Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([NH2:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCN(Cc1cc(Br)ccc1N)c1ccc(C(N)=O)nn1
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cc(Br)ccc1NCc1ccccc1)c1ccc(C(N)=O)nn1
Temperature: 50 °C
Yield: 75.1 %

Procedure:
To a mixture of 6-[N-(5-bromo-2-aminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (900 mg, 2.57 mmol), benzaldehyde (0.6 ml, 5.9 mmol) and methanol (50 ml) stirred at 50° C., was added portionwise sodium cyanoborohydride (400 mg, 6.36 mmol). The solution was stirred for 16 hours at 20° C., by which time the product crystallised. It was filtered off and washed with methanol (10 ml) to give 6-[N-(5-bromo-2-benzylaminobenzyl)-N-ethylamino]pyridazine-3-carboxamide (850 mg) m.p. 160-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:36])(=[O:35])[NH2:34])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:23][N:37]=[C:26]([C:27]5[CH:28]=[C:29]([S:33]([NH2:34])(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=5)[N:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a light yellow solid (200 mg, 77%). MS (ISP) 521.2 [(M+H)+]; mp 247° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[CH:14][C:13]2=[O:28])[C:3]([OH:29])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (620 mg, 0.002 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (190 mg, 0.008 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-propionic acid (295 mg, 49%) as a light brown solid.
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH3:29])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:16]1=[CH2:30]>C(O)C>[CH3:14][N:15]1[C:16]2([O:13][C:4]3[CH:5]=[CH:6][C:7]4[C:12]([C:3]=3[N:1]=[CH:30]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:17]([CH3:29])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: C=C1N(C)c2ccccc2C1(C)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1(C)c2ccccc2N(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A solution of 1-nitroso-2-naphthol (0.50 g, 2.89 mmol) and 1,3-dimethyl-3-carboethoxy-2-methylene-indoline (0.87 g, 2.77 mmol) in ethanol (70 ml) was heated under nitrogen and refluxed for 2 hrs. The solvent was then evaporated and the residue was chromatographed over silica (ethyl acetate/petroleum ether 1:10). After crystallization in ethanol, the yield of the pure product (colorless crystals) was 0.21 g (16%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][OH:19]>>[O:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][O:19][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: OCC1CCCO1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Product: O=C(O)c1ccc(OCC2CCCO2)nc1
Yield: 24 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 24% yield starting from ethyl 6-chloronicotinate and tetrahydrofuran-2-ylmethanol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.70 (d, 1 H), 8.14 (dd, 1 H), 6.90 (d, 1 H), 4.23-4.35 (m, 2 H), 4.10-4.21 (m, 1 H), 3.72-3.82 (m, 1 H), 3.61-3.71 (m, 1 H), 1.92-2.03 (m, 1 H), 1.74-1.93 (m, 2 H), 1.58-1.70 (m, 1 H); MS (ESI) m/z 224[M+H+], m/z 222[M−H+];
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:12]([NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][N:10]=1)C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[C:17]2[C:12]([NH:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][N:10]=1
Reactant: c1ccc(COc2ncc3[nH]cccc2-3)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ncc2[nH]cccc1-2
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
A mixture of 5-benzyloxypyrrolo[3,4-b]pyridine (Compound 7f, 1.38 g, 6.15 mmol), 5% Pd/C (0.30 g), and absolute ethanol (25 mL) was shaken under a hydrogen atmosphere (3 atm) for 30 minutes. The resulting mixture was filtered through diatomaceous earth (Celite (trademark)), and the filtratewas evaporated under reduced pressure. The residual solid was triturated inethyl ether to yield Compound 7i (0.80 g, 5.96 mmol, 97%) as an off-white crystalline solid: mp, 280.0°-282.0° C.: IR (KBr) 1640, 1615, 1605, 1455, 1430, 1400, 1380, 1365 cm-1 ; 1H NMR (DMSO-d6) δ 11.4 (br m, 2H), 7.56 (d, J=9.7 Hz, 1H), 7.16 (d, J=3.1 Hz, 1H), 6.01-5.93 (m, 2H); 13C NMR (DMSO-d6) 162.0, 131.9, 127.9, 125.0, 118.2, 112.2, 94.5; LRMS (m/z, relative intensity) 135 (41), 134 (M+, 100), 106 (66), 105 (42), 79 (59), 53 (31), 52 (52). Anal. calcd. for C7H6N2O: C, 62.68; H, 4.51; N, 20.88; found: C, 62.40; H, 4.40; N, 20.76.
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[C:30]([O:38][CH2:39]Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:39][O:38][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reactant: O=C(OCCl)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1)c1ccccc1

Procedure:
Following the procedure similar to that of Example 45 but using 12.8 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 20 g. of potassium bicarbonate, 10 ml. of chloromethyl benzoate in 50 ml. of dry dimethylformamide there was obtained, after filtration of the ether extract through silica gel followed by combination of those fractions showing only one identical spot on thin layer chromotography and evaporation to dryness under reduced pressure, 14 g. of the title compound; m.p. 84°-86°C. (methyl alcohol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17]CC)=[O:16])=[CH:7][C:6]=2[CH:20]=1.[OH-].[Li+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([F:13])([F:12])[F:14])[C:8]([C:15]([OH:17])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
A solution of the ester from Step 1 (13.02 g, 42 mmole) was dissolved in 200 mL of methanol and 20 mL of water, treated with lithium hydroxide (5.36 g, 0.128 mole) and stirred at room temperature for 16 hours. The reaction mixture was acidified with 1.2 N HCl, whereupon a solid formed that was isolated by filtration. The solid was washed with 200 mL of water and 200 mL of hexanes and dried in vacuo to afford the title compound as a yellow solid (10.00 g, 85%): mp 181–184° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][C:17]([O:19]C)=O)[CH2:4][CH2:3]1.[OH-].[Na+]>CO.CO.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:15][CH2:16][C:17]2=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)CCc1ccccc1NC1CCN(C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 3-(2-(1-methylpiperidin-4-ylamino)phenyl)propanoate (1.1 g, 3.98 mmol) in 20 mL MeOH/5 mL H2O was treated with 1N NaOH (8.8 mL, 8.76 mmol) and stirred at room temperature for 2 hours. The mixture was concentrated and made acidic with 6N HCl. Approximately half of this mixture was diluted with 1N HCl (15 mL) and heated at 110° C. overnight. After cooling, the mixture was concentrated on the rotoevaporator then made basic with saturated Na2CO3. This solution was extracted with 2×100 mL CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and concentrated to give a light brown residue, which was subjected to flash chromatography on silica gel using 5%, 2M NH3 in MeOH/CH2Cl2. A light yellow solid was obtained (320 mg, 78.2%). 1H-NMR (CDCl3) δ 7.24-7.16 (m, 3H), 7.02-6.97 (m, 1H), 4.47-4.34 (m, 1H), 2.99-2.95 (m, 2H), 2.83-2.70 (m, 2H), 2.68-2.55 (m, 4H), 2.33 (s, 3H), 2.13-2.06 (m, 2H), 1.72-1.69 (m, 2H). MS (ESI): 245.2 (M+1, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.O[CH:32]([CH2:35][CH2:36][CH:37]([N:40]1[C:44](=[O:45])[C:43]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]2[C:41]1=[O:50])[CH2:38][F:39])[CH:33]=[CH2:34].CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[F:39][CH2:38][CH:37]([N:40]1[C:41](=[O:50])[C:42]2=[CH:49][CH:48]=[CH:47][CH:46]=[C:43]2[C:44]1=[O:45])[CH2:36][CH2:35][CH:32]([N:24]1[C:20](=[O:30])[C:21]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:22]2[C:23]1=[O:25])[CH:33]=[CH2:34]
Reactant: C=CC(O)CCC(CF)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CC(CCC(CF)N1C(=O)c2ccccc2C1=O)N1C(=O)c2ccccc2C1=O
Reaction time: 72 h

Procedure:
To a solution of triphenylphosphine (103 g, 0.39 mol), phthalimide (57.8 g, 0.43 mol) and 3-hydroxy-7-fluoro-6-phthalimidoheptene (109 g, 0.39 mol) in dry THF (2 L) under nitrogen, was added dropwise a solution of diethylazodicarboxylate (75.4 g, 0.43 mol) in dry THF (1 L). The solution was kept <20° C. The reaction mixture was stirred for 72 hours. The THF layer was separated and evaporated to give an oil which was boiled in water (5×250 mL), the water was decanted and the residue was dissolved in dichloromethane. After washing with water, the organic phase was separated, dried over Na2SO4 and evaporated to eliminate triphenylphosphine oxide. Evaporation of the ether phase and chromatography of the residue (200 g) on silica gel (1.5 kg), elution with petroleum ether/ethyl acetate (2:3) afforded the title compound (8, R=--CH2F) as a white solid: 36.4 g (22.8%). TLC PE/EtOAc 1:1, Rf=0.78. NMR (1H, CDCl3, 90 MHz).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([F:28])[C:26]=1[OH:27])[CH:22]=O>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:22][C:21]3[CH:20]=[C:19]([F:18])[C:26]([OH:27])=[C:25]([F:28])[CH:24]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cc(F)c(O)c(F)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cc(F)c(O)c(F)c1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 3,5-difluoro-4-hydroxybenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][C@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=1[F:41]>CCOC(C)=O>[Si:1]([O:8][C@@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][C@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:38](=[O:39])[C:36]2[CH:35]=[CH:34][C:33]([F:41])=[C:32]([Br:31])[N:37]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(F)c(Br)n1
Reactant: C[C@H]1C[C@H](c2ccncc2N)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 9, 4-((1S,3S,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, N-(4-((1S,3S,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-yl)-6-bromo-5-fluoropicolinamide was obtained. LCMS (m/z): 652.5, 652.4 (MH+); LC Rt=5.83 min.
Reaction SMILES: IC.[CH2:3]([N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=[C:11]1[CH:22]([N:26]1[C:32](=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH:23]([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:34]CN(CC)CC>C(Cl)Cl>[CH2:3]([N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]=[C:11]1[CH:22]([N:26]1[C:32](=[O:33])[CH2:31][CH2:30][N:29]([CH3:34])[CH2:28][CH2:27]1)[CH:23]([CH3:25])[CH3:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Reactant: CCN(CC)CC
Solvent: CI
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCN(C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Iodomethane (23 μL, 0.37 mmol) was added to a solution containing 3-benzyl-7-chloro-2-[2-methyl-1-(7-oxo-[1,4]diazepan-1-yl)-propyl]-3H-quinazolin-4-one and Et3N (51.4 μL, 0.37 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at RT overnight, diluted with CH2Cl2 (5 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (1–2% CH3OH in CH2Cl2) gave the title compound (65 mg, 70%) as a pale yellow solid: MS (ES) m/e 453.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3](C)([CH3:6])[CH:4]=O.[CH:8]([O:13][CH3:14])([O:11][CH3:12])OC.Cl.O1CCOCC1.O(C)[Na]>CO>[CH3:14][O:13][CH:8]([O:11][CH3:12])[C:3]([CH3:6])([CH3:4])[CH2:2][OH:1]
Reactant: CC(C)(C=O)CO
Reactant: COC(OC)OC
Agent: CO[Na]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(OC)C(C)(C)CO
Reaction time: 8 h

Procedure:
A solution of 24.4 g (0.24 mol) of 3-hydroxy-2,2-dimethylpropanal (Aldrich), 26 g (0.25 mol) of trimethyl orthoformate, and 0.5 mL of 6.8 N HCl/dioxane in 300 mL of methanol was allowed to stand at room temperature overnight. A slight excess of NaOCH3 was added and the solvent evaporated at reduced pressure. The residue was dissolved in ether and the mixture filtered. After evaporation of solvent and fractionation twice through a 15 cm Vigreux column, the product was obtained as a water white oil, bp 43°-48°/0.2mm, 18.5 g (52%).
Reaction SMILES: [CH2:1]([N:8]([CH3:22])[C:9]([CH2:11][CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]=[O:21])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>C1COCC1>[C:23]1([CH:20]([C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:13](=[O:14])[CH2:12][CH2:11][C:9](=[O:10])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:22])[OH:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of (2S)-1-[3-(N-benzyl-N-methylcarbamoyl)propanoyl]pyrrolidin-2-al (200 mg) in THF (5 ml) was cooled to -25° C. A solution of phenyl magnesium bromide in THF (2M, 0.49 ml) was added dropwise to the solution. The reaction solution was stirred for 30 mins, at the same temperature, and for 30 mins at 0° C. A saturated aq. solution of ammonium chloride was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (EtOAc-CH3OH) to give the title compound (45 mg) having the following physical data:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]3[CH:19]=[N:20][C:21]([C:22](=[S:24])[NH2:23])=[C:11]3[CH2:10]2)=[O:8])[CH2:3][CH2:2]1.[CH:25]1([C:28]([CH2:30]Br)=O)[CH2:27][CH2:26]1>C(O)C>[CH:25]1([C:28]2[N:23]=[C:22]([C:21]3[N:20]=[CH:19][N:12]4[C:13]5[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:9]([C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[O:8])[CH2:10][C:11]=34)[S:24][CH:30]=2)[CH2:27][CH2:26]1
Reactant: NC(=S)c1ncn2c1CN(C(=O)N1CCOCC1)c1ccccc1-2
Reactant: O=C(CBr)C1CC1
Solvent: CCO
Product: O=C(N1CCOCC1)N1Cc2c(-c3nc(C4CC4)cs3)ncn2-c2ccccc21
Reaction time: 24 h

Procedure:
A mixture of 4,5-dihydro-5-(morpholinocarbonyl)imidazo[1,5-a]quinoxaline-3-thiocarboxamide (0.29 g) and 1-bromomethyl cyclopropyl ketone (0.165 g) in ethanol (10 ml) is stirred at 20°-25° for 1 day and then at 80° for 5.5 hr, after which it stirred at 20°-25° for an additional 20 hr. The mixture is then concentrated under reduced pressure and chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The product fractions are combined and rechromatographed using ethyl acetate/dichloromethane (25/75) to give a solid. Crystallization from dichloromethane/hexane gives the title compound; mp 193°-194°; MS (m/z) 407; IR (mineral oil) 1511, 1669, 1115, 1392, 1227 cm-1 ; NMR (CDCl3) 0.98, 2.09, 3.35, 3.66, 5.09, 6.79, 7.19, 7.28, 7.53, 8.01 δ.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[CH:4][N:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>>[CH:13]([NH:12][CH2:11][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[N:7]=2)[CH:18]=[CH:17][CH:16]=1)([CH3:15])[CH3:14]
Reactant: CC(C)NCc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CC(C)NCc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 65 was coupled with tyramine following procedure F. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 363. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H), 8.2 (m, 2H), 8.1 (m, 2H), 7.5 (d, 2H), 7.2 (m, 2H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), 3.8 (m, 1H), 3.3 (m, 4H), 2.7 (m, 1H), 1.1 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5].N1C=CC=CC=1.[F:28][CH2:29][C:30](Cl)=[O:31]>O1CCCC1>[F:28][CH2:29][C:30]([NH:1][C:2]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[CH3:14])=[O:5])=[O:31]
Reactant: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1N
Reactant: O=C(Cl)CF
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1NC(=O)c1cc([N+](=O)[O-])ccc1NC(=O)CF
Yield: 91.2 %

Procedure:
3.3 g of N-(2-amino-5-nitrobenzoyl)-2-methyl-4-chloroaniline and 1.6 g of pyridine are dissolved in 60 ml of tetrahydrofuran, and 1.93 g of fluoroacetyl chloride are added dropwise thereto under ice-cooling and stirring. The mixture is stirred for 30 minutes under ice-cooling and further stirred at room temperature for 2 hours. The mixture is concentrated under reduced pressure to remove tetrahydrofuran. Water is added to the residue and crystalline precipitates are collected therefrom. The crystals are recrystallized from a mixture of dimethylformamide and ethanol (1:3). 3.6 g of N-(2-fluoroacetamido-5-nitrobenzoyl)-2-methyl-4-chloroaniline are obtained as colorless needles.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:5]=12.Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=[C:12]([CH2:13][CH3:14])[C:5]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCc1c[nH]c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn(COCC[Si](C)(C)C)c2nccc(Cl)c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
Sodium hydride (0.877 g, a 55% dispersion in paraffin liquid) was added to a solution of compound (41c) (3.3 g) in DMF (61 mL) at 0° C., followed by stirring for 10 min. Then, [2-(chloromethoxy)ethyl]trimethylsilane (3.53 mL) was added to the reaction solution, followed by stirring at room temperature for 1 hr. After cooling, ice water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated saline in this order and was then dried over anhydrous sodium sulfate. After distillation of the solvent, the residue was purified by neutral silica gel column chromatography (n-hexane/ethyl acetate) to obtain compound (41d) (4.30 g, 76%) as a colorless oily substance.