Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([CH:9]([O:22][CH3:23])[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[O:11])[C:5]([F:8])=[CH:6][CH:7]=1.C(N(C(C)C)[CH:28]([CH3:30])[CH3:29])C.IC(C)C.CN(C=O)C>C1COCC1.O>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:10](=[O:11])[CH:9]([C:4]2[C:5]([F:8])=[CH:6][CH:7]=[C:2]([NH:1][CH:28]([CH3:30])[CH3:29])[C:3]=2[F:24])[O:22][CH3:23])=[CH:15][CH:16]=1)#[N:21]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(N)c1F
Reactant: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1c(F)ccc(NC(C)C)c1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a stirred solution of (RS)-2-(3-amino-2,6-difluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide (example 307.5) 81 mg) at rt in THF (5 ml) under an argon atmosphere were added N-ethyldiisopropylamine (0.017 ml) and 2-iodopropane (0.01 ml). The mixture was heated to reflux and stirring was continued for 17 h. More 2-iodopropane (0.1 ml) and N-ethyldiisopropylamine (0.17 ml) were added and stirring at reflux was continued for 7 h. DMF (5 ml) was added and the mixture was stirred at 120° C. for 21 h. The mixture had turned to light brown. More DMF (5 ml), N-ethyldiisopropylamine (0.35 ml,) and 2-iodopropane (0.2 ml) were added and stirring at 90° C. was continued for 17 h. The mixture was cooled to rt, diluted with 20 ml water and extracted with EtOAc. The combined organics were washed with water and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (cyclohexane=>cyclohexane/EtOAc 1:1) to give N-(4-cyano-benzyl)-2-(2,6-difluoro-3-isopropylamino-phenyl)-2-methoxy-acetamide (28 mg) as light brown gum.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:20][CH:19]=[CH2:18])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)Oc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(OC(C)=O)c1
Temperature: 80 °C
Yield: 56.9 %

Procedure:
Resorcinol monoacetate (10.0 g, 65.7 mmoles) in anhydrous DMF (100 mL) was treated with K2CO3 (18.2 g, 131 mmoles) and allyl bromide (6.83 mL, 78.9 mmoles). The mixture was heated at 80° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 8% to 10% ethyl acetate:hexanes) to provide the title compound as a colorless oil (7.19 g, 57%). MS (DCI) m/z 193 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[F:35][C:36]([F:43])([F:42])[CH2:37][S:38](Cl)(=[O:40])=[O:39]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:35][C:36]([F:43])([F:42])[CH2:37][S:38]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)(=[O:40])=[O:39]
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(Oc3ccc(NS(=O)(=O)CC(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A flask containing a solution of 29 (0.30 g, 0.85 mmol), Et3N (0.26 g, 2.55 mmol) and DMAP (0.032 g, 0.26 mmol) in CH2Cl2 (5 mL) was added trifluoroethanesulfonyl chloride (0.39 g, 2.13 mmol), dropwise, at RT and the reaction allowed to stir overnight at RT. After 18 h the reaction was diluted with 15 mL CH2Cl2 and rinsed with 10% aq. HCl (25 mL). The CH2CO2 layer was dried (MgSO4), concentrated to a dark amber oil, and purified by silica gel column chromatography with 10% EtOAc/hexanes to afford 270 mg (64%) of the title compound, 273, as a white foam. 1H NMR (400 MHz, DMSO-d6): δ 2.18 (s, 3H), 3.88 (s, 3H), 4.33 (q, J=9.8 Hz, 2H), 6.58 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.08 (dd, J1=2.4 Hz, J2=9.1 Hz, 1H), 7.18-7.36 (m, 5H), 7.61 (d, J=9.1 Hz, 1H), 7.70 (s, 1H), 10.07 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.CN(C)[CH:25]=[O:26]>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][CH:25]=[O:26])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: CN(C)C=O
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: NC(=O)c1nc2n(c1CNC=O)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was suspended in N,N-Dimethylformamide overnight to form crude 10-bromo-9-fluoro-3-(formamidomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide following extractive workup.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([OH:16])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:10][C:9]2[C:8](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:16])=[O:15])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3.45 g (25 mmol) of sodium carbonate and 1.0 g (7.3 mmol) of anthranilic acid in 50 ml of water at 60° was treated with 2.09 g (10.95 mmol) of p-toluenesulfonyl chloride and held at 70° for 30 min. The reaction mixture was cooled to ambient temperature and acidified with 10% HCl. After standing for 18 hr the product was collected by filtration, washed with water and dried to give N-4-methylphenylsulfonylanthranilic acid as a solid, mp 226-229°.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[C:13]([OH:34])(=O)[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N)COCCO.[Cl-].[NH4+]>ClCCCl>[C:13]([NH2:3])(=[O:34])[CH2:14][S:15][CH2:16][C:17]#[C:18][CH2:19][C:20]#[C:21][CH2:22][C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCCCCC#CCC#CCC#CCSCC(=O)O
Agent: NCCOCCO
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: CCCCCCCCC#CCC#CCC#CCSCC(N)=O
Temperature: 25 °C

Procedure:
3 g of carbonyldiimidazole are added to a solution of 3.18 g of 3-thia-5,8,11-eicosatriynoic acid in 50 cm3 of 1,2-dichloroethane, stirred at ambient temperature under an inert atmosphere. The mixture thus obtained is heated to a temperature of between 40° and 50° C. for 3 hours. The solution is then cooled to about 10° C. and 2.10 g of diglycolamine are added. 2 hours after the end of the introduction, the reaction mixture is poured into a saturated solution of ammonium chloride. The organic phase is separated off, washed with water, then dried over magnesium sulphate and finally treated with animal charcoal. The solvent is removed by evaporation under vacuum. The product obtained crystallizes on cooling. It is recrystallized from isopropyl ether. 3 g of N --2)-hydroxyethyl) oxyethyl]-3-thia-5,8,11-eicosatriynamide are thus isolated in the form of cream-white crystals having a melting point of 56° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][S:14](=[O:17])(=[O:16])O[S:12](=[O:19])(=[O:18])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:27]2[S:12](=[O:18])(=[O:19])[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:15][S:14]2(=[O:16])=[O:17])=[CH:24][CH:23]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1ccc(C2CS(=O)(=O)OS(=O)(=O)C2)cc1
Product: COc1ccc(CN2S(=O)(=O)CC(c3ccc([N+](=O)[O-])cc3)CS2(=O)=O)cc1

Procedure:
A solution of 4-(4-nitro-phenyl)-[1,2,6]oxadithiane 2,2,6,6-tetraoxide (as prepared in the previous step) is treated with 4-methoxy-benzylamine according to the procedure of Example 2, step (c) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][CH:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CO
Solvent: CS(C)=O
Product: OC(COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([CH:18](O)[CH3:19])=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.FC1C=C(B(O)O)C=CC=1.C(N(CC)CC)C.CS(Cl)(=O)=O.S([O-])(=O)(=O)C.CN(C)C=O.[N-:53]=[N+:54]=[N-:55].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:53]([CH:18]([C:9]1[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[CH3:19])=[N+:54]=[N-:55]
Reactant: CC(O)c1ccc2cccnc2c1-c1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)[O-]
Agent: OB(O)c1cccc(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[8-(3-fluorophenyl)quinolin-7-yl]ethanol (0.160 g, 0.598 mmol) (prepared in analogy to Example 7 step 1-4, using (3-fluorophenyl)boronic acid instead of (2-fluorophenyl)boronic acid as starting material) in methylene chloride (4 mL) was added triethylamine (0.125 mL, 0.898 mmol), followed by methanesulfonyl chloride (0.0579 mL, 0.748 mmol). After stirring at room temperature for 30 minutes, the resultant mixture was diluted with dichloromethane, washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The crude mesylate was dissolved in N,N-dimethylformamide (2 mL, 20 mmol) and treated with sodium azide (0.194 g, 2.99 mmol) at room temperature overnight. After diluted with ethyl acetate, the mixture was washed with water and brine and then dried over magnesium sulfate and evaporated to dryness. The crude product was used in the next step. LCMS calculated for C17H14FN4(M+H)+: m/z=293.1; found: 293.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[NH2:16].P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[C:13]([F:12])[CH:14]=1)=[O:9]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)c1cc(Cl)ccc1O
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A mixture of 5-chlorosalicylic acid (0.30 g, 1.738 mmol), 3-fluoro-4-morpholinoaniline (compound of Reference Example 74; 0.34 g, 1.738 mmol), phosphorus trichloride (0.08 ml, 0.869 mmol) and toluene (6 ml) was refluxed for 1.5 hours. The reaction mixture was cooled to the room temperature, and extracted with ethyl acetate after addition of water. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with diisopropyl ether to give the title compound (0.30 g, 49%) as a colorless crystal.
Reaction SMILES: [O:1]=[C:2]1[O:7][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:3]1[CH2:27][CH2:28][CH2:29][CH2:30][B:31]1[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]1.CN([CH2:43][CH2:44]N(C)C)C.C(I)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl>COCCOC.CCCCCCC>[CH2:43]([C@:3]1([CH2:27][CH2:28][CH2:29][CH2:30][B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)[C:2](=[O:1])[O:7][C@@H:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@@H:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:44]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1[C@H](CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CCI
Solvent: COCCOC
Solvent: CCCCCCC
Product: CC[C@]1(CCCCB2OC(C)(C)C(C)(C)O2)C(=O)O[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of (3R,5R,6S)-tert-butyl 2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate (1.00 g, 1.87 mmol) and TMEDA (2 mL, 13 mmol, 7 equiv) in 1,2-dimethoxyethane (9.4 mL, 0.2 M) was cooled to −78° C. and treated with ethyl iodide (3 mL, 37 mmol, 20 equiv) and potassium bis(trimethylsilyl)amide (9.4 mL, 0.9 M in THF, 9.4 mmol, 5 equiv) drop wise. After stirring for an additional 30 min at −78° C., the cooling bath was removed and the mixture was stirred over night. The reaction was incomplete by TLC and therefore was recooled to −78° C. and treated with additional potassium bis(trimethylsilyl)amide (9.4 mL, 0.9 M in THF, 9.4 mmol, 5 equiv) and ethyl iodide (3 mL, 37 mmol, 20 equiv). After the additions were complete, the bath was removed and the solution was stirred overnight. Once complete by TLC, the reaction mixture was quenched with 0.5N HCl (5-10 equiv), diluted with heptane and washed successively with water and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-60% ethyl acetate in heptane over 6 CV) gave (3S,5R,6S)-tert-butyl 3-ethyl-2-oxo-5,6-diphenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl)morpholine-4-carboxylate as colorless oil (0.68 g, 65%). Rf 0.40 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.31-7.15 (m, 10H), 7.08 (d, J=2.4 Hz, 1H), 6.02 (d, J=2.4 Hz, 1H), 2.35-2.22 (m, 2H), 2.22-2.07 (m, 2H), 1.47 (s, 9H), 1.26-1.21 (m, 4H), 1.15 (s, 12H), 1.00 (t, J=7.5 Hz, 3H), 0.85 (t, J=6.8 Hz, 2H); ESI-LCMS m/z calcd for C33H46BNO6: 563.3. found 564.3 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]3([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH2:15][NH:16][CH2:17][CH:13]3[CH2:12][O:11]2)=[CH:5][CH:4]=1.Cl[C:25]1[N:30]=[CH:29][C:28]([F:31])=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[F:31][C:28]1[CH:27]=[N:26][C:25]([N:16]2[CH2:17][CH:13]3[C:14]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)([N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[O:11][CH2:12]3)[CH2:15]2)=[N:30][CH:29]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: COc1ccc(CN2OCC3CNCC32c2cccnc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2OCC3CN(c4ncc(F)cn4)CC32c2cccnc2)cc1
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a stirred solution of 1-[(4-methoxyphenyl)methyl]-6a-(3-pyridyl)-3a,4,5,6-tetrahydro-3H-pyrrolo[3,4-c]isoxazole (1.33 g, 4.27 mmol) in 1,4-dioxane (30 mL) is added 2-chloro-5-fluoro-pyrimidine (2.55 g, 19.22 mmol) and diisopropylethylamine (3.72 mL, 21.36 mmol). The resulting solution is heated at 110° C. for 3 hours. The reaction is cooled and the solvent is evaporated under vacuum to give a residue. The residue is purified by silica gel chromatography using a 0-5% gradient of 0.14 M ammonia/methanol solution in dichloromethane to give the title compound (1.11 g, 54%). ES/MS (m/e): 408 (M+1).
Reaction SMILES: COC[O:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C@H:11]2[CH2:13][O:12]2)=[CH:7][CH:6]=1.[C:16]1([C:22]2[C:30]3[C:29]([N:31]4[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]4)=[N:28][CH:27]=[N:26][C:25]=3[S:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[OH:12][C@H:11]([CH2:13][NH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:29]2[C:30]3[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:23][S:24][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:32][CH2:33]1)[CH2:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([OH:4])=[CH:15][CH:14]=1
Reactant: COCOc1ccc(OC[C@H]2CO2)cc1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Product: Oc1ccc(OC[C@H](O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)cc1
Yield: 57 %

Procedure:
Synthesis followed SP6 (4 h), using 250 μmol (R)-2-((4-(methoxymethoxy)phenoxy)methyl)oxirane and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-MOM intermediate upon purification by prep. TLC (2 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) with 57% yield. Product was obtained by MOM removal according to SP8 (1.5 eq. TosOH, 10 h) and purification by prep. TLC (1 mm silica gel, CH2Cl2/MeOH 90:10) with 55% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11](CC1C=CC=CC=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC1CNC2

Procedure:
A mixture of 3-benzyl-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (13.0 g, 43.0 mmol), palladium on carbon (4.0 g, 5%) and ethanol (100 ml, 99%) was stirred under hydrogen. The mixture was filtered on celite, dried and evaporated. A white powder was isolated. Yield 8.4 g (92%). Mp 103.4-106° C.
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[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.O>[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]([CH2:36][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CC1CCCCC1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.2 %

Procedure:
In 1,2-dichloroethane (5 ml) were dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.3 g) and cyclohexanecarboaldehyde (0.43 g). To the solution was added sodium triacetoxyborohydride (0.43 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 3.5 hours, poured into water, neutralized with sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-[4-(2-butoxyethoxy)phenyl]-1-cyclohexylmethyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.37 g) as pale yellow oil.
Reaction SMILES: C(C[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]3)=[O:18])[CH2:13][CH2:12]1)(=O)C1C=CC=CC=1.[ClH:30].NO.[OH2:33]>N1C=CC=CC=1>[ClH:30].[C:19]1([CH:17]([OH:33])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](=[O:29])[CH2:23][CH2:22]4)=[O:18])[CH2:13][CH2:12]2)[CH:20]=[CH:21][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1CCc2cc(C(=O)N3CCN(CCC(=O)c4ccccc4)CC3)ccc2N1
Reactant: O
Agent: Cl
Agent: NO
Solvent: c1ccncc1
Product: O=C1CCc2cc(C(=O)N3CCN(CC(O)c4ccccc4)CC3)ccc2N1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
20 Grams of 6-[4-(2-benzoylethyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril and 5.33 g of hydroxylamine hydrochloride were dispersed in 40 ml of pyridine and the suspension was stirred at 100° C. for 4 hours. After the reaction was completed, the reaction mixture was poured into water and then extracted with chloroform, the extract was dried with anhydrous potassium carbonate, then the solvent was removed by evaporation. The thus obtained residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=50:1), then recrystallized from ethanol to yield 8.79 g of 6-[4-(3-hydroxyimino-3-phenylpropyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril 1/2-hydrate. White powdery substance. Melting point: 167°-169° C. (decomp.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]1[CH:12]([NH:32][C:33](=[O:39])OC(C)(C)C)[CH2:13][C:14]1[CH:22]=[C:21]([CH3:23])[C:20]2[C:16](=[CH:17][N:18](COCC[Si](C)(C)C)[N:19]=2)[CH:15]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH:56]1[CH2:61][CH2:60][CH:59]([N:62]2[CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]2=[O:72])[CH2:58][CH2:57]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][N:6]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]1[CH:12]([NH:32][C:33]([N:56]1[CH2:57][CH2:58][CH:59]([N:62]2[CH2:71][C:70]3[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=3)[NH:64][C:63]2=[O:72])[CH2:60][CH2:61]1)=[O:39])[CH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([CH3:23])[CH:22]=1)[NH:19][N:18]=[CH:17]2
Reactant: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Product: Cc1cn(Cc2cccc(F)c2)c(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3-fluorobenzyl)-4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (20.0 mg, 0.034 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (6.0 mg, 0.037 mmol, 1.1 equiv) and N′N-diisopropylethylamine (24.3 μL, 3 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (8.5 mg, 0.037 mmol, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 16.1 mg (74%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.50-1.68 (m, 4H), 2.27 (s, 3H), 2.46 (s, 3H), 2.77 (m, 2H), 3.20 (m, 2H), 4.01-4.16 (m, 2H), 4.20 (s, 2H), 4.32-4.43 (m, 1H), 5.13-5.22 (m, 2H), 6.60-6.67 (m, 2H), 6.70 (s, 1H), 6.76-6.86 (m, 2H), 6.87-6.94 (m, 1H), 6.96 (dd, J=8.3, 6.7, 1H), 7.07-7.14 (m, 2H), 7.16 (dd, J=7.9, 7.6, 1H), 7.25 (s, 1H), 7.92 (s, 1H). Mass spec.: 621.4 (MH)+.