Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:9]=1[O:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23](OC)=[O:24])[CH2:12]1>C1COCC1>[NH2:7][C:8]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:9]=1[O:10][C@@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[C@H:13]([CH2:23][OH:24])[CH2:12]1
Reactant: COC(=O)[C@@H]1C[C@H](Oc2cc(F)ccc2N)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2cc(F)ccc2N)C[C@H]1CO
Reaction time: 4 h

Procedure:
Lithium aluminium hydride (540.0 mg) added to a cooled (0-4° C.) solution of (2S,4S)-1-tert butyl 2-methyl 4-(2-amino-5-fluorophenoxy)pyrrolidine-1,2-dicarboxylate (3.36 g) in THF (30.0 ml). The reaction mixture was stirred at this temperature for 4 h. After this time the mixture was quenched with water (0.54 ml), NaOH (2M; 0.54 ml) and water (3×0.54 ml). The mixture was stirred for 1.5 h, then diluted with EtOAc and MgSO4 was added. The suspension was filtered through celite and the filtrate evaporated. The residue was purified by chromatography.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[S:3]1.[Li]CCCC.CN([CH:28]=[O:29])C>C1COCC1.CCCCCC>[CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:16][C:15]([CH3:17])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=2)[S:3]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C2=CC(C)(C)Sc3ccc(Br)cc32)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C2=CC(C)(C)Sc3ccc(C=O)cc32)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cold (-78° C.) solution of 2,2-dimethyl-4(2-methyl-thien-5-yl)-6-bromo-thiochrom-3-ene (Compound T, 430 mg, 1.2 mol) in THF (12 mL) was added n-BuLi in hexane (1.6 M solution, 1 mL). The mixture was gradually warmed to ambient temperature over 1 hour and recooled to -78° C. To this solution was added DMF (220 mg, 3 mmol) and the mixture was stirred at ambient temperature for 16 hours. The reaction was quenched by adding water (10 mL) and ethy lacetate (100 mL). The organic layer was washed with brine (10 mL), dried and the solvent was removed by distillation to obtain the title compound as a pale yellow oil.
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].C(O)(=O)C.[CH2:12]([O:14][CH:15]1[O:19][C:18](=[O:20])[CH:17]=[CH:16]1)[CH3:13].N12CCCN=C1CCCCC2>ClCCl>[N:1]([CH:16]1[CH:15]([O:14][CH2:12][CH3:13])[O:19][C:18](=[O:20])[CH2:17]1)=[N+:2]=[N-:3]
Reactant: CCOC1C=CC(=O)O1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC1OC(=O)CC1N=[N+]=[N-]
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
This procedure was carried out in a manner similar to that described by D. J. Guerin, et al., Org. Lett (1999), 1, 1107-1109. To a solution of azidotrimethylsilane (25.8 mL, 0.32 mol) in dichloromethane (400 mL) at room temperature under nitrogen was added acetic acid (18.1 mL, 0.32 mol), and the reaction was stirred for 20 min. 5-Ethoxy-5H-furan-2-one (II, R1=Et) (8.10 g, 0.063 mol) was added dropwise, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL, 0.013 mol). The reaction was stirred for 24 h, washed with sodium bicarbonate, dried over sodium sulfate and evaporated. Purification by flash chromatography (SiO2) eluted with 1:9 ethyl acetate:hexanes afforded 4-azido-5-ethoxy-dihydrofuran-2-one (7.85 g, 73% yield) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[N:4][N:5]2[C:10](Cl)=[CH:9][CH:8]=[CH:7][C:6]=12.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:3]2[C:2]([C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:24]4[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=4)[N:5]3[N:4]=2)=[CH:13][CH:14]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Fc1ccc(-c2nn3c(Cl)cccc3c2Br)cc1
Product: Fc1ccc(-c2nn3c(-c4ccnc(F)c4)cccc3c2-c2ccnc(F)c2)cc1
Yield: 34.4 %

Procedure:
In a similar manner to that in Example 28, from 3-bromo-7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridine (305 mg, 0.94 mmol) and 2-fluoropyridin-4-ylboronic acid (182 mg, 1.30 mmol) after heating to 100° C. for 1.5 hours was formed 2-(4-fluorophenyl)-3,7-bis(2-fluoropyridin-4-yl)pyrazolo[1,5-α]pyridine (90 mg, 24%). 1H NMR (CDCl3): δ 8.47 (d, 1H), 8.29 (d 1H), 7.89 (br d, 1H), 7.78 (d, 1H), 7.72 (s, 1H), 7.58 (dd, 2H), 7.44 (dd, 1H), 7.20 (br d, 1H), 7.15 (d, 1H), 7.13 (t, 2H), 7.05 (s, 1H); MS m/z 403 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:10]([C:11]2[CH:15]=[CH:14][O:13][N:12]=2)=[CH:9][C:8]([C:16]2[N:21]=[C:20]([NH2:22])[C:19]([NH2:23])=[CH:18][N:17]=2)=[N:7]1.ClCCl.[CH2:31]([O:33]CC)[CH3:32]>C(O)(=O)C>[NH2:22][C:20]1[C:19]([NH:23][C:31](=[O:33])[CH3:32])=[CH:18][N:17]=[C:16]([C:8]2[CH:9]=[C:10]([C:11]3[CH:15]=[CH:14][O:13][N:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=3[F:2])[N:7]=2)[N:21]=1
Reactant: Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Reactant: CCOCC
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cnc(-c2cc(-c3ccon3)n(Cc3ccccc3F)n2)nc1N
Temperature: 25 °C
Yield: 79 %

Procedure:
A solution of 2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,5-diamine hydrochloride (I-107) (30 mg, 0.077 mmol) in acetic acid (2 mL) was heated to 110° C. for 18 h. After cooling to room temperature, the solution was partitioned between ethyl actetate (50 mL) and saturated aqueous sodium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude product as a tan residue. Dichloromethane (3 mL) and diethyl ether (5 mL) were added, and the resulting white solid was filtered and washed with additional diethyl ether ether to give N-(4-amino-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidin-5-yl)acetamide (24 mg, 0.061 mmol, 79% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, 1H), 8.26 (s, 1H), 7.66 (br s, 1H), 7.34 (s, 1H), 7.18-7.13 (m, 1H), 7.01-6.96 (s, 1H), 6.92 (t, 1H), 6.77 (t, 1H), 6.56 (d, 1H), 5.96 (s, 2H), 5.57 (br s, 2H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[N:16]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([NH:23][C:24]([NH:12][S:9]([C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH2:3][O:2][CH3:1])(=[O:11])=[O:10])=[O:25])[N:18]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COCc1ccsc1S(N)(=O)=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCc1ccsc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.41 g of 3-(methoxymethyl)thiophene-2-sulfonamide and 0.55 g of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate in 20 mL of acetonitrile is added 0.3 mL of 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU). After being stirred for 2 hours at ambient temperature and pressure, the reaction mass is poured onto 25-50 g of ice and the resultant mixture acidified to pH 3 by the addition of hydrochloric acid. The desired solid product can be isolated by filtration. Alternatively, it can be extracted into methylene chloride which is then dried over magnesium sulfate, filtered and evaporated to dryness to yield the desired product is sufficiently pure form for the purposes of this invention.
Reaction SMILES: Br[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][N:12]=1>C(#N)C>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:2][CH3:3])=[CH:13][N:12]=1
Reactant: Oc1ccc(Br)nc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(Br)nc1

Procedure:
2.51 g (22.99 mmol) 1-bromoethane and 1.99 g (14.37 mmol) K2CO3 are added to a mixture of 1.0 g (5.75 mmol) 2-bromo-5-hydroxypyridine in 100 mL ACN. The mixture is stirred at reflux over night. Then the reaction mixture is poured onto water and extracted with TBME. The organic layer is dried with Na2SO4 and the solvent is removed under vacuo. The residue is purified by column chromatography (silica gel, PE/EtOAC 1/1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([OH:25])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[C:22]3[C:17](=[CH:18][C:19]([C:23]([O:25][CH2:31][CH3:32])=[O:24])=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Reaction time: 96 h

Procedure:
12.4 g 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-6-carboxylic acid are suspended in 80 ml of ethanol and 1.6 ml conc. Sulphuric acid are added. The reaction mixture is stirred for 96 hours at reflux temperature. The solid is suction filtered, dissolved in ethanol and made basic with sodium hydroxide solution. 5.3 g product are obtained as a solid.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])[N:3]=[CH:4]2)[N:12]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(I)c2)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 92.7 %

Procedure:
To a stirred solution of 2-(4-iodo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example E.71) (0.43 g, 1.0 mmol) in THF (7 mL) was added at 0° C. isopropyl-magnesium chloride lithium chloride (1M in THF, 1.22 mL, 1.22 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.43 g, 1.33 mmol) was added, the reaction mixture was stirred at room temperature for 5 h, poured into saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.55 g, 93%) as a light yellow oil. MS (ISP) 595.3 [(M+H)+].
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: C1CCNC1
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCCC1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol) and pyrrolidine (0.25 mL; 3.0 mmol) under microwave irradiation according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-pyrrolidin-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (60 mg, 61%) as an off-white powder. ES-HRMS m/e calcd for C19H29N4O (M+H+) 329.2336, found 329.2334.
Reaction SMILES: C(N)C1C=CC=CC=1.C(OC([NH:19][C@H:20]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([P:33](=[O:36])([OH:35])[OH:34])[CH3:32])=[O:29])[CH3:27])=[O:24])[CH2:21][OH:22])=O)C1C=CC=CC=1>>[NH2:19][C@H:20]([C:23]([NH:25][C@H:26]([C:28]([NH:30][C@H:31]([P:33](=[O:34])([OH:36])[OH:35])[CH3:32])=[O:29])[CH3:27])=[O:24])[CH2:21][OH:22]
Reactant: C[C@H](NC(=O)[C@H](CO)NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Solvent: NCc1ccccc1
Product: C[C@H](NC(=O)[C@@H](N)CO)C(=O)N[C@@H](C)P(=O)(O)O

Procedure:
In a manner analogous to that described in Example 3(ii) from the monobenzylamine salt of (1R)-1-[(N-benzyloxycarbonyl-L-seryl-L-alanyl)amino]-ethylphosphonic acid there was obtained (1R)-1-(L-seryl-L-alanylamino)-ethylphosphonic acid of melting point 256°-257° C. (decomposition); [α]D20 =-61.4°; [α]36520 =-222° (c=0.5% in water).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[C:27](Cl)(=[O:31])[CH:28]([CH3:30])[CH3:29]>CCCCCC.O>[CH:3]1[C:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][C:2]=1[NH:1][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29]
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a 500 mL three-neck flask were put 15 g (83 mmol) of 2-aminofluorene, 10 g (100 mmol) of triethylamine, and 250 mL of tetrahydrofuran (THF), and the mixed solution was stirred. Then, to this mixed solution, a mixed solution of 8.8 g (83 mmol) of isobutyryl chloride and 50 mL of THF was added dropwise under cooling with ice, and the mixture was stirred at room temperature for 12 hours. After the stirring, 200 mL of water was added to this mixture, and the mixture was stirred for 1 hour. After the stirring, the precipitated solid was washed with water and subjected to suction filtration to give a white solid. A hexane suspension of this solid was irradiated with ultrasonic waves, and a solid was collected by suction filtration, so that 20 g of a white solid of N-(9H-fluoren-2-yl)isobutyramide was obtained in a yield of 97%. The synthesis scheme of Step 1 is shown in (c-1) below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C)CC2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of 4-fluoro-3-nitro-benzoic acid methyl ester (10 g, 50.2 mmol), K2CO3 (7 g, 50.2 mmol) and 1-methyl-piperazine (11.2 mL, 100.4 mmol, 2 eq.) in 200 mL of N,N-dimethylformamide was stirred at 100° C. for 1 h. The solvent was then evaporated, the residue taken-up with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated to dryness. The crude was purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH 9:1 as eluant, affording 14 g of the title compound as orange oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH2:20][CH2:21][CH3:22])[CH3:2].[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:36]Br)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:23]([O:31][CH2:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[CH2:41][O:42][C:43](=[O:50])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:36][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:19])[CH2:17][CH3:18])=[CH:12][C:11]=2[CH2:20][CH2:21][CH3:22])[CH:5]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1CC
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)ccc1CC

Procedure:
In a manner similar to that of Example 1(o), by reacting 1.28 g (4.3 mmol) of 1-(2′-ethyl-5′-hydroxy-2-propylbiphenyl-4-yl)-1-propanone with 1.98 g (4.5 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide, an oil is obtained, which is used without purification.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]3=[CH:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:38].[Na+].ClC1C=CC=C(C(OO)=O)C=1.O>COC(C)(C)C>[C:1]([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@@:16]43[O:38][C@H:17]4[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC=C2C3=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1C[C@@H]2O[C@@]23C2=CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]2CC[C@]13C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 24.55 kg amount of (3β,5α)-cholesta-7,14-dien-3-ol benzoate (2) (prepared in the manner described in Example 1) and 6.41 g of sodium bicarbonate were suspended under nitrogen with good agitation in 240 liters of t-butyl methyl ether in a 200-gallon reactor and chilled to 0° C. A solution of 13.0 kg of m-chloroperbenzoic acid in 100 liters of t-butyl methyl ether at about 20° C. was added to the steroid-bicarbonate suspension over a 10 minute period. A mild exothermic reaction which raised the reaction mixture temperature to 10° C. was noted. The mixture was stirred for 2 hours then 150 liters of water were added. The mixture was stirred an additional hour and agitation was halted to allow separation of the phases. The lower aqueous layer was drained off and the remaining organic phase was treated with 50 liters of water, agitated vigorously, and then the aqueous portion was drained off. The product was filtered at about 10° C., washed with three 10 liter portions of methanol and air-dried to yield 19.1 k9 of (3) batch-A.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([O:13][C:14]4[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)=[CH:9][CH:8]=3)[C:3]([O:5][CH3:6])=[O:4])=[CH:34][CH:35]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 78.8 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 4.4 g of p-cyclohexylphenol to give 7.44 g of product as a pale yellow glass.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([C:22]([O:24]CC)=[O:23])[C:3]=1[F:27].C(O)C.[OH-].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8](=[O:20])[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([F:19])[CH:13]=3)[O:11][C:6]=2[C:5]([F:21])=[C:4]([C:22]([OH:24])=[O:23])[C:3]=1[F:27]
Reactant: CCOC(=O)c1c(F)c(N)c2c(=O)cc(-c3ccc(N)c(F)c3)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: Nc1ccc(-c2cc(=O)c3c(N)c(F)c(C(=O)O)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
121 mg (0.320 mmol) of Compound 92 obtained in Example 92 (2) was suspended in a mixed solvent of 10 mL of ethanol and 5 mL of methanol, 0.4 mL of a 5N aqueous solution of sodium hydroxide was added and the mixture was stirred at 50° C. for 2.5 hours. The reaction solution was cooled on ice, the solution was adjusted to pH 4 and the precipitated crystals were collected by filtration to give 101 mg of Compound 93 (yield: 90%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12](S(C)(=O)=O)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[Br:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1>N1C=CC=CC=1.CCOC(C)=O>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:19]([F:20])=[CH:18][C:10]3[NH:11][C:12]([O:34][C:30]4[CH:31]=[CH:32][CH:33]=[C:28]([Br:27])[CH:29]=4)=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)c1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Reactant: Oc1cccc(Br)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Fc1cc2[nH]c(Oc3cccc(Br)c3)nc2cc1-c1ccc(-c2ccccc2)cc1
Reaction time: 48 h

Procedure:
To a solution of compound 13-6 (1.53 g, 4.2 mmol) in 20 mL in pyridine was added 3-bromo-phenol (1.4 g, 8.4 mmol). The reaction mixture was heated to reflux and allowed to stir for 48 h. The reaction mixture was diluted with EtOAc (150 mL) and washed three times with 100 mL portions of saturated aqueous ammonium chloride. The combined organic layers were dried over MgSO4 filtered and concentrated in vacuo. The crude was purified on ISCO (EtOAc/Hexanes=1/1) to yield the title compound 13-7 along with recovered starting material 13-6.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Si:19]([O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.05 g, 0.2 mmol), (2-bromoethoxy)(tert-butyl)dimethylsilane (61 uL, 0.28 mmol, Aldrich, Cat. No. 428426), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 74 mg of product which was directly used in the next step reaction without further purification.