Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2CCC(=O)CCC=2C=CC=1.[Br-].C(CCCC[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#N.[H-].[Na+].[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]1[CH2:53][CH2:52][C:51]2[CH:54]=[CH:55][CH:56]=[CH:57][C:50]=2[CH2:49][CH2:48]1.N.[Li]>C(COC)OC.CCOCC.C(O)C>[NH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH:47]1[CH2:53][CH2:52][C:51]2[CH2:54][CH:55]=[CH:56][CH2:57][C:50]=2[CH2:49][CH2:48]1
Reactant: NCCCCCC1CCc2ccccc2CC1
Agent: N
Agent: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCc2ccccc2CC1
Solvent: CCOCC
Solvent: COCCOC
Solvent: CCO
Product: NCCCCCC1CCC2=C(CC=CC2)CC1

Procedure:
A mixture of 16.0 g. (0.1 mole) of 5,6,8,9-tetrahydro-7H-cycloheptabenzen-7-one and 42.4 g. (0.1 mole) of cyanobutyltriphenylphosphonium bromide in 500 ml of dimethoxyethane is stirred under nitrogen and treated portion-wise with 0.11 mole of 50% NaH dispersed in mineral oil. After several hours, the mixture is free of solvent and the product extracted into ether. The crude product is dissolved in ethanol, treated with NH3 and 10 g. of Raney nickel and hydrogenated at 1500 psi of hydrogen at 100°-120°. After uptake is complete, the mixture is cooled, freed of catalyst and the product isolated from solvent. The crude 7-aminopentyl-6,7,8,9-tetrahydro-5H-benzocycloheptene is taken up in 100ml of ether and added to 500 ml of liq. NH3. The solution is treated with 20 g of lithium in small pieces over 1 hour. Then absolute ethanol is added slowly dropwise to discharge the color. After removal of NH3, the mixture is cooled, treated with water, and extracted with ether. Removal of solvents leaves crude 7-aminopentyl-1,4,6,7,8,9-hexahydro-5H-benzocycloheptene which is converted to its N-benzoyl derivative and thence to the tetrol as described previously.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:32][C:33]1[C:37](B(O)O)=[C:36]([CH3:41])[O:35][N:34]=1.FC(F)(F)C1C=C([C@H]2OC(=O)N(CC3C(C4C(OC)=NC=C(C(C)C)C=4)=CN=C(S(C)(=O)=O)N=3)[C@H]2C)C=C(C(F)(F)F)C=1>>[F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:37]4[C:33]([CH3:32])=[N:34][O:35][C:36]=4[CH3:41])=[CH:24][N:23]=[C:22]([S:27][CH3:28])[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CSc1ncc(Br)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: COc1ncc(C(C)C)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Product: CSc1ncc(-c2c(C)noc2C)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfanyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 8, 500 mg, 0.943 mmole) and 3,5-dimethylisoxazole-4-boronic acid, pinacol ester (231 mg, 1.037 mmol) were treated in a similar fashion to INTERMEDIATE 17 Step A or EXAMPLE 64 Step A to give the title compound after filtration of the reaction mixture, evaporation and silica gel purification of the crude isolate. LCMS (M+H)+: 547.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)c(F)c1)C2
Yield: 97.3 %

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (20.2 g, 44.8 mmol) was suspended in ethanol (450 ml) and treated with 2N sodium hydroxide (150 ml). The mixture was heated under reflux for 1 hour then cooled, and concentrated in vacuo to ˜200 ml, then acidified with 2N hydrochloric acid. The white solid was collected by filtration, washed with water (500 ml) and dried in a vacuum oven to yield the title compound as a cream solid (18.45 g, 43.6 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[I:22]N1C(=O)CCC1=O>CC(C)=O>[I:22][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=2)[NH:19][CH:20]=1
Reactant: COc1cc(-c2cnc3[nH]ccc3c2)cc(OC)c1OC
Reactant: O=C1CCC(=O)N1I
Solvent: CC(C)=O
Product: COc1cc(-c2cnc3[nH]cc(I)c3c2)cc(OC)c1OC
Yield: 118.5 %

Procedure:
To a solution of 5-(3,4,5-trimethoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (510 mg, 1.79 mmol) in acetone (100 ml) was added N-iodosuccinimide (444 mg, 1.97 mmol) under stirring. After 1 hr the mixture was evaporated and purified by silica gel chromatography using 0-2% MeOH:DCM to give the title compound (870 mg, 118%). MS ESI (m/z): 411.1 (M+1)+, calc. 410.
Reaction SMILES: ClCCCO[C:6]1[C:15]([C:16]#[N:17])=[C:14]([NH:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:28][CH3:29])[CH:12]=2)[N:7]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[NH:25]1[C:26]2[C:22](=[CH:21][CH:20]=[C:19]([NH:18][C:14]3[C:13]4[C:8](=[CH:9][C:10]([O:28][CH2:11][CH2:10][CH2:9][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[C:11]([O:28][CH3:29])[CH:12]=4)[N:7]=[CH:6][C:15]=3[C:16]#[N:17])[CH:27]=2)[CH:23]=[N:24]1
Reactant: COc1ccc2nc(OCCCCl)c(C#N)c(Nc3ccc4cn[nH]c4c3)c2c1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCN1CCOCC1
Yield: 56 %

Procedure:
The title compound was prepared by the procedure of Example 167 using 0.408 g of (3-chloropropoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 1.4 ml of morpholine, 0.060 g of sodium iodide and 12 ml of ethylene glycol dimethyl ether to give 0.255 g (56%) of the desired product. MP 143-145° C.; HRMS: C25H26N6O3: m/z 458.2084; δ(mu)−1.7
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].[NH3:14]>CO.O>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: COC(=O)c1ccccc1N(C)C
Reactant: N
Solvent: O
Solvent: CO
Product: CN(C)c1ccccc1C(N)=O
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of methyl 2-dimethylamino-benzoate (1.79 g, 10 mmol) in 2 M ammonia in methanol (20 mL) was heated at 80° C. in a sealed reaction vessel for 3 d. Upon cooling to room temperature, it was diluted with water. The product was extracted with diethyl ether. The ethereal extracts were washed with brine and dried over anhydrous magnesium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 20% ethyl acetate in hexanes yielded 2-dimethylamino-benzamide (85 m g, 5%).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][N:37]([S:72]([C:75]1[S:76][CH:77]=[CH:78][CH:79]=1)(=[O:74])=[O:73])[C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:46]=1[NH:45][C:44]([C:47]([NH:49][CH2:50][CH2:51][S:52]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)=[CH:43]2>ClCCl>[S:52]1[CH2:51][CH2:50][N:49]=[C:47]1[C:44]1[NH:45][C:46]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][C:38]=2[N:37]([CH3:36])[S:72]([C:75]1[S:76][CH:77]=[CH:78][CH:79]=1)(=[O:73])=[O:74]
Reactant: CN(c1cccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN(c1cccc2cc(C3=NCCS3)[nH]c12)S(=O)(=O)c1cccs1
Reaction time: 0.17 h
Yield: 78.2 %

Procedure:
To a solution of triphenylphosphine oxide (1.42 g) in dichloromethane (20 mL) was slowly added trifluoromethanesulfonic anhydride (0.43 mL) at 0° C. The mixture was stirred for 10 min, and 7-[methyl(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.54 g) was added. The reaction mixture was stirred at room temperature for 3 hr and concentrated. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (0.25 g, yield 78%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 192-193° C.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[OH:3][CH:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1nccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1nccc2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
1-Acetyl-isoquinoline (2.0 g, 11.7 mmole) is dissolved in 50 ml methanol in a 100 ml one neck round bottom flask at 0° C. The solution is treated portionwise with sodium borohydride (495 mg, 13.1 mmole) and the reaction mixture is stirred for 1 h at 0° C. The volatiles are removed in vacuo and the residue is partitioned between 1×50 ml 1N sodium hydroxide and 4×25 ml dichloromethane. The combined organics are dried over potassium carbonate and are concentrated in vacuo to a pale oil. The crude material is chromatographed over 100 g silica gel (230-400 mesh), eluting with 15% acetone/hexane, while collecting 22 ml fractions. Fractions 23-37 are combined and concentrated to afford 1.99 g (98%) of 1-(1-hydroxyethyl)-isoquinoline.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:14])=[N:8][NH:9]2.O.NN>C(O)C.[Pd]>[F:1][C:2]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([CH3:14])=[N:8][NH:9]2
Reactant: Cc1n[nH]c2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2cccc(Oc3ccc(N)cc3F)c12
Temperature: 80 °C

Procedure:
75 mg (0.26 mmol) of 4-(2-fluoro-4-nitrophenoxy)-3-methyl-1H-indazole (from example II) are dissolved in 3 ml of ethanol, and 261 mg (5.22 mmol) of hydrazine hydrate and 10 mg of 10% palladium on activated carbon are added. The mixture is heated at 80° C. for two hours and then filtered through kieselguhr. The filtrate is concentrated under reduced pressure.
Reaction SMILES: C([O:8][C:9]([CH2:11][N:12]1[CH:17]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[C:16]([C:27]([O:29][CH3:30])=[O:28])=[C:15]([CH3:31])[N:14]=[C:13]1[CH3:32])=[O:10])C1C=CC=CC=1>CO.O.[Pd]>[CH3:30][O:29][C:27]([C:16]1[CH:17]([C:18]2[CH:19]=[C:20]([F:26])[C:21]([F:25])=[C:22]([F:24])[CH:23]=2)[N:12]([CH2:11][C:9]([OH:10])=[O:8])[C:13]([CH3:32])=[N:14][C:15]=1[CH3:31])=[O:28]
Reactant: COC(=O)C1=C(C)N=C(C)N(CC(=O)OCc2ccccc2)C1c1cc(F)c(F)c(F)c1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(C)N=C(C)N(CC(=O)O)C1c1cc(F)c(F)c(F)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
To a suspension of 10% Pd-C (30 mg) in MeOH (10 mL) and H2O (2 mL) was added a solution of 1,6-dihydro-1-{bezyloxycarbonylmethyl)-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (300 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to leave the product 1,6-dihydro-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine-1-acetic acid as a white solid (0.225 g). It was used in the next step without further purification.
Reaction SMILES: [S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][NH:11][CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[S:40]1[CH:44]=[CH:43][N:42]=[C:41]1[CH:45]=O.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[S:1]([C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][N:11]([CH2:12][C:13]2[N:14]([CH2:18][C:19]([N:21]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])[CH:15]=[CH:16][N:17]=2)[CH2:45][C:41]2[S:40][CH:44]=[CH:43][N:42]=2)=[CH:7][CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: O=Cc1nccs1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CNCCc1ccc(S(N)(=O)=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)C(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
To a solution of di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate (244 mg, 0.43 mmol), thiazole-2-carbaldehyde (68 mg, 0.61 mmol), AcOH (0.05 mL) in DCE (10 mL) at 0° C. was treated with NaBH(OAc)3 (212 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 2 hrs and decomposed with water. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by biotage over silica gel to afford di-tert-butyl 2,2′-((2-(2-(((4-sulfamoylphenethyl)(thiazol-2-ylmethyl)amino)methyl)-1H-imidazol-1-yl)acetyl)azanediyl)diacetate as a colorless oil (200 mg, 70%). MS (ESI), 663.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:14].C1COCC1>[Pd].CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:14]
Reactant: Cc1cc2cc([N+](=O)[O-])ccc2n1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(N)ccc2n1C
Reaction time: 1 h

Procedure:
A solution of 1,2-dimethyl-5-nitro-1H-indole (500 mg) in 1:1 THF:methanol (10 mL) was treated with 10% palladium on carbon (100 mg), stirred under hydrogen (1 atm) for 1 hour, filtered through diatomaceous earth (Celite®), and concentrated. The crude product was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:23]([N:25]([CH2:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35]([O:39][CH3:40])=[C:34]([NH2:41])[CH:33]=2)[CH2:26][CH3:27])[CH3:24].C(N(CC)CC)C>O1CCCC1.CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:41][C:34]3[CH:33]=[C:32]4[C:37]([CH:38]=[C:29]([CH2:28][N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH:30]=[N:31]4)=[CH:36][C:35]=3[O:39][CH3:40])=[O:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)Cc1cnc2cc(N)c(OC)cc2c1
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1cnc2cc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 13.5 %

Procedure:
4′-Chloro[1,1′-biphenyl]-4-carboxylic acid (100 mg, 0.430 mmol) was dissolved in tetrahydrofuran (5 ml). To the reaction solution were added oxalyl chloride (0.0375 ml, 0.430 mmol) and one drop of DMF, and the mixture was stirred at room temperature for 1.5 hrs. The reaction solution was concentrated under reduced pressure and the obtained pale-brown crystals were dissolved in DMF (1 ml). Thereto were added a solution of 3-[(diethylamino)methyl]-6-methoxy-7-quinolinylamine (111 mg, 0.430 mmol) obtained in Reference Example 13 in DMF (1 ml) and triethylamine (0.0719 ml, 0.516 mmol), and the mixture was stirred at room temperature for 4 hrs. Ethyl acetate (20 ml) was added to the reaction solution, and the mixture was washed with a mixed solution of aqueous potassium carbonate solution (10 ml) and saturated brine (5 ml), and then with a mixed solution of saturated brine (10 ml) and water (10 ml). The organic layer was purified by NH-silica gel column, and the precipitated crystals were washed with ethyl acetate:isopropyl ether=2:1. The crystals were collected by filtration and dried to give the title compound (27.5 mg) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([N:4]([CH3:25])[CH2:5][CH2:6][CH2:7]/[C:8](/[CH3:24])=[CH:9]/[CH2:10][CH2:11]/[C:12](/[CH3:23])=[CH:13]/[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)[OH:15])[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([N:4]([CH3:25])[CH2:5][CH2:6][CH2:7]/[C:8](/[CH3:24])=[CH:9]/[CH2:10][CH2:11]/[C:12](/[CH3:23])=[CH:13]/[C:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:15])[CH:2]=[CH2:3]
Reactant: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C(O)c1ccc(Br)cc1
Agent: [Mn+4]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C)CCC/C(C)=C/CC/C(C)=C/C(=O)c1ccc(Br)cc1
Reaction time: 2 h
Yield: 54 %

Procedure:
A solution of 162 mg of (2E,6E)-(RS)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-ol (Ex. 57.2) in 6 ml of methylene chloride is treated in succession with 28 mg of sodium carbonate and 730 mg of manganese(IV) oxide. After stirring for 2 hrs. the mixture is filtered, concentrated and the residue is dissolved in ethanol with 28 mg of fumaric acid, evaporated and precipitated with ethyl acetate/ether. There are obtained 87 mg of (2E,6E)-10-(allyl-methyl-amino)-1-(4-bromo-phenyl)-3,7-dimethyl-deca-2,6-dien-1-one.fumarate (1:1), MS: m/e 404 (M+H+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH:4]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:5]([C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)N1C(=O)OCC1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Product: COC(=O)C(CCc1ccccc1)C(CC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of the compound of example 50 (2.40 g, 6.07 mmol) in anhydrous THF (60 mL) was cooled to −78° C. A solution of NaHDMS in THF (1M, 6.7 mmol, 6.7 mL) was injected over 10 minutes. The reaction mixture was stirred for an additional 20 minutes, after which time, a solution of tert-butyl bromoacetate in anhydrous THF (5 mL) was slowly injected. After stirring for 1 h at −78° C., and 3 h at −48° C., the reaction was quenched by the addition of a saturated ammonium chloride solution. The mixture was extracted several times using ethyl acetate. The recombined organic layer was extracted successively with brine, saturated sodium hydrogen carbonate, brine and water. The solvent was evaporated following drying over sodium sulfate and filtration. The resultant crude material was flashed using 20% ethyl acetate in hexanes to give the product as a white solid. 1H-NMR(CDCl3, 300 MH: 1.40, 1.41(2s, 9H); 1.74–1.92(m, 5H); 2.45–2.95(m, 4H); 3.31(m, 1H); 3.69, 3.73(2 s, 3H); 4.11(m, 2H); 4.50, 4.66(2 m, 1H); 7.25(m, 10H).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[CH:24](=[N:2][CH:3]([CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(N)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A solution of the product from step (a) (149.6 g), magnesium sulphate (74.3 g), and triethylamine (246 ml) in dichloromethane (1500 ml) was stirred at room temperature under nitrogen and benzaldehyde (94.9 g, Aldrich) was added dropwise. The mixture was stirred at room temperature for 3 hours then filtered. The filtrate was concentrated, triturated in diethyl ether, filtered and concentrated to yield the desired product as a yellow oil (174 g). 1H NMR consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH2:10]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[CH2:16][C:17]([NH2:19])=[O:18]>>[CH3:1][C:2]1[C:3]2[C:8]([CH:9]3[C:14]=1[CH2:13][CH2:12][NH:11][CH:10]3[CH2:16][C:17]([NH2:19])=[O:18])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: CC1=C2CCNCC2c2ccccc21
Reactant: NC(=O)CCl
Product: CC1=C2CCNC(CC(N)=O)C2c2ccccc21

Procedure:
1,3,4,9b-Tetrahydro-5-methyl-2H-indeno[1,2-c]pyridine and chloroacetamide are reacted in accordance with the process described in Example 1. Reaction period four hours at 60°. M.P. of the title compound 167°-168° from acetone.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1.[O:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([NH:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:16])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: NOc1ccccc1
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Product: O=C(NOc1ccccc1)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-phenoxyamine under the same conditions as those in step (c) of example 1.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:17][CH2:16][C:1]1[CH:2]=[CH:3][C:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
2-(p-Tolyl)benzoxazole was reacted with N-bromosuccinimide in the presence of benzoyl peroxide by the standard procedure to produce the known compound, 2-(4-bromomethylphenyl)benzoxazole (A). 2-(2,4-Dihydroxyphenyl)benzotriazole (B) (0.1 mole) and 2-(4-bromomethylphenyl)benzoxazole (A) (0.1 mole) was stirred in a mixture of 2-butanone (300 ml.) and potassium carbonate (100 g.). After refluxing 16 hr., the mixture was poured onto 1000 g. ice/water. Filtration, washing with water and recrystallization from methyl cellosolve/ isopropyl alcohol gave the tan, crystalline product I.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C@@H](C2C=CC=CC=2)C)[C@H:3]1[OH:17]>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:4]1[C@H:3]([OH:17])[C:2]([F:18])([F:1])[CH2:7][CH2:6][CH2:5]1
Reactant: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: N[C@@H]1CCCC(F)(F)[C@H]1O
Reaction time: 16 h
Yield: 84.5 %

Procedure:
A solution of (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexanol 23 (2 g, 7.83 mmol) in methanol (100 mL) was degassed with nitrogen, treated with Pd(OH)2/C (0.55 g) and then placed under an atmosphere of hydrogen and stirred vigorously for 16 hours. The reaction was filtered, washing with methanol, and evaporated in vacuo to give 1.0 g (84%) of (1S,6R)-6-amino-2,2-difluorocyclohexanol 24 as a white solid: 1H NMR (500 MHz, CD3OD) δ 3.34 (1H, m), 2.74 (1H, m), 2.07 (1H, m), 1.89 (1H, m), 1.73 (2H, m), 1.50 (1H, m), 1.27 (1H, m).