Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15]O.Cl>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)nc2ccccc12
Agent: Cl
Product: COC(=O)c1cc(O)nc2ccccc12

Procedure:
To 2-hydroxyquinoline-4-carboxylic acid (V, 5.52 g) is added a saturated methanol/hydrochloric acid mixture in 50 ml aliquots over 5 days. The methanol/hydrochloric acid is then removed under reduced pressure and the residue is carefully treated with aqueous sodium bicarbonate. When the aqueous layer tests basic, the solid is collected, washed with water, and dried under reduced pressure to give methyl 2-hydroxyquinoline-4-carboxylate (VI), mp 240-241°.
Reaction SMILES: [OH:1][C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:4](=[O:14])[CH:3]=1.CCN(C(C)C)C(C)C.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C(Cl)Cl>[O:14]=[C:4]1[CH:3]=[C:2]([O:1][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CC(O)=CC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To tert-butyl 4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (680 mg, 3.41 mmol) in DCM (12 mL) was added DIEA (1.192 mL, 6.83 mmol) and tosyl chloride (651 mg, 3.41 mmol). The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography (0 to 50% EtOAc/heptane). Pure fractions were combined, evaporated and dried to give desired product as a white solid (0.98 g, 81%). LCMS (m/z): 354.1 (MH+), 0.97 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.99 (d, J=8.22 Hz, 2H) 7.54 (d, J=7.83 Hz, 2H) 5.77 (s, 1H) 4.33 (s, 2H) 2.43 (s, 3H) 1.41 (s, 9H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[OH:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([OH:40])[CH:39]=1)[C:34]([OH:36])=O>>[OH:40][C:38]1[CH:37]=[C:33]([CH:32]=[C:31]([OH:30])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: O=C(O)c1cc(O)cc(O)c1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Product: CN(C(=O)c1cc(O)cc(O)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dihydroxybenzoic acid followed according to example 12 by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dihydroxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 502 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:15]([NH:14][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[O:16]
Reactant: O=C=Nc1cccc2[nH]ccc12
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)Nc1cccc2[nH]ccc12
Yield: 68.3 %

Procedure:
3-Fluoro-4-(trifluoromethyl)benzylamine (0.22 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.24 g). mp 198° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.43 (d, 2H), 6.52 (m, 1H), 6.98 (m, 3H), 7.26 (m, 1H), 7.39 (m, 2H), 7.57 (dd, 1H), 7.77 (t, 1H), 8.40 (s, 1H), 11.05 (s, 1H); MS (DCI+) m/z 349.9 (M+H)+. Anal. Calcd. for C17H13N3F4O: C, 58.12; H, 3.73; N, 11.96. Found C, 58.52; H, 3.99; N, 11.55.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[CH3:8][N:9]([CH2:11]N(C)C)[CH3:10]>>[CH3:8][N:9]([CH2:11][C:5]1[O:1][C:2]([CH2:6][OH:7])=[CH:3][CH:4]=1)[CH3:10]
Reactant: OCc1ccco1
Reactant: CN(C)CN(C)C
Product: CN(C)Cc1ccc(CO)o1

Procedure:
In a series of experiments with 2-furanmethanol we have found that the use of bis(dimethylamino)methane gives better yields of 5-(dimethylaminomethyl)-2-furanmethanol than those obtained using dimethylamine and a source of formaldehyde (e.g. aqueous formaldehyde, paraformaldehyde and trioxan). Furthermore the product obtained after distillation was also purer. The yields referred to above were 76-94% and these compare very favourably with the yields reported by R. F. Holdren (12%) (J. Amer. Chem. Soc. 69(464)1947) and Gill and Ing (70%) (J. Chem. Soc. 4728 (1958)).
Reaction SMILES: [OH:1][NH:2][C:3]1([C:11]#N)[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1.S(=O)(=O)(O)[OH:14].[CH3:18][OH:19]>ClCCl>[CH3:18][O:19][C:11]([C:3]1([NH:2][OH:1])[CH2:8][CH2:7][N:6]([O:9][CH3:10])[CH2:5][CH2:4]1)=[O:14]
Reactant: CO
Reactant: CON1CCC(C#N)(NO)CC1
Reactant: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)C1(NO)CCN(OC)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a suspension of 4-hydroxyamino-1-methoxy-piperidine-4-carbonitrile (230 g, 1.34 mol) in dichloromethane (2400 ml) at room temperature was added concentrated sulfuric acid (358 ml, 658.8 g, 6.72 mol) dropewise, and the reaction mixture was stirred at 40° C. for one hour. Methanol (925.1 ml, 731.7 g, 22.8 mol) was added at 40° C. dropewise, and the mixture stirred at 40° C. for 4 hours. The dichloromethane was distilled off allowing to heat the reaction mixture at 60° C. for 24 hours. The reaction mixture was poured on ice (3 kg) and neutralized by careful addition of concentrated aqueous sodium hydroxide first, followed by saturated aqueous sodium hydrogen carbonate. The aqueous phase was saturated with sodium chloride, extracted with ter-butyl methyl ether (10×300 ml), the combined organic layers washed with brine, dried over sodium sulfate and concentrated to afford a first crop of product (163.8 g). Further extraction of the aqueous layer with ethyl acetate delivered another 35 g of crude product. Yield: 198.8 g of 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester as a red-brown, viscous oil. This material was used without further purification in the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:23][C@H:22]1[CH2:34][CH2:35][CH2:36][OH:37])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28])[CH2:23][C@H:22]1[CH2:34][CH2:35][CH:36]=[O:37])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCCO)N(C(=O)OCc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CCC=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.33 h

Procedure:
Oxalyl chloride (0.32 ml) was dissolved in 7.9 ml of dry dichloromethane, and 0.56 ml of dry dimethylsulfoxide was added thereto at -45° to -56° C. in a nitrogen stream, followed by stirring at the same temperature for 20 minutes. To the reaction mixture was added a solution of 1.30 g of (2R,4R)-1-benzyloxycarbonyl-2-(3-hydroxypropyl)-4-t-butyldimethylsilyloxypyrrolidine in 6.2 ml of dry dichloromethane at -50° to -60° C., followed by stirring at the same temparature for 15 minutes. Then, 2.2 ml of triethylamine was added thereto at -50° to -60° C. The temparature was elevated to room temperature, and the reaction mixture was washed successively with brine, dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and distilled to obtain (2R,4R)-1-benzyloxycarbonyl-2-(2-formylethyl)-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1>CN(C=O)C>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)[CH2:17][CH2:18]2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)cc1
Temperature: 80 °C

Procedure:
To a solution of 1-[2-(4-nitrophenyl)ethyl]piperazine hydrochloride (30 mg, 0.11 mmol) in DMF (2 mL) was added 1-(2-bromoethyl)-4-nitrobenzene (31 mg, 1.3 mmol) and TEA (46 uL, 0.33 mmol). The mixture was heated to 80° C. for 16 hours. LC showed some desired product at that point. The desired 1,4-bis[2-(4-nitrophenyl)ethyl]piperazine was purified by mass-directed HPLC. LC-MS (IE, m/z): 385 [M+1]+. (0.052 μM)
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]([NH:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([CH2:26]OS(C)(=O)=O)=[CH:24][CH:23]=1)=[O:19]>>[N:10]1[C:11]2[CH:2]([NH:1][CH2:26][C:25]3[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=4)=[O:19])=[CH:33][CH:32]=3)[CH2:3][CH2:4][CH2:5][C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1ccc(CNC(=O)c2ccccn2)cc1
Reactant: NC1CCCc2cccnc21
Product: O=C(NCc1ccc(CNC2CCCc3cccnc32)cc1)c1ccccn1

Procedure:
Using General procedure H: Reaction of 8-amino-5,6,7,8-tetrahydroquinoline (148 mg, 1.00 mmol) with methanesulfonic acid 4-{[(pyridine-2-carbonyl)-amino]-methyl}-benzyl ester (214 mg, 0.67 mmol) for 3 h at room temperature followed by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH 48:1:1) gave AMD9397 (81 mg, 33%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.72-1.83 (m, 2H), 2.00-2.06 (m, 1H), 2.16-2.20 (m, 1H), 2.75-2.83 (m, 2H), 3.82-3.84 (m, 1H), 3.88 (d, 1H, J=13.2 Hz), 3.98 (d, 1H, J=12.9 Hz), 4.65 (d, 2H, J=6.0 Hz), 7.05-7.06 (m, 1 H), 7.32-7.42 (m, 6H), 7.85 (ddd, 1H, J=7.8, 7.8, 1.8 Hz), 8.23 (d, 1H, J=7.8 Hz), 8.34 (br s, 1H), 8.37 (d, 1H, J=3.3 Hz), 8.52 (d, 1H, J=3.9 Hz). 13C NMR (75.5 MHz, CDCl3) δ 20.05, 29.00, 29.24, 43.68, 51.85, 57.85, 122.19, 122.70, 126.56, 128.37 (2C), 129.01 (2C), 132.83, 137.07, 137.23, 137.73, 140.41, 147.20, 148.46, 150.23, 157.82, 164.57. ES-MS m/z 373 (M+H). Anal. Calcd. for C23H24N4O.0.3H2O: C, 73.11; H, 6.56; N, 14.83. Found: C, 72.98; H, 6.58; N, 14.63.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH2:11].C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:12]1(/[CH:10]=[CH:11]/[C:2]2[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C=CC1CCCCC1
Reactant: OCc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OCc1ccc(/C=C/C2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 23 h
Yield: 31.1 %

Procedure:
4-Iodobenzyl alcohol (2.34 g) was dissolved in DMF (40 mL), added with vinylcyclohexane (1.32 g), triethylamine (1.81 mL), and bis(triphenylphosphine)palladium (II) chloride (700 mg), and stirred for 23 hours at 80° C. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residues were purified by silica gel column chromatography (8 to 30% ethyl acetate/hexane) to obtain the title compound (672 mg) as a yellow solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][N:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=2)[N:14]=[C:13]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[CH:28]=1)(=O)C.[OH-].[Li+].O>O1CCCC1CO>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([C:13]2[N:12]([CH2:11][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[OH:4])[C:20]3[C:15]([N:14]=2)=[N:16][CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=3)[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2OC(C)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: COc1cccc(-c2nc3ncc(-c4ccccc4)cc3n2Cc2ccccc2O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.9 %

Procedure:
2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenyl acetate (Compound of Example 153) (177 mg) was dissolved in tetrahydrofuran-methanol (1:1, v/v, 20 ml). To the solution was added 2 N lithium hydroxide (6.8 ml). The mixture was stirred at room temperature for 1.5 hour. The reaction mixture was poured into water and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration to obtain 2-[[2-(3-methoxyphenyl)-6-phenyl-1H-imidazo[4,5-b]pyridin-1-yl]methyl]phenol (133 mg, 83%). The crystals were recrystallized from tetrahydrofuran-ethyl acetate.
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].CO>C(Cl)Cl.O>[Br:1][C:13]1[CH:12]=[C:7]([CH:6]=[CH:5][C:4]=1[OH:3])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)c(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
Dibromine (0.185 L, 3614.92 mmol) was added dropwise a stirred suspension of methyl 4-hydroxybenzoate (500 g, 3286 mmol) in DCM (4 L) at 0° C. under N2. The mixture was left to stir for 24 hrs at RT under N2 (need to trap HBr). A solution of sodium metabisulfite (62.5 g, 329 mmol) in 2 L of water was then added, while keeping the temperature around 15° C., followed by 500 mL of MeOH. The organic layer was washed with water, brine, dried over magnesium sulfate, filtered and concentrated to dryness to afford methyl 3-bromo-4-hydroxybenzoate (710 g, 94%) as a white solid. NMR Spectrum (CDCl3): 3.89 (s, 3H), 5.95 (s, 1H), 7.05 (d, 1H), 7.92 (dd, 1H), 8.19 (d, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:22])=[C:10]([C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[OH:21])=[O:13])[CH:11]=1>C(O)(=O)C>[Cl:5][C:6]1[CH:7]=[C:8]([N+:1]([O-:4])=[O:2])[C:9]([OH:22])=[C:10]([C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[OH:21])=[O:13])[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(c1cc(Cl)ccc1O)c1cc(Cl)ccc1O
Solvent: CC(=O)O
Product: O=C(c1cc(Cl)ccc1O)c1cc(Cl)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Nitric acid (4 ml) was added dropwise to a stirred solution of bis(5-chloro-2-hydroxyphenyl)ketone (2.7 g) in glacial acetic acid (50 ml). The solution was stirred at room temperature for 1 hr and during this time a yellow solid separated from solution. The mixture was poured into ice water and the product collected by filtration. Thin layer chromatography indicated that the product was a mixture of two compounds which were separated by column chromatography on silica gel. Elution with hexane containing increasing amounts of ethyl acetate afforded 5-chloro-2-hydroxyphenyl 5-chloro-2-hydroxy-3-nitrophenyl ketone (150 mg) m.p. 153° C., followed by bis-(5-chloro-2-hydroxy-3-nitrophenyl)ketone (1.5 g), m.p. 187° C.
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=CN=3)CC3CC(CC(C3)C1)C2.[C@@H:25]12[CH2:31][C@@H:28]([CH2:29][CH2:30]1)[CH2:27][C@@H:26]2[O:32][C:33]1[C:41]([CH:42]2[CH2:44][CH2:43]2)=[CH:40][C:36]([C:37]([OH:39])=O)=[C:35]([F:45])[CH:34]=1.COCCS(N)(=O)=O.[N:54]1([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1>>[N:54]1([S:58]([NH:61][C:37](=[O:39])[C:36]2[CH:40]=[C:41]([CH:42]3[CH2:43][CH2:44]3)[C:33]([O:32][C@H:26]3[CH2:27][C@H:28]4[CH2:31][C@@H:25]3[CH2:30][CH2:29]4)=[CH:34][C:35]=2[F:45])(=[O:60])=[O:59])[CH2:57][CH2:56][CH2:55]1
Reactant: O=C(O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: NS(=O)(=O)N1CCC1
Agent: COCCS(N)(=O)=O
Agent: O=C(O)c1cnc(OCC23CC4CC(CC(C4)C2)C3)c(C2CC2)c1
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 56 %

Procedure:
Following the procedure as described in Example 271 and making variations as required to replace 6-(adamantan-1-ylmethoxy)-5-cyclopropylnicotinic acid with 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace 2-methoxyethanesulfonamide with azetidine-1-sulfonamide. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.080 g, 56%): 1H NMR (300 MHz, DMSO-d6) δ 11.54 (br s, 1H), 7.09 (d, J=8.3 Hz, 1H), 6.85 (d, J=13.1 Hz, 1H), 4.42-4.36 (m, 1H), 4.01 (t, J=7.6 Hz, 4H), 2.39-2.34 (m, 1H), 2.30-2.45 (m, 1H), 2.19-2.06 (m, 2H), 2.01-1.90 (m, 1H), 1.87-1.77 (m, 1H), 1.60-1.32 (m, 4H), 1.26-1.04 (m, 3H), 0.88-0.80 (m, 2H), 0.68-0.59 (m, 2H); MS (ES−) m/z 409.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([C:17](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].CC(O)=O.[CH3:34][N:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](C=O)=[CH:36]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:37]3[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[N:35]([CH3:34])[CH:36]=3)[CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.4 %

Procedure:
TEA (0.14 ml, 1.0 mmol) was added to suspension of Intermediate 2 (290 mg, 0.86 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (164 mg, 1.03 mmol) and NaBH(OAc)3 (219 mg, 1.03 mmol) following the procedure described in Example 31, A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (380 mg) as a light orange solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][N:21]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2[NH2:47])[NH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([C@@H:23]3[CH2:22][N:21]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:24]3)[N:39]=[C:38]([I:37])[C:46]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](n2nc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (389 mg) obtained in Step 2 above, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (188 mg), and potassium carbonate (363 mg) were suspended in DMF (4.0 ml), followed by stirring overnight at 80° C. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (191 mg). Physical properties: m/z [M+H]+ 699.1
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[C:20](=[O:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].C(O)(=O)C>CO.O>[Si:3]([O:10][CH2:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCCCCCCCC(=O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCCCCCC(O)/C=C/c1cccc(CO[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
483 mg of sodium borohydride is added to a solution of 6.5 g of the above-produced ketone in 270 ml of methanol under argon at 0° C. and stirred for one hour at this temperature. Then, it is mixed with 1.5 ml of glacial acetic acid, diluted with 150 ml of water and extracted three times with 200 ml of ethyl acetate each. The organic phase is washed neutral with brine, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/0-20% ethyl acetate, 5.65 g of 1-[3-(tert-butyldimethylsilyloxymethyl)-phenyl]-(1E)-undecen-3-ol is obtained as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[Br:23][C:24]1[CH:25]=[CH:26][C:27]([OH:35])=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1.CN(C)C=O.[H-].[Na+]>O>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([O:35][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:28]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH:29]=1
Reactant: COC(=O)Cc1cc(Br)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cc(Br)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.7 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (4.58 g), methyl 2-(5-bromo-2-hydroxyphenyl)acetate (3.0 g) and N,N-dimethylformamide (100 mL) was added sodium hydride (60%, oil, 0.54 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (4.46 g, 70%) of methyl 2-[5-bromo-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 100-101° C.