Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:39]([N:38]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)N(Cc1ccccc1)Cc1ccccc1
Yield: 80 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and N,N-dibenzylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 80%.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[CH:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][C:36](CO)=[CH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[CH:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH2:37][C:36]([CH2:1][Br:5])=[CH:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CO)CC1CO[Si](C)(C)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A mixture of carbon tetrabromide (3.18 g, 9.6 mmol) and triphenyl phosphine (3.15 g, 12.9 mmol) were added to [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl alcohol (3.09 g, 8.0 mmol) in dichloromethane under ice bath and then, the reaction mixture was stirred for 30 min at 0° C. After overnight at room temperature, the reaction mixture was extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (2.43 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=3)[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([Sn]([N:35]=[N+:36]=[N-:37])(CCCC)CCCC)CCC.[OH-].[Na+]>C1(C)C=CC=CC=1>[N:21]1[NH:35][N:36]=[N:37][C:20]=1[C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(-c2n[nH]c3ccc(C#N)cc23)cc1OC
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2n[nH]c3ccc(-c4nn[nH]n4)cc23)cc1OC
Reaction time: 14 h
Yield: 52.5 %

Procedure:
To a solution of 3-(3,4-dimethoxyphenyl)-1H-indazole-5-carbonitrile (190 mg, 0.68 mmol) in toluene (10 mL) was added tributyltin azide (930 μL, 3.4 mmol). The solution was heated to reflux for 12 hours when 3 N NaOH (80 mL) was added and the solution extracted with ethyl acetate (2×20 mL). The aqueous layer was then acidified with 4 N HCl to pH<1 and extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (Na2SO4) and concentrated to an oil. After remaining at room temperature for 14 hours, the product crystallized from solution to recover, after filtration and drying, the title compound (115 mg, 53% yield). 1H NMR (DMSO-d6) δ 13.4 (s, 1H), 8.70 (s, 1H), 8.04 (d, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.49 (s, 1H), 7.12 (d, 1H), 3.85 (s, 3H), 3.81 (s, 3H); ES-MS (m/z) 323 [M+1]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:29])[C:15]2[O:14][CH:13]([CH2:12][N:31]3[CH2:36][CH2:35][S:34][CH2:33][CH2:32]3)[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4c(C)cccc4C)c3O2)cc1
Reactant: C1CSCCN1
Product: Cc1cccc(C)c1-c1cc(Cl)cc2c1OC(CN1CCSCC1)C2

Procedure:
The title compound was prepared (0.55 g, 39%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-([5-chloro-7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.338 mmol) and thiomorpholine (0.72 g, 6.76 mmol). mp 224-226° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC[O:33][C:34]([C@H:36](OS(C(F)(F)F)(=O)=O)[CH3:37])=[O:35]>>[Cl:1][C:2]1[C:3]([F:30])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:28][CH3:29])=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C@H:36]([C:34]([OH:35])=[O:33])[CH3:37])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN1CCCC1
Reactant: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(CCN1CCCC1)[C@@H](C)C(=O)O

Procedure:
N-(3-Chloro-2-fluorophenyl)-7-methoxy-6-{[(2-pyrrolidin-1-ylethyl)amino]methyl}quinazolin-4-amine was coupled with ethyl O-trifluoromethanesulfonyl-D-lactate and hydrolysed using analogous methods to those described for the equivalent steps in Example 46 to give N-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-(2-pyrrolidin-1-ylethyl)-L-alanine; 1H NMR Spectrum: (DMSO-d6) 1.27 (d, 3H); 1.83 (m, 4H); 2.86 (m, 8H); 3.44 (q, 1H); 3.84 (d, 1H); 3.94 (d, 1H); 4.01 (s, 3H); 7.25 (s, 1H); 7.33 (t, 1H); 7.53 (m, 1H); 7.63 (m, 1H); 8.42 (s, 1H); 8.48 (s, 1H); 9.78 (brs, 1H; Mass Spectrum: (M+H)+ 502.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[CH:4][N:3]=1.[O:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.C([BH3-])#N.[Na+]>ClCCl.O.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)=[CH:4][N:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1cnc(Cl)nc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Clc1ncc(NC2CCOCC2)c(Cl)n1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 22.2 %

Procedure:
In a 100 mL round bottomed flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL of dichloromethane was added dihydro-2H-pyran-4(3H)-one (0.794 g, 7.93 mmol), cooled to 0° C. then added the solution of titanium tetrachloride (0.740 ml, 6.71 mmol) in 10 mL of dichloromethane. The reaction was removed from the ice bath and with continued stirring, slowly warmed to room temperature. After 3.5 h, sodium cyanoborohydride (1.15 g, 18.29 mmol) was added in 4 equal portions over 10 minutes and the reaction was stirred at room temperature for 16 h. The suspension was diluted with water (150 mL) and transferred to an appropriate separatory funnel. The layers were separated and then extracted the aqueous layer with MTBE (1×150 mL). The organic layers were combined, washed with sat. NaCl, dried over Na2SO4, filtered and concentrated in vacuo affording a clear orange oil. The crude oil was purified by silica chromatography (30% EtOAc/Hexanes); the appropriate fractions were combined and concentrated in vacuo to afford 2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g, 60% pure, 22% yield). MS [M+H] found 249.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: O=C=Nc1cccc(Br)c1
Solvent: C1CCOC1
Product: O=C(NCC(F)(F)F)Nc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.9 %

Procedure:
3-Bromophenyl isocyanate (1.0 ml, 8.1 mmol) was added slowly to a stirred solution of 2,2,2-trifluoroethyl amine (3.2 ml, 40 mmol) in THF (10 ml) at 0° C. under N2. After 1 hour the reaction was allowed to warm to RT and kept at this temperature for 16 hours. The volatiles were removed in vacuo to give the title compound (2.5 g, solid). 1H NMR (400 MHz, DMSO-d6): 9.00 (1H, s), 7.86 (1H, t), 7.33 (1H, ddd), 7.26 (1H, t), 7.18 (1H, ddd), 6.89 (1H, t), 4.03-3.92 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[C:12](I)=[CH:11][CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1)#[CH:21].C(N(CC)CC)C>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.CN(C)C=O>[C:1]1([C:7]2[C:12]([C:21]#[C:20][C:22]3([OH:30])[CH:27]4[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]4)[CH2:23]3)=[CH:11][CH:10]=[C:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: Ic1ccc(N2CCOCC2)nc1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(N3CCOCC3)nc2-c2ccccc2)CN2CCC1CC2
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A mixture of 500 mg of 2-phenyl-6-morpholino-3-iodopyridine, 230 mg of 3-ethynyl-3-quinuclidinol, 79 mg of tetrakis(triphenylphosphine)palladium(0), 1.3 mg of cuprous iodide, 0.57 ml of triethylamine and 1 ml of N,N-dimethylformamide was heated under stirring for 4 hours in an oil bath kept at 75° C. in a nitrogen atmosphere. The mixture was extracted by adding aqueous dilute ammonia and ethyl acetate thereto, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to NH-silica gel column chromatography, and eluted with 50% ethyl acetate/hexane, ethyl acetate and then 2.5% methanol/ethyl acetate, and crystallized from ethyl acetate, to give 296 mg of the target compound.
Reaction SMILES: [Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21].[N:22]1([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:34][C:31]3[CH:30]=[CH:29][C:28]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:33][N:32]=3)[N:8]=[CH:9][C:4]=2[C:3]=1[CH3:21]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(S(C)=O)ncc12
Reactant: Nc1ccc(N2CCOCC2)cn1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cn3)ncc12
Temperature: 25 °C
Yield: 26.7 %

Procedure:
6-Bromo-8-cyclopentyl-2-methanesulfinyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 2.70 mmol) and 5-morpholin-4-yl-pyridin-2-ylamine (0.668 g, 3.73 mmol) were heated to reflux in toluene (10 mL) for 16 hours. The reaction mixture was cooled to room temperature and the precipitate that formed was collected by filtration and washed on the funnel with toluene (3×10 mL). The solid obtained was refluxed in ethyl acetate (15 mL), cooled and filtered to give 6-bromo-8-cyclopentyl-5-methyl-2-(5-morpholin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one as a dark brown-gray solid (0.350 g, 26.7%). 1H NMR δ (400 MHz, CDCl3) 8.78 (s, 1H), 8.17 (d, J=9.0 Hz, 1H), 8.02 (d, J=2.7 Hz, 1H), 7.97 (s, 1H), 7.32 (dd, J=2.9, 9.0 Hz, 1H), 5.99 (m, 1H), 3.89 (m, 4H), 3.16 (m, 4H), 2.61 (s, 3H), 2.30 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.68 (m, 2H).
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21].[I-].[Na+].C(N(CC)CC)C>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate, 226 mg (1.5 millimoles) of tertbutyldimethylsilyl chloride and 210 mg (1.4 millimoles) of sodium iodide. To the mixture was added 220 μl (1.6 millimoles) of triethylamine under an argon atmosphere at a room temperature. The resultant was heated up to 40° C. and agitated at the same temperature overnight, followed by concentration under a reduced pressure. To the residue was added 20 ml of ethyl acetate, and the resultant was washed twice with 10 ml portions of water. The organic layer was dried and then concentrated to dryness under a reduced pressure to give 340 mg (yield 90%) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:20]([NH2:22])=[O:21])[N:16]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[CH:18][N:17]([C:20]([NH2:22])=[O:21])[N:16]=3)=[CH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)n1ccc(-c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)n1ccc(-c2ccc(Oc3ccc(N)cc3)cc2)n1
Yield: 62.9 %

Procedure:
A solution of 3-[4-(4-nitrophenoxy)phenyl]-1H-pyrazole-1-carboxamide (100 mg, 0.308 mmol) in ethanol was flushed with nitrogen for 5 min, then palladium (10% on carbon, 20 mg) was added. The mixture was shaken under 40 psi of hydrogen for 16 hours. The mixture was then filtered through a bed of Celite and the solvent was removed in vacuo. The crude product was purified by column chromatography to give 57 mg (60%) of the title compound as a solid, mp 158-160° C. 1H NMR (CDCl3): δ8.22 (d, J=3.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 7.10 (bs, 1H), 6.90 (d, J=9.0 Hz, 2H), 6.70 (d, J=9.0 Hz, 2H), 6.66 (d, J=3.0 Hz, 1H), 5.25 (bs, 1H), 3.61 (bs, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.[C:13]([O:17][C:18]([N:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]1B(O)O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>CCOC(C)=O>[CH:11]([C:8]1[N:6]2[CH:7]=[C:2]([C:21]3[N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1)=[O:12]
Reactant: O=Cc1cnc2ccc(Br)cn12
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(-c2ccc3ncc(C=O)n3c2)cc2ccccc21
Yield: 51 %

Procedure:
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde (step 1 of Intermediate 1, 150 mg, 0.6729 mmol), 1-(tert-butoxycarbonyl)-1H-indol-2-ylboronic acid (228 mg, 0.8742 mmol), dichlorobis(triphenylphosphine) palladium (II) (30 mg, 20% mmol) and 2M aqueous Na2CO3 (1 mL) were added to DMF (5 mL) and refluxed for 2 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The solvent was evaporated to obtain solid residue, which was purified by column chromatography (silica gel, 1% methanol in chloroform) to obtain the title compound. Yield: 51%; 1H NMR (DMSO-d6; 300 MHz): δ 11.91 (s, 1H), 9.99 (s, 1H), 9.81 (s, 1H), 8.55 (s, 1H), 8.17 (dd, 1H, J=9.3, 1.8 Hz), 7.95 (d, 1H, J=9.3 Hz), 7.56 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=8.4 Hz), 7.142 (t, 1H, J=7.2 Hz), 7.03 (m, 2H); MS: m/z 260 (M−1)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]([CH3:31])[C:18]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C(O)(=O)C>ClCCCl>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH:21]3[CH2:20][CH2:19][C:18]([N:17]([CH3:31])[CH3:16])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:23][CH2:22]3)[CH2:2][CH2:3]2)=[CH:8]1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(N2CCC(c3c[nH]c4ccccc34)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-piperidine-4-yl-1H-indole (200 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (20 ml). Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg, 1.4 mmole) were added to this mixture. The reaction mixture was then stirred for 24 hours at RT. The reaction mixture was worked up by distilling off the 1,2-dichloroethane and diluting with water (10 ml). The reaction mixture was adjusted to pH 11 with 5M NaOH and extracted with EE (3×20 ml). The organic phase was dried with Na2SO4 and concentrated by evaporation. The product was a mixture of two diastereoisomeric compounds, which were separated by chromatography with methanol. The polar and the non-polar diastereoisomers were obtained in each case as a colourless oil in a yield of 90 mg (22%).
Reaction SMILES: [NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:18]>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH2:9][CH3:10])=[C:3]([C:6]#[N:7])[C:4](=[S:18])[NH2:5]
Reactant: S
Reactant: CCOC(N)=C(C#N)C#N
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(N)=C(C#N)C(N)=S
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
A mixture of 51.2 g of 3-amino-3-ethoxy-2-cyano-2-propenenitrile (above) and 37.8 g of triethylamine in 200 ml of pyridine was continuously stirred and heated to 70° while 60 g of gaseous hydrogen sulfide was bubbled in during 1.5 hours. Heating was continued at 65°-70° for 0.5 hour. Thin-layer chromatographic analysis indicated that no reaction had occurred. The mixture was heated overnight at 55° but still no reaction had occurred. An additional 150 ml of pyridine was added and the mixture was heated to 75°-80° while 17 g of hydrogen sulfide was bubbled in during 0.5 hour. Thin-layer chromatographic analysis indicated that a reaction had occurred, but was incomplete. An additional 18 g of hydrogen sulfide was added during 1 hour at 75°-80°; thin-layer chromatography indicated that the reaction was completed. The reaction mixture was evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give a first crop of 28 g of 3-amino-2-cyano-3-ethoxypropenethioamide; m.p. 170°-171°. A second crop of 15 g of this product (m.p. 169°-171°) was obtained by diluting the mother liquor with ice-water. A small sample of crop I was recrystallized again from ethanol (charcoal) to give an analytical sample; m.p. 180°-181°. A total of 43.0 g of 3-amino-2-cyano-3-ethoxypropenethioamide was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](OC)=[O:13])=[CH:8][CH:7]=1>CO>[CH3:2][N:3]([CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:34])[C:23]2[CH:24]=[CH:25][C:26]([N:29]3[CH:33]=[N:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)[CH2:18][CH2:17]1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:13])[NH2:1])=[CH:8][CH:7]=1
Reactant: N
Reactant: COC(=O)c1ccc(CCN(C)C2CCN(C(=O)c3ccc(-n4cncn4)cc3)CC2)cc1
Solvent: CO
Product: CN(CCc1ccc(C(N)=O)cc1)C1CCN(C(=O)c2ccc(-n3cncn3)cc2)CC1
Temperature: 110 °C
Reaction time: 69.5 h

Procedure:
45 ml of a saturated solution of ammonia in methanol was added to 600 mg of 4-{N-methyl-N-[2-(4-methoxycarbonylphenyl)ethyl]amino}-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine. The mixture was stirred at 110° C. for 69.5 hours in a sealed tube. The reaction mixture was cooled to room temperature and then subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol/ammonia water=200/20/1). The product was washed with diethyl ether for crystallization, followed by recrystallization from ethanol to obtain 320 mg of 4-{N-methyl-N-[2-(4-carbamoylphenyl)ethyl]amino}-1-[4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC=C)=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:4]=1)#[N:2].N1CCOCC1>C1COCC1.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:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:21])[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=3)[C:11](=[O:32])[NH:10]2)=[C:5]([S:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH:4]=1)#[N:2]
Reactant: C=CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)NC1c1ccc(C#N)cc1S(=O)(=O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2S(=O)(=O)c2ccccc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The reaction was carried out under argon. Allyl 4-[4-cyano-2-(phenylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (220 mg, 0.378 mmol) and morpholine (1.5 eq., 43 mg, 0.567 mmol) were initially charged in dry THF (6 ml) at RT. The reaction mixture was degassed repeatedly (evacuation followed by venting with argon). Under protective gas, tetrakis(triphenylphosphine)palladium(0) (0.05 eq., 22 mg, 0.019 mmol) was added, and the reaction mixture was stirred at RT for 16 h (HPLC control). The mixture was then concentrated, and the residue was taken up in ethyl acetate (100 ml). The organic phase was washed successively with 0.1 N hydrochloric acid (6 ml), saturated ammonium chloride solution (3×50 ml), water (30 ml) and saturated sodium chloride solution (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Gromsil C-18; mobile phase: acetonitrile/water+0.1% TFA 10:90→80:20). The target product was obtained as a solid (104 mg, 51% of theory).