Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18])=[CH:12][CH:11]=1.[CH3:24][O:25][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]=[C:40]=[O:41])=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][C:40](=[O:41])[NH:39][C:36]2[CH:35]=[CH:34][C:33]([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:42])=[CH:38][CH:37]=2)=[O:18])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)OCCO)cc1
Reactant: COC(=O)CCCCCOc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCOc1ccc(NC(=O)OCCOC(=O)Nc2ccc(OCCCCCC(=O)OC)cc2)cc1
Temperature: 60 °C
Yield: 95 %

Procedure:
To a mixture of 6-[4-(2-Hydroxyethoxycarbonylamino)phenoxy]hexanoic acid methyl ester 37 (5 g, 15.38 mmol) in toluene (50 ml) was added 6-(4-Isocyanatophenoxy)hexanoic acid methyl ester 36 (4 g, 15.2 mmol) at room temperature and heated to 60° C. for 2 hours. Toluene was distilled off and water (50 ml) was added. The solid was filtered and dried to give crude 38, which was purified by column chromatography on silica gel using chloroform as eluant to get pure 38 (8.5 g, 94%) as a white powder. M.p: 118-120.5° C.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19])[CH:13]=[CH:14][CH:15]=1.C([C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)CC>O>[CH:31]1([C:28]2[CH:27]=[CH:26][C:25]([C:18](=[O:19])[CH2:17][C@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)[CH3:21])=[CH:30][CH:29]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COc1cccc([C@H](C)CC(=O)Cl)c1
Reactant: CCC[C@H]1CC[C@H](c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cccc([C@H](C)CC(=O)c2ccc(C3CCCCC3)cc2)c1
Reaction time: 0.25 h

Procedure:
To a methylene chloride suspension of aluminum chloride, a methylene chloride solution of (R)-3-(3-methoxyphenyl)butyric acid chloride was added dropwise under ice cooling. After stirring at the same temperature for 15 minutes, a methylene chloride solution of trans-4-propylcyclohexylbenzene was added dropwise. After the completion of the reaction, the reaction system was added to iced water and the organic layer was separated by adding methylene chloride. The organic layer was washed twice with water and then washed with saturated brine. The aqueous layer was washed with methylene chloride and, after combining the organic layer, the solvent was concentrated to obtain a crude product of (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one. The resulting crude product was purified by column chromatography and recrystallized from ethanol to obtain (R)-1-(4-cyclohexylphenyl)-3-(3-methoxyphenyl)-butan-1-one (R-isomer of the compound represented by the formula (XI-c)).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:18][CH2:17][CH2:16][C@H:15]([N:19]([CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=3)[C:20]3[N:21]=[N:22][N:23]([CH3:25])[N:24]=3)[C:14]3[CH:41]=[C:42]([CH3:49])[C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:13]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[F:35][C:33]([F:34])([F:36])[C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([C:37]([F:40])([F:38])[F:39])[CH:30]=1)[CH2:26][N:19]([C:20]1[N:21]=[N:22][N:23]([CH3:25])[N:24]=1)[C@H:15]1[CH2:16][CH2:17][CH2:18][N:12]([CH:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[C:13]2[CH:44]=[C:43]([C:45]([F:46])([F:47])[F:48])[C:42]([CH3:49])=[CH:41][C:14]1=2
Reactant: CCOC(=O)C1CCC(N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCC(C(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-4-{5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl}-cyclohexanecarboxylic acid ethyl ester (0.14 mmol) in methanol (5 mL), add 5N sodium hydroxide (14 mmol). After heating the mixture at 60° C. for 2 h, cool to room temperature and dilute with water (20 mL). Neutralize the mixture using 5M HCl and extract the organics using ethyl actate (3×5 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the crude product over silica gel, eluting with methanol/dichloromethane (0-5%) to obtain the separated cis and trans isomers. MS (ES+): 679 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:9]=2)[CH:6]=1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:10]3[CH:9]=[C:8]([CH2:7][N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)[O:12][N:11]=3)=[CH:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: Cc1cn(Cc2cc(-c3ccc(O)cc3)no2)cn1
Reactant: Fc1ccc(CBr)cc1
Product: Cc1cn(Cc2cc(-c3ccc(OCc4ccc(F)cc4)cc3)no2)cn1

Procedure:
An experiment was performed in the same manner as in Example 139 to synthesize 4-[5-(4-methyl-imidazol-1-ylmethyl)-isoxazol-3-yl]-phenol as an intermediate, and then a synthesis was performed using 4-fluorobenzyl bromide in the same manner as in Example 142.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH3:25])=[CH:11][C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:24])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1.CO.[OH-].[Na+].Cl>C1COCC1>[CH3:24][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:11]=[C:10]([CH3:25])[C:9]3[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][O:7][C:8]=3[C:13]=2[CH3:14])=[CH:22][CH:21]=[C:20]([CH3:23])[N:19]=1
Reactant: COC(=O)Cc1coc2c(C)c(OCc3ccc(C)nc3C)cc(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(COc2cc(C)c3c(CC(=O)O)coc3c2C)c(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4,7-dimethyl-1-benzofuran-3-yl)acetate (142.0 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (1.21 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was neutralized with 1N HCl. The precipitate was collected by filtration. The solid was crystallized from IPA-EtOAc to give the title compound (100 mg).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.[NH2:25][CH2:26][CH2:27][CH2:28][OH:29]>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([NH:25][CH2:26][CH2:27][CH2:28][OH:29])=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: NCCCO
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(NCCCO)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, and 3-amino-propan-1-ol. 1H NMR (400 MHz, DMSO-d6): δ 8.70 (t, J=5.81 Hz, 1H), 7.59 (d, J=9.12 Hz, 1H), 7.47-7.50 (m, 2H), 7.24 (t, J=5.41 Hz, 1H), 6.82 (d, J=9.21 Hz, 1H), 4.58-4.60 (m, 1H), 3.46-3.51 (m, 2H), 3.39-3.44 (m, 2H), 3.20-3.23 (m, 2H), 2.00-2.03 (m, 2H), 1.82-1.85 (m, 3H), 1.68-1.76 (m, 4H), 1.22-1.31 (m, 2H). m/z: 412.2 [M+H]+
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1.N1C=CC=CC=1.[S:16](Cl)([CH3:19])(=[O:18])=[O:17]>ClCCl>[S:16]([O:1][CH:2]1[CH2:7][CH:6]([CH3:8])[O:5][C:4](=[O:9])[CH2:3]1)([CH3:19])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CC1CC(O)CC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1CC(OS(C)(=O)=O)CC(=O)O1
Reaction time: 0.25 h

Procedure:
To a solution of 4-hydroxy-6-methyltetrahydropyran-2-one (1.5 parts) in dichloromethane (40 parts) was added pyridine (1.1 parts) and then, over 15 minutes, mesyl chloride (1.65 parts). The reaction was set aside at ambient temperature under N2 for 18 hours at which point GLC analysis indicated less than 1.5% of the starting material remained. The reaction mixture was filtered and the organic phase then washed with water before evaporating to obtain 4-mesyloxy-6-methyl-tetrahydropyran-2-one (0.5 parts).
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[C:13]=2[O:20][CH3:21])=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C(O)(=O)C.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[F:1][C:2]1[C:3]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:25][CH3:24])[C:13]=2[O:20][CH3:21])=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6]
Reactant: COc1c(C=O)cccc1Oc1c(C#N)ccc(C)c1F
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2c(C#N)ccc(C)c2F)c1OC
Yield: 57 %

Procedure:
3-Fluoro-2-(3-formyl-2-methoxyphenoxy)-4-methylbenzonitrile (0.10 g, 0.35 mmol), methylamine (33% in ethanol; 0.5 mL, 4.0 mmol) and sodium cyanoborohydride (30 mg, 0.48 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (25 mL) for 67 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (41 mg, 0.35 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 3-fluoro-2-(2-methoxy-3-(methylaminomethyl)phenoxy)-4-methyl-benzonitrile fumarate (83 mg, 57%) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].OCC[N:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH3:19])[C:12]1=[O:20]>N1C=CC=CC=1>[C:5]([O:4][CH2:1][CH2:2][N:11]1[C:16]([CH3:17])=[C:15]([CH3:18])[N:14]=[C:13]([CH3:19])[C:12]1=[O:20])(=[O:7])[CH3:6]
Reactant: Cc1nc(C)c(=O)n(CCO)c1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCn1c(C)c(C)nc(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
Acetic anhydride (2 ml) was added under ice-cooling to compound 026 (0.91 g, 5 mM) dissolved in pyridine (10 ml), and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo and dilute aqueous K2CO3 was added thereto, the resultant mixture being extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (Florisil, 60 g) packed with benzene and eluted with benzene-ethyl acetate (5:1) to obtain compound 061 (0.58 g, yield: 51.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1I>>[Br:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Sc1ccccc1Cl
Reactant: Fc1ccc(I)c(Br)c1
Product: Fc1ccc(Sc2ccccc2Cl)c(Br)c1

Procedure:
Prepared from 2-chloro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [CH2:1]1[CH2:31][O:30][C:3]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:4][O:5][CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17]C4CCCCO4)[C:11]=3[O:10][CH:9]=2)[O:2]1.Cl.O>C1COCC1>[CH2:1]1[CH2:31][O:30][C:3]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([CH2:4][O:5][CH2:6][CH2:7][C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[O:10][CH:9]=2)[O:2]1
Reactant: c1ccc(C2(COCCc3coc4c(OC5CCCCO5)cccc34)OCCO2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Oc1cccc2c(CCOCC3(c4ccccc4)OCCO3)coc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
3-(2-(2,2-ethylenedioxy-2-phenylethoxy)ethyl)-7-tetrahydropyranyloxybenzofuran (239 mg) was dissolved in THF (3 ml). To this solution, 6N hydrochloric acid (1 ml) was added and the resulting solution was stirred at room temperature for 30 minutes. The reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=2/1) using silica gel to obtain the desired compound (189 mg, yield: 98%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH2:8])=[O:6].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][NH:8][C:15]([NH:14][CH2:12][CH3:13])=[O:16])=[O:6]
Reactant: NNC(=O)c1cccc(F)c1
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)NNC(=O)c1cccc(F)c1
Reaction time: 24 h

Procedure:
To a solution of 3-fluorobenzhydrazide (5.0 g, 0.033 mol) in tetrahydrofuran (100 mL) was added ethyl isocyanate (2.6 g, 0.036 mol) at room temperature. After stirring for 24 hr, the resultant precipitate was collected by suction-filtration to give 1-(3-fluorobenzoyl)-4-ethyl semicarbazide in quantitative yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=1[OH:24])[CH2:14]2.CCN(CC)CC>CN(C1C=CN=CC=1)C.ClCCl>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:24][C:18]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH:8]1[CH:9]2[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][CH:7]1[CH2:16]3)[CH2:15]2
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(O)c(C2C3CC4CC(C3)CC2C4)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Oc1ccc(C)cc1C1C2CC3CC(C2)CC1C3
Temperature: 0 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
Ethyl chloroformate (0.64 mL, 6.7 mmol) was added dropwise to a solution of 2-admantyl-4-methylphenol (1.09 g, 4.5 mmol), Et3N (1.25 mL, 9 mmol) and DMAP (catalytic amount) in dichloromethane (8 mL) cooled in an ice-water bath to 0° C. The mixture was allowed to warm to room temperature while stirring overnight, then filtered and the filtrate was concentrated. The residue was purified by column chromatography (10-20% ethyl acetate-hexanes) to yield 2-admantyl-4-methyl-phenyl ethyl carbonate as a yellow oil (1.32 g, 94%).
Reaction SMILES: CS(O[C@H:6]1[C@@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)(=O)=O.CN(C=O)C.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[N:26]([C@H:6]1[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([F:19])[CH:13]=2)[CH2:9][N:8]([CH3:20])[CH2:7]1)=[N+:27]=[N-:28]
Reactant: CN1C[C@H](Oc2ccc(Cl)c(F)c2)[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C[C@@H](N=[N+]=[N-])[C@H](Oc2ccc(Cl)c(F)c2)C1
Temperature: 90 °C
Yield: 89.4 %

Procedure:
To a solution of 424 (400 mg, 1.24 mmol) and DMF (2.0 mL) was added sodium azide (0.806 g, 12.4 mmol). The mixture was heated at 90° C. overnight. The mixture was cooled, diluted with H2O (30 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with water (3×30 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford 300 mg of trans-(±)-3-azido-4-(4-chloro-3-fluorophenoxy)-1-methylpyrrolidine (426) which was used for next step without further purification: LC-MS (ESI) m/z 271 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:10]=[CH:9][CH:8]=[C:6]([OH:7])[CH:5]=1)[OH:4].[I-].[Na+].[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN(C)C=O.O1CCCC1>[CH2:28]([O:4][C:3]1[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][CH:10]=1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: Oc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1cccc(O)c1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
To a suspension of 29.6 g of sodium hydride in 215 ml of N,N-dimethylformamide was added dropwise over 1.5 hours a solution of 54.33 g of resorcinol in 145 ml of N,N-dimethylformamide and 72 ml of tetrahydrofuran. The resulting mixture was cooled to 0° C. and 7.4 g of sodium iodide added followed by the dropwise addition of 155.0 g of hexadecylbromide over 1 hour. The bath was removed and the mixture stirred at ambient temperature for 17 hours. The mixture was diluted with 500 ml of iced dilute hydrochloric acid, extracted with ether and filtered. The ether layer was dried over magnesium sulfate and evaporated to an oil which was purified by chromatography on silica gel using ethyl acetate-hexanes giving 37.2 g of the desired compound as a white solid, m.p. 58°-59° C.
Reaction SMILES: [N:1]1([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[N:1]1([CH2:14][CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=CCCCn1cnc2cnc3ccccc3c21
Solvent: C1CCOC1
Product: OC(CCCn1cnc2cnc3ccccc3c21)c1ccccc1

Procedure:
The general method described in Step 7 of Example 1 was used to react 4-(1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde (7.94 g, 33.2 mmol) with phenylmagnesium bromide (33.2 mL of a 1 M solution in THF, 33.2 mmol) to provide 4-(1H-imidazo[4,5-c]quinolin-1-yl)-1-phenylbutan-1-ol (7.2 g) as an off-white solid that was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:15]([OH:18])([CH3:17])[CH3:16]>CN(C)C=O>[CH:15]([O:18][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)([CH3:17])[CH3:16]
Reactant: CC(C)O
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OC(C)C)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation was repeated, except that 6.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.54 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 2.7 ml of isopropanol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 6.10 g of the title compound, melting at 75°-76° C.
Reaction SMILES: C1(C[O:8][C:9](=[O:45])[CH2:10][O:11][C:12]([O:14][CH2:15][O:16][C:17]2[C:18](=[O:44])[C:19]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[O:33])=[CH:20][N:21]3[C:26]=2[C:25](=[O:27])[N:24]2[C@@H:28]([CH3:31])[CH2:29][O:30][C@@H:23]2[CH2:22]3)=[O:13])C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[F:43][C:37]1[CH:38]=[C:39]([F:42])[CH:40]=[CH:41][C:36]=1[CH2:35][NH:34][C:32]([C:19]1[C:18](=[O:44])[C:17]([O:16][CH2:15][O:14][C:12]([O:11][CH2:10][C:9]([OH:45])=[O:8])=[O:13])=[C:26]2[C:25](=[O:27])[N:24]3[C@@H:28]([CH3:31])[CH2:29][O:30][C@@H:23]3[CH2:22][N:21]2[CH:20]=1)=[O:33]
Reactant: [H][H]
Reactant: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)OCc4ccccc4)c3C(=O)N12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1CO[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4F)c(=O)c(OCOC(=O)OCC(=O)O)c3C(=O)N12

Procedure:
Phenylmethyl({[({[(3S,11aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazin-6-yl]oxy}methyl)oxy]carbonyl}oxy)acetate (prepared as described in example 17) (247 mg, 0.394 mmol) 10 w.t. % palladium on carbon (190 mg) were stirred in an ethyl acetate/methanol mixture under 1 atm hydrogen atmosphere for 30 minutes. The reaction was filtered through celite and concentrated under reduced pressure to yield a white solid. 1H NMR (CDCl3) δ 10.28 (m, 1H), 8.32 (s, 1H), 7.28 (m, 1H), 6.76 (m, 2H), 5.92 (d, J=6.4 Hz, 1H), 5.86 (d, J=6.4 Hz, 1H), 5.28 (dd, J=10, 3.2 Hz, 1H), 4.55 (br s, 4H), 4.37-4.28 (m, 3H), 3.91 (m, 1H), 3.63 (m, 1H), 3.35 (m, 1H), 1.34 (d, J=6 Hz, 3H). ES+ MS: 538 (M+1).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([NH:15][CH2:16][CH2:17][CH2:18][OH:19])[C:5]2=[N:4][CH:3]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=3.[Cu](C#N)[C:26]#[N:27]>CN1CCCC1=O>[OH:19][CH2:18][CH2:17][CH2:16][NH:15][C:14]1[C:5]2[N:6]([C:2]([C:26]#[N:27])=[CH:3][N:4]=2)[C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:9][CH:8]=2
Reactant: OCCCNc1nc2cc(OC(F)(F)F)ccc2n2c(Br)cnc12
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Product: N#Cc1cnc2c(NCCCO)nc3cc(OC(F)(F)F)ccc3n12
Temperature: 160 °C

Procedure:
To a stirred solution of 3-(1-Bromo-7-trifluoromethoxy-imidazo[1,2-a]quinoxalin-4-ylamino)-propan-1-ol (1.00 g; 2.47 mmol; 1 eq) prepared as in example 51 step 2 in degassed N-methylpyrrolidone (10 mL) are successively added under argon tetrakis-triphenylphosphine palladium (570 mg; 0.49 mmol; 0.2 eq) and copper cyanide (885 mg; 9.90 mmol; 4 eq). The resulting solution is then heated at 160° C. for 3 hours until reaction is complete on TLC. The mixture is then quenched with an aqueous solution saturated with sodium hydrogenocarbonate (50 mL) and the resulting basic solution (pH>8) is extracted with ethyl acetate (100 mL). The organic layer is separated, washed with an aqueous solution saturated with sodium hydrogenocarbonate (50 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford a brown oil. Chromatography of this crude oil on silica gel (gradient of ethyl acetate/cyclohexane from 1:9 to 5:5) afforded the title compound contaminated by 21% of residual triphenylphosphine oxide. Therefore, the mixture was further purified by a second column chromatography (chloroform/ethyl acetate 7:3) yielding the pure title compound (424 mg; 1.21 mmol; 49%).
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13](Cl)[N:14]=[CH:15][C:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]2[C:10]([CH3:25])=[CH:9]1)=O)(C)(C)C.[F:26][C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([F:34])[CH:33]=1)[NH2:30]>C(OCC)C>[C:19]([NH:18][C:17]([C:16]1[C:11]2[C:10]([CH3:25])=[CH:9][NH:8][C:12]=2[C:13]([NH:30][C:29]2[CH:28]=[C:27]([F:26])[CH:33]=[C:32]([F:34])[CH:31]=2)=[N:14][CH:15]=1)=[O:23])([CH3:20])([CH3:21])[CH3:22]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)NC(C)(C)C)c12
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCOCC
Product: Cc1c[nH]c2c(Nc3cc(F)cc(F)c3)ncc(C(=O)NC(C)(C)C)c12

Procedure:
Prepared in a similar manner to Example 4(d) from 4-tert-butylcarbamoyl-7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1-carboxylic acid ter-butyl ester (68 mg) and using 3,5-difluoroaniline (38 ul) instead of 3-bromoaniline. Isolated by MDAP rather than trituration with diethyl ether to give the title compound (28 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=S)=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[NH3:26]>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][O:7][C:8]2[C:9]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[NH:26])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1
Reactant: N
Product: N=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1
Reaction time: 48 h

Procedure:
A mixture of N-[3-(4-chlorobenzyloxy)pyrid-2-yl]-N'-phenylthiourea (3.00 g, 0.008 mol), yellow mercuric oxide (2.17g, 0.01 mol) and methanolic ammonia solution (40 ml) was stirred for 48 hours. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent and recrystallisation from acetonitrile gave the desired product. Yield 1.8 g (63%), m.p. 173°-174 ° C.