Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].S(=O)(=O)(O)O.[CH:10](O)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][O:4][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCl
Reactant: OC(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: ClCCOC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
To a solution of 3.27 g of 2-chloroethanol in dry benzene (3.5 ml) was added 0.8 g of conc. sulfuric acid and the mixture was heated, under argon atmosphere, at 50° C. To the mixture was added slowly a solution of 5.0 g of benzhydrol in dry benzene (6.5 ml) and, after 30 minutes from the addition, the whole mixture was refluxed for 1.5 hours. After the mixture was allowed to cool, the benzene layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, to give 6.7 g of benzhydryl 2-chloroethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[C:11]([N+:16]([O-])=O)[C:10]=1[NH:19][C:20](=[O:27])[CH:21](C(=O)CC)[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:16][C:11]1[CH:12]=[C:13]([Br:15])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]=1[NH:19][C:20](=[O:27])[CH2:21][CH3:22]
Reactant: CCC(=O)C(C)C(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CCC(=O)Nc1c(N)cc(Br)cc1OCc1ccccc1
Temperature: 70 °C
Yield: 112.2 %

Procedure:
A solution of 22 g (48.5 mmol) N-(2-benzyloxy-4-bromo-6-nitro-phenyl)-propionyl-propionamide, 4.9 g (30 mmol) iron(III) chloride and 7.2 g activated charcoal in 180 ml methanol was heated to 70° C. 23.8 ml (490 mmol) Hydrazine hydrate were added dropwise and the reaction mixture was refluxed for 90 min. After cooling to room temperature, the reaction was filtered through celite, the filter cake washed with dichloromethane, the filtrate reduced in volume and poured into water. The precipitate was filtered and washed with diethyl ether to afford 19 g (89%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=2)[C:3]1=[O:21].[C:22]12([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>>[C:22]12([CH2:32][C:33]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)[C:9]4[C:4](=[CH:5][C:6]([Br:20])=[CH:7][CH:8]=4)[C:3]3=[O:21])=[O:34])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: COc1ccc(-c2nn(N)c(=O)c3cc(Br)ccc23)cc1
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: COc1ccc(-c2nn(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c3cc(Br)ccc23)cc1

Procedure:
The product from Example 174A and 2-(adamant-1-yl)acetyl chloride were treated using a method similar to that described in Example 53 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.28 (s, 1H), 8.50 (d, J=2.1 Hz, 1H), 8.14 (dd, J=8.6, 2.2 Hz, 1H), 7.70 (d, J=8.7 Hz, 1H), 7.51-7.55 (m, 2H), 7.11-7.15 (m, 2H), 3.85 (s, 3H), 2.05 (s, 2H), 1.92-1.98 (bs, 3H), 1.58-1.70 (m, 12H); MS (ESI+) M/Z, 524 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][O:12][CH:13]=2)=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][O:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: Clc1ccc(C2=COCCC2)cc1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: Clc1ccc(C2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3,4-dihydro-2H-pyran (350 mg, 1.80 mmol) in ethyl acetate (8 mL) was added platinum oxide (41 mg, 0.18 mmol) and the reaction was charged with a hydrogen balloon and stirred at room temperature for 6 hours. The reaction was filtered, and the filtrate was evaporated to give crude title compound (340 mg, 96.3%) as white solid.
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:3]2[CH2:2][CH2:1][NH:6][C:4]2=[O:5])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C1NCCN1
Product: O=C1NCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
A mixture of 17.2 g of ethyleneurea and 19.5 g of p-fluorobenzene sulphonyl chloride is heated at 110° for 3 1/2 hrs. The residue is recrystallized from a mixture of methanol and water to afford 1-(4-fluorophenylsulphonyl)-2-oxo-tetrahydroimidazole which melts at 183°-185°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1>CS(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:10]([F:14])=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(F)cc1[N+](=O)[O-]
Yield: 58.7 %

Procedure:
By using 0.59 g of N-(4,5-difluoro-2-nitrophenyl)glycine ethyl ester, 155 mg of imidazole, 1.80 g of pyridine and 10 ml of DMSO, 0.41 g (59%) of N-[4-fluoro-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester was obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH2:6].Br[CH2:15][C:16]([CH3:18])=[CH2:17].O>C1COCC1>[Br:3][C:4]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:5]=1[NH:6][CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)CNc1cc([N+](=O)[O-])ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
To a suspension of NaH 60% dispersion in oil (97 mg, 0.0023 mol) in 2 mL of anhydrous THF at 0° C. was added 2-bromo-5-nitroaniline (500 mg, 0.0023 mol) in 2 mL of THF dropwise, the temperature was raised to rt to complete deprotonation then lowered to 0° C. 3-bromo-2-methylpropene (232 mL, 0.0023 mol) was added very slowly and the reaction mixture was stirred at 0° C. for 3 h then neutralized with water (5 mL). The mixture was extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to an oil that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 8:2) to give 200 mg (32%) of 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline (structure 55A of Scheme XLVII, where R1 =methyl, R2 =H). Data for 2-bromo-N-(2-methyl-2-propenyl)-5-nitroaniline: 1H NMR (400 MHz, CDCl3) 7.55 (d,J=8.5, 1H), 7.40 (dd,J=8.5, 2.8, 1H), 7.39 (d,J=2.8, 1H), 4.96 (s, 2H), 4.95 (bs, 1H), 3.82 (d,J=5.9, 2H), 1.81 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([O:8][CH3:9])([CH3:7])[C:4](=[O:6])[CH3:5].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CO>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:5][C:4](=[O:6])[C:3]([O:8][CH3:9])([O:2][CH3:1])[CH3:7]
Reactant: COC(C)(OC)C(C)=O
Reactant: COC(OC)N(C)C
Solvent: CO
Product: COC(C)(OC)C(=O)C=CN(C)C
Yield: 90.1 %

Procedure:
100 g (0.76 mol) of 3,3-dimethoxy-2-butanone were stirred, at 120° C. for 48 h, with 90.2 g of N,N-dimethylformamide dimethylacetal (0.76 mol). The methanol which was formed during the reaction was continuously removed from the reaction solution by distillation. When the solution was cooled, spontaneous crystallization occurred, with this crystallization being brought to completion by adding a little heptane. This resulted in 128.24 g of crude product 8 (yield 90%), which was subjected to reaction without any further purification.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:22])[C:7]([N:9]1[CH2:17][C:16]([O:20][CH3:21])([O:18][CH3:19])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH3:22])[C:7]([N:9]1[CH2:17][C:16]([O:20][CH3:21])([O:18][CH3:19])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: COC(=O)[C@@H]1CC(OC)(OC)CN1C(=O)C(C)CSC(C)=O
Agent: N
Product: COC(=O)[C@@H]1CC(OC)(OC)CN1C(=O)C(C)CS

Procedure:
The product from Example 130 is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield (S)-1-(3-mercapto-2-methyl-1-oxopropyl)-4,4-dimethoxy-L-proline, methyl ester.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[CH:9](O)=[O:10]>>[CH:9]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: O=CO
Reactant: NCc1ccccn1
Product: O=CNCc1ccccn1

Procedure:
A mixture of 32.4 g. of 2-aminomethylpyridine and 96 ml. of 97% formic acid is heated under reflux for 3.5 hrs. The resulting solution is subjected to vacuum distillation, the desired product being isolated as the fraction boiling at 120° C./0.03 mm, 37.3 g. The product which is isolated as a yellow oil crystallized to a solid having a melting point at about room temperature.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:25]12CCN(CC1)C[CH2:26]2.O>CS(C)=O>[CH3:19][C:18]([CH3:21])([CH3:20])[CH2:17][N:8]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:26]#[N:25])[N:7]=1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(Cl)n1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Temperature: 75 °C
Reaction time: 21 h
Yield: 861.5 %

Procedure:
(2-Chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amine (10.0 g, 24.0 mmoles) and sodium cyanide (5.6 g, 0.12 moles) are dissolved in 40 ml of DMSO and 1,4-diaza bicyclo[2,2,2]octane (0.27 g, 2.4 mmoles) is added at rt. The mixture is stirred at 75° C. for 21 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 8.4 g of desired 4-[(2,2-dimethyl-propyl)-(4-iodo-benzyl)-amino]-pyrimidine-2-carbonitrile in 86% yield.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=O.[C:10]([CH2:12]C(O)=O)#[N:11].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:10]([CH2:12][CH:1]=[C:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)#[N:11]
Reactant: N#CCC(=O)O
Reactant: O=CC1CC2C=CC1C2
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CCC=C1CC2C=CC1C2
Yield: 72.1 %

Procedure:
A stirred solution of 100 g (0.82 mol) of 2-formyl-5-norbornene (Aldrich Chemical Co.), 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 79.6 g (68% yield) of 2-(2-cyanoethylidene)-bicyclo[2.2.1]hept-5-ene: b.p. 76°-78° C./1 mm; ir 3060, 2260, 1420, 1330, 915, 840, 755, 720; nmr 1.3-2.5 (4H, m), 2.9-3.4 (4H, m), 5.0-5.5 (1H, m), 5.9-6.2 (2H, m); ms 145.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)=[O:10]>>[C:15]1([CH3:18])[CH:16]=[CH:17][C:12]([O:11][C:9]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:10])=[CH:13][CH:14]=1
Reactant: COP(OC)OC
Reactant: Cc1ccc(OC(=O)Cl)cc1
Product: COP(=O)(OC)C(=O)Oc1ccc(C)cc1
Yield: 93 %

Procedure:
From 10.3 g (85 mmole) of trimethylphosphite and 10.3 g (60 mmole) of p-tolyl chloroformate (prepared according to M. J. Zabik and R. D. Schuetz, J. Org. Chem. 32 (1967) 300). (100° C., 2 hours). Yield 93%. Bp0.2 131° C., nD20 1.4972.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][N:14]=1)[C:11](=[O:15])[N:10]([CH3:16])[C:9]1[CH:17]=[C:18]([O:21][CH2:22][C@@H:23]([NH:28]C(=O)OC(C)(C)C)[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[CH:20][C:8]2=1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:28][C@@H:23]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:8]2[C:7]3[C:12](=[CH:13][N:14]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=3)[C:11](=[O:15])[N:10]([CH3:16])[C:9]=2[CH:17]=1
Reactant: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@@H](N)CC(C)C)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6.7 %

Procedure:
To a stirred solution of (S)-tert-butyl (1-((2-acetamido-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (140 mg, 0.059 mmol) in CH2Cl2 (15 mL) at 0° C. was added TFA (1.2 mL, 15.58 mmol) and the reaction mixture was stirred at RT for 40 min. After the completion of reaction, the volatile organics were evaporated under reduced pressure and the residue was purified by preparative HPLC (0.1% TFA in water/Acetonitrile) to yield (S)—N-(8-((2-amino-4-methylpentyl)oxy)-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-2-yl)acetamide (2 mg, 3.93 μmol, 6.6% yield) as a mono TFA salt. LC/MS (ESI) m/e 383.2 [(M+H)+, calcd for C21H22N4O3 383.2]; LC/MS retention time (method C): tR=1.80 min; HPLC retention time (method A): tR=5.14 min; HPLC retention time (method B): tR=5.62 min; 1H NMR (400 MHz, CD3OD) δ 9.28 (s, 1H), 8.93 (s, 1H), 8.35 (d, J=8.80 Hz, 1H), 7.17 (s, 1H), 7.15 (d, J=2.00 Hz, 1H), 4.46 (d, J=8.80 Hz, 1H), 4.28 (dd, J=6.40, 10.80 Hz, 1H), 3.76-3.79 (m, 4H), 2.29 (s, 3H), 1.65-1.88 (m, 3H), 1.08 (d, J=4.40 Hz, 3H), 1.07 (d, J=4.40 Hz, 3H).
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH2:27][CH2:28][CH2:29][NH:30][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:31]
Reactant: CN(C)CCCN
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C

Procedure:
Behenic acid (LUNAC BA, manufactured by Kao Corporation) and dimethyl aminopropylamine were subjected as starting materials to amidation reaction to give behenic acid dimethylaminopropylamide. The purity was 98%, and other components include unreacted behenic acid, unreacted amine, water, etc. The composition of the fatty acid residue (R4CO) was C17H35CO/C19H39CO/C21H43CO/C23H47CO=1%/9%/88%/2%.
Reaction SMILES: [H-].[Na+].[CH:3]([OH:6])([CH3:5])[CH3:4].Cl[C:8]1[C:13]([C:14]2[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=2)=[CH:12][CH:11]=[CH:10][N:9]=1>O1CCCC1>[CH3:19][C:17]1([CH3:20])[CH2:16][O:15][C:14]([C:13]2[C:8]([O:6][CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:18]1
Reactant: CC(C)O
Reactant: CC1(C)COC(c2cccnc2Cl)=N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Oc1ncccc1C1=NC(C)(C)CO1
Reaction time: 1.25 h
Yield: 95 %

Procedure:
12 g of sodium hydride (50% in oil=0.25 mole) are added during 10 minutes to 150 ml of dry tetrahydrofuran and 40 ml of isopropanol to give a suspension, the temperature of which rises to 50° C. A solution of 10.52 g (0.05 mole) of 2-chloro 3-(4,4-dimethyl 2-oxazolinyl)pyridine in 30 ml of dry tetrahydrofuran is then added during 20 minutes and the mixture is left to stand for 1.25 hours at ambient temperature. Excess isopropanol and the tetrahydrofuran are then removed under a partial vacuum and the residue is taken up in 50 ml of water and 100 ml of diisopropyl ether. The ethereal phase is then evaporated under reduced pressure to give 12.5 g of 3-(4,4-dimethyl 2-oxazolinyl)2-isopropoxy pyridine in the form of a clear brown oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:6][CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CCCCC#CCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC#CCCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
7.47 g (65 mmol) of methanesulfonyl chloride are added dropwise within 30 minutes at 10° C. to a solution of 7.56 g (60 mmol) of 3-octyn-1-ol and 12.45 ml (90mmol) triethylamine in 225 ml of methylene chloride, and the mixture is stirred for one hour. The reaction solution is washed with water, saturated sodium bicarbonate solution and again with water, dried and concentrated.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[CH3:3][C:4]1[CH:5]=[C:6]([C@@H:21]([OH:38])[C@H:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:16])[CH3:17])[CH:12]([CH3:13])[CH3:14]
Reactant: Cc1cc(C(=O)C(C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc([C@@H](O)[C@@H](C)N2CCC(O)(c3ccc(F)cc3)CC2)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 74.3 %

Procedure:
A mixture of sodium borohydride (0.564 g, 14.92 mmol) and ethanol (60 mL) was stirred 10 min and then 1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (7.66 g, 14.92 mmol in 10 mL of ethanol) was added with two 30 mL ethanol rinses. The reaction was stirred at ambient temperature overnight. The white solid which precipitated was collected by filtration and dried to yield 5.72 g (74%) of (1R*,2R*)-1-(3-methyl-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol which was suitable for use without further purification and had: mp 188-189° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:8]=1
Reactant: COC(=O)CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCc1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 95.5 %

Procedure:
A mixture of methyl 3-(4-{[4-(methyloxy)phenyl]carbonyl}phenyl)propanoate (167) (0.45 g, 1.51 mmol) and AlCl3 (0.82 g, 6.03 mmol) were refluxed in benzene (20 mL) for 1 h and then cooled to 0° C. in an ice bath. Water (15 mL) was added slowly, and the mixture was extracted with ether (2×50 mL). The combined ethereal extract was washed with water, brine, and dried over Na2SO4. Concentration gave light brown oil, which was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 45% EtOAc:hexanes to afford 0.41 g (96%) of the title compound 168 as colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.68 (t, J=7.7 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 3.68 (s, 3H), 5.44 (s, 1H), 6.89 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H). LCMS (ESI): m/z 285 (M+H)+, m/z 283 (M−H)−.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:23].O>C(O)(=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:23])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[C:16]([C:18]([OH:20])=[O:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(C(=O)O)ccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c(Cl)c3ccc(C(=O)O)cc3nc21

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4-carboxyanthranilic acid (2.5 g) and POCl3 (20 ml) was refluxed overnight. The reaction mixture was poured into water, acidified with acetic acid and the solids which formed were collected by filtration. The solid was taken up in 10% NaOH, washed with ether and then the aqueous layer was acidified with concentrated HCl. The mixture was extracted with ether, the ether layer was dried over MgSO4 filtered and evaporated to afford 1 g of 1-ethyl-4-chloro-7-carboxy-1H-pyrazolo[3,4-b]quinoline, as a yellow powder.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([O:25][CH:26]([CH3:28])[CH3:27])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([N:38]([CH3:46])[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])=[O:37])=[CH:32][CH:31]=1>>[CH:1]1([CH:7]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([N:38]([CH3:46])[CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:37])=[CH:34][CH:35]=2)[C:9]2[C:10]([O:25][CH:26]([CH3:27])[CH3:28])=[N:11][N:12]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: CC(C)Oc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: CC(C)Oc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 36.4 %

Procedure:
Using cyclohexyl{3-(1-methylethoxy)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.20 g) synthesized in Example 64(2) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.13 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 36%) was obtained as a white solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2)=[O:16].[OH-:42].[Ca+2].[OH-:44]>ClCCl>[Cl:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][S:37]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:44])=[O:42])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]12[CH2:20][CH:21]3[CH2:27][CH:25]([CH2:24][CH:23]([CH2:22]3)[CH2:28]1)[CH2:26]2)=[O:16]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCSCCCO)ccc1Cl
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCS(=O)(=O)CCCO)ccc1Cl
Reaction time: 0.5 h
Yield: 28 %

Procedure:
3-Chloroperoxybenzoic acid (0.14 g, 70%) was added to a solution of 2-chloro-5-[3-(3-hydroxypropylthio)propoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 10, 0.1 g) in dichloromethane (10 ml). After 1 hour calcium hydroxide (0.1 g) was added and stirring continued for a further 30 min. The reaction mixture was dried (MgSO4), filtered through celite and concentrated. The residue was triturated with ethanol to leave the title compound as a white solid (0.030 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH:31]([CH2:33][CH3:34])[CH3:32])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH:31]([CH2:33][CH3:34])[CH3:32])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCC(C)NS(=O)(=O)c1ccc(C)c(Br)c1
Product: CCC(C)NS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N-sec-butyl-4-methyl-benzenesulfonamide (Intermediate 146), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.