Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[C:6]1[NH:10][N:9]=[N:8][N:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([N:8]1[N:9]=[N:10][C:6]([CH:5]([CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[C:4]([O:3][CH2:1][CH3:2])=[O:16])=[N:7]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)C(c1nnn[nH]1)C1CCCC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(c1nnn(Cc2ccccc2)n1)C1CCCC1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
To a stirred mixture of α-cyclopentyltetrazole-5-acetic acid, ethyl ester (step 1 of Example 14) and K2CO3 (12.3 g, 89.0 mmol) in acetone (200 mL) was added benzyl bromide (4.84 mL, 40.7 mmol) at ambient temperature. The resulting mixture was stirred at 50° C. for 14 h and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (10:1) to give 2.95 g (27% in 2 steps) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([OH:36])=O)=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19].[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]([N:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][N:23]2[C:31]([C:34]([NH:37][CH2:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)=[O:36])=[CH:32][CH:33]=[C:22]2[CH2:21]1)=[O:19]
Reactant: NCc1ccncc1
Reactant: O=C(O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2
Product: O=C(NCc1ccncc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3cccc4ccccc34)cc1Cl)C2

Procedure:
The title compound was prepared by the coupling the 10-[2-chloro-4-(naphthalen-1-yl)phenyl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step C, with 4-(aminomethyl)pyridine (1.25 equiv) in the manner of Example 1, Step G.
Reaction SMILES: Br[C:2]1[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]2[C:11](=[O:23])[N:12]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:13]([CH3:16])[C:14]=2[CH3:15])=[O:8])[C:3]=1[CH3:24].[Br-].[CH:26]1([Zn+])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:26]1([C:2]2[O:6][N:5]=[C:4]([C:7]([NH:9][C:10]3[C:11](=[O:23])[N:12]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:13]([CH3:16])[C:14]=3[CH3:15])=[O:8])[C:3]=2[CH3:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1Br
Reactant: [Zn+]C1CCCCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)noc1C1CCCCC1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To 5-bromo-N-(2-cyclohexyl-1,5-dimethyl-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-4-methylisoxazole-3-carboxamide (75 mg, 0.189 mmol) was added cyclohexylzinc(II) bromide (0.5M in THF) (1133 μL, 0.566 mmol) and bis(tri-t-butylphosphine)palladium(0) (9.65 mg, 0.019 mmol) and the mixture was stirred at 100° C. in the microwave for 30 minutes. The resulting mixture was diluted with EtOAc and filtered and the solvent was removed under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:12]=2[CH2:11][CH:10]([CH3:21])[NH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:9]2[CH:10]([CH3:21])[CH2:11][C:12]3[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:14][C:13]=3[C:7]([C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21
Product: CCCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 2-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid n-propyl ester (compound in Paragraph A) and 4-fluorobenzoyl chloride; MS (ES): 407 (MH+). The racemic sample was submitted to chiral separation using a 10 mm×250 mm Chiralcel OD column and a 10% iPrOH/hexane isocratic mobile phase to give two isomers.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]([OH:23])[CH3:22])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1>ClCCl.O=[Mn]=O>[C:21]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:12]([C:11]1[C:2]([Cl:1])=[N:3][C:4]3[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20]2)(=[O:23])[CH3:22]
Reactant: CC(O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)cc(-c1cc3ccccc3nc1Cl)n2C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A mixture of 2-(2-chloro-3-quinolinyl)-5-(1-hydroxyethyl)-1H-indole-1-carboxylate (8-2, 840 mg, 1.99 mmol, 1 equiv) and MnO2 (863 mg, 9.93 mmol, 5.00 equiv) in dichloromethane (30 mL) was heated at reflux for 1 h. Additional MnO2 (500 mg, 5.75 mmol, 2.89 equiv) was added and heating was continued for 1 h. The catalyst was filtered and washed with dichloromethane (100 mL). The combined filtrate was concentrated to give tert-butyl 5-acetyl-2-(2-chloro-3 quinolinyl)-1H-indole-1-carboxylate (8-3) as a white foam. 1H NMR (500 MHz, CDCl3) δ 8.38 (d, 1H, J=8.8 Hz), 8.27 (d, 1H, J=0.7 Hz), 8.21 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 8.04 (dd, 1H, J=8.8, 1.2 Hz), 7.89 (d, 1H, J=8.1 Hz), 7.80 (br t, 1H, J=7.6 Hz), 7.63 (br t, 1H, J=7.5 Hz), 6.76 (s, 1H), 2.70 (s, 3H), 1.27 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1ccc(Br)cc1F
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (13.1 g, 50.0 mmol) in THF (50 mL) at −78 C was treated with a 3 M solution of methyl magnesium bromide in diethyl ether (16.7 mL, 50 mmol) and allowed to warm with stirring to 0 C over a 2-3 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (100 mL) and EtOAc (200 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 5% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-ethanone as a liquid (9.25 g, 85%). The ethanone (2.17 g, 10 mmol) was then dissolved in ethanol (25 mL), treated with hydrazine hydrate (535 uL, 11 mmol), and heated at reflux for 8 h. The reaction mixture was then evaporated and purified by silica gel flash chromatography with 30% then 60% EtOAc/hexanes as eluant to afford the hydrazone as a solid (2.29 g, 99%). The hydrazone (3.69 g, 16 mmol) was then treated with ethylene glycol (25 mL) and heated at 165° C. for 6 h after which time the cooled reaction mixture was poured onto water (100 mL). The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (2.62 g, 78%). The indazole (2.32 g, 11 mmol) was then dissolved in anhydrous DMF (50 mL) and treated with a 60% dispersion of sodium hydride in mineral oil (420 mg, 10.5 mmol). After 30 min of stirring, cyclopentyl bromide (1.53 mL, 14.3 mmol) was added and the reaction stirred for 24 h. The reaction mixture was quenched by pouring onto water (500 mL) which was neutralized with a small portion of a 1 N aqueous HCl solution and extracted with EtOAc (2×200 mL, then 100 mL). The combined organic extracts were dried over MgSO4, filtered, and evaporated to an oil, which was purified by silica gel flash chromatography with 25% then 80% EtOAc/hexanes as eluant to afford product as a clear yellow tinted oil (1.65 g, 54%). 1H NMR (CDCl3) 1.68-1.78 (m, 2 H), 1.93-2.01 (m, 2 H), 2.08-2.16 (m, 4 H), 2.54 (s, 3 H), 4.77-4.87 (m, 1 H), 7.18 (dd, J=8.4, 1.5, 1 H), 7.32 (dd, J=8.4, 0.7, 1 H), 7.55 (d, J=1.5, 1 H). 13C NMR 12.1 (CH3), 24.7 (CH2), 32.2 (CH2), 59.5 (CH), 112.2 (CH), 120.5, 121.8 (CH), 122.5, 123.2 (CH), 141.1, 141.4. LC/MS 7.71 min, [M+1]+ 281.
Reaction SMILES: Cl.ClC[CH:4](O)[C@H:5]1[O:9][C@@H:8]([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[C@H:7]([OH:20])[C@@H:6]1[OH:21].[NH2:23][C@H:24]([C:28]([OH:30])=[O:29])[CH2:25][CH2:26][SH:27].[I-].[K+]>O>[C@@H:8]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:5]([CH2:4][S:27][CH2:26][CH2:25][C@@H:24]([C:28]([OH:30])=[O:29])[NH2:23])[C@@H:6]([OH:21])[C@H:7]1[OH:20]
Reactant: N[C@@H](CCS)C(=O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)CCl)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CSCC[C@H](N)C(=O)O)[C@@H](O)[C@H]1O

Procedure:
condensing 5′-chloromethyl adenosine hydrochloride with L-homocysteine in the presence of water and potassium iodide at 70 to 80° C. to obtain S-adenosyl-L-homocysteine (SAH), and
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[O:13])=[O:10])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:13])=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(NC(=O)NC(=O)Cc2ccc(F)cc2)cc1
Reaction time: 18 h
Yield: 99.5 %

Procedure:
To a solution of 1-(2-(4-fluorophenyl)acetyl)-3-(4-nitrophenyl)urea (200 mg, 0.63 mmol) in ethyl acetate (10 mL) was added 10% palladium on carbon (15 mg) and the flask was filled with hydrogen using a balloon. The mixture was stirred for 18 h, filtered and the catalyst was washed with ethyl acetate. The filtrate was concentrated in vacuo to give a solid which was was triturated with small amount of ether and dried in vacuo to obtain the desired compound (180 mg) as pale yellow solid. MS(ESI+) m/z 287.4 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CN(C)[CH:21]=[O:22]>C1COCC1>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:21]=[O:22])[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
To a solution of butyllithium (50.6 ml of a 2.5M solution in hexanes, 126.5 mmol) in THF (200 mL) at -78° C., was added 2-bromo-6-methoxynaphthalene (15.00 g, 63.3 mmol) portionwise. Upon completion of addition, the mixture was stirred for 30 min at -78° C. N,N-Dimethylformamide (6.94 g, 94.95 mmol) was added dropwise. The cooling bath was withdrawn and the reaction allowed to warm to ambient temperature. It was then quenched with saturated aqueous NH4Cl (200 mL) and the THF was stripped off in vacuo. The aqueous residue was extracted with ethyl acetate (3×200 mL). The organics were combined, dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; 1:4 ether, hexanes) to afford 8.86 g (75%) of 6-methoxy-2-naphthalenecarboxaldehyde as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:24]1([S:30]([NH:12][NH:11][C:9](=[O:10])[C:8]2[CH:13]=[CH:14][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)NN)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)NNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
4-tert-Butyl-benzoic acid hydrazide (0.5 g, 2.60 mmol) was dissolved in THF (29 mL). N,N-diisopropylethylamine (1.81 mL, 10.4 mmol) was added, and the reaction was cooled to 0° C. Phenylsulfonyl chloride (0.36 mL, 2.86 mmol) was added followed by DMAP (5 mg, 0.04 mmol). The reaction was allowed to warm to room temperature, and the reactants all dissolved. The solution went from a yellow color to a deep red over the course of 4 hours. The reaction was then concentrated down and purified by flash chromatography eluting with 3:1 hexanes/EtOAc. The desired product was isolated (0.32 g, 37.1%). MS: 333.1 (M+1 for C17H20N2O3S); mp 197-199° C.; TLC: SiO2 Rf=0.56 (1:1 hexane/EtOAc). Analysis C17H20N2O3S: (calc) C, 61.42; H, 6.06; N, 8.43. (found) C, 61.38; H, 6.09; N, 8.27. IR (KBr, cm−1) 3213, 2965, 1648, 1403, 1349, 1179. 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 9H), 7.39-7.55 (m, 8H), 7.92-7.93 (m, 2H), 8.06 (s, 1H).
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[H][H]>C(O)(C)(C)C.O>[ClH:1].[C:2]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:14])[CH2:9][CH2:10]1)(=[NH:3])[NH2:4]
Reactant: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)O)CC1
Yield: 79.8 %

Procedure:
5.5 g of o-benzyloxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride was dissolved in a solution of 60 ml of t-butyl alcohol and 60 ml of water. 225 mg of 10% paradium-carbon was added to the solution, and the mixture was stirred at room temperature for 1 hour in the presence of hydrogen (starting pressure: 2.4 kg/cm2). The catalyst was removed by filtration, and the solvent was removed. The residue was washed with t-butyl alcohol to obtain 3.5 g (yield: 79.7%) of o-hydroxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 192° to 194° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][C:38]([C:40](C)(C)[O:41][SiH2]C(C)(C)C)=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[C:9]1[C:25]1[C:26]2[S:39][C:38]([CH2:40][OH:41])=[CH:37][C:27]=2[N:28]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[N:29]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O[Si](C)(C)C(C)(C)C)cc3n2C(=O)OC(C)(C)C)c2sc(C(C)(C)O[SiH2]C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(O)cc3n2C(=O)OC(C)(C)C)c2sc(CO)cc21
Temperature: 0 °C

Procedure:
To a solution of 2-[1-tert-butoxycarbonyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-thieno[3,2-c]pyrazol-3-yl]-6-(tert-butyl-dimethyl-silanyloxy)-indole-1-carboxylic acid tert-butyl ester [3.2 g, 4.5 mmol, Intermediate (75)] in tetrahydrofuran (30 mL) at 0° C. was added a 1.0 M TBAF solution in tetrahydrofuran. The green solution was stirred at 0° C. until the reaction is complete and was then diluted with water. The resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was chromatographed through silica gel (dichloromethane/ethyl acetate, 90/10 as eluant) to produce 2-(1-tert-butoxycarbonyl-5-hydroxymethyl-1H-thieno[3,2-c]pyrazol-3-yl)-6-hydroxy-indole-1-carboxylic acid tert-butyl ester [1.5 g (66%, Intermediate (76)]. LC/MS: 486.2 (M+H), RT=3.30 minutes.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[CH:14]=[C:13]1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH:5](=[C:12]1[NH:16][C:15](=[O:17])[CH2:14][C:13]1([OH:18])[N:1]=[O:3])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1C=C(O)C(=Cc2ccccc2)N1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=NC1(O)CC(=O)NC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
An aqueous solution of sodium nitrite (0.075 g, 1.1 mmol) was added to an ice-cooled suspension of 2 mmol (0.432 g) 5-benzylidene-4-hydroxy-1,5-dihydro-pyrrol-2-one (prepared by the method of H. Poschenrieder et al (Arch. Pharm. Pharm. Med. Chem. 1998, vol. 331, pp. 389-394) and Stachel et al (J. Heterocycl. Chem. 1980, vol. 17, pp. 1195-1199 and Liebigs Ann. Chem. 1985, pp. 1692-1696)) in 5 ml glacial acetic acid, while stirring, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated and orange crystals of 5-benzylidene-4-hydroxy-4-nitroso-1,5-dihydro-pyrrol-2-one were obtained in a yield of 65% by recrystallization from ethanol. The substance decomposes at 205° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][C:7]1([CH3:14])[O:12][C:11](=[O:13])[CH:10]=[CH:9][O:8]1.O>N1C=CC=CC=1>[Cl:4][C:10]1[C:11](=[O:13])[O:12][C:7]([CH3:14])([CH3:6])[O:8][CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CC1(C)OC=CC(=O)O1
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)OC=C(Cl)C(=O)O1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Sulfuryl chloride (2.44 mL, 0.03 mol) was added dropwise to a solution of 2,2-dimethyl-1,3-dioxin-4-one (3.2 g, 0.025 mol) in pyridine (16 mL) under cooling with ice. The mixture was stirred for 30 minutes, while the temperature was maintained, and was further stirred at room temperature for two hours. The reaction mixture was cooled with ice, and water was added to the reaction mixture. The reaction mixture was extracted with dichloromethane, and the formed dichloromethane layer was dried over sodium sulfate anhydrate and concentrated. The concentration residue was purified through silica gel column chromatography (eluent=n-hexane:ethyl acetate=95:5), to thereby yield 2.08 g of the title compound as an oily substance (yield: 51.2%).
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:11][CH:10]=1>>[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:19])[C:16]([O-:18])=[O:17])=[CH:13][CH:14]=1.[Na+:2]
Reactant: Cc1ccsc1-c1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccsc1-c1ccc(C(C)C(=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
To 19.5 ml of 1 N sodium hydroxide solution was added 4.9 g (0.02 mole) of 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid. After stirring for 30 minutes, the insoluble substance was removed by extraction with 20 ml of chloroform. The aqueous layer was concentrated under reduced pressure with heating. The residue was recrystallized from a toluene-water-dioxane mixture to obtain dihydrate of sodium 2-[4-(3-methyl-2-thienyl)phenyl]propionate having melting point of 206°-207° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][CH2:10][O:11][CH:12]([CH2:22][O:23]CC1C=CC=CC=1)[CH2:13][O:14]CC1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[ClH:42]>CCO.[Pd]>[ClH:42].[NH2:8][CH2:9][CH2:10][O:11][CH:12]([CH2:22][OH:23])[CH2:13][OH:14]
Reactant: c1ccc(COCC(COCc2ccccc2)OCCN(Cc2ccccc2)Cc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: NCCOC(CO)CO
Temperature: 80 °C
Reaction time: 10 h
Yield: 83.3 %

Procedure:
Charged a solution of N,N-dibenzyl-2-(1,3-bis(benzyloxy)propan-2-yloxy)ethanamine (2000 g, 4.0 mol, 1.0 eq) in EtOH (10000 mL, 5.0 v), Pd/C (10%, 400 g, 20% wt) and acetic acid (970 g, 16.2 mol, 4.0 eq) to a 20 L pressure reactor. The resulting mixture was stirred for 10 hours at 80° C. under hydrogen (20 atm). The reaction progress was monitored with NMR. The reaction mixture was cooled to 20˜30° C. and filtered. HCl (36%, 500 ml, 6.0 mol, 1.5 eq) was added to the filtrate, stirred for 10 minutes and concentrated under vacuum to give 572 g (83.4%) of 2-(2-aminoethoxyl)propane-1,3-diol hydrochloride as an oil. H-NMR of 3 (300 MHz, D2O, ppm): 3.79 (2H, q), 3.60 (2H, m), 3.50 (3H, m), 3.15 (2H, q).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[S:3]([C:6]1[CH:7]=[C:8]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].CCN(CC)CC.[CH2:28]([N:31]([CH2:35][C:36]1[S:40][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:38][CH:37]=1)[CH2:32][CH:33]=[CH2:34])[CH:29]=[CH2:30]>C(Cl)Cl>[CH2:32]([N:31]([CH2:28][CH:29]=[CH2:30])[CH2:35][C:36]1[S:40][C:39]([S:41]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([C:2]([F:1])([F:19])[F:20])(=[O:5])=[O:4])[CH:7]=3)[CH2:14][CH2:15]2)(=[O:43])=[O:42])=[CH:38][CH:37]=1)[CH:33]=[CH2:34]
Reactant: O=S(=O)(c1cccc(NC2CCNCC2)c1)C(F)(F)F
Reactant: C=CCN(CC=C)Cc1ccc(S(=O)(=O)Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)Cc1ccc(S(=O)(=O)N2CCC(Nc3cccc(S(=O)(=O)C(F)(F)F)c3)CC2)s1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 4-(3-trifluoromethanesulfonyl-phenylamino)-piperidine (731 mg, 237 mmol) and Et3N (0.5 mL, 3.58 mmol) in CH2Cl2 (20 mL) was treated with the diallylamino sulfonyl chloride 269b 23° C. A thick precipitate appeared within 5 min, and the mixture was stirred overnight (even if complete within minutes). Dilution with CH2Cl2 (50 mL), washing (1120; brine), drying (MgSO4), and evaporation afforded the crude product, which was filtered over silica gel (AcOEt:cyclohexane 1:1) to afford 1.15 g (86%) of the title bisallylamine, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11].Cl[C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:13]1[CH:23]=[C:17]2[N:18]([CH3:22])[CH2:19][CH2:20][CH2:21][N:16]2[C:15](=[O:24])[N:14]=1
Reactant: OCCc1cccc(F)c1F
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1cccc(F)c1F)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E11 starting from 2-(2,3-difluorophenyl)ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:12]CC)=O)[CH:8]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[CH2:21]([NH:24][C:10](=[O:12])[CH:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][CH3:23]
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Reactant: CCCN
Product: CCCCCCC(C(=O)NCCC)n1cnc([N+](=O)[O-])c1

Procedure:
Ethyl 2-(4-nitro-1H-imidazole-1-yl)octanoate (17 moles, 5.0 g) was reacted with propylamine as in Example 1 to yield 2.5 g of N-propyl-2-(4-nitro-1H-imidazol-1-yl) octanoamide. (MS).