Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Br)(Br)Br.[C:5]([NH:15][C@:16]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]=[O:26])=[C:20]([O:27][CH:28]=[O:29])[CH:19]=1)(OCC1C=CC=CC=1)=[O:6]>C(OCC)C>[CH3:33][C@:16]1([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]=[O:26])=[C:20]([O:27][CH:28]=[O:29])[CH:19]=2)[C:30](=[O:32])[O:31][C:5](=[O:6])[NH:15]1
Reactant: C[C@@](Cc1ccc(OC=O)c(OC=O)c1)(NC(=O)OCc1ccccc1)C(=O)O
Agent: BrP(Br)Br
Solvent: CCOCC
Product: C[C@@]1(Cc2ccc(OC=O)c(OC=O)c2)NC(=O)OC1=O
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Phosphorous tribromide (0.81g, 3 mmol) in dry ethylether (5 ml) is added dropwise to a solution of (S)-N-carbobenzyloxy-3-(3,4-diformyloxyphenyl)-2-methylalanine (0.4g, 1 mmol) in dry ethylether (10 ml). After stirring 3 hours at 20°-25° under dry nitrogen, the reaction mixture is diluted with dry petroleum ether (40°-60°) (100 ml) and refrigerated 18 hours. The solvent is decanted from the gum which has separated. The gum is dissolved in methylene chloride (2 ml) and precipitated with ethyl ether as a gum. The product (B) is separated and dried 0.1mm/25° for 3 hours over phosphorous pentoxide to afford 0.24g (80%) of gummy solid.
Reaction SMILES: C(O)(=O)C.[CH3:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].[Br:16]N1C(=O)CCC1=O>O>[Br:16][C:10]1[CH:11]=[CH:12][C:7]([NH:6][CH3:5])=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNc1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(Br)cc1[N+](=O)[O-]
Yield: 93.1 %

Procedure:
Pouring 60 milliliter of acetic acid over 5.0 g (33 mmol) of N-methyl-2-nitroaniline and 5.9 g (33 mmol) of N-bromosuccinimide, the resultant solution was refluxed with heating for 7 hours. After completion of the reaction, the reacted solution was poured into 500 milliliter of water, and precipitated solids were separated with filtration. Dissolving the resultant solids into ethyl acetate, the resultant solution was dried with the use of magnesium sulfate. After filtration, the solvent was removed by distillation under reduced pressure, and after drying the solids under reduced pressure at room temperature, 7.1 g of 4-bromo-N-methyl-2-nitroaniline as orange solids were obtained (yield: 93%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]2[C@@H:19]([C@:20]3([CH3:28])[C:25]([CH:26]=1)=[CH:24][C:23](=[O:27])[CH2:22][CH2:21]3)[CH2:18][CH2:17][C@@:16]1([CH3:29])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C1CCCCC=1.N#N>[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:26][C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[CH:24]=2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: N#N
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of methyl 7-methyl-3-oxochola-4,6-dien-24-oate (9) (0.62 g, 1.56 mmoles), 5% palladium on carbon (72 mg), 1, 8-diazobicyclo[5.4.0]undec-7-ene (15 ml), cyclohexene (4.9 ml) and ethanol (3.6 ml) was heated under reflux in an N2 for 6 hrs. The cooled mixture was filtered, and the catalyst washed with ethanol (4 times). The combined filtrate and washes were evaporated in vacuo . The residue was dissolved in EtOAc (30 ml), washed with 0.5M HCl, H2O, saturated brine and dried (MgSO4). Evaporation in vacuo gave 0.62 g of pure 10 as a pale yellow syrup. NMR (CDCl3): δ 0.71 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.05 (d, 3H, 7-Me); 1.15 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 5.70 (s, 1H, 4-H).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27][CH3:28])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4]C.ClCCCCCN1C(OC)=NC2C1=NC(O[C@@H](C)CC)=NC=2N.N1CCCCC1.CO>ClCCl>[CH3:28][O:27][C:12]1[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:29])[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH3:4])[N:15]=2
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1
Agent: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 38 from 9-(5-chloropentyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine but with purification on silica using a 0-25% methanol in dichloromethane gradient.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH2:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[N:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34](Cl)=[O:35])=[C:27]2[CH:26]=1>ClCCl>[CH3:1][C:2]1[S:3][C:4]([NH:14][C:34]([C:33]2[CH:32]=[N:31][N:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[N:30][C:29]=23)=[O:35])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1
Reactant: O=C(Cl)c1cnn2cnc(Cl)cc12
Reactant: Cc1nc(-c2ccccc2C)c(N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(Cl)nc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To an ice-cooled solution of 2-methyl-4-o-tolyl-thiazol-5-ylamine (55.0 mg, 0.27 mmol, 1.0 equiv) and diisopropylethylamine (52.0 mg, 0.41 mmol, 1.5 equiv) in dichloromethane (10 mL) was added a solution of 5-chloropyrazolo[1,5-c]pyrimidine-3-carbonyl chloride (58.0 mg, 0.27 mmol, 1.0 equiv) in dichloromethane (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 3% methanol in dichloromethane) afforded 74.0 mg (73%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide as a solid. LCMS (ESI) m+H=384.0 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 9.73 (s, 1H), 8.70 (s, 1H), 8.63 (d, 1H), 7.44-7.30 (m, 4H), 6.93 (d, 1H), 2.72 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([C:21]([CH3:24])([CH3:23])C)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=1)[CH:21]([CH3:23])[CH3:24])[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)OCC)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CNCc1ccc(F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 32.6 %

Procedure:
Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-tert-butyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 3.5 h, and then was quenched with saturated aqueous ammonium chloride (30 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.34 g, 13.6 mmol, 77%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.55 mL, 13.6 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.71 g, 27.2 mmol) were added sequentially. The mixture was stirred at 25° C. for 36 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 10-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-3-methyl-butyric acid ethyl ester (1.25 g, 4.44 mmol, 33%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ: 0.96 (9H, s), 1.28 (3H, t, J=7.0 Hz), 2.39 (1H, dd, J1=3.5 Hz, J2=11.4 Hz), 2.46 (1H, dd, J1=3.9 Hz, J2=9.5 Hz), 2.73 (1H, dd, J1=3.7 Hz, J2=11.7 Hz), 3.71 (2H, d, J=13.2 Hz), 3.78 (1H, d, J=13.4 Hz), 4.14-4.20 (2H, m), 6.95-7.00 (2H, m), 7.22-7.26 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[N-:25]([C:28]#[N:29])[C:26]#[N:27].[Na+].CO>CN(C=O)C>[NH2:29][C:28](=[N:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[C:14]([O:23][CH3:24])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1)[NH:25][C:26]#[N:27]
Reactant: N#C[N-]C#N
Reactant: COc1cc(NC(=O)Nc2cccc(N)c2)ccc1-c1cnco1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(NC(=O)Nc2cccc(N=C(N)NC#N)c2)ccc1-c1cnco1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
To a solution of 50 mg (0.15 mmol) of 49B in 1 ml of DMF was added excess HCl—ether. A precipitate was obtained. Stirring was continued for 0.5 hr and the slurry was then evaporated to dryness. The residue was diluted with 2 ml of DMF and 40 mg (0.45 mmol) of sodium dicyanamide added. The reaction was heated at 50° C. for 3 hr during which time a lightly cloudy, pale yellow solution was obtained. After removal of the solvent, the residue was diluted with 3 ml of water and stirred for 1 hr. The insolubles were removed by filtration to give 76 mg of the crude product. This material was dissolved into methanol and absorbed onto approx. 1 g of silica gel and subjected to flash chromatography on a 30 cc column of silica gel. Elution with 5% MeOH-EtOAc afforded 9 mg (0.023 mmol, 15%) of 49C as a pale yellow solid. (M+H)+ 392+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:13]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])[C:20](O)=[O:21])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:30][C:27]([C:24]1[CH:23]=[C:19]([CH:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:25]=1[OH:26])[C:20]([NH:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=1)=[O:21])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: NCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles) of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 25 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, the precipitate which appears is filtered out and rinsed with the minimum quantity of ethyl acetate. After concentration of the solution under reduced pressure, the residue is precipitated from a mixture of ethyl acetate/diethyl ether (1/4) and filtered. The crystals are washed abundantly with diethyl ether in order to finally produce, after drying, a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[CH:4][CH:3]=1.[NH3:16].CO>C(O)CO.O>[CH3:9][O:8][C:6]1[N:7]=[C:2]([NH2:16])[CH:3]=[CH:4][C:5]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: N
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Solvent: OCCO
Solvent: O
Solvent: CO
Product: COc1nc(N)ccc1-n1cnc(C)c1
Temperature: 100 °C
Yield: 100 %

Procedure:
To a mixture of 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (1.000 g, 3.73 mmol) and cuprous oxide (0.053 g, 0.373 mmol) in 8.3 mL of ethylene glycol was added a 7 N solution of ammonia in methanol (7.99 mL, 55.9 mmol). The reaction mixture was heated in a high-pressure vessel at 100° C. overnight. Upon cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum to give 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-amine (762.0 mg, 3.73 mmol, 100% yield) as brown semisold. LC-MS (M+H)+=205.10. 1H NMR (500 MHz, CDCl3) δ ppm 7.53 (1H, s), 7.26 (1H, d, J=8.2 Hz), 6.78 (1H, s), 6.07 (1H, d, J=8.2 Hz), 3.86 (3H, s.), 2.25 (3H, s).
Reaction SMILES: Br[CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH2:30])([CH3:20])([CH3:19])[CH3:18].C(OCC)C>C1(C)C=CC=CC=1>[C:17]([O:21][C:22](=[O:33])[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28](=[O:32])[C@H:29]([CH3:31])[NH:30][CH:2]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])([CH3:19])([CH3:18])[CH3:20]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C(Br)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[C@H](NC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Di-t-butyl bromomalonate (15.9 g.) was added to a stirred solution of L-alanyl-L-proline t-butyl ester (26 g.) in toluene (30 ml.) which was cooled to 0° C., and the mixture was allowed to warm up to laboratory temperature during 2 hours and was stirred at that temperature for 14 hours. Diethyl ether (300 ml.) was added, the mixture was filtered to remove unreacted L-alanyl-L-proline t-butyl ester as the hydrobromide salt thereof, andthe filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (400 ml.) and the mixture was washed successively twice with aqueous 0.5N-citric acid solution (100 ml. each time), once with water (100 ml.) and once with saturated aqueous sodium chloride solution (100 ml.), dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of dichloromethane and ethyl acetate as eluant, and there was thus obtained as an oil N-[di-t-butoxycarbonylmethyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: N#N.[CH3:3][Mg]Cl.[O:6]=[C:7]1[CH:30]=[C:29]2[C@:24]([CH3:42])([CH2:25][CH2:26][C@H:27]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[CH2:28]2)[C@@H:23]2[C@@H:8]1[C@H:9]1[C@:20]([CH3:43])([CH2:21][CH2:22]2)[C@@H:12]([C@H:13]([CH3:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1.[NH4+].[Cl-].Cl>C1COCC1>[CH3:3][C:7]1([OH:6])[CH:30]=[C:29]2[C@:24]([CH3:42])([CH2:25][CH2:26][C@H:27]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:34])[CH3:35])[CH:39]([CH3:41])[CH3:40])[CH2:28]2)[C@@H:23]2[C@@H:8]1[C@H:9]1[C@:20]([CH3:43])([CH2:21][CH2:22]2)[C@@H:12]([C@H:13]([CH3:19])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:11][CH2:10]1
Reactant: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Reactant: C[Mg]Cl
Agent: Cl
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)[Si](O[C@H]1CC[C@@]2(C)C(=CC(C)(O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCC(=O)O)[C@@]4(C)CC[C@@H]32)C1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of anhydrous CeCl3 (1.21 g, 4.94 mmoles) was stirred at room temperature in a N2 atmosphere with dry THF (16.5 ml) for 2 hrs. MeMgCl (3N in THF, 16.5 ml) was added dropwise at room temperature, and the suspension was stirred from 30 min. A solution of 7-oxo-3b-triisopropylsilyloxychol-5-en-24-oic acid (4) (5.38 g, 9.9 mmoles) in dry THF (16.5 ml) was added dropwise over 20 min keeping the temperature of the reaction mixture below 20° with a cold H2O bath. After stirring at room temperature for 2 hrs, the reaction mixture was poured carefully with efficient stirring into a mixture of 90% saturated NH4Cl solution and 100 g of ice. The gummy suspension was acidified with 2N HCl, stirred well for 30 min and extracted with CH2Cl2 (three times). The combined extracts were washed with H2O and saturated brine and dried (MgSO4). Evaporation in vacuo gave 5.46 g of crude 5 as a tan foam. NMR(CDCl3) indicated a mixture of 7-isomers: δ 0.70 (two peaks, 18-Me); 5.14 & 5.20 (6-H) The mixture was used directly in the next reaction (Example 5).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH:37][CH3:38]>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:37]([CH3:38])[CH3:36])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[CH:19]=1)=[CH:15][C:14]([Cl:27])=[CH:13][CH:12]=2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(OS(=O)(=O)C(F)(F)F)nc3ccc(Cl)cc23)c1
Reactant: CNC
Product: CC(C)c1cccc(-c2c(C(=O)OC(C)(C)C)c(N(C)C)nc3ccc(Cl)cc23)c1

Procedure:
The title compound was prepared in analogy to example 79 step A from 6-chloro-4-(3-isopropyl-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 78 step C, 250 mg, 0.47 mmol) and dimethylamine (2M solution in THF, 2 ml, 2.36 mmol). Pale yellow solid (130 mg, 65%). LC-MS (ESI): 425 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:28][CH2:27][CH2:25][OH:26])=[O:21])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 72 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (68 mg, 0.21 mmol) was converted, using ethanolamine instead of 4-aminotetrahydropyran, to the title compound (55 mg, 72%) which was obtained as an off white solid. MS: m/e=372.1 [M+H]+.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].O>CO>[OH:32][CH2:31][C@@H:30]([NH:29][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:28])[CH3:33]
Reactant: C[C@H](N)CO
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Solvent: CO
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](C)CO)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.8 g) and (S)-(+)-2-amino-1-propanol (0.71 g) were dissolved in methanol (30 ml) and heated to reflux for 12 hours. The reaction mixture was cooled and with the slow addition of excess of water at 40° C. to precipitate the crystals, the mixture was cooled again and stirred at 20° C. for 1 hour. Following with filtration and washing with water, the filtered solid was recrystallized using isopropanol and ether, filtered and dried to give 1.66 g (yield: 83%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:21][CH2:22][CH2:23][OH:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH2:21][CH2:22][CH:23]=[O:24])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:20])[C:6]([CH3:19])=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH:8]=2)[O:3]1
Reactant: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCCO)CC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc2c(c1C)OC(C)(CCC=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A mixture of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propan-1-ol (200 mg), pyridinium chlorochromate (PCC)(350 mg), and 4A° molecular sieves (100 mg) in dichloromethane (15 mL) was stirred at RT for overnight. The mixture was passed through a silica gel column chromatography eluting with 30% EtOAc in hexane to give 40 mg of 3-[2,7,8-trimethyl-6-(tetrahydro-pyran-2-yloxy)-chroman-2-yl]-propionaldehyde as an oily product. 1H-NMR (300 MHz, CDCl3) δ (ppm): 9.79 (s, 1H, CHO), 6.67 (s, 1H), 5.23 (d, J=2.2 MHz, 1H), 3.90 (m, 1H), 3.58 (m, 1H), 2.75-2.60 (m, 4H), 2.15, 2.08 (2s, 6H), 2.00-1.58 (m, 10H), 1.23 (s, 3H). 13C-NMR (CDCl3, 75 MHz) δ (ppm): 202.64, 148.26, 145.87, 125.57, 125.41, 117.39, 112.93, 112.87, 97.34, 97.22, 74.33, 62.11, 62.05, 38.58, 32.34, 32.09, 31.60, 31.53, 30.76, 25.41, 23.85, 23.64, 22.36, 19.11, 19.08, 12.11, 11.96. MS (m/z): 333 (MH+), 355 (M+Na+).
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O1CCCC1>[C:12]([N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:1][CH2:2]1)(=[O:14])[CH3:13]
Reactant: C1CCC2(CC1)CCNCC2
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(CCCCC2)CC1

Procedure:
A solution of 7 ml of 3-azaspiro[5.5]undecane and 9.7 ml of acetic anhydride in 19.5 ml of tetrahydrofuran was refluxed for 3 hours. The volatiles were evaporated to a yellow oil which was distilled in a Kugelrohr still giving a yellow oil, BP 90°-100° C./200-atm. The distillate was purified by chromatography on silica gel using 1:1 ethyl acetate:hexanes giving 7.89 g of the desired product as a colorless oil.