Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1.[C:11](Cl)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([N:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:3]=[N:2]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]nn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nn1
Yield: 88.8 %

Procedure:
3.47 g of ethyl 1,2,3-triazole-4-carboxylate and 7.55 g of trityl chloride were dissolved in 100 ml of chloroform and 3.77 ml of triethylamine was added dropwise thereto under stirring and cooling in an ice-bath. The resulting mixture was stirred for 30 minutes at room temperature. Chloroform was distilled off and the residue was dissolved in ethyl acetate and the mixture was washed with an aqueous solution of sodium chloride and then dried with sodium sulfate. Ethyl acetate was distilled off and the residue was purified by silica gel column chromatography with benzene and chloroform eluent to give 8.37 g of ethyl N-trityl-1,2,3-triazole-4-carboxylate with mp 201°-203° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[NH:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:25])[N:5]([CH3:28])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([CH2:14][C:15]2[C:16]([NH2:22])=[N:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:8][C:7]=1[O:23][CH3:24])[CH3:2]
Reactant: CCOC(=O)Nc1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)c1c(OC)cc(Cc2cnc(N)nc2N)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8.7 g. of 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-carbanilic acid ethyl ester and 1.44 g. of sodium hydride (50% dispersion in oil) in 75 ml. of absolute dimethylformamide was stirred at room temperature for 1 hour and then treated with 4.26 g. of methyl iodide. After stirring at room temperature for 3 hours, the dimethylformamide was removed at 60° C. under vacuum. The residue was dissolved in a mixture of 500 ml. of ethyl acetate and 150 ml. of water. After separation of the phases, the aqueous phase was extracted with 500 ml. of ethyl acetate. The combined ethyl acetate extracts were washed with 300 ml. of water, dried over magnesium sulfate and evaporated under vacuum. After recrystallization of the residue from alcohol, there was obtained 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-dimethoxy-N-methyl-carbanilic acid ethyl ester having a melting point of 187°-188° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:16][NH2:17])=[N:5][CH:6]=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CO[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=N>CO>[Cl:2][C:3]1[C:4]2[N:5]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:17][N:16]=2)[CH:6]=[C:7]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[CH:15]=1
Reactant: COC(=N)c1ccccn1
Reactant: CC(C)(C)OC(=O)c1cnc(NN)c(Cl)c1
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc(Cl)c2nnc(-c3ccccn3)n2c1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 7.6 %

Procedure:
To a solution of tert-butyl 5-chloro-6-hydrazinonicotinate hydrochloride salt (5.5 g, 17.4 mmol) in methanol (80 mL) was added methylpyridine-2-carboximidoate (4.73 g, 34.7 mmol). The mixture was heated to 65° C. After 2.5 h, the mixture was cooled to ambient temperature. The solid crashed out was filtered off and the filtrate was concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave 0.44 g of the title compound and 1.3 g of a side product. The side product (1.3 g) was dissolved in methanol (28 mL) and acetic acid (0.53 mL) was added. The mixture was heated to 65° C. After 7 h, the reaction was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to give another 1.0 g of the title compound: LC-MS [M+1]=331.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[N:12]1([CH:17]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=3)=[O:23])[CH2:18]2)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C=O)C.C1COCC1>[N:1]1([CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:22]([N:19]3[CH2:20][CH2:21][C@H:17]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)[CH2:18]3)=[O:23])=[CH:29][CH:28]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(c1ccc(CCl)cc1)N1CCC(N2CCCC2)C1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2ccc3ccccc32)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.3 %

Procedure:
A solution of indole (0.15 mmol, 19 mg) in a mixture of DMF/THF (1:4, 2 mL) is treated with sodium hydride (50 mg) followed by [1,3′]bipyrrolidinyl-1′-yl-(4-chloromethyl-phenyl)-methanone (0.15 mmol, 43 mg), stirred at room temperature overnight and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL) and purified by reverse-phase semi-preparative HPLC1 to give the title product as a white powder (8 mg), identified by HPLC and mass spectral analyses. Retention time 1.86 min., MS [374.2 m/e (M+H)].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[O:32]1[CH2:36][CH2:35][CH2:34][CH:33]1[C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:42]4[CH2:43][CH2:44][N:39]([C:37]([CH:33]5[CH2:34][CH2:35][CH2:36][O:32]5)=[O:38])[CH2:40][CH2:41]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(tetrahydrofuran-2-carbonyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=613.98 (M+H+); retention time=0.73 minutes.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[C:9]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[O:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)(=O)[CH3:10].[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29]>O.C(O)C.CC(O)C.C(OCC)C>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[OH:3][N:2]=[C:9]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[O:15][CH2:16][CH2:17][CH2:18][C:19]1[N:20]=[CH:21][NH:22][CH:23]=1)[CH3:10]
Reactant: CC(=O)c1cccc(OCCCc2c[nH]cn2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CC(=NO)c1cccc(OCCCc2c[nH]cn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.125 g (1.81 mmol) of hydroxylamine hydrochloride and 0.5 g (0.006 mol) of sodium acetate in 10 ml of water is stirred for 10 minutes, and a solution of 0.125 g (0.512 mmol) of 4-[3-(3-ethanoylphenoxy)propyl]-1H-imidazole in 3 ml of ethanol is then added slowly. The mixture is stirred at room temperature for 1 hour and then heated at 80° C. for 2 hours. After cooling, the solvent is removed under reduced pressure and the white residue obtained is extracted with chloroform. The chloroform is dried (MgSO4) and then evaporated. The oil obtained is dissolved in 4 ml of 2-propanol and treated with 1.3 equivalents of oxalic acid in 3 ml of 2-propanol. The addition of diethyl ether yields the product, which is separated by filtration, washed with ether and recrystallized in a 2-propanol/diethyl ether mixture, m.p. 149-151° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]([C:25]1[O:26][C:27]2[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=2[C:29]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24])=[N+]=[N-]>C1COCC1.O>[C:30]1([C:29]2[C:28]3[CH:36]=[CH:37][CH:38]=[CH:39][C:27]=3[O:26][C:25]=2[CH:23]([NH2:20])[CH3:24])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(N=[N+]=[N-])c1oc2ccccc2c1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1oc2ccccc2c1-c1ccccc1
Temperature: 60 °C

Procedure:
Triphenylphosphine (231 mg, 0.883 mmol) was added to a solution of 2-(1-azidoethyl)-3-phenylbenzofuran (186 mg, 0.706 mmol) in THF (9 mL) and water (1 mL). The mixture was heated at 60° C. for 2 h and then cooled to RT. Volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) affording 1-(3-phenylbenzofuran-2-yl)ethanamine as an oil (327 mg, quantitative). LCMS: RT 2.21 min [M−NH2]+ 221.1
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][C:9]([C:24]#[N:25])=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([Br:33])[C:9]([C:24]#[N:25])=[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(c2c(C#N)cc3c(N)ncnn23)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2c(C#N)c(Br)c3c(N)ncnn23)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To the solution of tert-butyl 4-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylate (54 mg, 0.158 mmol) in DMF (2 mL), NBS (28.07 mg, 0.158 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was concentrated to dryness. Trituration with acetone afforded product (60 mg, 90%). 1H NMR (400 MHz, DMF-da) 7.52 (s, 1H), 4.42-4.38 (m, 4H), 4.88-4.78 (m, 1H), 2.20-2.08 (m, 4H), 1.62 (s, 9H); LC-MS m/z [M+H]+ 420.9% 422.9, LC-MS RT 3.24 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[N:4](C(OCC2C=CC=CC=2)=O)[C:3]1=[O:24]>CO.[H][H].[Pd]>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[NH:4][C:3]1=[O:24]
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Yield: 98.2 %

Procedure:
8.5 g of tert.-butyl (4S)-1-methyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 200 ml of methanol, and 0.1 g of palladium black is added thereto. The mixture is shaken at room temperature in hydrogen gas atmosphere under atmospheric pressure. After the reaction the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue obtained is washed with n-hexane. 5.0 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 98.2%
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[CH:36][N:35]=4)=[O:32])=[C:26]([F:44])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.C(O)(C(F)(F)F)=O.C(OCC)(=O)C>ClCCCl>[NH2:1][C:2]1[C:7]2=[C:8]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]4[CH:39]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:37]=[CH:36][N:35]=4)=[O:32])=[C:26]([F:44])[CH:25]=3)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c3c(N)ncnn23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccn4)c(F)c3)c12
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A suspension of Example 270 (930 mg, 1.5 mmol) in 60 mL 1,2-dichloroethane was treated with 15 mL TFA at rt. The reaction quickly became homogeneous and at 10 min no starting material remained by RP-HPLC. The reaction mixture was concentrated in vacuo, and the residue taken up again in fresh 1,2-dichloroethane and concentrated again; this was repeated 2 times. The residue was taken up in THF (15 mL) and EtOAc (85 mL) and washed with aq. sodium carbonate. The organic layer was dried with sodium sulfate and concentrated in vacuo to provide a tan solid. Trituration with ethyl acetate provided the title compound (705 mg, 91%) as a tan solid. 1H-NMR (DMSO-d6) δ 10.14 (bs, 1H), 10.06 (bs, 1H), 8.54 (d, 1H), 8.26 (t, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.31-7.40 (m, 2H), 7.24 (dd, 1H), 6.65 (s, 1H), 3.18 (tt, 1H), 3.01 (broad d, 2H), 2.61 (td, 2H), 1.92 (broad d, 2H), 1.54 (ddd, 2H); MS [M+H]+=515.2; LCMS RT=2.34.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](Cl)=[O:6].[NH2:11][CH:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)[C:13]#[N:14].N1C=CC=CC=1>C1(C)C=CC=CC=1>[S:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[CH:12]([C:13]#[N:14])[NH:11][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: N#CC(N)c1cccs1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: N#CC(NC(=O)c1ccnc(Cl)c1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
3 g (0.017 mol) of 2-chloroisonicotinoyl chloride was added dropwise to a solution of 2.8 g (0.02 mol) of 2-amino-2-(2-thienyl)acetonitrile and 1.6 g (0.02 mol) of pyridine in 30 ml of toluene while the temperature was kept at 10° to 15° C. The mixture was stirred at room temperature for 1 h. A saturated aqueous common salt solution was added thereto. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure and the crude product was purified according to silica gel column chromatography to obtain 1.5 g (yield: 31.8%) of light brown crystals having a melting point of 123° to 125° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][C:49]=1[F:50])[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C(=O)C.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([NH:27][C:28]2[CH:29]=[C:30]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]5[CH2:46][CH2:45]5)=[O:43])[N:40]=4)[N:37]=3)[CH:47]=[CH:48][C:49]=2[F:50])=[O:15])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: O=C(O)c1ccn(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1ccn(Cc2ccccc2)c1
Yield: 24.3 %

Procedure:
Using 1-benzyl-1H-pyrrole-3-carboxylic acid (276 mg, 1.37 mmol), tetrahydrofuran (3.0 mL), N,N-dimethylformamide (20 μL, 0.26 mmol), oxalyl chloride (120 μL, 1.37 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.92 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (114 mg, 24%) was obtained as a white powder.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]([NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[CH3:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>ClCCCl>[CH3:1][NH:2][C:3]1[S:25][C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:5]=1[CH3:6]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C(C)NC(=O)c1cccnc1
Solvent: ClCCCl
Product: CNc1sc(-c2cccnc2)nc1C
Temperature: 130 °C
Yield: 68.7 %

Procedure:
To a 10 mL microwave vessel containing DCE (5 mL) was added N-(1-methylcarbamoyl-ethyl)nicotinamide (207 mg, 1.0 mmol) followed by Lawesson's reagent (2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide, 404 mg, 1.0 mmol) in one portion. The heterogeneous mixture was heated in a microwave for 5 min at 130° C. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate (NaHCO3). The layers were separated and the organic layer was washed once with brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (ethyl acetate) to give the desired product as an orange solid (141 mg, 68%): mp 84-87° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (d, J=1.7 Hz, 1H), 8.51 (dd, J=4.9, 1.7 Hz, 1H), 8.08 (dt, J=8.0, 1.7 Hz, 1H), 7.29 (m, 1H), 3.00 (s, 3H), 2.30 (s, 3H); ESIMS m/z 206.4 (M+1), m/z 204.2 (M-1).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22]Br>C1(C)C(C)=CC=CC=1>[N:17]1([CH2:16][CH2:15][C:11]2[CH:10]=[C:9]([O:8][CH3:7])[CH:14]=[CH:13][CH:12]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cccc(CCN)c1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: COc1cccc(CCN2CCCC2)c1
Temperature: 25 °C

Procedure:
A stirred suspension of anhydrous sodium carbonate (0.923 g), 2-(3-methoxyphenyl)ethylamine (0.5 g) and 1,4-dibromobutane (0.43 ml) in dry xylene (5.5 ml) was heated under reflux for 16 hours. The reaction mixture was allowed to cool to room temperature and was filtered. The filtrate was extracted with 5N hydrochloric acid. The acidic extracts were washed with ether and then basified with 5N sodium hydroxide solution and extracted with ether. The ether extracts were washed with water, dried and the ether removed by evaporation to give 3-(2-pyrrolidin-1-ylethyl)anisole.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.[C-:14]#[N:15].[K+]>CN(C)C=O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([C:14]#[N:15])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCOc1ccc([N+](=O)[O-])c(Br)n1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc([N+](=O)[O-])c(C#N)n1
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To a solution of the compound prepared in Example 279 (0.317 g) in N,N-dimethylformamide (6 mL) was added potassium cyanide (0.100 g) at room temperature. The mixture was heated at 80° C. for 18 hours and then cooled to room temperature. The solids were filtered, and the filtrate diluted with ethyl acetate, washed with 1N hydrochloric acid and water. The organic layer was filtered, evaporated in vacuo and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to obtain the title compound (0.096 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]=O)=[CH:25][CH:24]=3)=[CH:22][C:13]=12.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[S:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[CH:25][CH:24]=3)=[CH:22][C:13]=12
Reactant: C1COCCN1
Reactant: COc1cc(Nc2c(C#N)cnc3sc(-c4ccc(C=O)cc4)cc23)c(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3sc(-c4ccc(CN5CCOCC5)cc4)cc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.2 %

Procedure:
A suspension of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[2,3-b]pyridine-5-carbonitrile (0.1 g, 0.24 mmol) in 1 mL of N,N-dimethylformamide and 4 mL of dichloromethane is prepared. To the mixture is added morpholine (0.03 mL, 0.32 mmol). The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (0.26 g, 1.2 mmol) is added. After stirring at 0° C. for 30 minutes a drop of acetic acid is added and the mixture is stirred at 0° C. for an additional 4 hours. Additional morpholine (0.01 mL, 0.1 mmol) and sodium triacetoxyborohydride are added and the reaction mixture is allowed to warm to room temperature and stirred overnight. The resultant light brown solution is partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride and water, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is triturated with acetone and water to provide 86 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[4-(morpholin-4-ylmethyl)phenyl]thieno[2,3-b]pyridine-5-carbonitrile as a white solid, mp 106–108° C.; 1H NMR (DMSO-d6) δ 2.38 (br s, 4H), 3.51 (br s, 2H), 3.59 (br s, 4H), 3.86 (s, 3H), 7.40 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.67 (d, J=8.0 Hz, 2H), 7.77 (s, 1H), 8.19 (s, 1H), 8.42 (s, 1H), 9.80 (s, 1H); MS 525.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17]O)=[N:9]2)=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:25]>O=S(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH2:17][Cl:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: OCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: ClCc1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 813 mg (2.75 mmol) of trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]benzyl alcohol in 40 ml of CHCl3, 1.0 ml of SOCl2 was added, followed by stirring at room temperature for 24 hours. A small amount of MeOH was added to the reaction mixture and the solvent was distilled off under reduced pressure, whereby trans-3-[2-(7-chloroquinolin-2-yl)ethenyl]-benzyl chloride was obtained as pale yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][CH:15]=[C:14]2[CH2:24][CH2:25][C:26]#[N:27])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]([Si](C)(C)C)=[N+:30]=[N-:31]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:14]([CH2:24][CH2:25][C:26]3[NH:31][N:30]=[N:29][N:27]=3)=[CH:15][CH:16]=[C:17]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c(CCC#N)ccc2-c2ccccc2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Temperature: 110 °C
Yield: 62 %

Procedure:
To a stirred solution of 4-[2-(2-cyano-ethyl)-5-phenyl-pyrrol-1yl]-benzoic acid tert-butyl ester (2.31 mmol, 1.0 eq.) in toluene (12 ml) were added Azidotrimethylsilane (TMSN3) (4.62 mmol, 2.0 eq.) and Sn(Bu)2O (dibutyltin(IV) oxide) (0.23 mmol, 0.1 eq.). The resulting mixture was heated to 110° C. overnight. The solvent was evaporated in vacuo and the residue loaded onto a 40 g RediSep silica-gel column for purification. Gradient elution with methanol/DCM (0% to 7% methanol in DCM over 25 minutes) gave the product 4-{2-phenyl-5-[2-(1H-tetrazol-5-yl)ethyl]-pyrrol-1-yl}-benzoic acid tert-butyl ester as a light yellow oil after combination of the appropriate fractions and evaporation of the solvent in vacuo, 62% yield.