Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C(Br)C#C>CN(C)C=O>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])[C:2]#[CH:1]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOc1cccc(C=O)c1
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (6.16 g, 0.055 mole), 3-hydroxybenzaldehyde (6.1 g, 0.05 mole), and dry dimethylformamide (DMF, over Na2SO4 ; 30 mL) were stirred briefly at 25° C., and then propargyl bromide (6.6 g, 0.055 mole) was added in 30 mL of dry DMF according to the method of F. Albericio et al., "Preparation and Application of the5-(4-(9-Fluorenylmethyloxycarbonyl)-Aminomethyl-3,5-Dimethoxyphenoxy)-ValericAcidHandle for the Solid Phase Synthesis of C-Terminal Peptide Amides under Mild Conditions," J. Org. Chem. vol. 55, pp. 3730-3743 (1990). The reaction mixture was heated to 110° C. for 8 h, and the solvent was then removed under high vacuum. Ethyl acetate was added, inorganic salts were removed by filtration, and the organic extract was washed sequentially with water, 2 M NaOH, and saturated aqueous NaCl. The organic phase was dried overnight (MgSO4), and the solvent was removed to yield a yellow liquid that was purified by silica gel chromatography using hexane-ethyl acetate (8.5:1.5) as the eluting solvent. Yield: 6.5 g (81%). 1H NMR (CDCl3): d 2.54 (t, 1H, CH), 4.73 (t, 2H,--OCH2 --), 7.2-7.48 (m, 4H, Aromatics), 9.96 (s, 1H, CHO). GC-MS (m/z): M+ =160.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Cl.[OH:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Fc1cccc(CCl)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1ccc(OCc2cccc(F)c2)cc1
Yield: 101.8 %

Procedure:
Accordingly, 3-fluorobenzyl chloride (14.5 g, 100 mmol) is added under stirring and under nitrogen atmosphere to a solution of 4-hydroxybenzaldehyde (12.2 g, 100 mmol) and of NaOH (4.0 g, 100 mmol) in ethanol (100 mL). The mixture is gradually heated in 25 minutes to reflux and stirred at reflux temperature for 6 hours and 20 minutes. The reaction mixture is filtrated and then concentrated at reduced pressure to obtain 4-(3-fluoro-benzyloxy)benzaldehyde (23.43 g) as a yellow solid residue. Dichloromethane (250 mL) is added to the residue, the insoluble is filtered and the resulting solution is concentrated under reduced pressure to provide 4-(3-fluorobenzyloxy)benzaldehyde as a yellow solid, in 80.4% yield.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C=O.CC(=O)[O:29]CC>C(Cl)Cl.CO.C(P(CCCC)CCCC)CCC>[Si:1]([O:8][CH2:9][C@@H:10]1[CH:15]=[C:14]([CH2:16][OH:29])[C:13](=[O:17])[CH2:12][N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)CC1=O
Reactant: CCOC(C)=O
Agent: C=O
Agent: CCCCP(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(=O)C(CO)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Yield: 102 %

Procedure:
To a solution of (S)-tert-butyl 2-((tert-butyldimethylsilyloxy)methyl)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 7, 18 g, 52.71 mmol) in a mixture of DCM (900 mL) and MeOH (350 mL) was added successively formaldehyde (42.8 mL, 527.06 mmol) and tributylphosphine (0.692 mL, 3.16 mmol) at rt. The solution was stirred at room temperature for 2-3 hr until TLC (4:1 Hex/EA) showed that the reaction was complete. It was concentrated under reduced pressure and purified by 120 g silica gel column (0-50% Hex/EA) to afford the title compound (20.00 g, 102%) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.[NH4+].[Cl-]>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: C1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1

Procedure:
1-chloromethyl-4-nitro-benzene Compound 1i (5.0 g, 29 mmol) and piperidine (5.8 mL, 58 mmol) were combined in THF (30 mL) at ambient temperature. The reaction was refluxed for 4 hours, then diluted with aqueous 10% NH4Cl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to provide 1-(4-nitro-benzyl)-piperidine Compound 1j (5.0 g) as a pale yellow oil requiring no further purification (see, Mitsuru Shiraishi, et al., J. Med. Chem., 2000, 43, 2049-2063). 1H NMR (DMSO-d6) δ 8.18 (d, 2H); 7.59 (d, 2H); 3.57 (s, 2H); 2.43-2.25 (m, 4H); 1.58-1.32 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][N:9]=CC2C(=O)C3C(C)(C)C2(C)CC3)=[CH:6][C:5]([C:22]([CH3:24])=[CH2:23])=[CH:4][N:3]=1.[BH4-].[Na+].Cl>CCO>[CH:22]([C:5]1[CH:6]=[C:7]([CH2:8][NH2:9])[C:2]([CH3:1])=[N:3][CH:4]=1)([CH3:24])[CH3:23]
Reactant: C=C(C)c1cnc(C)c(CN=CC2C(=O)C3CCC2(C)C3(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncc(C(C)C)cc1CN
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a stirring solution of 96.6 mg (0.370 mmol) of 1-(2-methyl-5-(prop-1-en-2-yl)pyridin-3-yl)-N-((oxobornyl)methylene)methanamine and 88.5 mg (0.372 mmol) of CoCl2.6H2O in 4 mL of EtOH at 50° C. was added 160 mg of NaBH4 in 2 portions. After heating the mixture at 50° C. under Ar for 5 h, the reaction mixture was cooled and 5 N HCl was added to a pH=1. The mixture was stirred at r.t. for 15 h and concentrated. Water was added, and NH4OH was added to a pH=9. The aqueous layer was extracted with the extract of (40 mL of CHCl3: 5 mL of MeOH: 5 mL H2O) (2×). The combined extracts were dried over Na2SO4, filtered, and concentrated. (5-isopropyl-2-methylpyridin-3-yl)methanamine was used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[N:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]3=[N:12][C:11]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][C:27]1([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CC(O)(C)C.C(OCC)(=O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([CH2:9][NH:8][C:4]3[N:3]=[C:2]([N:30]4[CH2:31][CH2:32][C:27]([CH3:26])([OH:33])[CH2:28][CH2:29]4)[CH:7]=[CH:6][N:5]=3)=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:12]=2)[CH:15]=1
Reactant: Clc1ccc2nc(-c3ccccc3)c(CNc3nccc(Cl)n3)n2c1
Reactant: CC1(O)CCNCC1
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CC1(O)CCN(c2ccnc(NCc3c(-c4ccccc4)nc4ccc(Cl)cn34)n2)CC1
Temperature: 95 °C

Procedure:
A mixture of 4-chloro-N-((6-chloro-2-phenylimidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine (50 mg, 0.135 mmol) and 4-methylpiperidin-4-ol (200 mg, 1.74 mmol) in t-BuOH (0.5 ml) was heated 95° C. until the reaction was completed. The mixture was diluted with ethyl acetate and the resulting mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated by evaporation. The crude product was purified by silica gel chromatography (methanol/methylene chloride gradient) to title compound. M/e+ 449 for C24H26ClN6O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.89 (d, J=5.8 Hz, 1H), 7.76 (d, J=6.9 Hz, 2H), 7.57 (d, J=9.5 Hz, 1H), 7.47 (m, 3H), 7.39 (d, J=7.7 Hz, 1H), 7.16 (dd, J=9.5, 1.8 Hz, 1H), 5.99 (d, J=6.2 Hz, 1H), 5.05 (d, J=5.5 Hz, 2H), 5.00 (bs, 1H), 4.00 (m, 2H), 3.40 (m, 2H), 1.62 (m, 4H), 1.29 (s, 3H) ppm.
Reaction SMILES: [CH:1]([Cl:4])([Cl:3])[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[O:16])[CH:10]=[C:11]([CH:13]=[O:14])[CH:12]=1.[OH-].[K+]>CN(C=O)C.CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]([OH:16])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:10]=[C:11]([CH:13]([OH:14])[C:1]([Cl:4])([Cl:3])[Cl:2])[CH:12]=1
Reactant: COc1cc(C=O)cc(C=O)c1
Reactant: ClC(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(C(O)C(Cl)(Cl)Cl)cc(C(O)C(Cl)(Cl)Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 0.60 g (5 mmol) of chloroform in 2 mL DMF was added 0.1 64 g (1.0 mmol) of 5-methoxy-1,3-diformylbenzene (Provent, C; Chautemps, P.; Gellon, G.; Pierre, J.-L. Tetrahedron Lett. 1996, 347 1393-96). The reaction mixture was chilled to 0° C. and a solution of 39.5 mg (0.7 mmol) of potassium hydroxide in 0.2 mL of methanol was added. The reaction mixture was stirred for 20 min at 0° C., then was quenched by addition of 1 mL of 1 N hydrochloric acid. The reaction mixture was adjusted to pH=7, then extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:24](=[O:25])[N:23]([N:26]=[C:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[C:22]4[CH:33]=[CH:34][S:35][C:21]=4[C:20]=3[OH:36])=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:24](=[O:25])[N:23]([NH:26][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)[C:22]4[CH:33]=[CH:34][S:35][C:21]=4[C:20]=3[OH:36])=[N:15][S:16](=[O:17])(=[O:18])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1N=C1CCCCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=c1c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2sccc2n1NC1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69 %

Procedure:
The product of Example 324C (0.167 g, 0.30 mmol) in tetrahydrofuran (6 mL) and methanol (0.030 mL, 0.8 mmol) at 0° C. was reacted with lithium borohydride (2.0 M solution in tetrahydrofuran, 0.250 mL, 0.50 mmol). The reaction was stirred at 25° C. for 1.5 hour, acidified to pH 2 with 1 M aqueous hydrochloric acid and diluted with water (25 mL). The resulting precipitate was collected by filtration and dried to constant weight to give the title compound (0.114 g, 69%). MS (APCI+) m/z 551 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.36 (m, 10 H) 5.25 (s, 2 H) 6.50 (s, 1 H) 7.43 (m, 8 H) 7.69 (d, J=8.82 Hz, 1 H) 8.29 (d, J=5.15 Hz, 1 H) 14.10 (s, 1 H) 14.87 (s, 1 H).
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH3:16][O:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([NH2:31])[CH:29]=[CH:30][C:23]=2[CH2:22][CH2:21]1.Cl[C:33]1[N:38]=[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[C:36]([Cl:52])=[CH:35][N:34]=1.C(=O)([O-])[O-]>C(O)(C)C>[Cl:52][C:36]1[C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])=[N:38][C:33]([NH:31][C:28]2[CH:29]=[CH:30][C:23]3[CH2:22][CH2:21][N:20]([CH2:19][CH2:18][O:17][CH3:16])[CH2:26][CH2:25][C:24]=3[CH:27]=2)=[N:34][CH:35]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)cc2CC1
Reaction time: 1 h

Procedure:
10-Camphorsulfonic acid (53 mg, 0.23 mmol) was added to 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.22 mmol) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (72 mg, 0.21 mmol) in Isopropyl alcohol (2 mL). The mixture was irradiated in a CEM microwave (140° C., 30 min) MP-Carbonate (2.69 mmol/g loading; 0.18 g, 0.47 mmol) was added and the mixture stirred for 1 h and filtered, washing with DCM. The filtrate was conc. in vacuo. The residue was taken up in DCM with a few drops of MeOH and chromatographed (ISCO, 2×12 g, 0-12% MeOH:DCM) to afford 2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide as a colorless wax (83 mg, 75%). LCMS 531 (M+H), 1H-NMR (CDCl3): 9.42 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 8.12 (s, 1H), 7.86 (d, 1H, J=7.5 Hz), 7.55 (dd, 1H, J=7.5, 8.2 Hz), 7.24 (m, 3H), 7.02 (d, 1H, J=7.8 Hz), 6.90 (s, 1H), 3.55 (m, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.74 (m, 12H).
Reaction SMILES: [OH:1][CH:2]1[CH2:14][CH2:13][C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.S([O-])([O-])(=O)=O.[Ce+3].[NH4+].S([O-])([O-])(=O)=O.Br([O-])(=O)=O.[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.O>[OH:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([CH2:13][CH2:14][C:2](=[O:1])[CH2:3][CH2:4]2)[CH2:6][CH2:7]1
Reactant: OCC1CCC2(CCC(O)CC2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ce+3]
Solvent: CC#N
Solvent: O
Product: O=C1CCC2(CC1)CCC(CO)CC2
Temperature: 80 °C
Yield: 69.7 %

Procedure:
9-Hydroxy-3-hydroxymethyl-spiro[5.5]undecane (0.29 g) and ammonium cerium sulfate (0.830 g) were added to a suspension of sodium bromate (0.230 g ) in acetonitrile and water (9 ml; 70:30). The mixture was heated at 80 ° C. for 3 hrs, cooled to 0 ° C., and treated with sodium bicarbonate to neutral pH. After evaporation under reduced pressure to small volume and extraction with ethyl acetate, the organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 0.220 g of a crude residue, that was purified by flash-chromatography (SiO2 ; ethyl acetate/n-hexane 60/40) to give 0.200 g of 9-hydroxymethyl-3-oxo-spiro[5.5]undecane (II-d) a light oil. TLC: Rf=0.35 (SiO2 plates, ethyl acetate/n-hexane 60/40). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 3.50 (2H, d), 2.36 (2H, t), 2.28 (2H, t), 1.85-1.09 (13H, m).
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:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>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:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (20 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (116 mg) in dichloromethane (20 ml) at −78° C. After finishing the dropping, an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and 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 silica gel column chromatography (methanol:ethyl acetate=1:8), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (118 mg) (Compound 323) as yellow crystals, and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (33.5 mg) (Compound 324) as yellow crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].S(O[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:23])(C)(=O)=O.[CH2:24]1[C:29]2[NH:30][C:31]3[C:36]([C:28]=2[CH2:27][CH2:26][NH:25]1)=[CH:35][CH:34]=[CH:33][CH:32]=3>C(#N)C>[CH2:24]1[C:29]2[NH:30][C:31]3[C:36]([C:28]=2[CH2:27][CH2:26][N:25]1[CH2:12][CH2:13][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]1=[O:23])=[CH:35][CH:34]=[CH:33][CH:32]=3
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CS(=O)(=O)OCCn1c(=O)oc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=c1oc2ccccc2n1CCN1CCc2c([nH]c3ccccc23)C1

Procedure:
Potassium carbonate (0.828 g, 6 mmol), 3-(2-mesyloxyethyl)benzoxazolin-2-one (1.494 g, 5.814 mmol) and 1,2,3,4-tetrahydropyrido[3,4-b]indole (1 g, 5.814 mmol) in acetonitrile (30 ml) were heated under reflux under nitrogen for 16 hours. The solvent was evaporated in vacuo and the residue partitioned between ethyl acetate (80 ml) and water (30 ml). The water was separated and hydrochloric acid (0.5M, 40 ml) was added. The resultant white precipitate was collected by filtration and suspended in sodium hyroxide (2M, 60 ml) and washed with chloroform (3×50 ml). The combined chloroform extracts were washed with water (30 ml), dried (MgSO4), and the solvent filtered and evaporated in vacuo. The residue was treated with diethyl ether/ethyl acetate (3:1, 40 ml) and a fine flocculent precipitate resulted. The resultant filtrate was evaporated in vacuo and the residue chromatographed on silica (ethyl acetate 40-60 petrol 3:2) to give the title product, melting point 135°-137° C.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[C:34](B2OC(C)(C)C(C)(C)O2)=[N:35][CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].Cl[Cu]>[F:32][C:33]1[C:34]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC1(C)OB(c2ncccc2F)OC1(C)C
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CN(C)C=O
Product: CNc1cnccc1-c1ncccc1F
Temperature: 100 °C
Yield: 92.2 %

Procedure:
To a solution of compound (4-bromo-pyridin-3-yl)-methyl-amine (50 mg, 0.267 mmol, example 25, intermediate b) and 3-fluoro pyridine-2-boronic acid pinacol ester (Milestone Pharmtech LLC) (89.4 mg 0.4 mmol) dissolved in dry DMF (3 mL) in a sealed tube was added cesium carbonate (348.4 mg, 1.07 mmol) and the reaction mixture was purged with argon for 10 min. Then Pd(OAc)2 (9.38 mg, 0.013 mmol), dppf (1.48 mg, 0.0026 mmol) and CuCl (26.46 mg, 0.27 mmol) were added to the reaction mixture and again purged with nitrogen for 15 min. The reaction mixture was heated at 100° C. for 16 hours. The reaction mixture was cooled to 25° C., filtered through a bed of celite and washed with EtOAc. The organic layer was washed with water, dried over sodium sulphate and evaporated to yield the desired compound as a light yellow solid (50 mg, 92%) which was used in next step without further purification. MS (ESI): m/z=204.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]4[NH:38][N:37]=[N:36][N:29]=4)=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:13](=[O:30])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:31])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2cccnc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(-c2cccnc2-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A solution of the product of step C (1.0 eq.) is added trimethylstannylazide (3 eq.) in toluene (3 mL) and heated to reflux for 36 h. The mixture is cooled to rt, concentrated and then can be purified by flash chromatography on SiO2 to give the titled compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][N:26]=1>CN1C(=O)CCC1>[C:31]([C:29]1[CH:28]=[CH:27][N:26]=[C:25]([NH:2][C:3]2[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=2)[CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][N:9]=2)[CH:30]=1)#[N:32]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Agent: Cl
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(Nc2cccc(CNc3ncnc4c(C(N)=O)cccc34)c2)c1

Procedure:
50 mg (0.15 mmol) 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 21 mg (0.11 mmol) 2-Chloro-4-cyanopyridine were dissolved in 200 μl NMP and irradiated in the microwave at 200° C. for 3 h. The reaction mixture was directly purified using preparative HPLC. The product was treated with HCl in methanol and concentrated in the SpeedVac.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.O>CN(C=O)C>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([O:10][CH2:9][C:8]2[CH:11]=[CH:12][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:19][N:18]=1)#[N:21]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(C#N)nc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Sodium hydride (1.44 g, 33 mmol) was dissolved in DMF (20 mL), and 4-methoxybenzyl alcohol (3.74 mL, 33 mmol) was then added to the solution under a nitrogen atmosphere and under ice cooling. The obtained mixture was stirred at room temperature for 30 minutes. Thereafter, 5-bromo-2-cyanopyridine (4.58 g, 25 mmol) was added to the reaction solution, and the obtained mixture was further stirred at room temperature for 30 minutes. Thereafter, water was added to the reaction solution, and it was then extracted with ethyl acetate and washed with water. The water layers were combined and extracted with methylene chloride. The organic layers were combined, were dried over sodium sulfate, and were then concentrated. The obtained residue was recrystallized from ethyl acetate, so as to obtain the title compound (3.57 g, yield: 60%) in the form of yellow crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[N:10]1([C:2]2[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: N#Cc1ncccc1Br
Reactant: c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: N#Cc1ncccc1-n1ccc2ccccc21
Temperature: 110 °C
Reaction time: 60 h
Yield: 88.8 %

Procedure:
To a solution of 3-bromo-2-cyanopyridine (Sakamoto, T. et al., Chem. Pharm. Bull. 1985, 33(2), 565-571) (340 mg, 1.86 mmol) and indole (436 mg, 3.72 mmol) in toluene (15 mL) was added Cs2CO3 (737 mg, 2.26 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (83 mg, 0.143 mmol) and Pd2(dba)3 (42 mg, 0.046 mmol) and the reaction stirred at 110° C. for 2.5 d. The mixture was concentrated and purified by column chromatography on silica gel (EtOAc/Hexanes, 2:1) to give 3-indol-1-yl-pyridine-2-carbonitrile (362 mg, 89%) as a beige solid.