Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][C@H:27]2[C@H:32]([CH:33]([F:35])[F:34])[CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:37](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][C@H:27]2[C@H:32]([CH:33]([F:35])[F:34])[CH2:31][CH2:30][N:29]([CH3:37])[CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(O[C@@H]2CNCC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(O[C@@H]2CN(C)CC[C@H]2C(F)F)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of (±)-trans-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4-difluoromethyl-piperidin-3-yloxy)-pyridazine dihydrochloride (0.18 mmol, 0.095 g) and aqueous formaldehyde (37%, 0.89 mmol, 0.075 mL) in dry DCM (2.0 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.07 mmol, 0.45 g). The mixture was shaken for 4 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give (±)-3-butyl-4-(4-cyclohexyloxy-phenyl)-6-((trans-3,4)-4-difluoromethyl-1-methyl-piperidin-3-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 475 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.30-7.58 (3H, m), 7.08 (2H, d), 6.02-6.42 (1H, m), 5.54-5.94 (1H, m), 4.36-4.50 (1H, m), 3.83-4.19 (1H, m), 3.45-3.78 (1H, m), 2.89-3.35 (6H, m), 2.11-2.87 (3H, m), 1.92-2.08 (3H, m), 1.74-1.89 (2H, m), 1.18-1.67 (10H, m), 0.81 (3H, t).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[N:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:9]=2)[N:4]([S:30]([C:33]2[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH:3]=1.[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[N:46]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:40][C:41]1[CH:42]=[C:43]([CH:59]=[CH:60][CH:61]=1)[CH2:44][N:45]1[CH:49]=[C:48]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[N:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[CH:9]=3)[N:4]([S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:3]=2)[CH:47]=[N:46]1
Reactant: CC1(C)OB(c2cnn(Cc3cccc(F)c3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cn4)cnc32)cc1
Yield: 74.6 %

Procedure:
Using the same reaction conditions as described in step-ii of example-1, tert-butyl 4-(6-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-3-yl)piperazine-1-carboxylate (Intermediate 66M) (1.0 g, 1.515 mmol) was coupled with 1-(3-fluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 11) (596 mg, 1.969 mmol) using sodium carbonate (402 mg, 3.787 mmol) and Pd(PPh3)2Cl2 (54 mg, 0.075 mmol) in toluene/ethanol/water (10/3/3 mL) to afford 800 mg (74.6% yield) of the titled compound after purification by column (Silica gel 60/120) using 1.5% methanol in DCM as eluent. MS: m/z=708.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:16])[C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][C:26](Cl)=[O:27]>CC(C)=O>[O:16]=[C:5]1[C:4]2[CH:3]=[C:2]([O:1][C:26](=[O:27])[CH:25]=[CH2:24])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=C(Cl)CCCl
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(=O)Oc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 25 °C
Yield: 18.7 %

Procedure:
5 g (22 mmol) 2-hydroxy-9H-thioxanthen-9-one was dissolved in 100 acetone. 50 mg BHT, 10.6 g 77 (mmol) K2CO3 and 5.6 g (44 mmol) 3-chloropropionyl chloride were added. The mixture was refluxed for 3 hours. The salts were removed by filtration after cooling down to room temperature and the solvent was removed under reduced pressure. The residue was treated with 100 ml water and the crude 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester was isolated by filtration. 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester was further purified using preparative column chromatography on a Prochrom LC80 column, using Kromasil Si 60A 10μ as silica and methylene chloride as eluent at a flow rate of 150 ml/min. 1.16 g of 2-propenoic acid 9-oxo-9H-thioxanthen-2-yl ester (19%) was isolated. The isolated compound had a purity of 99%. This analysis was confirmed by 1H-NMR spectroscopy.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](Br)=[CH:4][N:3]=1.[S:23]1[CH2:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH2:25][CH2:24]1>C([O-])([O-])=O.[Na+].[Na+].C(O)CCC.C(OCC)(=O)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>[NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][S:23][CH2:24][CH:25]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(Br)cnc2N)cc1F
Reactant: CC1(C)OB(C2=CCSCC2)OC1(C)C
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: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CCSCC3)cnc2N)cc1F
Temperature: 130 °C
Yield: 95 %

Procedure:
A degassed mixture of tert-butyl 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoate (400 mg, 1.09 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (296 mg, 1.31 mmol), Pd(PPh3)4 (126 mg, 0.109 mmol) in 2.0 M Na2CO3 aqueous solution (1.63 mL) and n-butanol (5 mL) was microwave heated to 130° C. for 15 min. The reaction was diluted with ethyl acetate (20 mL), and then washed with water (10 mL) and brine (10 mL). The organics were dried over sodium sulfate, filtered, concentrated, and then purified by flash chromatography (10-60% ethyl acetate/heptane eluent) to provide tert-butyl 4-(2-amino-5-(3,6-dihydro-2H-thiopyran-4-yl)pyridin-3-yl)-2-fluorobenzoate (400 mg, 95% yield). LCMS (m/z): 387.1 (MH+), 0.87 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.83-7.76 (m, 2H), 7.68 (d, J=1.96 Hz, 1H), 7.37-7.34 (m, 1H), 7.33-7.29 (m, 2H), 7.28-7.24 (m, 2H), 7.24-7.18 (m, 1H), 5.10 (t, J=5.87 Hz, 1H), 3.83-3.69 (m, 2H), 2.81-2.70 (m, 2H), 2.63-2.49 (m, 3H), 2.08 (dd, J=2.74, 13.30 Hz, 2H), 1.72 (dq, J=2.93, 12.59 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([F:19])=[C:14]([CH:18]=2)[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1>ClCCl.CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([F:19])=[C:14]([C:15]([NH:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=3)=[O:17])[CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1F
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(Cl)c3)ccc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 5-{[(3-chlorophenyl)methyl]oxy}-2-fluorobenzoic acid (343 mg, 1.22 mmol) in dichloromethane (5 ml) was treated with oxalyl chloride (1.5 eqs, 160 ul, 1.83 mmol) and DMF (1 drop). Effervescence was observed and the mixture was stirred at room temperature for 1 hour. The solvent was then evaporated in vacuo and azeotroped with toluene. A portion of the resulting solid (122 mgs, 0.41 mmol) was dissolved in dichloromethane (5 ml) and treated with triethylamine (2.5 eqs, 142 ul, 1.02 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (1.5 eqs, 124 mg, 0.61 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was then diluted with methanol and purified by SCX cartridge eluting with methanol. Fractions combined and evaporated to give the title compound as a white solid (227 mg). MS (ES+) m/z 428 [M+H]+ (C23H1935ClFNO4).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3Cl)[CH3:10])[N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C)C(=O)C.O.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.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:13](=[O:22])[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)[CH3:10])[N:3]=1
Reactant: C[C@H](Nc1ncnc(N)n1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@H](Nc1ncnc(N)n1)c1cc2cccc(-c3cnn(C)c3)c2c(=O)n1-c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
(S)-3-(1-(4-Amino-1,3,5-triazin-2-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)— one (32) (100 mg, 0.26 mmol, 1.0 eq), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (106 mg, 0.51 mmol, 2 eq), PdCl2(dppf) (16 mg, 0.02 mmol, 0.08 eq), and Na2CO3(81 mg, 0.765 mmol, 3.0 eq) were suspended in a mixture of N,N-dimethylacetamide (20 mL) and water (1 mL). The resulting mixture was degassed and back-filled with argon three times and stirred at 120° C. under an argon atmosphere for 16 h. The mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-4% MeOH-DCM) to afford the product, 3-((S)-1-(4-amino-1,3,5-triazin-2-ylamino)ethyl)-8-(1-methyl-1H-pyrazol-4-yl)-2-phenylisoquinolin-1 (2H)-one (33). ESI-MS m/z: 439.25 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[O-:8][C:9]#[N:10].CN([S+](N(C)C)N(C)C)C.CCOCC>C(#N)C>[CH2:2]([N:10]=[C:9]=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCBr
Reactant: N#C[O-]
Agent: CN(C)[S+](N(C)C)N(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CCCCCCN=C=O
Reaction time: 2 h
Yield: 85 %

Procedure:
1-Bromohexane, 3.3 g (0.02 mole), was added to a stirred solution of 6.2 g (0.03 mole) of tris(dimethylamino)sulfonium cyanate in 12 ml of acetonitrile at 25°. The course of the reaction was followed by glc analysis. One-half of the 1-bromohexane had reacted after 6 min., and the reaction was virtually complete after 2 hours. Ether, 20 ml, was added to the reaction mixture to precipitate dissolved salts, and the reaction mixture was filtered. Distillation of the filtrate gave 2.16 g (85%) of 1-hexyl isocyanate as a colorless liquid, b.p. 50°-51° (10 mm).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].CO.Cl.[C:17](=O)([O-])[O-].[Na+].[Na+]>O>[NH2:1][C:2]1[C:3]([Cl:13])=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[CH3:11])[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(Cl)cc(C(=O)O)c(Cl)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(Cl)c(C)c(N)c1Cl

Procedure:
30 g of 3-amino-2,5-dichloro-4-methylbenzoic acid are initially introduced into 140 ml of MeOH. HCl gas is now passed in for 20 minutes and the mixture is then boiled under reflux for a further 5 hours. After cooling, the mixture is poured into water and rendered alkaline with sodium carbonate. The ester which has precipitated is isolated and dried. Yield: 30.8 g, melting point: 53°-55°.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH:29]=[CH2:30])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O-:32].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[CH2:29][CH2:30][O:32][CH3:31])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=Cc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Reactant: C[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COCCc1ncnc2c1ncn2[C@@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a stirred solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-vinyl-9H-purine (100 mg, 0.23 mmol) in DCM (5.0 mL) was added NaOMe (0.5M in MeOH, 4.6 mL, 2.2 mmol) at 0° C. The reaction was stirred for 2 h at 0° C. and r.t. overnight. The mixture was diluted with DCM and washed with saturated aq NH4Cl. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (0 to 10% MeOH/DCM) to yield 70 mg (66%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Si:25]([O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>O.CO>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][CH2:37][C:36]2[CH:35]=[CH:34][C:33]([O:32][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[CH:40][CH:39]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2NCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (3.48 g, 10 mmols), 4-tert-butyldimethylsilyloxybenzaldehyde (2.19 g, 12 mmols), acetic acid (1 ml) and methanol (40 ml) was stirred at room temperature for 1 hour, to which was added sodium cyanoborohydride (0.75 g, 12 mmols). Next, this was stirred at room temperature for 3 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, then dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to give an oil of tert-butyl[3-[2-(4-tert-butyldimethylsilyloxybenzylamino)-5-chlorophenoxy]benzyl]carbamate (2.40 g, 42.4%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1.[O:39]1CCCC1>>[C:1]1([C@H:7]([OH:39])[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Product: O[C@H](CCc1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 61 %

Procedure:
A solution of 1,3-diphenylpropanone (1.07 g; 5.09 mmol) in tetrahydrofuran (10 mL) was cooled to −23° C. and treated with an asymmetric reducing agent, (+)-B-chlorodiisopinocampheyl-borane (1.80 g; 5.60 mmol) in 20 mL THF, and the resulting solution was allowed to stand overnight at −23° C. After evaporating to dryness, the residue was treated with ether (65 mL) and diethanolamine (1.0 g) and stirred for 3 hrs. The mixture was then filtered to remove solids and concentrated, and the residue was purified using gradient elution (5% ethyl acetate/hexane to 10% ethyl acetate) on a silica gel column to obtain 660 mg (61%) of (1R)1,3-diphenyl-1-propanol as a crystalline white solid, 1HNMR (360 MHz, CDCl3): d 1.95-2.15 (m, 3H); 2.59-2.78 (m, 2H); 4.65 (dd, 1H, J=5.4, 7.8); 7.14-7.35 (m, 10H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[OH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][OH:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:15][CH2:16][CH2:17][N:18]([CH2:27][CH2:28][OH:29])[C:19]1[CH:26]=[CH:25][C:22]([C:23]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=3[N:1]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N(CCO)CCO)cc3)nc2n1
Temperature: 150 °C
Yield: 10.2 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-nicotinamide (300 mg, 1.52 mmol) and 4-(bis-(2-hydroxyethyl)amino)-benzaldehyde (318 mg, 1.52 mmol) in N,N-dimethylacetamide (10 mL) were added NaHSO3 (297 mg, 1.67 mmol) and p-TSA (376 mg, 1.98 mmol) and the reaction mixture was heated at 150° C. for 4 h, cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with water and the solid was filtered off to give the crude product. The crude product was purified by column chromatography to give 2-(4-(bis(2-hydroxyethyl)amino)phenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (60 mg, 10%). Selected data: MS (ES) m/z: 387.05; MP 277-279° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])/[CH:4]=[CH:5]/[C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:9][CH:10]=1.[N+:20]([CH3:23])([O-:22])=[O:21]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH:5]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)=[CH:9][CH:10]=1)[CH2:23][N+:20]([O-:22])=[O:21]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)/C=C/c1ccc(-c2ccnc(SC)n2)s1
Solvent: CCOC(C)=O
Product: COC(=O)CC(C[N+](=O)[O-])c1ccc(-c2ccnc(SC)n2)s1

Procedure:
A solution of (E)-3-[5-(2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-acrylic acid methyl ester (200 mg, 0.684 mmol), nitromethane (3 ml) and Triton B (0.3 ml) was heated to 80° C. for 4 hours. After cooling, the mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water and brine. Drying over sodium sulfate and evaporation gave a red-brown oil. Yield: 100 mg (41%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2ccc(OCCCBr)cc2N1
Yield: 88 %

Procedure:
7-hydroxy-3,4-dihydroquinolin-2(1H)-one (195 mg, 1.2 mmol), 1,3-dibromopropane (960 mg, 4.8 mmol) and anhydrous K2CO3 (166 mg, 1.2 mmol) were dissolved in EtOH and the solution was heated to reflux overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with saturated aq NaHCO3, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=2:1) to give 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (intermediate 3) (300 mg, 88%) as a white solid. HPLC: 99%, RT 2.775 min. MS (ESI) m/z 284.0 [M+H]+.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)C=CC=CC=1.[CH3:29][C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2O)[N:31]=1>>[CH3:29][C:30]1[O:34][N:33]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([O:16][CH2:15][CH2:14][CH2:13][C:11]3[N:10]=[CH:9][NH:8][CH:12]=3)=[CH:37][CH:36]=2)[N:31]=1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1nc(-c2ccccc2O)no1
Product: Cc1nc(-c2ccc(OCCCc3c[nH]cn3)cc2)no1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of (5-methyl-1,2,4-oxadiazol-3-yl)phenol (prepared according to Swain, C. J. et al. J. Med. Chem. 1991, 34, 140) are treated as described in Example 56, but isolated in the form of the free base.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:23]=1.[C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)#[N:25]>>[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([CH:10]4[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:14][CH2:15]4)=[N:7][C:6]=3[CH:23]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(C#N)cc4)ccc3o2)CC1
Yield: 30.1 %

Procedure:
Following the General Procedure-1, the titled compound (45 mg) was prepared from Intermediate 7 (140 mg, 0.37 mmol) and 4-Cyanophenylboronic acid (53 mg, 0.37 mmol) as an off-white solid. M.P.: 137.3-141.2° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.88 (d, 1.4, 1H), 7.74 (dd, J 1.8, 8.5, 2H), 7.69 (dd, J 1.8, 8.5, 2H), 7.58 (d, J 8.5, 1H), 7.53 (dd, J 1.8, 8.5, 2H), 4.15 (d, J 10.4, 2H), 3.20-3.10 (m, 1H), 3.00 (t, J 11.2, 2H), 2.20-2.12 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5]1[CH2:7][CH2:6]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:2]([C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:4][CH:5]1[CH2:7][CH2:6]1)#[N:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CC1)C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C#N)CC1CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.4 %

Procedure:
To a solution of (S)-tert-butyl 1-amino-3-cyclopropyl-1-oxopropan-2-ylcarbamate (3.7 g, 16 mmol) and triethylamine (6.55 g, 65 mmol) in methylene chloride (50 mL) was added trifluoroacetic acid anhydride (6.81 g, 32 mmol) dropwise at 0° C. The resulting mixture was allowed to warm to room temperature and stirred for 4 h. The mixture was washed with water (150 mL), citric acid (150 mL, 5 M) and brine (150 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated to give product (3.31 g, 97%) as a yellow solid; MS (EI): m/e 233.1 [M+Na]+.