccccc1I
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: OCC(F)(F)F
Product: Ic1cccc2c3c([nH]c12)CCNC3
Reaction time: 3 h
Yield: 84.8 %

Procedure:
1-(2-Iodophenyl)hydrazine hydrochloride (1.67 g, 6.2 mmol) and 4-piperidone monohydrate hydrochloride (0.952 g, 6.2 mmol) were dissolved in trifluoroethanol (15 mL) and concentrated hydrochloric acid (5 mL) and heated at 87° C. and stirred for 3 h. The solid was filtered, washed with cold isopropyl alcohol (50 mL), and dried to give 6-iodo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (1.76 g, 85%) as a tan solid. 1H NMR (CD3OD, 300 MHz) δ 7.49 (d, 1H, J=7.7 Hz), 7.43 (d, 1H, J=8 Hz), 6.82 (t, 1H, J=7.7 Hz), 4.40 (s, 2H), 3.60 (t, 2H, J=6.25 Hz), 3.18 (t, 2H, J=5.85 Hz) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34](=[O:35])(=[O:36])[NH:37][CH2:38][CH2:39][OH:40])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(NCCO)c1ccc(Br)cc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Temperature: 25 °C
Yield: 42.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.200 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.082 g, 0.071 mmol), 4-bromo-N-(2-hydroxyethyl)-benzenesulfonamide (0.2 g, 0.71 mmol) and 2.0 M aqueous sodium carbonate (1.0 mL, 2.0 mmol) were added simultaneously to the reaction mixture under argon. The reaction was refluxed for 2 hours and then cooled to room temperature. Water was added and the mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography to afford {6-chloro-4-[4-(2-hydroxy-ethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.100 g, 42%) as a solid. MS calcd. for C22H21ClNO5S [(M−H)−] 446, obsd. 446.4.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:20](OC)(=[O:25])[CH2:21][C:22]([CH3:24])=O>>[CH2:1]([NH:13][CH2:14][CH2:15][N:16]1[C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[N:19][CH2:18][CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCNCCNCCN
Product: CCCCCCCCCCCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 271.1 g (1 mole) of N-dodecyldiethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. After 18 g of water and 32 g of methanol had been distilled off at 140° to 150° C., there was obtained 4-dodecylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one in slight red liquid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>ClCCl>[CH3:1][O:2][CH:3]([O:9][CH3:10])[CH2:4][O:5][CH2:6][CH2:7][O:8][C:20](=[O:21])[C:19]([Br:18])([CH3:24])[CH3:23]
Reactant: COC(COCCO)OC
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(COCCOC(=O)C(C)(C)Br)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of 2-(2,2-dimethoxy-ethoxy)-ethanol (11 g, 0.073 mol) and triethylamine (12 mL, 0.088 mol) in dichloromethane (150 mL) was cooled to 0° C. and a solution of 2-bromo-2-methyl propionyl bromide (8.5 mL, 0.069 mol) in 50 mL of dichloromethane was added dropwise in ca. 30 min. After stirring overnight at room temperature the resulting suspension was filtered and the yellow solution was washed with saturated NaHCO3 aqueous solution (2×100 mL) and dried with MgSO4. After filtration the solvent was removed under reduced pressure and the yellow oily residue was purified by distillation (b.p. 70° C./0.02 mbar) to give 14.0 g (0.061 mol, yield: 89%) of product as a colourless oil. 1H NMR (400.03 MHz, CDCl3, 298 K) δ=1.94 (s, 6H, (CH3)2CBr), 3.39 (s, 6H, OCH3), 3.56 (d, J=5.3 Hz, 2H, CHCH2), 3.76 (t, J=4.8 Hz, CH2OCH2), 4.33 (t, J=4.8 Hz, 2H, CH2OCO), 4.50 (t, 1H, CH(OCH3)2. 13C{1H} NMR (100.59 MHz, CDCl3, 298 K) δ=30.90 (2C, C(CH3)2), 54.13 (2C, CH3O), 55.79 (1C, BrC(CH3)2), 65.24 (1C, CH2OC(═O)), 69.21 (1C, CHCH2O), 71.18 (1C, OCH2CH2), 102.83 (1C, CH).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][C:26]1[S:27][C:28]([S:32](Cl)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1.C(N(CC)CC)C>>[CH3:25][C:26]1[S:27][C:28]([S:32]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:34])=[O:33])=[C:29]([CH3:31])[N:30]=1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)s1

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (24.8 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (12.7 mg, 26%).
Reaction SMILES: C([O:8][C:9](=[O:32])[C:10]([CH2:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:30][N:28]([CH3:29])[C:27]([CH2:26][C:10]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH:11]([CH3:13])[CH3:12])[C:9]([OH:32])=[O:8])=[O:31]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)NC(CC(=O)N(C)C)(C(=O)OCc2ccccc2)C(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NC(CC(=O)N(C)C)(C(=O)O)C(C)C)cc1

Procedure:
To a solution of dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyric acid benzyl ester (1.77 grams, 3.83 mmol) in ethanol (100 mL) was added 10% palladium on activated carbon (644 mg). The mixture was agitated under 3 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated leaving dimethylcarbamoylmethyl(4-methoxybenzenesulfonyl)amino-3-methylbutyric acid as a white foam, 1.42 grams (100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.N#N>CS(C)=O>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:17])[CH3:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(C)CC(O)CNc1nc2ccccc2nc1Cl
Agent: N#N
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CC(=O)CNc1nc2ccccc2nc1Cl
Temperature: 0 °C
Yield: 60.7 %

Procedure:
A mixture of 2a (6.96 g, 24.8 mmol), 28.4 ml Et3N and sulphur trioxide trimethylamine complex (7.9 g, 56.8 mmol) in 28.4 ml DMSO, is stirred overnight (under N2) at room temperature, then ice water (50 ml) is added. The aqueous phase is extracted in CH2Cl2 (3×30 ml). The collected organic phases are dried (CaCl2) and then evaporated under reduced pressure. The residues are purified by chromatography on a silica column, eluent: C6H12/Et2O (85:15) to give a beige solid (4.18 g, 61%); 1H NMR (100 MHz, CDCl3) δ: 0.93 (s, 3H), 1.00 (s, 3H), 2.34 (m, 1H), 2.40 (s, 2H), 4.38 (d, 2H), 6.39 (t, 1H), 7.59 (m, 4H); 13C NMR (25 MHz, CDCl3) δ: 22.56, 25.01, 49.28, 51.55, 125.34, 125.87, 127.98, 130.14, 136.65, 137.92, 140.99, 147.30, 205.01. Analysis calculated for C14H16N3OCl: C, 60.54; H, 5.81; N, 15.13. Experimental: C, 60.32; H, 6.06; N, 14.95.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][N:10]([C:12](=[O:27])[CH2:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11][C:4]=2[CH:3]=1.O.[NH2:29][NH2:30]>O1CCOCC1>[C:15]1([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][C:12]([N:10]2[CH2:9][CH2:8][C:5]3[N:6]=[N:7][C:2]([NH:29][NH2:30])=[CH:3][C:4]=3[CH2:11]2)=[O:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(CC(c1ccccc1)c1ccccc1)N1CCc2nnc(Cl)cc2C1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: NNc1cc2c(nn1)CCN(C(=O)CC(c1ccccc1)c1ccccc1)C2

Procedure:
7.6 g of 3-chloro-6-(3,3-diphenylpropionyl)-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine in 40 cc of hydrazine hydrate and 40 cc of dioxane are stirred at a bath temperature of 100° during 12 hours. The mixture is cooled with ice, whereupon the title compound precipitates and is recrystallized from ethanol/water (ratio 6:1). The title compound has a M.P. of 208°-211° (decomp.).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)[CH3:2].C1C(=O)N([Br:17])C(=O)C1.CCOC(C)=O>C(Cl)(Cl)Cl>[Br:17][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]=1[NH2:9]
Reactant: CCc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(N)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.5 %

Procedure:
4-Ethylphenylamine (1.00 g, 7.52 mmol, 1 equiv) was dissolved in chloroform (40 mL) and placed into an ice bath. NBS (1.34 g, 1 equiv) was then added into the solution in small portions. The mixture was warmed to room temperature and stirred for 2 hours. EtOAc (˜200 mL) was added and the mixture was filtered. The filtrate was washed with saturated aqueous K2CO3 (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexanes to afford the title compound as light brown oil (1 g). MS (ES) m/z 200.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(O)c2C)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c1F
Reaction time: 0.5 h
Yield: 145.9 %

Procedure:
To a solution of 3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (106 mg, 0.30 mmol, 1.0 eq) in DMF (6 mL) was added Cs2CO3 (147 mg, 0.45 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (65 mg, 0.136 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for 1 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 50:1 to 40:1) to give the title compound as a colorless oil (90 mg, 66%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1.[CH3:18][C:19]([CH3:21])=O>C(Br)C=C>[CH2:21]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1)[CH:19]=[CH2:18]
Reactant: CC(C)=O
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C

Procedure:
Anhydrous potassium carbonate (55 g) in acetone (400 ml) and allyl bromide (41.5 ml) were added to a stirred solution of methyl 4-hydroxybenzoate (60.8 g). The mixture was heated at reflux for 18 hours. The reaction mixture was cooled to ambient temperature, filtered and the residue washed with ethyl acetate. The filtrates and washings were combined, evaporated and the residue dissolved in dichloromethane. The organic phase was washed with 1M aqueous sodium hydroxide (2×75 ml), water, brine and dried (MgSO4). Evaporation gave methyl 4-allyloxybenzoate as an oil (76.4 g) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+:28].[C:29]([O:33][CH2:34][CH3:35])(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]2[N:14]3[CH2:31][C:30]([C:29]([O:33][CH2:34][CH3:35])=[O:32])=[C:18]([O-:20])[C:13]3=[CH:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[K+:28]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C([O-])c2cc3cc(OCc4ccccc4)ccc3n2C1
Temperature: 34 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a 5000 mL, 3-neck round bottom flask equipped with a mechanical stirrer, a temperature probe, a nitrogen inlet, and a heating mantle was added ethyl 5-(benzyloxy)-1H-indole-2-carboxylate (150 g, 508 mmol) followed by anhydrous THF (2000 mL). To the resulting mixture was added potassium t-butoxide (1.0 M in THF, 762 mL, 762 mmol) via an addition funnel over 15 min (temperature increased from 20° C. to 26° C. over the addition time). The mixture was stirred for 1 h and ethyl acrylate (166 mL, 1.52 mol) was added via addition funnel over 15 min (temp increase to 34° C.). The addition funnel was replaced with a reflux condenser and the mixture heated to reflux and stirred for 18 h (the product started to appear as a white precipitate after only 0.5 h of heating). The flask was cooled to room temperature. The resulting precipitate was collected by vacuum filtration. The filtrate was concentrated to approximately 750 mL and diluted with MTBE (approx. 500 mL). Additional product precipitated and this material was filtered and added to the original filter cake. The combined solids were washed with cold THF:MTBE (1:1) and vacuum oven dried (45° C., 2 Ton) to give potassium 7-(benzyloxy)-2-(ethoxycarbonyl)-3H-pyrrolo[1,2-a]indol-1-olate as an off-white solid (120 g, 61% yield). Exact mass calculated for C21H19NO4 (protonated keto-enol form): 349.1, found: LCMS m/z=350.3, [M+H+]; 1H NMR (400 MHz, d6-DMSO) δ ppm 1.18 (t, J=7.1 Hz, 3 H), 3.99 (q, J=7.1 Hz, 2 H), 4.59 (s, 2 H), 5.09 (s, 2 H), 6.14 (s, 1 H), 6.80 (dd, J1=8.8, J2=2.3 Hz, 1 H), 7.11 (d, J=2.3 Hz, 1 H), 7.30 (m, 2 H), 7.38 (m, 2 H), 7.46 (m, 2 H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:18]([NH2:21])[CH:19]=[CH2:20].C(=O)([O-])O.[Na+]>>[CH2:18]([NH:21][C:2]1[N:3]=[C:4]([NH:12][CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:19]=[CH2:20]
Reactant: C=CCN
Reactant: CC(C)=CCNc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NCC=C(C)C)c2scc(C)c2n1
Yield: 69.7 %

Procedure:
268 mg (1.0 mmol) of 2-chloro-7-methyl-4-(3-methyl-2-butenylamino)thieno[3,2-d]pyrimidine and 914 mg (16.0 mmol) of allylamine were heated in a sealed tube at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, followed by adding a saturated aqueous sodium hydrogen carbonate solution thereto and extraction with ethyl acetate (50 ml×2). After the organic layer was washed with brine and dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/4) to give 201 mg (yield: 69.8%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]1[N:28]2[CH:29]=[CH:30][N:31]=[C:27]2[CH:26]=[CH:25][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32][C:33]([Cl:38])([Cl:37])[C:34](Cl)=[O:35].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:32][C:33]([Cl:38])([Cl:37])[C:34]([C:29]1[N:28]2[C:23]([CH2:22][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][S:15]([C:18]([F:20])([F:19])[F:21])(=[O:17])=[O:16])=[CH:24][CH:25]=[CH:26][C:27]2=[N:31][CH:30]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 57.9 %

Procedure:
To a solution of 3.55 g (7.64 mmol) of 5-[N-tert-butoxycarbonyl-N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.80 g (22.92 mmol) of 4-dimethylaminopyridine in 35 ml of chloroform was added dropwise 2.6 ml (22.92 mmol) of trichloroacetyl chloride, while stirring at room temperature for 3 minutes. The reaction mixture was heated for 15 hours under reflux. The reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, which was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline solution, which was dried over magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.70 g of the desired compound (58.2%, pale yellow liquid).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1)#[N:2].C[O-].[Na+].[C:13](O)(=[O:15])C>CO>[CH3:9][C:5]1[N:4]=[C:3]([C:1](=[NH:2])[O:15][CH3:13])[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: Cc1cccc(C#N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1cccc(C)n1
Reaction time: 3 h

Procedure:
To the solution of 2-cyano-6-methylpyridine (30 g) and methanol (300 ml) was added 28% sodium methoxide solution in methanol (14.7 g). After the solution was left to stand for 3 hours, acetic acid (4.6 g) was added thereto, followed by concentration under reduced pressure. The resultant residue was dissolved in ether (300 ml) and washed with water (100 ml). After the extract was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure to obtain methyl 6-methyl-2-picoline imidate.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][CH:22]([CH3:32])[C:23](=[O:31])[CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1>C1COCC1>[C:5]([O:4][C:1](=[O:3])[CH2:2][C:23]([OH:31])([CH2:24][CH2:25][C:26]1[CH:30]=[CH:29][S:28][CH:27]=1)[CH:22]([CH3:21])[CH3:32])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CC(C)C(=O)CCc1ccsc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(O)(CCc1ccsc1)CC(=O)OC(C)(C)C

Procedure:
The title compound was prepared as described in General Method 9 using t-butyl acetate (42.6 mmol), diisopropyl amine (42.6 mmol), nBuLi (42.6 mmol), 4-methyl-1-thiophen-3-yl-pentan-3-one (Example C-5; 21.3 mmol), and THF (100 mL). The title compound was purified by flash chromatography over silica gel eluting with hexane:EtOAc 97:3. 1NMR (CDCl3): δ0.95 (dd, 6 H), 1.47 (s, 9 H), 1.7-2.0 (m, 3 H), 2.36-2.54 (AB q, 2 H), 2.6-2.8 (m, 2 H), 6.93-6.95 (m, 2 H), 7.23-7.25 (m, 1 H).
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CO
Reactant: O=S(Cl)Cl
Product: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (20 ml) was dropwise added to 2-hydroxymethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine (2.8 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, the thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 2.1 g of 2-chloromethyl-3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)pyridine. The product was added to ethanol (30 ml) containing a solution of 2-mercaptobenzimidazole (1.3 g) and sodium hydroxide (1.2 g) in water (10 ml) and the mixture was refluxed under heating for 2 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from isopropyl alcohol to give 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 90°-94° C.