Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:19][CH:20]([CH2:23][O:24][C:25]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:21][OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1.C(OCC)C>N1C=CC=CC=1>[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50]([O:22][CH2:21][CH:20]([CH2:23][O:24][C:25]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:52])=[O:51])=[CH:46][CH:45]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCOC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(=O)(=O)c1ccc(C)cc1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
A solution of 2-O-octadecyl-3-O-trityl-glycerol (10 g, 17.04 mmol) in 52 mL anhydrous pyridine is added dropwise during 30 min. to a solution of p-toluenesulfonyl chloride (5.1 g, 26.75 mmol) in 39 mL anhydrous pyridine with stirring. After 2 days at room temperature, diethyl ether (162 mL) is added, and the precipitate formed is removed by filtration. The organic phase is washed successively with water (6×50 mL), 0.5N HCl (2×29 mL), 0.5N sodium carbonate (2×29 mL), and water (4×50 mL). Evaporation of the solvent in vacuo gives an oily product which becomes solid after drying in vacuo. The product, 1-O-p-toluenesulfonyl-2-O-octadecyl-3-O-trityl-glycerol (10.5 g, 85% yield), is used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)=[CH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[O:16][CH2:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[N:8]=2)=[CH:17][CH:18]=1
Reactant: O=C(NC1(CO)CCCCC1)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccc(C2=NC3(CCCCC3)CO2)cn1
Yield: 55 %

Procedure:
To a solution of 6-chloro-N-[1-(hydroxymethyl)cyclohexyl]nicotinamide ax47 (2.17 g, 8.06 mmol, 1 eq) in chloroform (80 ml) is added thionyl chloride (1.8 ml, 24.18 mmol, 3 eq). The mixture is stirred at reflux for 2 h 30 before removing the volatiles under vacuum. The residue is dissolved in acetone and treated with potassium carbonate (2 eq), at reflux. After an aqueous work-up, the organic phase is dried over magnesium sulfate and concentrated in vacuo to give 1.86 g of a yellow solid. Purification over silicagel (eluent: dichloromethane/methanol/ammonia 99:1:0.1) finally yields 0.56 g of 2-(6-chloropyridin-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-ene ax49.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[F:7][CH:8]1[CH:13]([O:14][C:15]2[CH:20]=[C:19]([CH:21]=O)[CH:18]=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:11][N:10]([CH2:24][CH:25]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][N:40](COCC[Si](C)(C)C)[C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:26][C:27]#[N:28])[CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:7][CH:8]1[CH:13]([O:14][C:15]2[CH:20]=[C:19]([CH2:21][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])[CH:18]=[C:17]([F:23])[CH:16]=2)[CH2:12][CH2:11][N:10]([CH2:24][CH:25]([N:29]2[CH:33]=[C:32]([C:34]3[C:35]4[CH:42]=[CH:41][NH:40][C:36]=4[N:37]=[CH:38][N:39]=3)[CH:31]=[N:30]2)[CH2:26][C:27]#[N:28])[CH2:9]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCC(Oc5cc(F)cc(C=O)c5)C(F)C4)c3)ncnc21
Reactant: C[C@@H]1CCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1CCCN1Cc1cc(F)cc(OC2CCN(CC(CC#N)n3cc(-c4ncnc5[nH]ccc45)cn3)CC2F)c1
Reaction time: 8 h
Yield: 27.9 %

Procedure:
To a mixture of (2R)-2-methylpyrrolidine (2.3 μL, 0.023 mmol) and 4-[3-fluoro-4-(3-fluoro-5-formylphenoxy)piperidin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile (13.5 mg, 0.0217 mmol) (diastereomer 2) in DCM (0.10 mL) was added resin of sodium triacetoxyborohydride (13 mg, 0.032 mmol). The resulting mixture was stirred overnight. The reaction solution was filtered, washed with additional DCM, and concentrated. The residue was purified with LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product (3.4 mg, 23%). LCMS (M+H)+: 691.4.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH3:8][N:9]([CH3:34])[CH2:10][CH:11]([OH:33])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1COCC1>[CH3:34][N:9]([CH3:8])[CH2:10][CH:11]([O:33][C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[CH:24]\[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(O)CN(C)C
Reactant: O=C1CCC(=O)O1
Solvent: C1CCOC1
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCCC(CN(C)C)OC(=O)CCC(=O)O

Procedure:
Succinic anhydride (0.60 g, 5.99 mmol, 1.1 equiv) was added in one portion to a dry THF (11 mL) solution of 1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-ol (2.0 g, 5.45 mmol, 1.0 equiv) and the resultant was refluxed for 18 hours under argon. The mixture was concentrated and the residue was partitioned between EtOAc (10 mL) and deionized water (20 mL). The layers were separated and the aqueous layer was extracted with two additional portions of EtOAc (25 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to provide crude 4-(1-(dimethylamino)-4-((9Z,12Z)-octadeca-9,12-dienyloxy)butan-2-yloxy)-4-oxobutanoic acid, a thick, yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12]1([S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:26]([NH:25][S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])=[O:27])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1cccc2ccccc12
Reactant: COc1nc(N)nc(OC)n1
Solvent: CC#N
Product: COc1nc(NC(=O)NS(=O)(=O)c2cccc3ccccc23)nc(OC)n1

Procedure:
To a suspension of 16 g of 2-amino-4,6-dimethoxy-1,3,5-triazine in 400 ml of acetonitrile was added 23.3 g of 1-naphthalenesulfonyl isocyanate dropwise with stirring. The mixture was stirred for 14 hours and the resultant solid product removed by filtration. After washing with ethyl ether the product melted at 171°-172° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH2:26])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH:30]=O.C([BH3-])#N>C(O)C.C(O)(=O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH2:30][C:29]4[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:28]=4[Cl:27])=[N:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Nc1ccc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cc(Cc2ccc(NCc3c(F)cccc3Cl)nc2)c2cccnc21

Procedure:
5-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 30 mg, 0.083 mmol, prepared as described in Example 68, Scheme 185) was combined with 2-chloro-6-fluoro-benzaldehyde (616, 26.2 mg, 0.165 mmol) in a 2 mL microwave reaction vial. The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100° C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give compound 617, which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl.Cl[CH2:10][C:11]1[CH:16]=[CH:15][N:14]2[CH:17]=[CH:18][N:19]=[C:13]2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].[Na].N1C=CN=N1>CN(C)C=O>[N:1]1([CH2:10][C:11]2[CH:16]=[CH:15][N:14]3[CH:17]=[CH:18][N:19]=[C:13]3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: ClCc1ccn2ccnc2n1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: c1cn2ccc(Cn3cncn3)nc2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
To a solution of 1H-[1,2,4]triazole (2.2 g, 31.9 mmol) in anhydrous N,N-dimethylformamide (20 ml) under a nitrogen atmosphere was added sodium hydride (1.18 g, 29.4 mmol, 60% dispersion in oil) with caution in a portionwise manner. This mixture was then stirred for 20 min at room temperature. To a separate solution of 7-chloromethylimidazo[1,2-α]pyrimidine hydrochloride (5.0 g, 24.5 mmol), also dissolved in N,N-dimethylformamide (50 ml) under nitrogen, was added potassium carbonate (6.76 g, 49.0 mmol) and the mixture stirred for 5 min at room temperature. To the 7-chloromethylimidazo[1,2-α]pyrimidine solution was added the triazole sodium salt as a solution in N,N-dimethylformamide and the mixture stirred at room temperature for 16 h. Solvent was removed under reduced pressure and the resulting residue purified by flash column chromatography on silica eluting with dichloromethene, methanol and aqueous ammonia solution (33%) in the ratios 90:5:0.5 respectively to give 7-([1,2,4]triazol-1-ylmethyl)imidazo[1,2-α]pyrimidine (3.38 g, 69%) as a tan solid: δH (360 Mz, d6-DMSO) 5.63 (2H, s), 6.90 (1H, d, J 7), 7.71 (1H, d, J 1.3), 7.91 (1H, d, J 1.4), 8.04 (1H, s), 8.73 (1H, s), 8.97 (1H, d, J 7); m/z (ES+) 201 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1.CN1CCOCC1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>CN(C)C=O.O1CCCC1>[Br:21][C:17]1[CH:16]=[C:15]([NH:14][C:5]2[C:6]([C:12]#[N:13])=[CH:7][N:8]=[C:9]3[C:4]=2[CH:3]=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:11]=[N:10]3)[CH:20]=[CH:19][CH:18]=1
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ncc(N)cc2c1Nc1cccc(Br)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=CC(=O)Nc1cnc2ncc(C#N)c(Nc3cccc(Br)c3)c2c1
Reaction time: 3 h
Yield: 17.9 %

Procedure:
To a solution of 1.4 g (4.12 mmol) of 6-amino-4-(3-bromo-phenylamino)-[1.8]naphthyridine-3-carbonitrile and 1.67 g (16.5 mmol) of N-methyl-morpholine in a mixture of 6 ml of N,N-dimethylformamide and 35 ml of tetrahydrofuran was added with stirring at 0° C. a solution of 0.52 g (5.76 mmol) of acryloyl chloride in 10 ml of tetrahydrofuran over 10 min. After 3 hr at 0° C., the most of the solvent was removed saturated sodium bicarbonate was added. Solid was collected and washed with water. After air drying, the solid was extracted with 500 ml of boiling tetrahydrofuran. The tetrahydrofuran was removed and the residue was purified on a silica gel column eluting with ethyl acetate-methanol mixtures giving 0.29 g of the title compound as a yellow solid: mass spectrum (electrospray, m/e): M+H 394, 396.
Reaction SMILES: C[O:2][C:3](=[O:47])[CH2:4][C:5]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[N:10]=1.O[Li].O.O.C1COCC1>CO>[C:35]([O:34][C:32]([N:29]1[CH2:28][CH2:27][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:39]=[CH:40][C:41]([C:43]([F:44])([F:46])[F:45])=[CH:42][C:5]=4[CH2:4][C:3]([OH:47])=[O:2])[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=3)=[CH:25][CH:24]=2)[CH2:31][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccc(C(F)(F)F)cc4CC(=O)O)n3)cc2)CC1

Procedure:
tert-Butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)-4-(trifluoromethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (A107) (0.157 g, 0.236 mmol) and LiOH.H2O (0.080 g, 0.711 mmol) were suspended in MeOH (2 mL), water (2 mL) and THF (2 mL) and the resulting mixture stirred for 16 hours at room temperature. The volatiles were evaporated under reduced pressure to give the title compound A108; LCMS-A: rt 6.828 min; m/z 653.3 [M+H]+.
Reaction SMILES: Br[C:2]1[N:30]=[CH:29][CH:28]=[CH:27][C:3]=1[C:4]([NH:6][C@H:7]([C:9]1[N:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:20])[C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:8])=[O:5].CN(C=O)C.[NH:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1.C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:12]=1[C:11](=[O:20])[N:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]([C@@H:7]([NH:6][C:4](=[O:5])[C:3]1[CH:27]=[CH:28][CH:29]=[N:30][C:2]=1[C:39]1[CH:40]=[N:36][NH:37][CH:38]=1)[CH3:8])=[CH:18]2
Reactant: OB(O)c1cn[nH]c1
Reactant: C[C@H](NC(=O)c1cccnc1Br)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: C[C@H](NC(=O)c1cccnc1-c1cn[nH]c1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of (S)-2-bromo-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (52) (125 mg, 0.26 mmol) in a 1:1 mixture of DMF and EtOH (9 mL), 1H-pyrazole-4-boronic acid (37 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (0) (21 mg, 0.018 mmol) and aqueous Na2CO3 solution (1.0 M, 0.78 mL, 0.78 mmol) were added sequentially. The resulting mixture was stirred at 85° C. for 16 h. The mixture was allowed to cool to RT and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by prep-TLC plate (10% MeOH-DCM) to afford the product (S)-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)-2-(1H-pyrazol-4-yl)nicotinamide (compound 58). ESI-MS m/z: 471.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([BH3-])#N.[Na+].O>CO.C(O)(=O)C>[CH3:4][CH:3]([N:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[CH:2]([CH3:6])[CH3:1]
Reactant: CC(=O)C(C)C
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)C(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
3-Methyl-2-butanone (0.76 mL, 7.24 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (1.0 g, 4.83 mmol) in methanol (10 mL) and acetic acid (1 mL) and stirred for 30 min at ambient temperature. Sodium cyanoborohydride (1.81 g, 28.98 mmol) was added and the mixture refluxed for 12 h, cooled and then poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using 5-10% ethyl acetate/petroleum ether as eluent afforded 1-(1,2-Dimethylpropyl)-4-(4-nitrophenyl)piperazine (0.46 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: Cc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Reaction time: 10 h
Yield: 80.7 %

Procedure:
10.0 g of 3-Hydroxy-4-iodo-benzoic acid methyl ester, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were stirred in anhydrous DMF at 80° C. for 10 h. Then, 14.3 g of 1-(2-bromo-ethyl)-3-methyl-benzene, and 10.0 g of K2CO3 were added and stirring was continued at 80° C. for 10 h. 400 ml of EA were then added and the mixture was washed twice using 200 ml of water each. The organic layer was then dried using MgSO4 and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 11.5 g of the title compound, colorless oil.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:46][CH2:45][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:30][C:31]5[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=5)[C:34]([O:36]C(C)(C)C)=[O:35])[C:20]4=[O:44])[CH2:18][CH2:17]3)[C:5]2=[O:47])[CH2:3][CH2:2]1.Cl>O1CCOCC1.C([SiH](CC)CC)C>[CH:1]1([N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[N:6]([CH2:13][CH2:14][CH2:15][N:16]3[CH2:46][CH2:45][C:19]4([N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][N:21]([CH2:30][C:31]5[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=5)[C:34]([OH:36])=[O:35])[C:20]4=[O:44])[CH2:18][CH2:17]3)[C:5]2=[O:47])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 3-((8-(3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.27 g, 0.42 mmol) was added 4M solution of HCl in dioxane (4 mL) and triethylsilane (0.1 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.215 g, 83%); 1H NMR (DMSO-d6): δ 0.88-0.90 (m, 2H), 1.01-1.06 (m, 2H), 1.90 (d, 2H, J=14.4 Hz), 2.12 (br, 2H), 2.87-2.91 (m, 3H), 3.21 (br, 2H), 3.45-3.69 (m, 4H), 3.90 (t, 2H, J=7.2 Hz), 4.64 (d, 4H, J=4.4 Hz), 6.80 (t, 1H, J=7.2 Hz), 7.00 (d, 2H, J=8.4 Hz), 7.07-7.09 (m, 2H), 7.19-7.28 (m, 4H), 7.48-7.57 (m, 2H), 7.88 (d, 2H, J=7.2 Hz), 10.33 (br, 1H), 13.02 (br, 1H); MS for C34H37N5O4 m/z 580.13 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1)=[O:2].[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:2]1[CH2:18][CH2:19][O:20][CH:1]1[C:3]1[C:12]([Br:13])=[CH:11][C:10]2[C:9]([CH3:15])([CH3:14])[CH2:8][CH2:7][C:6]([CH3:17])([CH3:16])[C:5]=2[CH:4]=1
Reactant: CC1(C)CCC(C)(C)c2cc(C=O)c(Br)cc21
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Yield: 70.2 %

Procedure:
To a solution of 1.8 g (6.3 mmol) of 2-formyl-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene in 70 mL of benzene was added 3.5 mL of ethylene glycol (63 mmol) followed by p-toluenesulfonic acid monohydrate (180 mg, 0.9 mmol). The reaction mixture was heated at reflux for about 3 hours and is then concentrated under reduced pressure. The residue was partitioned between ether and saturated sodium bicarbonate solution. The ether layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography 1.4% ethyl acetate/) on a Biotage 40M SiO2 cartridge to afford 1.5 g (72%) of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a crystalline solid.
Reaction SMILES: II.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[NH:8][C:7]2=O.[N+:17]([C:20]1[N:24]=[CH:23][NH:22][N:21]=1)([O-:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([S:14][CH3:15])[N:8]=[C:7]2[N:22]1[CH:23]=[N:24][C:20]([N+:17]([O-:19])=[O:18])=[N:21]1
Reactant: CSc1nc2ccc(Br)cc2c(=O)[nH]1
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(-n2cnc([N+](=O)[O-])n2)c2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 89 %

Procedure:
Iodine (16.5 g, 65.1 mmol) was added to a suspension of compound 5a (8.03 g, 29.6 mmol), 3-nitro-1H-1,2,4-triazole (11.8 g, 103.6 mmol), triphenylphosphine (18.1 g, 69.1 mmol) in 630 mL of toluene. The reaction mixture was rapidly heated to 95° C. for 15 minutes after which 25 mL of N,N-diisopropylethylamine was added and the mixture was stirred for another 50 minutes. The reaction was cooled to room temperature and concentrated under reduced pressure. The crude product was precipitated from ethanol, to give 6 as a yellow solid (9.67 g, 89%). mp: 204° C.,
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:28]>CN(C=O)C.CCOC(C)=O>[CH3:28][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[CH:11]=[CH:10][C:9]2=[O:22])=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccc(=O)n(Cc3ccc(CO)cc3)c2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCc1ccc(Cn2cc(-c3ccc(OC)cc3)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
According to Scheme 24 Step 3: A mixture of 1-(4-(hydroxymethyl)benzyl)-5-(4-methoxyphenyl)pyridin-2(1H)-one (1 eq, 0.25 mmol, 0.08 g), NaH (55%, 1.5 eq, 0.37 mmol, 18 mg) and iodomethane (3 eq, 0.75 mmol, 0.11 g) in DMF (2 mL) was stirred at room temperature overnight. The crude was diluted with AcOEt. The organic layer washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 5 g SiO2, CH2Cl2/MeOH 99/1), yielding the title compound (0.14 mmol, 46 mg, 55%) as white solid.