Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:12]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cnc(OC)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OC)c(N)c1
Yield: 92.7 %

Procedure:
A solution of methyl 6-methoxy-5-nitronicotinate (5.4 g) in ethyl acetate (120 mL) is hydrogenated using 5% palladium on carbon (1 g) as catalyst. When hydrogen uptake ceased the mixture is filtered through a pad of diatomaceous earth and the filtrate evaporated. The residue is triturated with n-pentane and methyl t-butyl ether to give methyl 5-amino-6-methoxynicotinoate (4.3 g) as a light-brown solid, m.p.108-9° C. [Elemental analysis: C, 52.99; H, 5.49; N, 15.25%. calculated: C, 52.74; H, 5.53; N, 15.38%.]
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[CH:25]1([CH2:24][CH2:23][C:12]2[CH:13]=[C:14]([OH:15])[C:9](=[O:8])[NH:10][N:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C(#CC1CCCCC1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCC2CCCCC2)cc1O
Yield: 11 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-(cyclohexylethynyl)pyridazine (Intermediate 17) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (1:1). The resulting crude product was purified by preparative HPLC under acidic conditions. The solid obtained was recrystallised from methyl tert-butyl ether and ethyl acetate to afford 6-(2-cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one as a cream solid (11% yield).
Reaction SMILES: C([N:8]([C@@H](C1C=CC=CC=1)C)[C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH3:18])[C:14]([O:16][CH3:17])=[O:15])C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@:10]1([CH3:18])[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@]1(C)CCC[C@H]1N(Cc1ccccc1)[C@H](C)c1ccccc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COC(=O)[C@@]1(C)CCC[C@H]1N
Yield: 93.2 %

Procedure:
According to the procedure of Example 53, Step 2, using methyl (1S,2R)-2-{benzyl[(1R)-1-phenylethyl]amino}-1-methylcyclopentanecarboxylate (1.025 g, 2.92 mmol), 4.4% HCO2H/MeOH (30 mL) and 10% Pd/C (1.058 g), methyl (1S,2R)-2-amino -1-methylcyclopentanecarboxylate (527 mg, 2.72 mmol, 93%) was obtained as a colorless solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.29 (s, 3H) 1.56-1.62 (m, 1H) 1.64-1.76 (m, 3H) 2.07-2.13 (m, 1H) 2.15-2.22 (m, 1H) 3.24-3.31 (m, 1H) 3.64-3.71 (m, 3H) 8.18 (s, 3H).
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:42])[C@H:13]([CH3:41])[NH:14][CH:15](C(OCC)=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2C=CC=CC=2)=[O:27])[CH2:22][CH2:21]1)(C)(C)C.[BrH:44].C(O)(=O)C.C(OCC)C>C(O)(=O)C>[BrH:44].[BrH:44].[CH2:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C@H:13]([C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]([OH:43])=[O:5])=[O:42])[CH3:41])[CH2:21][CH2:22]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)N1CCC(CCCCCN[C@@H](C)C(=O)N2CCC[C@H]2C(=O)O)CC1
Reaction time: 1 h

Procedure:
In 1.5 ml of acetic acid is dissolved 0.66 g of N-[N-[5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-L-proline tert-butyl ester, and 2 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 1 hour. 50 ml of ethyl ether is added to the reaction solution, followed by shaking, and the precipitate is rinsed twice with 50 ml of ethyl ether. The resulting yellow, viscous material is dissolved in 5 ml of water, and the solution is extracted with 10 ml of ethyl acetate. The aqueous layer is lyophilized to give 0.4 g of N-[N-1-ethoxycarbonyl-5-(4-piperidyl)pentyl]-L-alanyl-L-proline.dihydrobromide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cn2nc(Oc3ccc(Cl)c(NC(=O)C4CC4)c3)ccc2n1)C1CC1
Yield: 87.1 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.435 mmol), cyclopropanecarbonyl chloride (71.8 mg, 0.652 mmol), triethylamine (132 mg, 1.30 mmol) and tetrahydrofuran (17 mL) as starting materials and in the same manner as in Example 96, the title compound (156 mg, 87%) was obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:11]1([C@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:9])[CH2:10][NH:19][C@@H:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:18])=[CH:4][CH:3]=1
Reactant: Brc1ccc([C@H]2CO2)cc1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC(C)OC(C)C
Product: C[C@@H](NC[C@@H](O)c1ccc(Br)cc1)c1ccccc1
Temperature: 80 °C
Yield: 64.4 %

Procedure:
A mixture of (2S)-2-(4-bromophenyl)oxirane (55.0 g) and (R)-1-phenylethylamine (98.2g, 810 mmol) was heated at 80° C. for 6 hours. Addition of isopropyl ether (200 ml) to the residue after distillation of excess phenethylamine and successive filtration yielded (1S)-1-(4-bromophenyl)-2-((1R)-1-phenylethylamino)ethanol (57.0 g) as white crystals. Further crystallization was performed by the concentration of the filtrate in vacuo and cooling the residue in refrigerator. Filtration of the crystal with isopropyl ether (30 ml) yielded additional title compound (5.60 g) as crystals (72.4% yield, 3 steps).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][OH:35])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:46])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:47]=[CH:48][CH:49]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][OH:35])=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:46])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(OCCO)c(NS(C)(=O)=O)c3)cc12
Yield: 13.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(2-hydroxyethoxyl)phenyl) methanesulfonamide (150 mg, 0.208 mmol) was hydrolyzed by lithium hydroxide (88 mg, 2.08 mmol), THF/Methanol/water (3/3/1.5 ml) to afford 15 mg (15.38% yield) of the title compound. 1H NMR (DMSO-d6, 300 MHz): δ11.9 (s, 1H), 9.00 (s, 1H), 8.49 (s, 1H), 7.81 (s, 1H), 7.59 (s, 1H), 7.51-7.41 (m, 3H), 7.15-7.12 (d, 1H), 7.05-7.03 (m, 1H), 6.87 (s, 1H), 4.06 (m, 2H), 3.78 (m, 2H), 3.00 (s, 3H), 2.18-2.14 (d, 6H), MS: m/z=550.1 (M+1), HPLC: 87.11% in Method B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C=CC=1)N.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccc(Br)c1
Solvent: Nc1cccc(Br)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1cccc(Br)c1
Yield: 66 %

Procedure:
This compound was prepared using 125 mg (0.5 mmol) of 2-[(3-bromophenyl)-hydrazono]malononitrile, which was derived from 3-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol) as. described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 93 mg (66%) of the title compound as an orange solid. 1H NMR (ppm, DMSO-d6): 6.2 (br s, 4H), 7.21-7.32 (m, 2H), 7.50-7.62 (m, 1H), 7.90 (s, 1H), 10.71 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:21][O:20][C:5]1[C:6]2[N:7]=[C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])[S:9][C:10]=2[C:2]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)c2sc(NC(=O)c3ccc(C)s3)nc12
Reactant: OB(O)c1ccncc1
Product: COc1ccc(-c2cccnc2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 8 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid (4-methoxy-7-pyridin-3-yl-benzothiazol-2-yl)-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-bromo-4-methoxy-benzothiazol-2-yl)-amide (192 mg, 0.50 mmol) and 4-pyridylboronic acid (123 mg, 1.0 mmol) using the general procedure A as a white solid in 8% yield. MS: m/e=381 (M+).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH2:7][OH:8])=[O:2].C(N(CC)CC)C.[S:28](Cl)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[S:28]([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O:8][CH2:7][CH2:6][C:5]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:4][NH:3][CH:1]=[O:2])(=[O:30])=[O:29]
Reactant: O=CNCC(CCO)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(CNC=O)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a suspension of 4-formylamino-3,3-diphenylbutanol (21.5 g) in methylene chloride (250 ml) were added triethylamine (22 ml), 4-dimethylaminopyridine (catalyst amount) and tosyl chloride (15.3 g) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and dissolved in water-ethyl acetate. The ethyl acetate layer was washed with 1N-hydrochloric acid, further washed with water, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate 4:1~1:1) to provide the title compound (32 g) as colorless syrup.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[N:13][CH:14]=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:4][CH2:3][CH:2]([CH3:5])[CH3:1])=[N:13][CH:14]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)COc1ccc(Br)cn1
Yield: 86.3 %

Procedure:
To 2-methyl-propan-1-ol (10 g, 0.41 mol) was added NaH (60%, 8.2 g, 0.204 mol) portionwise under a nitrogen atmosphere at room temperature over 10 minutes. The mixture was refluxed for 30 minutes. A solution of 5-bromo-2-fluoro-pyridine (24 g, 0.136 mol) in DMF (400 mL) was added dropwise and the mixture refluxed for 18 hours. The reaction mixture was then diluted with water (1 L) and extracted with EtOAc (3×500 mL). The combined organics were washed with brine (3×300 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue obtained was purified by flash column chromatography eluting with petroleum ether to yield the title compound as a colourless oil (27 g).
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=1.C1([Li])C=CC=CC=1.CN(C)[CH:27]=[O:28]>>[CH3:17][O:16][C:10]1[C:11]([O:14][CH3:15])=[CH:12][CH:13]=[C:8]([OH:7])[C:9]=1[CH:27]=[O:28]
Reactant: CN(C)C=O
Reactant: COc1ccc(OC2CCCCO2)cc1OC
Agent: [Li]c1ccccc1
Product: COc1ccc(O)c(C=O)c1OC

Procedure:
3,4-Dimethoxyphenol tetrahydropyranyl ether (47.6 g, 0.2 M) was lithiated with phenyllithium (from 21.02 ml bromobenzene and 2.89 g lithium), formylated by the addition of dry dimethylformamide (15 ml) and subsequently hydrolysed in an analogous manner to that described in example 2(E). The crude product was distilled under high vacuum to give 2,3-dimethoxy-6-hydroxybenzaldehyde as a yellow oil which solidified on standing. After trituration with 40/60 petrol and filtration the product had m.p. 53°-54° C. (Found: C, 59.18; H, 5.54. C9H10O4 requires C, 59.33; H, 5.53%). (C) 5-(2-Formyl-3-hydroxy-4-methoxyphenoxy)pentanoic acid
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>>[CH:15]([C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:24]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]
Reactant: O=CC1(c2cccc(O)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: Cn1c(=O)ccc2cc(COc3cccc(C4(C=O)CCOCC4)c3)ccc21
Yield: 45 %

Procedure:
Using a similar procedure to that described in Example 14, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-formyl-4-(3-hydroxyphenyl)tetrahydropyran to give 4-formyl-4-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 45% yield as a glassy solid.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.Cl([O-])(=O)(=O)=O.[CH2:26]1[C:33]2[CH2:32][CH2:31][CH2:30][N+:29]=2[CH2:28][CH2:27]1>C1COCC1>[F:13][C:14]1[C:19]([C:33]23[CH2:32][CH2:31][CH2:30][N:29]2[CH2:28][CH2:27][CH2:26]3)=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: C1CC2=[N+](C1)CCC2
Reactant: Fc1cccc(F)n1
Agent: [Li]CCCC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ccc(C23CCCN2CCC3)c(F)n1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A solution of 2.5M nBuLi (675 μL, 1.7 mmol) in hexanes was added to diisopropylamine (220 μL, 1.6 mmol) in THF (4.5 mL) at ambient temperature. After 10 minutes of stirring, the reaction mixture was cooled to -78° C., 2,6-difluoropyridine (145 μL, 1.6 mmol) was introduced, and stirring was continued for 1 hour at -78° C. 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate (500 mg, 2.4 mmol) was then added, and the cold bath was removed. After warming to ambient temperature, a solution of 2N HCl was added and the phases were separated after pouting the reaction mixture over EtOAc. The aqueous phase was basified with 15% NaOH solution and extracted with CH2Cl2 (2×). The CH2Cl2 extracts were combined, dried (MgSO4), concentrated and chromatographed (silica gel; CHCl3 /MeOH, 98:2) to afford a clear oil (180 mg, 50%). MS (CI/NH3) m/e: 225 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.5-1.63 (m, 2H), 1.78-1.89 (m, 2H), 1.92-2.10 (m, 4H), 2.63-2.70 (m, 2H), 3.08-3.12 (m, 2H), 6.72 (dd, J=8.1, 3.0 Hz, 1H), 8.33 (dd, J=18.0, 8.1 Hz, 1H).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:54][NH:55][S:56]([NH2:59])(=[O:58])=[O:57]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:59][S:56](=[O:58])(=[O:57])[NH:55][CH3:54])=[O:35])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: CNS(N)(=O)=O
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CNS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5 and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with (methylsulfamoyl)amine, the title compound was obtained (0.08 g, 29%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.77-8.64 (m, 1H), 7.62-7.51 (m, 1H), 6.65-6.52 (m, 1H), 5.30-5.18 (m, 1H), 3.95-3.85 (m, 2H), 2.83-2.72 (m, 3H), 2.28-1.66 (m, 8H), 1.57-1.42 (m, 2H), 1.01-0.90 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 421.1 (M+1).
Reaction SMILES: [CH2:1]([C:7]1([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:19]2[CH:18]=[C:17]3[C:20](=[O:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C1COCC1.C(O)C>[CH2:25]([C:7]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:19]2[CH:18]=[C:17]3[CH:20]([OH:24])[CH:21]([CH3:23])[CH2:22][C:16]3=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(=O)C(C)C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCC1(CCCCCC)c2ccccc2-c2cc3c(cc21)C(O)C(C)C3
Reaction time: 12 h
Yield: 96 %

Procedure:
In a 1000 mL round flask, 9,9-dihexyl-2-methyl-2,3-dihydrocyclopenta[b]fluoren-1(9H)-one (85 g, 211.1 mmol) was dissolved in THF 400 mL and ethanol 400 mL, and then stirred. Sodium borohydride (NaBH4) (10 g, 265.0 mmol) was added to the reaction product in five lots, and then stirred for 12 hours. The resultant mixture, after removal of solvent, was dissolved in ethylacetate, and then washed with water three times. The organic layer was dried over magnesium sulfate, followed by removal of volatile materials and drying, to thereby obtain 82.0 g of 9,9-dihexyl-2-methyl-1,2,3,9-tetrahydrocyclopenta[b]fluoren-1-ol (yield: 96.0%) (two isomers), as highly viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:10]=1)[CH:8]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:8]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
5-Methoxy-2-[3-(4-morpholinyl)propoxy]-benzaldehyde (33.4 g) and 14.5 g of phenethylamine are refluxed in 120 ml. of toluene for about 1 hour. After cooling to about 50° C., the solvent is removed using a rotary evaporator and the oily residue is distilled to give 42.1 g of the title compound, boiling point 240°-245° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[N:14]1[C:22](=[O:23])[C:21]2[C@@H:20]3[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]3)[C:16]=2[NH:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH:5]1([CH2:4][N:15]2[C:16]3[C@@:17]4([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:20]([CH2:19][CH2:18]4)[C:21]=3[C:22](=[O:23])[N:14]2[C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[CH2:3][CH2:2]1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: BrCC1CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccc(F)cc2F)n1CC1CC1
Temperature: 100 °C
Yield: 42.9 %

Procedure:
A mixture of (bromomethyl)cyclopropane (2 mL, 20.6 mmol), (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 14; 414 mg, 1.36 mmol) and tetra-n-butylammonium iodide (0.80 g, 2.2 mmol) in N,N-dimethylformamide (5 mL) was heated in a sealed tube in an oil-bath at 100° C. for 20 h. The reaction mixture was cooled to room temperature and then diluted with dichloromethane (200 mL). The solution was washed with water (5×30 mL), aqueous sodium thiosulfate solution (2×30 mL) and brine (30 mL), then dried (magnesium sulfate), filtered, and evaporated, and the residue was purified on an Isco 120 g column, eluting with 30-100% ethyl acetate/hexanes to give (4S,7R)-1-(cyclopropyl)methyl-7,8,8-trimethyl-2-(2,4-difluoro-phenyl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (209 mg, 43%) as an pale yellow gum. APCI-MS (M+H) 359.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[C:5]2=[O:13].[H-].[Na+].Br[CH2:17][C:18]([O:20]CC)=[O:19].[ClH:23]>CN(C=O)C>[Cl:11][C:10]1[C:9]([Cl:23])=[C:8]2[C:4]([C:5](=[O:13])[C:6](=[O:12])[N:7]2[CH2:17][C:18]([OH:20])=[O:19])=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2cc(Cl)c(Cl)cc2C1=O
Reactant: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)CN1C(=O)C(=O)c2ccc(Cl)c(Cl)c21
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of 5,6-dichloroisatin (1.0 g, 4.65 mmol) in DMF (20 ml) was cooled in an ice-bath. Sodium hydride (5.11 mmol, 0.20 g 60% dispersion in mineral oil) was added and the mixture was stirred for 20 min. Ethyl 2-bromoacetate (0.37 ml, 5.11 mmol) was added and stirring was continued for 2 hours. The resulting mixture was poured into diluted hydrochloric acid (200 ml, 4M), heated to reflux for 2 hours, filtered, cooled and extracted with ethyl acetate. The organic extract was dried over magnesium sulphate and evaporated to dryness to leave the desired product (0.85 g, 67%).
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=[O:13])[O:3]1)=[O:2].[CH3:15]O>Cl>[C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[O:3]1)=[O:2]
Reactant: O=C(O)CC1OC(=O)c2ccccc21
Reactant: CO
Agent: Cl
Product: COC(=O)CC1OC(=O)c2ccccc21

Procedure:
Phthalide-3-acetic acid (XCI, 9.6 g, 50 mmol) is dissolved in methanol (50 ml) saturated with anhydrous hydrochloric acid and the mixture is cooled to 0°-5° for 18 hr. The solvent is concentrated under reduced pressure, treated with sodium bicarbonate, and extracted with methylene chloride (800 ml). The organic phase is washed with saturated aqueous sodium bicarbonate, saline, dried over magnesium sulfate, filtered and concentrated to give the title compound, mp 62°-63°; NMR (CDCl3, TMS) 7.94-7.50, 5.90, 3.77 and 2.92 δ.