Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([S:9]([N:12]2[C:16]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:7]2[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)o1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(C(C)=O)o2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of tert-butyl {[1-[(5-acetyl-2-furyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (180 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 82.8 mg, 53%).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@@H:13]([N:15]([CH3:37])[C:16]([C@@:18]23[CH2:23][CH:22]2[CH2:21][N:20](CC2C=CC=CC=2)[C@H:19]3[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].CC(O)=O>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@@H:13]([N:15]([CH3:37])[C:16]([C@@:18]23[CH2:23][CH:22]2[CH2:21][NH:20][C@H:19]3[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:38])([F:39])[F:1])[CH:8]=1
Reactant: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: C[C@@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(C)C(=O)[C@@]12CC1CN[C@H]2c1ccccc1
Yield: 53.8 %

Procedure:
To Intermediate 41, the more polar isomer (1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid [(S)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (0.06 g, 0.11 mmol) was combined with palladium on carbon 20% (Pearlman's catalyst, 0.08 g) and HOAc (8 mL) and hydrogenated at 40 psi for 16 hours. The material was filtered thru celite and concentrated, then partitioned between saturated sodium bicarbonate solution and methylene chloride, the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified via prep tic using ETOAc as the eluant to give the title compound (0.027 g, 54% yield).
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:41])([CH3:40])[C:30]=2[CH:29]=1)[CH2:4][CH3:5]>O1CCCC1>[CH2:3]([NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[C:28]1[CH:37]=[CH:36][C:35]2[C:34]([CH3:39])([CH3:38])[CH2:33][CH2:32][C:31]([CH3:40])([CH3:41])[C:30]=2[CH:29]=1)[CH2:4][CH3:5]
Reactant: CCCNCCCOc1ccc(-c2ccc(C(=O)OCC)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCNCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1-c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 64.4 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 584 mg (14.6 mmol) of sodium hydroxide with 770 mg (1.46 mmol) of ethyl 4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 9a) in 30 ml of tetrahydrofuran. 470 mg of 4′-(3-propylaminopropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=226° C., yield=64%).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.O.[CH3:13][N:14]1C(=O)CCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[CH3:11][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][CH:5]=[CH:4][C:3]=2[C:2]=1[C:13]#[N:14]
Reactant: Cc1ccc2[nH]ccc2c1Br
Reactant: CN1CCCC1=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1ccc2[nH]ccc2c1C#N
Temperature: 145 °C
Yield: 48.5 %

Procedure:
A mixture of 300 (150 mg, 0.714 mmol), Pd2(dba)3 (131 mg, 0.143 mmol), dppf (159 mg, 0.286 mmol), Zn(CN)2 (84 mg, 0.714 mmol), and zinc (4.6 mg, 0.0714 mmol) in NMP (10 mL) under nitrogen atmosphere was heated at 145° C. for 18 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (20 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated to dryness. The crude was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford 54 mg (48.5%) 5-methyl-1H-indole-4-carbonitrile (302) as yellow solid: MS (ESI) m/z=157.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:20](I)[CH3:21].C(O)C>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:20][CH3:21])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-Nitro-1H-indole-2-carboxylic acid ethyl ester (5 g, 21.3 mol) was dissolved in DMF (50 mL). The reaction mixture was cooled to 0° C. Sodium hydride (1.02, 25.5 mmol, 60% in mineral oil) was added to the above solution in portions over 10 minutes. The mixture was stirred at room temperature for 30 minutes. Ethyl iodide (6.5 g, 42 mmol) was added to the above solution and the reaction mixture was stirred overnight. Ethanol (30 mL) was added to the reaction mixture and the mixture was poured into cold water (800 mL). The crude product was collected by filtration and used directly in next step without further purification (5 g).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:30])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:30])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:28])([F:29])[F:27])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1cccc(OCC(F)(F)F)c1)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OCC(F)(F)F)c1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
To a solution of zinc chloride (2.81 g, 20.6 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.56 g, 41.2 mmol) and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off. To the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate (4.10 g, 10.3 mmol) in diethyl ether (50 ml) and the mixture was stirred at room temperature for 30 min. 1N Hydrochloric acid was added to the reaction solution under ice-cooling for quenching, water (200 ml) was added, and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-((3-(2,2,2-trifluoroethoxy)phenyl)methyl)propionate (3.51 g, 85%) as a colorless oil.
Reaction SMILES: [F:1][CH:2]([F:52])[C:3]1[C:7]([CH:8]=O)=[C:6]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:28]4[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:48])=[N:31][N:32]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[C:20]([CH3:27])([CH3:26])[CH2:19]4)[C:12]=3[CH2:11]2)[N:5]([CH3:51])[N:4]=1.Cl.[NH2:54]O.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[F:52][CH:2]([F:1])[C:3]1[C:7]([C:8]#[N:54])=[C:6]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:28]4[C:36]([CH3:37])=[CH:35][CH:34]=[C:33]5[C:29]=4[C:30]([CH3:48])=[N:31][NH:32]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][C@@H:21]([O:24][CH3:25])[C:20]([CH3:26])([CH3:27])[CH2:19]4)[C:12]=3[CH2:11]2)[N:5]([CH3:51])[N:4]=1
Reactant: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4c3c(C)nn4S(=O)(=O)c3ccc(C)cc3)nc3c2CN(c2c(C=O)c(C(F)F)nn2C)CC3)CC1(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: CO[C@@H]1CCN(c2nc(-c3c(C)ccc4[nH]nc(C)c34)nc3c2CN(c2c(C#N)c(C(F)F)nn2C)CC3)CC1(C)C
Temperature: 25 °C

Procedure:
A vessel was charged with (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde (54 mg, 0.074 mmol), hydroxylamine hydrochloride (77 mg, 1.105 mmol), and DMSO (491 μL). The vessel was capped and placed in a sand bath preheated to 100° C. and the reaction mixture was stirred at that temperature. After 2 h the mixture was diluted with methanol and transferred to a round-bottomed flask. Potassium carbonate was added, and the mixture stirred for 2 h at 60° C., then allowed to cool to room temperature. The mixture was then filtered through Celite and concentrated, redissolved in methanol, filtered through a syringe filter, and purified by HPLC (15-100% CH3CN in water with 0.1% NH4OH) to provide (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbonitrile. 1H NMR (400 MHz, CD3OD) δ ppm 7.44 (d, J=8.6 Hz, 1 H), 7.31 (d, J=8.6 Hz, 1 H), 6.54-6.92 (m, 1 H), 4.64 (d, J=14.8 Hz, 1 H), 4.53 (d, J=14.8 Hz, 1 H), 3.85-3.95 (m, 1 H), 3.80 (s, 3 H), 3.67-3.75 (m, 2 H), 3.52 (dd, J=13.4, 1.3 Hz, 1 H), 3.37 (s, 3 H), 3.01-3.10 (m, 4 H), 2.26 (s, 3 H), 2.01 (s, 3 H), 1.97-2.06 (m, 1 H), 1.67-1.79 (m, 1 H), 1.01 (s, 3 H), 0.93 (s, 3 H); MS (ESI+) m/z 576.4 (M+H)+.
Reaction SMILES: [Sn](Cl)Cl.[CH3:4][N:5]([CH3:21])[CH2:6][C:7]([CH3:20])([CH3:19])[CH2:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O.[OH-].[Na+]>Cl>[CH3:21][N:5]([CH3:4])[CH2:6][C:7]([CH3:19])([CH3:20])[CH2:8][NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN(C)CC(C)(C)CNc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: CN(C)CC(C)(C)CNc1ccccc1N
Reaction time: 16 h
Yield: 91.1 %

Procedure:
To a flask containing a solution of tin (II) chloride dehydrate (1.71 g, 7.6 mmol) in concentrated HCl (5 mL) is added a solution of N,N,2,2-tetramethyl-N′-(2-nitrophenyl)propane-1,3-diamine (635 mg, 2.5 mmol). The reaction is stirred for 16 h and is neutralized by the addition of 4M aqueous NaOH. The mixture is extracted with CH2Cl2 and the organic layer is separated, dried (Na2SO4) and concentrated to afford the title compound (504 mg, 90%) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1S.OCC[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[N:10]1([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: OCCN1CCNCC1
Reactant: Sc1cccs1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: c1csc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
2-[1-(2'-hydroxyethyl)piperazino] thiophene 18 was prepared by warming a solution containing thiophene-2-thiol (1.16 g, 10.0 mmol.) and 1-(2-hydroxyethyl) piperazine (1.43 g, 11.0 mmol.) in toluene to reflux under an argon atmosphere for two hours. Completion of the reaction was confirmed by thin layer chromatography using a 4:1 ratio blend of hexane and ethyl acetate as the eluent. The reaction mixture was cooled to room temperature, and the solvent was removed in vacuo. The residue was then concentrated onto 5 g of silica. The silica was added to a medium pressure chromatography column packed with silica. The column was eluted with a 4:1 ratio blend of hexane and ethyl acetate to yield the pure piperazino-thiophene 18 (1.62 g, 76.4% yield) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[CH:15]=O)[N:7]([CH3:18])[C:6]=2[CH:19]=1.[CH2:20]([S:22]([NH2:25])(=[O:24])=[O:23])[CH3:21].C1(C)C=CC=CC=1.[BH4-].[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:17]=[C:14]([CH2:15][NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:13]=[N:12][CH:11]=3)[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CCS(N)(=O)=O
Reactant: Cn1c(-c2cncc(C=O)c2)nc2ccc(Cl)cc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCS(=O)(=O)NCc1cncc(-c2nc3ccc(Cl)cc3n2C)c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A flask was charged with 5-(6-chloro-1-methyl-1H-benzo[d]imidazol-2-yl)nicotinaldehyde (100 mg, 0.368 mmol), ethanesulfonamide (80 mg, 0.736 mmol) and toluene (3 mL), and titanium isopropoxide (157 mg, 0.552 mmol) was added dropwise. The mixture was stirred at 120° C. overnight. The mixture was concentrated in vacuo and the residue was taken up in DCM (20 mL) and MeOH (20 mL), and NaBH4 (0.0557 g, 1.47 mmol) was added at 0° C. The mixture was stirred at 0° C. for 30 min. Water (1 mL) was added and the mixture was stirred for 5 min. DMF (5 mL) was added and the suspension was filtered. The filtrate was purified by Xbridge RP 18 eluting with a 20 to 70% ACN-water gradient to give the title compound. HRMS: (ESI) m/z 365.0839 [(M+H)+ Calcd for C16H18ClN4O2S 365.0834]. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (t, J=7.33 Hz, 3H) 3.06 (q, J=7.33 Hz, 2H) 3.92 (s, 3H) 4.33 (s, 2H) 7.30 (dd, J=8.46, 2.15 Hz, 1H) 7.73 (d, J=8.59 Hz, 1H) 7.77 (s, 1H) 7.86 (d, J=2.02 Hz, 1H) 8.25 (t, J=2.02 Hz, 1H) 8.72 (d, J=2.02 Hz, 1H) 8.97 (d, J=2.27 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:34]3[CH:33]=[CH:32][N:31]=[C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)[CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: COc1cc(OC)c(F)c(-c2cc3[nH]nc(I)c3cn2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccnc(N5CCN(C)CC5)c4)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=467.2.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH2:30][CH3:31].[OH-].[Na+].Cl>C(O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([CH2:30][CH3:31])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: CCc1cc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)ccc1OCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(SCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)ccc1OCC(=O)O
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-chloro-phenyl)-allylsulfanyl]-2-ethyl-phenoxy}-acetic acid methyl ester (100 mg, 0.22 mmol, example 17) was dissolved in ethanol (10 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1N HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evaporated to give the title compound in 10 mg yield.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[NH2:12][C:13]1([C:33](O)=[O:34])[CH2:17][C:16]([CH3:32])([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=2)[O:15][CH2:14]1>CO.C(Cl)Cl>[NH2:12][C:13]1([CH2:33][OH:34])[CH2:17][C:16]([CH3:32])([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:20][CH:19]=2)[O:15][CH2:14]1
Reactant: CCCCCCCCc1ccc(C2(C)CC(N)(C(=O)O)CO2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(C2(C)CC(N)(CO)CO2)cc1
Reaction time: 2 h
Yield: 33.4 %

Procedure:
A solution of lithium aluminum hydride (2.70 ml, 5.40 mmol) (Aldrich) was added carefully to THF (17.99 ml) under nitrogen. 3-amino-5-methyl-5-(4-octylphenyl)tetrahydrofuran-3-carboxylic acid (0.6 g, 1.799 mmol) was added in small portions causing vigorous bubbling. The reaction stirred for about 2 h. TLC in 10% MeOH in methylene chloride showed (Hannessian's stain visualization) reaction complete. The reaction was quenched by addition of water (200 uL) and the reaction stirred about 30 min. 10% NaOH (0.6 mL) was added and the reaction stirred about 30 min. Finally, water (200 uL) was added and the reaction stirred about 30 min. The resulting solid was collected by vacuum filtration and washed with ether. The filtrate was concentrated to a colorless oil. The residue was purified by flash column chromatography (40 g Redi-Sep) eluting with 10-20% methanol in methylene chloride and the product fractions combined. Solvents were removed under reduced pressure. The residue was redissolved in methylene chloride and filtered through a syringe filter into a vial and washed through with methylene chloride. Solvent was removed under reduced pressure to provide (3-amino-5-methyl-5-(4-octylphenyl)tetrahydrofuran-3-yl)methanol (0.192 g, 0.601 mmol, 33.4% yield) as a colorless oil that solidified on standing to a white solid:
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reactant: CN(C)CCCCl
Product: CN(C)CCCOc1cccc(-c2cc(NC(N)=O)c(C(N)=O)s2)c1

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(3-chloropropyl)dimethylamine.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:11])=[N:6][N:7]([CH3:10])[C:8]=1[CH3:9])([O-])=O>[Ni].N>[NH2:1][C:4]1[C:5]([CH3:11])=[N:6][N:7]([CH3:10])[C:8]=1[CH3:9]
Reactant: Cc1nn(C)c(C)c1[N+](=O)[O-]
Agent: [Ni]
Agent: N
Product: Cc1nn(C)c(C)c1N

Procedure:
The compounds from (b) above (2.3 g; 0.014 moles) was catalytically hydrogenated using Raney nickel (1 g) in methanolic ammonia (100 mL) under a hydrogen atmosphere at 50 psi. The catalyst was filtered and the solution concentrated in vacuo, leaving a residue that was triturated several times with ethyl ether. The decanted solvent was concentrated to dryness, leaving a pale red solid. Yield: 1.3 g (70%).
Reaction SMILES: [C:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=2[Br:22])=[C:6]([CH2:25][CH2:26][CH3:27])[C:5]=1[OH:28])(=[O:3])[CH3:2].[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:28][C:5]1[C:6]([CH2:25][CH2:26][CH3:27])=[C:7]([CH:23]=[CH:24][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Br:22])(=[O:31])[CH3:30]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O

Procedure:
In a mixture of pyridine (10 ml) and acetic anhydride (10 ml) was dissolved 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-bromobenzoic acid (2 g). The solution was heated at 100° to 120° C. for 14 hours, which was then concentrated. The residue was dissolved in chloroform. The solution was washed with dilute hydrochloride acid, which was then dried on sodium sulfate. From the resultant was removed the solvent by evaporation, and the residue was chromatographed on a column of silica gel. Elution was conducted with hexane-ethyl acetate (3:1), (2:1), (1:1) and ethyl acetate in that order. Ethyl acetate fractions were combined and concentrated. The residue was crystallized from chloroform-hexane to give 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoic acid (1.0 g), m.p. 155°-156° C.
Reaction SMILES: O[CH2:2][C:3]1[C:4](=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1.Cl>C(O)C>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:11]3[C:10]4[C:5]([CH2:4][C:3]=3[CH:2]=[N:22]2)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:17][CH:16]=1
Reactant: O=C1C(CO)=Cc2ccccc21
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: Clc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethyl inden-1-one (Example 1(ii)(a) (4.0 g; 25.00 mmol), p-chlorophenylhydrazine hydrochloride (Aldrich) (4.52 g; 25.25 mmol), 10M hydrochloric acid (1 cm3) and ethanol (30 cm3) were heated under reflux for 22 hours. After cooling, the solvent was evaporated and the residual dissolved in dichloromethane and washed with 2M sodium hydroxide. The organic extracts were then dried (Na2SO4), filtered and concentrated in vacuo. Purification was by column chromatography (Eluant: dichloromethane] and recrystallisation (ethanol) gave off-white needle shaped crystals, m.p. 128-129° C.; b.p. 185° C.; 0.05 mmHg.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[F:48])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C@@H:6]([C:11]1[C:42]([CH3:43])=[N:41][C:40]2=[CH:44][C:37]3=[N:38][N:39]2[C:12]=1[C:13]1[CH:47]=[C:46]2[C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[C:32]2[CH:45]=[C:36]3[CH:35]=[CH:34][CH:33]=2)=[CH:15][C:14]=1[F:48])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1-c1cc2c(cc1F)OCCN2CCCCCc1ccccc1-c1cccc-3c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)-c1cc2c(cc1F)OCCN2CCCCCc1ccccc1-c1cccc-3c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
A solution of methyl (2S)-2-(tert-butoxy)-2-{32-fluoro-4-methyl-29-oxa-5,7,8,26-tetraazaheptacyclo[24.6.2.16,9.110,14.02,7.015,20.030,34]hexatriaconta-1(32),2,4,6(36),8,10(35),11,13,15(20),16,18,30,33-tridecaen-3-yl}acetate (0.023 g, 0.036 mmol) in MeOH (˜2 mL) was treated with 1.0 N aq. NaOH (0.360 ml, 0.360 mmol) and heated (70° C. oil bath) for 4 h, then temperature was lowered to 50° C. and stirring continued for 16 h. The reaction was cooled and purified by prep-HPLC to afford desired product. 1H NMR (500 MHz, DMSO-d6) δ 7.98-7.83 (m, 2H), 7.59-7.49 (m, 1H), 7.40-7.29 (m, 2H), 7.29-7.20 (m, 2H), 7.17 (br. s., 2H), 7.00 (d, J=6.4 Hz, 1H), 6.82 (d, J=10.4 Hz, 1H), 4.84 (br. s., 1H), 4.19 (br. s., 3H), 2.94-2.79 (m, 2H), 2.72 (d, J=12.2 Hz, 2H), 2.62 (br. s., 3H), 1.69 (br. s., 1H), 1.59-1.18 (m, 6H), 0.92 (br. s., 9H). UPLC-MS (M+H)=635.4.