Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17]C1C=C(CC(O)=O)C=CC=1>>[F:17][C:3]1[CH:2]=[C:1]([CH:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([OH:16])[CH:13]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1cccc(F)c1
Reactant: Oc1ccc2c(c1)CC(c1ccccc1)C2
Product: Oc1ccc2c(c1)CC(c1cccc(F)c1)C2

Procedure:
2-(3-Fluorophenyl)indan-5-ol was prepared as described for 2-phenylindan-5-ol in Example 25(a-e) using 5 g of 3-fluorophenylacetic acid. 1H-NMR (400 MHz, d6-DMSO): 9.09 (s, 1H), 7.37-7.29 (m, 1H), 7.14-7.7.09 (m, 2H), 7.02-6.98 (m, 2H), 6.64 (d, 1H, J 1.7 Hz), 6.55 (dd, 1H, J 2.3, 8.1 Hz), 3.63 (k, 1H, J 8.3 Hz), 3.24-3.12 (m, 2H), 2.94-2.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([OH:19])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:6]=1)=[O:4].N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[C@@H:14]2[CH2:18][C@H:17]([O:19][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:16]=[CH:15]2)=[C:7]([NH:20][CH2:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:6]=1)=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@H]3C=C[C@@H](O)C3)c2n1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OC)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6-(2,2-Diphenyl-ethylamino)-9-((1R,4S)-4-hydroxy-cyclopent-2-enyl)-9H-purine-2-carboxylic acid methyl ester (2.80 g, 6.14 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry tetrahydrofuran (30 ml) is added followed by dry pyridine (0.97 g, 12.3 mmol). Ethyl chloroformate (2.66 g, 24.6 mmol) is added slowly and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the residue is partitioned between dichloromethane (200 ml) and 1M HCl (2×200 ml). The organic layer is washed with water (2×100 ml) and brine (2×100 ml), dried over MgSO4, filtered and the solvent is removed in vacuo. The title compound is obtained after purification by flash column chromatography (silica, 4% MeOH in dichloromethane). MS (ES+) m/e 528.3 (MH+).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[H-].[Na+].[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH2:23][CH2:22][CH2:21][N:13]3[C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1)[CH3:27]
Reactant: Oc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCI
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 1.2 g (2.7 mmoles) of 2-(4-hydroxyphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo-[1,2-a]imidazole dihydrobromide of Example 10 in 25 ml of dry dimethylformamide cooled in an ice bath was treated with 360 mg (9.0 mmoles) of 60% sodium hydride dispersion and allowed to warm to room temperature. A solution of 420 mg (2.7 mmoles) of ethyl iodide in 2 ml of dimethylformamide was added dropwise, and after 2 hours an additional 105 mg (0.67 mmole) of ethyl iodide was added followed by another 90 mg (2.25 mmoles) of 60% sodium hydride suspension. After stirring overnight, the mixture was poured into 10 volumes of ice water and extracted three times with ethyl acetate. The organic phase was washed with water, dried over anhydrous potassium carbonate and concentrated in vacuo. The residue was flash chromatographed on silica and the fractions eluting with 4 to 6% methanol in chloroform were combined, concentrated in vacuo, and recrystallized from ethyl acetate to afford the titled compound, mp 133°-135° C. Anal. Calcd. for C19H19N3O: C, 74.73, H, 6.27; N, 13.76. Found: C, 74.23; H, 6.01; N, 13.74.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[CH3:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: Cc1ccc(C(=O)CCCCl)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(C(CCCCl)=NNC(N)=S)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-methylbutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration and dissolved in methylene chloride. The organic solution was washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.15 g of an off-white solid. Recrystallization of the solid from isopropyl alcohol gave 8.65 g (64%) of the tide compound as an off-white solid, mp133-135° C.
Reaction SMILES: [SH:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[SH:3].[Na].[Na].O.C[N:13]([CH:15]=[O:16])C>>[O:16]=[C:15]1[NH:13][N:6]=[CH:5][C:4]2[S:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[S:3][C:2]1=2
Reactant: CN(C)C=O
Reactant: N#CC(C#N)=C(S)S
Agent: [Na]
Solvent: O
Product: N#CC(C#N)=C1Sc2cn[nH]c(=O)c2S1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a stirred solution of 20 g (0.1 mole) disodiumdimercaptomethylene malononitrile dissolved in 250 ml of DMF was added 16.5 g (0.1 mole) of 4,5-dichloro-3-pyridiazone. The reaction mixture was stirred at room temperature (approximately 20° C.) for 0.25 hours and was thereafter poured with stirring into 1 liter of water. The resulting mixture was allowed to stand for four hours during which time a yellow-gray precipitate slowly formed. This precipitate was separated by filtration, washed with water, and dried in vacuo to yield 21.1 g (90% yield from the pyridiazone) of a yellow-gray solid, m.p. (decomposition) 310°-340° C.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH:10]1[C:15]([C:16]2[C:25](=[O:26])[C:24]3[CH:23]=[CH:22][C:21]([OH:27])=[CH:20][C:19]=3[O:18][CH:17]=2)=[CH:14][CH:13]=[C:12]([OH:28])[CH:11]=1.O>C(O)C>[OH:27][C:21]1[CH:20]=[C:19]2[C:24]([C:25](=[O:26])[C:16]([C:15]3[CH:10]=[CH:11][C:12]([OH:28])=[C:13]([N+:6]([O-:9])=[O:7])[CH:14]=3)=[CH:17][O:18]2)=[CH:23][CH:22]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: O=c1c(-c2ccc(O)c([N+](=O)[O-])c2)coc2cc(O)ccc12

Procedure:
20 ml of a mixture of concentrated sulfuric acid and nitric acid (3:1) are added dropwise to a solution of 1 g of daidzein in 200 ml of dry ethanol at room temperature while stirring vigorously. The mixture is stirred for another 2 hours, and 400 ml of water are then added. The compound precipitates, is filtered off with suction and washed with water until neutral. The yellow product is recrystallized from alcohol.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16].C(OC(=O)C=CC1C=C(C)C=CC=1O)C.CC(CCC1C=CC=CC=1)CCO>>[CH3:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][CH2:4][O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: Cc1ccc(O)c(C=CC(=O)OCCC(C)CCc2ccccc2)c1
Agent: CC(CCO)CCc1ccccc1
Agent: CCOC(=O)C=Cc1cc(C)ccc1O
Product: Cc1ccc(O)c(/C=C/C(=O)OCCC(C)CCc2ccccc2)c1

Procedure:
According to the same procedure, 3-(2-hydroxy-5-methyl-phenyl)-acrylic acid 3-methyl-5-phenyl-pentyl ester was prepared from 3-(2-hydroxy-5-methyl-phenyl)-acrylic acid ethyl ester, 3-methyl-5-phenyl-pentanol and tetraisopropyl-o-titanate.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:15][CH3:16])[CH2:11][C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.C(OC(C)C)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].CC(C)([O-])C.[Li+]>C1COCC1>[CH2:30]([O:29][C:27](=[O:28])[NH:14][C:12](=[O:13])[CH2:11][C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:4][CH:5]=1)[CH2:15][CH3:16])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC[C@H](CC(N)=O)Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Product: CC[C@H](CC(=O)NC(=O)OCc1ccccc1)Nc1ccc(C(F)(F)F)cc1
Temperature: -12 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
A clean, dry and nitrogen gas purged flask was charged with (3R)-3-(4-trifluoromethyl-phenylamino)-pentanoic acid amide (20.11 g, 77.27 mmol) and isopropyl ether (100 mL) and the mixture was cooled to −12° C. Benzyl chloroformate (13.25 mL, 92.8 mmol) was then added followed by the slow addition of 1.0 M lithium tert-butoxide in THF solution (185.5 mL). The lithium tert-butoxide solution was added at such a rate that the internal temperature remained below 0° C. Fifteen minutes after the completion of base addition, the reaction was quenched by adding the mixture to isopropyl ether (100 mL) and 1.5 M hydrochloric acid (130 mL). The phases were separated and the organic layer was washed with saturated aqueous sodium chloride solution (130 mL). The phases were separated, the organic layer was dried (MgSO4), filtered, and concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. Additional isopropylether (200 mL) was added and the solution was again concentrated under partial vacuum (at 40° C.) to a total volume of 100 mL. After cooling, the solution was seeded with (3R)-[3-(4-trifluoromethyl-phenylamino)-pentanoyl]-carbamic acid benzyl ester and allowed to stir at room temperature overnight. The remaining solvent was displaced with cyclohexane using partial vacuum distillation (45° C. bath, 200 mL followed by 100 mL), the resultant slurry was cooled and stirred for 40 minutes, filtered, and dried to provide 25.8714 g (85%) of the title compound.
Reaction SMILES: [I-].[C:2]1([CH:8]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:9][C:10]([C:12]2[N:17]3[C:18](=[O:29])[C@@H:19]([NH:20][C:21](=[O:28])[CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[C@H:16]3[S:15][CH2:14][C:13]=2[CH2:30][P+:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].C[C:60](C)=[O:61]>>[S:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][C:21]([NH:20][C@:19]1([O:61][CH3:60])[C:18](=[O:29])[N:17]2[C:12]([C:10]([O:9][CH:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:11])=[C:13]([CH:30]=[P:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:14][S:15][C@H:16]12)=[O:28]
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Reactant: CC(C)=O
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CO[C@@]1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@@H]21

Procedure:
To a solution of [4-diphenylmethoxycarbonyl-7β-thiopheneacetamido-ceph-3-em-3-ylmethyl]triphenylphosphonium iodide (0.1 g) in acetone:water (12 ml:2 ml) is added in an ice-bath and the pH adjusted to pH 11 with 2 N sodium hydroxide. The reaction mixture is diluted with an equal volume of solvent and filtered. The precipitate is washed with acetone and ether and dried to give benzhydryl 7β-thiopheneacetamido-7-methoxy-3-(triphenylphosphoranylidenemethyl)-ceph-3-em-4-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[OH-].[Na+].[CH2:23]([OH:26])[CH2:24][CH3:25]>>[CH2:23]([O:26][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH2:24][CH3:25]
Reactant: CCCO
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1

Procedure:
2-Chloro-adenosine (3.5 g) was added to a hot solution of NaOH (3.2 g) in n-propanol (80 ml), the mixture was heated under reflux for 3 hours. The volatiles were removed in vacuo, the residue taken into water (40 ml), cooled and acidified with 1M hydrochloric acid to pH 7. After 15 min the suspension was filtered and the filtrate evaporated. The residue was taken up in ethanol, and adsorbed onto silica which was placed on a chromatography column. Elution with 9:1, and then 4:1 CHCl3 afforded the sub-title compound (0.65 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH:38][C:39]([CH3:43])([CH3:42])[CH2:40][OH:41])(=[O:37])=[O:36])[CH:31]=[CH:32][C:33]=1[Cl:34]>>[Cl:34][C:33]1[CH:32]=[CH:31][C:30]([S:35](=[O:37])(=[O:36])[NH:38][C:39]([CH3:42])([CH3:43])[CH2:40][OH:41])=[CH:29][C:28]=1[NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(N)c1
Product: CC(C)(CO)NS(=O)(=O)c1ccc(Cl)c(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-4-chloro-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.10) according to general procedure II. Yellow solid. MS (ISP) 634.0 [(M−H−]; mp 246° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]=[CH:11][CH:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C>>[CH:11]([CH:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH2:10]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CC(O)CCCCCC
Product: C=CC(CCCCC)Oc1ccc(C=O)cc1

Procedure:
By the method of example 13, 4-hydroxybenzaldehyde and 1-nonen-3-ol are coupled under Mitsunobu conditions, producing 4-((1-ethenylhexyl)oxy)benzaldehyde. By the methods described in example 1, this benzaldehyde is chain-extended and condensed with glyoxylic acid to provide the title compound as a colorless oil after chromatography, which solidifies on standing giving a colorless solid, mp 46°-50°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][C@@H:13]1[CH2:18][NH:17][CH2:16][C@H:15]([CH3:19])[NH:14]1.C[C@H]1CN(CC2C=CC([N+]([O-])=O)=CC=2)CCN1C(OC(C)(C)C)=O>>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:17]2[CH2:16][C@H:15]([CH3:19])[NH:14][C@H:13]([CH3:12])[CH2:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1

Procedure:
The title compound was prepared from 4-nitrobenzaldehyde and (2R,6S)-2,6-dimethylpiperazine using a method similar to that described for D1 in Description 1A. MS (ES): MH+ 250.2
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[CH:21]1[NH:26][C:25]2=[C:27]([CH2:37][CH3:38])[N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:29]=[C:24]2[C:23](=[O:39])[NH:22]1)[CH3:2].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([O:3][C:4]1[N:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH3:20])[CH2:15][CH2:14]2)(=[O:11])=[O:12])=[CH:6][C:5]=1[C:21]1[NH:22][C:23](=[O:39])[C:24]2[C:25](=[C:27]([CH2:37][CH3:38])[N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[N:29]=2)[N:26]=1)[CH3:2]
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C1NC(=O)c2nn(Cc3ccccn3)c(CC)c2N1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 200 °C
Yield: 84.4 %

Procedure:
To a solution of 4-{6-ethoxy-5-[3-ethyl-4,5,6,7-tetrahydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-pyridinylsulfonyl}-1-ethylpiperazine (50 mg, 0.09 mmol, from step (b) above) in toluene (1 mL), was added 10% Pd/C (25 mg, 50% w/w) and trifluoroacetic acid (14 μL). The mixture was heated to 200° C. under nitrogen at 34.5 kPa (5 psi) for 6 hours. The resulting mixture was filtered and concentrated in vacuo to a pale yellow oil. This was dissolved in DCM (5 mL) and washed with NaHCO3 (2 mL), dried over MgSO4 and concentrated to give a brown oil (42 mg, 84%) as product.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:34]([O:36]C)=[O:35])[CH2:21][C:22]3[CH:32]=[C:31]([CH3:33])[C:25]4[NH:26][C:27]([O:29][CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:34]([OH:36])=[O:35])[CH2:21][C:22]3[CH:32]=[C:31]([CH3:33])[C:25]4[NH:26][C:27]([O:29][CH3:30])=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:38]=[CH:39][CH:40]=[CH:41][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]c(OC)nc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc2cc(C[C@@H](OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)C(=O)O)cc(C)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 100 mg (4.18 mmol) LiOH in 6 mL water was added to a solution of 980 mg (1.83 mmol) (R)-1-methoxycarbonyl-2-(2-methoxy-7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 18 mL THF and the reaction mixture was stirred overnight at RT. 1.05 mL of 4 M HCl was added, the THF was evaporated down i.vac., whereby the crude product was produced in the form of an oil. The water was decanted off, the residue was dissolved in DCM/MeOH and dried over Na2SO4. After the desiccant and solvent had been eliminated the residue was further reacted without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:14])[CH2:12][O:11][NH:10][C:9]1=[O:13].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23]Cl>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[CH2:23][N:10]1[C:9](=[O:13])[C:8]([CH3:14])([CH3:7])[CH2:12][O:11]1
Reactant: CC1(C)CONC1=O
Reactant: Fc1cccc(Cl)c1CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)CON(Cc2c(F)cccc2Cl)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.6 %

Procedure:
To a stirred suspension of 3.6 grams (0.026 mole) of potassium carbonate and 0.14 gram (0.0005 mole) of 1,4,7,10,13,16-hexaoxacyclooctadecane in 50 ml of acetonitrile was added dropwise a solution of 3.0 grams (0.026 mole) of 4,4-dimethyl-3-isoxazolidinone (Example 30, Step B) and 4.7 grams (0.025 mole) of (2-chloro-6-fluorophenyl)methyl chloride in 25 ml of acetonitrile. The complete addition required 30 minutes. Upon completion of addition the reaction mixture was stirred at ambient temperature for 18 hours, and then filtered. The filtrate was diluted with 200 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. The oil solidified and was recrystallized from petroleum ether to give 3.0 grams of 2-[(2-chloro-6-fluorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone; mp 49°-51°.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.C(O)(=O)C>C(O)(C)C>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(ON)C1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.2 %

Procedure:
To a mixture of phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) (90 mg, 0.40 mmol) and tert-butyl 3-(aminooxy)pyrrolidine-1-carboxylate (Reference Example 9) (82 mg, 0.40 mmol) in isopropanol (6 mL) was added 4 Å molecular sieves. The pH of the solution was adjusted to pH 4-5 with glacial acetic acid. The reaction mixture was heated to reflux. After 3 days, the reaction mixture was cooled to ambient temperature. The mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. Purification by column chromatography (silica gel, 9.75:0.25 CH2Cl2/MeOH to 9.5:0.5 CH2Cl2/MeOH) followed by ion-exchange chromatography (SCX-2, 1:3 7 N NH4OH in MeOH/MeOH) gave tert-butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]pyrrolidine-1-carboxylate (52.3 mg, 32%) as a mixture of isomers: mp 80-82° C.; 1H NMR (500 MHz, DMSO-d6) major isomer δ 1.37-1.39 (9H, m), 2.08-2.10 (2H, m), 3.13-3.17 (1H, m), 3.31-3.50 (3H, m), 4.92 (1H, br s), 6.23 (1H, s), 7.41-7.53 (6H, m), 8.08 (1H, d, J=5.4 Hz), 8.79 (1H, s), 11.85 (1H, s); ESI MS m/z 407 [C23H26N4O3+H]+; HPLC (Method A) 85.8% (AUC), tR=18.0 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Mg].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:6]([C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:27][CH:28]=2)[OH:7])[C:8]([O:15][CH3:16])=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12]
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1c(C)c(C(O)c2ccc(OCc3ccccc3)cc2)c(OC)c(OC)c1OC
Reaction time: 2 h
Yield: 93.3 %

Procedure:
An anhydrous tetrahydrofuran (20 ml) solution of 3,4,5,6-tetramethoxy-2-methylbenzaldehyde (3.65 g, 0.015 mol) was added dropwise under ice cooling to a Grignard reagent (30 ml tetrahydrofuran solution) prepared from 4-(benzyloxy)bromobenzene (8.00 g, 0.030 mol) and magnesium (0.81 g, 0.033 mol), and the resulting solution was stirred for 2 hours. The reaction solution was poured in an aqueous solution of saturated ammonium chloride and extracted with ether. The extract was washed with saturated brine and then dried. The reaction solution was filtered, the filtrate was concentrated and the obtained crude product was purified by silica gel column chromatography (hexand:ethyl acetate=4:1) to obtain the titled compound (5.93 g, 0.014 mol, 92%).