Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>>[OH:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][C@@H:8]1[C@@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:11](=[O:23])[CH2:10][CH2:9]1
Reactant: CCCCC[C@@H](CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCC[C@H](O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OC

Procedure:
A solution of 2.26 g. of methyl 15(S)-acetoxy-9-oxo-prostanoate (Example 15) in 300 ml. of absolute alcohol containing 790 mg. of potassium carbonate is stirred at ambient temperature for 72 hours then concentrated to near dryness under reduced pressure. The resulting mixture is extracted with ether. The combined extracts are washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate and taken to dryness to give 1.83 g. of an oil. Purification by silica gel chromatography affords the subject compound as an oil; λ max. 2.92 (hydroxyl group), 5.74 μ (carbonyl groups); [α]D25 - 23°C. (0.2% in CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][NH:31][O:32][CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([N:31]([O:32][CH3:33])[CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CNOC
Product: CON(C)C(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and N,O-dimethylhydroxylamine gave 188. MS: (ESI+) 457.0
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[S:9][N:8]=[C:7]([CH3:10])[C:6]=1[Cl:11].C([O:14][C:15](=O)[CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:19](=[CH:20][N:21]([CH2:26][CH:27]([CH3:29])[CH3:28])[N:22]=2)[CH:18]=1)C>O1CCCC1>[Cl:11][C:6]1[C:7]([CH3:10])=[N:8][S:9][C:5]=1[NH:4][C:15](=[O:14])[CH2:16][C:17]1[CH:25]=[CH:24][C:23]2[C:19](=[CH:20][N:21]([CH2:26][CH:27]([CH3:28])[CH3:29])[N:22]=2)[CH:18]=1
Reactant: Cc1nsc(N)c1Cl
Reactant: CCOC(=O)Cc1ccc2nn(CC(C)C)cc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nsc(NC(=O)Cc2ccc3nn(CC(C)C)cc3c2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.3 %

Procedure:
Sodium methoxide (0.42 g, 0.0078 mol) was added to a solution of 5-amino-4-chloro-3-methylisothiazole (0.46 g, 0.0031 mol) in tetrahydrofuran (THF) (15 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of ethyl[2-(2-methylpropyl)indazol-5-yl]acetate (0.80 g, 0.0031 mol) in THF was added dropwise and, once the addition was complete, the mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution and then the organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was triturated with diethyl ether to give N-(4-chloro-3-methylisothiazol-5-yl)-[2-(2-methylpropyl)indazol-5-yl]acetamide (0.78 g) as a pale-brown solid (m.p. 133–135° C.).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:4])=[O:3].NN>CCO>[CH3:1][S:2]([CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)CCCCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CS(=O)(=O)CCCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A solution of 2-(4-methanesulfonyl-butyl)-isoindole-1,3-dione ((Example 201: step b) 0.866 g, 3.08 mmol) in EtOH (30 mL) was treated with hydrazine and stirred at room temperature 18 h. The solid precipitate was removed by filtration and the filtrate was concentrated in vacuo. To remove any excess hydrazine, the resulting waxy solid was titrated with toluene and with THF and placed under high vacuum overnight to afford the product (0.400 g, 86%) as a waxy, off-white solid. 1NMR (MeOD): δ 3.153 (dd, 2H, J=8.8 Hz, J=0.0 Hz), 2.962 (s, 3H), 2.582 (dd, 2H, J=7.6 Hz, J=0.0 Hz), 1.811 (m, 2H) 1.747 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>CC(O)C>[C:30]([O:29][C:27]([N:24]1[CH2:25][CH2:26][CH:21]([CH2:20][NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:22][CH2:23]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (420 mg, 2.0 mmol) followed by triethylamine (200 mg, 2.0 mmol). The reaction mixture was stirred at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-{[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 85.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Br:19][CH2:20][CH2:21][CH2:22]Br>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[N:10]([CH2:22][CH2:21][CH2:20][Br:19])[C:9]1=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCCCBr
Reactant: Cc1cn(Cc2ccccc2)c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccccc2)c(=O)n(CCCBr)c1=O
Temperature: 60 °C

Procedure:
To a solution of 1-benzyl-5-methyl-1H-pyrimidine-2,4-dione (1.0 g, 4.6 mmol) in N,N-dimethylformamide (15 mL) was added tetrabutylammonium bromide (60 mg, 0.2 mmol) and sodium hydroxide (200 mg, 5.1 mmol). The suspension was stirred vigorously, heated to 60° C. for 1.5 h and then cooled to ambient temperature. 1,3-Dibromopropane (0.5 mL, 5.1 mmol) was added, the reaction was heated to 50° C. for 16 h and then concentrated in vacuo. The residue was taken up in ethyl acetate:water (1:1 200 mL), the layers separated and the aqueous layer extracted with ethyl acetate (2×50 mL). The organic layers were combined and washed with 1 M sodium hydroxide (1×50 mL), water (1×50 mL), brine (1×100 mL), dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by pressurized silica gel chromatography (25-30% ethyl acetate in hexane) to provide 1-benzyl-3-(3-bromopropyl)-5-methyl-1H-pyrimidine-2,4-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([O:14][Na])([CH3:13])[CH3:12]>CC(O)C>[O:14]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)O[Na]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(C)O
Product: CC(C)Oc1ccc([N+](=O)[O-])cn1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
A freshly oven dried 500 mL round-bottom flask was charged with 2-chloro-5-nitropyridine (5.0 g, 31.6 mmol) and anhydrous iPrOH (50 mL). The resultant solution was cooled in an ice bath and iPrONa (50 mmol) in iPrOH (250 mL) added slowly, followed by stirring at the same temperature for 30 min and then at room temperature for 14 h. The reaction was quenched with H2O (5 mL), filtered through celite, and concentrated under reduced pressure. The residue was diluted with EtOAc and washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography to afford 2-isopropoxyl-5-nitropyridine (4.6 g, 79%) which was used directly for the next step: 1H NMR (400 MHz, CDCl3) δ 9.02 (d, 1H), 8.30 (dt, 1H), 6.75 (d, 1H), 5.40 (sep, 1H), 1.38 (d, 6H); MS (ES) (M++H) expect 183.1. found 183.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([CH:12]([NH2:16])[CH2:13][CH2:14]Br)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[C:5]([CH:12]([NH2:16])[CH2:13][CH2:14][N:1]=[N+:2]=[N-:3])([O:7][C:8]([CH3:10])([CH3:11])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)C(N)CCBr
Reactant: [N-]=[N+]=[N-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(N)CCN=[N+]=[N-]
Temperature: 25 °C
Yield: 85.1 %

Procedure:
An aqueous solution (5 mL) of NaN3 (1.4 g; 21.5 mmol) and 2-3 drops of Aliquat 336 are added to a stirred solution of 3-BOC-amino-propyl bromide (5 g; 21.5 mmol) in toluene (10 mL); the mixture is heated at the reflux temperature for 4 hrs. After cooling at r.t., the organic phase is separated, dried over Na2SO4, and evaporated to dryness in vacuum to give 3-BOC-amino-propyl azide (3.75 g; 18.3 mmol) as a transparent oil (yield 85%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][Mg]Cl.[F:13][C:14]([F:23])([F:22])[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(OCC)C.C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([OH:21])([C:14]([F:13])([F:22])[F:23])[CH2:3][C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:20]
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Reactant: CCOC(=O)C(=O)C(F)(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 M solution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl ether was added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL of anhydrous THF. The reaction became slightly warm to the touch and a white precipitate quickly developed. After 2 hours, the reaction was diluted with diethyl ether and quenched with 1 N aqueous HCl. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown oil. Chromatography on silica gel eluting with hexanes-EtOAc (98:2), afforded the title compound as a clear, colorless oil (4.6 g, 67%).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([N:8]=C=O)[CH2:6][C@@H:5]([NH:11][S:12]([CH:15]2[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:4]1)[CH3:2].[ClH:18].CCOCC.CCOC(C)=O>O>[ClH:18].[NH2:8][C@@H:7]1[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:11][S:12]([CH:15]2[CH2:17][CH2:16]2)(=[O:14])=[O:13])[CH2:6]1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N=C=O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1N
Temperature: 100 °C
Yield: 85 %

Procedure:
A mixture of N-((1S,3R,4S)-3-ethyl-4-isocyanatocyclopentyl)cyclopropanesulfonamide (0.972 g, 3.76 mmol) and aqueous HCl (6 N, 31.4 mL, 188 mmol) was heated at about 100° C. for about 60 h. Aqueous HCl (12 N, 5 mL) was added and the reaction mixture was heated at about 100° C. for about 18 h. The reaction mixture was cooled to ambient temperature and concd under reduced pressure. The residue was treated with Et2O (10 mL) and EtOAc (10 mL). The mixture was concd under reduced pressure. Water (5 mL) was added and the sample was lyophilized to give N-((1S,3S,4R)-3-amino-4-ethylcyclopentyl)cyclopropane-sulfonamide hydrochloride (0.859 g, 85%) as a white solid: LC/MS (Table 1, Method a) Rt=1.28 min; MS m/z 233 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[C:8]([NH:17][CH:18]([CH3:20])[CH3:19])[C:9]3[N:10]2[C:13](=[O:16])[NH:14][N:15]=3)=[CH:5][CH:4]=1.[H][H]>CCO.[Pd]>[CH:18]([NH:17][C:8]1[C:9]2[N:10]([C:13](=[O:16])[NH:14][N:15]=2)[C:11]2[C:6]([N:7]=1)=[CH:5][CH:4]=[C:3]([CH3:2])[CH:12]=2)([CH3:20])[CH3:19]
Reactant: CC(C)Nc1nc2ccc(CO)cc2n2c(=O)[nH]nc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2nc(NC(C)C)c3n[nH]c(=O)n3c2c1

Procedure:
A solution of 8-hydroxymethyl-4-isopropylamino-2H-[1,2,4]triazolo[4,3-a]quinoxalin-1-one (20 mg) in EtOH (15 mL) was treated 10% Pd/C (10 mg), and the mixture was agitated under 45 psi hydrogen atmosphere for 68 hrs. The reaction mixture was filtered through diatomaceous earth, the filtrate concentrated, and the residue purified by silica gel chromatography to provide the title compound as a solid. MS (M+H)+=258.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36]Br)[CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].[CH2:47]([NH:49][CH2:50][CH3:51])[CH3:48].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[C:29]([O:34][CH2:35][CH2:36][N:49]([CH2:50][CH3:51])[CH2:47][CH3:48])[CH:28]=3)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3ccc(OCCBr)cc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Reactant: CCNCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: CCN(CC)CCOc1ccc2cc(-c3nn(C(=O)OC(C)(C)C)c4ccc(OCc5ccccc5)cc34)n(C(=O)OC(C)(C)C)c2c1
Yield: 32.1 %

Procedure:
The compound 5-benzyloxy-3-[1-tert-butoxycarbonyl-6-(2-diethylaminoethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester is prepared according to procedure N using 1.23 g of 5-benzyloxy-3-[6-(2-bromoethoxy)-1-tert-butoxycarbonyl-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester, 50 ml of acetonitrile, 401 mg of potassium iodide, 204 mg of diethylamine, and 770 mg of cesium carbonate. After treatment, the reaction crude is purified by chromatography on a cartridge of 20 g of silica; eluent: 98/2, 95/5, 92/8 dichloromethane/methanol to obtain 390 mg of 5-benzyloxy-3-[1-tert-butoxycarbonyl-6-(2-diethylaminoethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:8])[C:4]([CH3:7])=[CH:5][CH:6]=1.N1C=CC=CC=1.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][C:2]1[N:3]([NH:8][C:17](=[O:18])[CH2:16][Cl:15])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C)n1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C)n1NC(=O)CCl
Reaction time: 8 h
Yield: 54.9 %

Procedure:
The product of Example 1 (13.2 g) and pyridine (9.48 g) were stirred in ethyl acetate (200 ml) at room temperature with dropwise addition of 13.56 g chloroacetyl chloride. The mixture was stirred overnight, stripped, dissolved in methylene chloride, washed with water, dried and stripped. The residue was chromatographed in a silica gel (325 g) column (chloroform elution), to yield the title product (12.27 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]1[C:22]([O:24]CC)=[O:23].O[Li].O>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][N:6]1[C:10]([C:11]([F:13])([F:12])[F:14])=[CH:9][C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[C:7]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1cccc(Cl)c1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1Cc1cccc(Cl)c1

Procedure:
To crude ethyl 1-(3-chlorobenzyl)-3-(4-chlorophenyl)-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate (732 mg, max. 1.57 mmol) in EtOH (2 mL) and H2O (2 mL) was added LiOH.H2O (347 mg, 8.28 mmol). The reaction mixture was stirred at reflux temperature overnight. The reaction mixture was concentrated, diluted with H2O (5 mL) and acidified with aqueous 1 M KHSO4 (10 mL) while cooling with an ice-bath. The precipitate was filtrated, washed with H2O (2×) and dried on filter to give ACI-07 (533 mg, 82% over two steps).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[CH:17]=[C:18]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:30][CH:29]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])[CH:8]=[CH:9][C:10]=1N1CCCC1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O.C(C1C=C(C2C=C(C3C=CC(C(OCC)=O)=CC=3)C=CC=2OCCCC=O)C=CC=1[N:59]1[CH2:63][CH2:62][CH2:61][CH2:60]1)(C)(C)C>C(N(CC)CC)C>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:21]([O:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])([N:59]3[CH2:63][CH2:62][CH2:61][CH2:60]3)[CH2:20][CH:19]=[C:18]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:33]=3)[CH:17]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCO)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCC=O)c(-c3ccc(N4CCCC4)c(C(C)(C)C)c3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C2=CCC(OCCCC=O)(N3CCCC3)C(c3cccc(C(C)(C)C)c3)=C2)cc1
Yield: 78 %

Procedure:
In a manner similar to that of Example 30a, by reacting 900 mg of ethyl 3″-tert-butyl-4′-(4-hydroxybutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate obtained in Example 18e with 0.3 mL of oxalyl chloride, 0.54 mL of DMSO and 0.25 mL of triethylamine, 700 mg of ethyl 3″-tert-butyl-4′-(4-oxobutoxy)-4″-pyrrolidin-1-yl[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=78%) in the form of a yellow oil.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[OH:4])#[CH:2].I[C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1>>[OH:4][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1)[C:1]#[C:2][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 89.6 %

Procedure:
Following the basic procedure of Example 11(d), by reacting 1.2 g (5 mmol) of α-ethynyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenemethanol with 1.1 g (5 mmol) of 4-iodotoluene, 1.49 g (45%) of the expected compound was recovered, after chromatography on a silica column eluted with dichloromethane, in the form of a brown oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]2[C:10]3([CH2:31][O:32][C:4]=2[CH:3]=1)[C:18]1[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=1)[N:12]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]([F:29])([F:28])[F:27])[C:11]3=[O:30].O.NN.[N:36](OCCC(C)C)=O.[PH2](O)=O.C(=O)(O)[O-].[Na+]>COCCOC>[F:27][C:26]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2([C:5]3[CH:6]=[C:7]4[C:2](=[CH:3][C:4]=3[O:32][CH2:31]2)[NH:36][N:9]=[CH:8]4)[C:11]1=[O:30]
Reactant: CC(C)CCON=O
Reactant: N#Cc1cc2c(cc1F)OCC21C(=O)N(Cc2ccccc2C(F)(F)F)c2ccccc21
Agent: NN
Agent: O=C([O-])O
Agent: O=[PH2]O
Solvent: O
Solvent: COCCOC
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2C12COc1cc3[nH]ncc3cc12
Yield: 9.2 %

Procedure:
To a stirred solution of 6-fluoro-2′-oxo-1′-[2-(trifluoromethyl)benzyl]-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (0.44 g, 1.0 mmol) in 1,2-dimethoxyethane (20 mL) was added hydrazine monohydrate (1.0 mL, 21 mmol). The reaction mixture was stirred at reflux for 19 h and concentrated in vacuo. The residue was dissolved in ethanol (20 mL) and isoamyl nitrite (1.50 mL, 10.7 mmol), and hypophosphorous acid (2.0 mL, 18 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 18 h, neutralized with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×100 mL). The combined organic extracts was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 1′-[2-(trifluoromethyl)benzyl]-1H-spiro[furo[3,2-f]indazole-5,3′-indol]-2′(1′H)-one (0.04 g, 10%): mp 124-126° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.83-7.0 (m, 2H), 7.67-7.63 (m, 1H), 7.54-7.49 (m, 1H), 7.27-7.18 (m, 4H), 7.08-7.03 (m, 1H), 6.95-6.94 (m, 1H), 6.81-6.77 (m, 1H), 5.07-4.83 (m, 4H); MS (ES−) m/z 436.2 (M−1).
Reaction SMILES: [Li].[CH3:2][CH:3]([CH2:5][CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C@@H:19](O)[CH2:20][C@@H:21]2[OH:29])[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:4]>O1CCCC1>[OH:29][C@@H:21]1[C@@:22]2([CH3:23])[C:17](=[CH:16][CH2:15][C@@H:14]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:13]3[CH2:12][CH2:11][C@@H:10]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][CH:3]([CH3:2])[CH3:4])[CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CCC[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 60.1 %

Procedure:
A three-necked standard taper round-bottom flask equipped with a mechanical stirrer, dry ice condenser, a nitrogen inlet and an ammonia inlet was thoroughly dried, flushed with nitrogen, cooled in a dry ice-acetone bath and charged with ammonia (60 ml). Lithium (0.4 g, 0.06 mole) was added portionwise under an atmosphere of nitrogen with stirring. A solution of 4,6-cholestadien-1α,3β-diol (4, 0.518 g, 1.29 mmoles) in freshly distilled tetrahydrofuran (60 ml) was added and, after removal of the cooling bath, the reaction mixture was stirred for 3 hours. Ammonium chloride (ca 0.5 g) was added and after stirring for 1 hour, saturated ammonium chloride solution was added. The ammonia was allowed to evaporate. Water was added o the residue and the solution was extracted with ether. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under vacuum. Filtration of the residual solid (0.509 g) dissolved in low boiling petroleum ether through a column of silica gel gave 0.3 g (60%) of carbinol 5.