Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isobutylimidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (900 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (358 mg) in dichloromethane (15 ml) at −78° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature, and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by basic silica gel column chromatography (ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-isobutylimidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (619 mg) (Compound 382) as yellow amorphous.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O>>[C:18]1([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][C:15]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Product: COC(=S)c1cc(-c2nc(-c3ccccc3)c(-c3ccccc3)s2)c(C)s1

Procedure:
A solution of 75 mg (0.3 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 92 mg, 0.3 mmol) of 2-bromo-1,2-diphenylethan-1-one in a manner similar to Example 8, step (a) to give, after preparative thin-layer chromatrography purification, methyl 4-(4,5-diphenyl(1,3-thiazol-2-yl))-5-methylthiothiophene-2-carboxylate (9 mg, 7%) as a solid. 1H-NMR (DMSO-d6; 300 MHz) δ8.94 (br s, 0.4H), 8.66 (s, 1H), 8.60 (br s, 0.3 H), 8.08 (s, 1H), 7.93 and 7.20 (AB quartet, 2H, J=8.7 Hz), 7.68 and 7.35 (AB quartet, 2H, J=8.2 Hz), 2.77 (s, 3H), ), 2.33 (s, 3H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C22H17NO2S3, 424.0 (M+H), found 424.3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[O:4][CH2:3]1.[CH2:14]([C:16]1[C:17](=[O:22])[NH:18][CH2:19][C:20]=1[CH3:21])[CH3:15].C1C[O:26][CH2:25]C1>>[CH2:14]([C:16]1[C:17](=[O:22])[N:18]([C:25]([NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[O:4][CH2:3]2)=[O:26])[CH2:19][C:20]=1[CH3:21])[CH3:15]
Reactant: CCC1=C(C)CNC1=O
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)OCC(N)C2
Product: CCC1=C(C)CN(C(=O)NC2COc3cc(OC)ccc3C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.43 g (52 mmol) of N,N'-carbonyldiimidazole were added to a solution of 8.2 g (46 mmol) of 3-amino-7-methoxychroman in 60 ml of THF. During this operation, the solution became warm. After the solution had been stirred at room temperature for one hour, it was evaporated in vacuo. The residue was melted together with 6.51 g (52 mmol) of 3-ethyl-4-methyl-3-pyrrolin-2-one at 160°-170° C. for 1.5 to 2 hours and the mixture was then chromatographed over silica gel using the eluting agent ethyl acetate/petroleum ether 3:1. The main fraction was evaporated and the residue was recrystallized from methanol. 3-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-7-methoxychroman of melting point 118°-119° C. was obtained. This product was introduced by the customary procedure into chlorosulfonic acid which had been cooled to -15° C. The mixture was allowed to come to room temperature and was subsequently stirred for 1 hour. After customary work-up, the sulfochloride was converted into the sulfonamide as described in Example 1. 3-(3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)-6-sulfamoyl-7-methoxychroman had a melting point of 225°-227° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C(Cl)(Cl)Cl.C(#N)C>[NH:11]1[CH:15]=[N:14][C:13]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)=[N:12]1
Reactant: c1nc[nH]n1
Reactant: N#Cc1ccc(CBr)cc1
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: N#Cc1ccc(Cc2nc[nH]n2)cc1

Procedure:
A solution containing α-bromo-4-toluonitrile (19.6 g) and 1,2,4-triazole (30.5 g) in a mixture of chloroform (250 mL) and acetonitrile (50 mL) is stirred at reflux for 15 hours. The solution is cooled and washed with 3% aqueous sodium bicarbonate (200 mL) and the organic solution is then dried (MgSO4) and evaporated. The residue is chromatographed on silica gel (300 g). Elution with chloroform/isopropanol (10:1) affords 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile, which forms a hydrochloride salt, m.p. 200°-205°, when its solution in ethyl acetate is treated with ethereal HCl.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+]>[Cu]I.C(O)C>[CH3:32][O:33][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: O=C([O-])[O-]
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCO
Product: COc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 210 °C
Reaction time: 5 h
Yield: 5.7 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.52 mmol), copper(I) iodide (90 mg, 0.52 mmol), 1,10-phenanthroline (93 mg, 0.52 mmol) and cesium carbonate (219 mg, 0.67 mmol) were added to ethanol (5 mL) in a stainless container. The resulting mixture was stirred at 210° C. for 5 hours under nitrogen. The reaction mixture was concentrated and purified by prep-HPLC and TLC to give the product (7.2 mg, 5.7%). LCMS (ESI): RT (min)=0.79, M+H+=243.0, method=A. 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=9.2 Hz, 1H), 3.96 (s, 3H), 2.01 (s, 1H), 0.81-0.79 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.O=[C:16]([CH3:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[NH2:24][C:25]([CH3:39])=[CH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=1)=[O:28].C(O)(=O)C>CC(O)C>[CH3:23][C:16]1[NH:24][C:25]([CH3:39])=[C:26]([C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=2)[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(N)=CC(=O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)c2ccc(C(F)(F)F)cc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
164 mg (0.87 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 113 mg (0.87 mmol) of ethyl 3-oxobutanoate, 200 mg (0.87 mmol) of 3-amino-1-[4-(trifluoromethyl)phenyl]but-2-en-1-one and 5 μl (0.087 mmol) of acetic acid in 8 ml of 2-propanol and heated under reflux under argon for 30 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 59 mg (13% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [H-].[Na+].Cl[CH:4](Cl)[C:5]([OH:7])=[O:6].[OH:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[C:12]([CH3:20])([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CO>O1CCOCC1.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:10]2[O:9][CH:4]([C:5]([OH:7])=[O:6])[O:19][C:12]([CH3:20])([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:11]=2[CH:21]=1
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1(c2ccccc2)OC(C(=O)O)Oc2ccc(Cl)cc21
Temperature: 80 °C

Procedure:
60 mg of dibenzo-18-couronne-6 were added at 150° C. to a mixture of 10 ml of dioxane and 1.35 g of sodium hydride as a 50% oil suspension and then a solution of 0.61 ml of dichloroacetic acid in 10 ml of dioxane was added thereto over 5 minutes followed by addition of solution of 1.25 g of 2-hydroxy-5-chloro-α-methyl-benzhydrol in 5 ml of dioxane over 10 minutes at 20° C. The mixture was heated for 6 hours at 80° C., cooled to 20° C. and 2 ml of methanol were added thereto. The mixture was poured into iced water and was extracted three times with ethyl acetate. The organic extracts were washed 5 times with 0.1 N sodium hydroxide and the combined aqueous phases were acidified to a pH of 1 with 2 N hydrochloric acid and extracted 3 times with methylene chloride. The organic extracts were dried and evaporated to dryness to obtain raw 6-chloro-4-methyl-4-phenyl-[4H]-1,3-benzodioxin-2-carboxylic acid (mixture of two racemates diastereoisomers).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:26](=[O:37])[C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:24]1[N:25]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:26](=[O:37])[C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[N:31][O:30][C:28]=2[N:29]=1)[CH2:22][CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: CCC(c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(c1nc2onc(C(F)(F)F)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of 12 (52 mg, 0.083 mmol) in CH2Cl2 (4.0 mL) stirred at room temperature was added TFA (1.0 mL). The reaction mixture was stirred at room temperature for 30 min. Solvent was removed in vacuo, the residue was purified by preparative HPLC to give 13 as a white solid (42 mg, 96%). MS (ESI): 528 (M+H)+.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47](Br)[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1.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>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH:38][C:39]3[N:40]=[CH:41][C:42]4[CH:48]=[C:47]([C:6](=[O:8])[CH3:7])[C:46](=[O:50])[N:45]([CH:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)[C:43]=4[N:44]=3)=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4cc(Br)c(=O)n(C5CCCC5)c4n3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 110 °C

Procedure:
Tributyl(1-ethoxyvinyl)tin (0.39 mL, 1.15 mmol) was added to a mixture of 4-[6-(6-bromo-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (440 mg, 0.77 mmol), prepared as in Example 2, and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.077 mmol) in toluene (5 mL). The reaction mixture was heated at 110° C. for 1 hour then cooled to room temperature. The solid so formed was collected by filtration and washed with toluene, then dried to give 4-[6-(6-acetyl-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3yl]-piperazine-1-carboxylic acid tert-butyl ester. M++1: Calc'd. 534.6. Found 534.2.
Reaction SMILES: [CH2:1]([CH:5]([CH:12]=[CH2:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[C:14]([O-])(=[O:16])[CH3:15].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:14]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:12]=[CH2:13])(=[O:16])[CH3:15]
Reactant: CC(=O)[O-]
Reactant: C=CC(CCCC)CCCCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: C=CC(CCCC)CCCCCOC(C)=O
Yield: 93 %

Procedure:
6- Butyloct-7-en-1-ol (800 mg, 4.34 mmol) was converted to the acetate in a standard procedure with acetic anhydride, pyridine and 4-dimethylaminopyridine (DMAP). Subsequent purification by PMLPC yielded 914 mg (93%) of 6-butyloct-7-en-1-yl acetate.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([N:17]([CH3:36])[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:26]=1[NH:25][C:24]([C:27]1[S:28][CH:29]([CH2:32][C:33](O)=[O:34])[CH2:30][N:31]=1)=[CH:23]2)(=[O:16])=[O:15].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:5][O:4][N:3]([CH3:2])[C:33](=[O:34])[CH2:32][CH:29]1[S:28][C:27]([C:24]2[NH:25][C:26]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]([S:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH3:6])(=[O:15])=[O:16])[CH3:36])=[N:31][CH2:30]1
Reactant: CNOC
Reactant: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C3=NCC(CC(=O)N(C)OC)S3)[nH]c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (48 mg) in N,N-dimethylformamide (10 mL) was added triethylamine (85 uL) under ice-cooling, and the mixture was stirred for 10 min under ice-cooling. (2-{7-[[(2-Methoxyphenyl)sulfonyl](methyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (200 mg), 1H-1,2,3-benzotriazol-1-ol (90 mg) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (130 mg) were added to the mixture, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:methanol=100:0-95:5) to give the title compound (180 mg, yield: 85%) as a pale-yellow amorphous solid. MS:489(MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[N:20]2)=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[N:20]2)=[C:12]([CH:18]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)ccc1-n1nnnc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1-n1nnnc1C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Potassium carbonate (110 g, 0.793 mol) was added to a solution of ethyl 5-hydroxy-2-(5-methyltetrazol-1-yl)benzoate (98.5 g, 0.397 mol) in 500 mL of DMF. After vigorous stirring for 30 minutes, benzyl bromide (75 g, 0.438) was added and the reaction was stirred overnight. The solution was filtered and then concentrated under reduced pressure (at 50° C.). The resulting solid was slurried in 400 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure to give 115 g of ethyl 5-benzyloxy-2-(5-methyltetrazol-1-yl)benzoate as a brown oil.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH3:18])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CN1CCCC1c1cncc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: C#Cc1cncc(C2CCCN2C)c1

Procedure:
Repeating the procedure of Example 16, but using trimethylsilylacetylene in place of phenylacetylene, 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine and the fumarate derivative thereof were obtained as follows. 5-Trimethylsilylethynyl-3-(1-methyl-2-pyrrolidinyl) pyridine (516 mg, 2 mmol) and cesium carbonate (200 mg, 0.6 mmol) were dissolved in methanol (10 mL) and heated under reflux for 5 h. After cooling the solvents were removed in vacuo and the residue dissolved in ethyl acetate (40 mL) and washed with water (10 mL). The aqueous layer was extracted with ethyl acetate (40 mL) and the combined organic extracts washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude product was chromatographed on "flash" silica gel with ethyl acetate:hexane (1:9, 1:4, 1,3) to afford 5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 218 mg, 59%.
Reaction SMILES: [CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][NH:28][CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH:1]1([CH:4]([N:8]2[CH:12]=[C:11]([C:13]3[N:18]4[CH:19]=[CH:20][N:21]=[C:17]4[CH:16]=[C:15]([C:22]4[CH:31]=[C:30]5[C:25]([CH2:26][CH2:27][N:28]([CH3:34])[CH2:29]5)=[CH:24][CH:23]=4)[N:14]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: N#CCC(C1CC1)n1cc(-c2nc(-c3ccc4c(c3)CNCC4)cc3nccn23)cn1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CN1CCc2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CC5)c4)n3)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
To 3-cyclopropyl-3-(4-(7-(1,2,3,4-tetrahydroisoquinolin-7-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 54; 10 mg, 0.024 mmol) in DCM/MeOH (1 mL/1 mL) was added formaldehyde (49 mg, 0.49 mmol) and sodium triacetoxyborohydride (16 mg, 0.073 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and concentrated under reduced pressure. The residue was purified by silica gel chromatography (DCM/MeOH/NH4OH 10:1:0.1) to give the final product (5.0 mg, 48% yield). MS (apci) m/z=424.3 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH:17]([C:21](=O)C)[CH2:18][C:19]#[N:20].[CH2:24](N(CC)CC)C>C(O)C>[C:19]([C:18]1[N:3]2[C:4]([CH3:24])=[CH:5][CH:6]=[C:7]([CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:2]2=[N:1][C:17]=1[CH3:21])#[N:20]
Reactant: CCN(CC)CC
Reactant: CC(=O)C(Cl)CC#N
Reactant: Nc1ncccc1CCc1ccccc1
Solvent: CCO
Product: Cc1nc2c(CCc3ccccc3)ccc(C)n2c1C#N

Procedure:
In similar manner, reaction of 2-amino-3-(2-phenylethyl)pyridine (which is prepared by amination of 3-(2-phenyl ethyl)-pyridine with sodium amide in ammonia and N,N-dimethylaniline) with 3-chloro-4-oxo-pentanonitrile in ethanol in the presence of triethylamine gives 3-cyano-methyl-2-methyl-8-(2-phenylethyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.CN(C=O)C.[Br:22][CH2:23][C:24](Br)=[O:25]>O1CCOCC1>[Br:22][CH2:23][C:24]([NH:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:16][CH:15]=1)=[O:25]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)aniline (14.0 g, 59 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (11.91 g, 5.18 mL, 59 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water. The resulting precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 8.73 g (61%) Of the title compound as a pale yellow crystals, mp 128°-134° C. (decomp), became wet at 89°-93° C.: 1H NMR (DMSO-d6) δ10.35 (s, 1H), 7.52 (d, J=8.8, 2H), 7.26 (d, J=8.8, 2H), 4.43 (s, 2H), 4.04 (s, 2H); 13C NMR (DMSO-d6) δ164.58, 138.00, 137.15, 126.97, 118.94, 62.51, 30.43; MS (El, m/z) 243 (M+).
Reaction SMILES: [BrH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]>CCOCC>[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Br:1])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: Br
Reactant: CC(C)Cc1ccc(CO)cc1
Solvent: CCOCC
Product: CC(C)Cc1ccc(CBr)cc1
Reaction time: 1 h

Procedure:
HBr gas was bubbled through a solution of (4-isobutyl-phenyl)-methanol (5 g, 28 mmol) in Et2O (50 mL) for 10-15 minutes. The reaction was stirred for 1 h and was poured onto ice (100 g). Et2O was added and the organic solution was washed with brine (2×). The organic solution was dried (MgSO4), filtered, and concentrated to provide the title compound (6 g). 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.10 (d, 2H), 4.49 (s, 2H), 2.45 (d, 2H), 1.84 (m, 1H), 0.89 (d, 6H).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH2:9]=[O:10].C(N(CC)CC)C>>[OH:10][CH2:9][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4]
Reactant: CCOP([O-])OCC
Reactant: C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CO)OCC
Yield: 68.4 %

Procedure:
The procedure of Kluge was followed (Org. Syn. 1986, Vol. 64, 80-84). The following ingredients were combined: 69 g (0.50 mol) of diethyl phosphite, 15 g (0.50 mol) of paraformaldehyde, and 5.1 g (0.05 mol) of triethylamine. The stirred mixture was immersed in a preheated oil bath at 120° C. and heated for one hour. Upon cooling, the triethylamine was removed on the rotary evaporator at 80° C., and the residue was then distilled bulb-to-bulb (150-160° C., 0.10 mm) to provide 57.5 g (68%) of title compound as a colorless liquid.