Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([C:21]2([O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].CO>C(OCC)(=O)C>[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:24]3[CH2:23][CH2:22][C:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-phenyl-4-(4-trifluoromethylphenoxy)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 49% overall yield. FDMS m/e=510 (M+ of free base). α[D]589 =-11.99 (c=0.42, methanol).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Agent: NC(CO)(CO)CO
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of cyclopropanesulfonyl chloride (38 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 9.7 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]2)=[N:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=2[F:28])[N:21]=[C:20]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:19]=1[CH3:36].Cl.O1CCOCC1>CN1C(=O)CCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:29])=[CH:25][C:26]=3[F:28])[N:21]=[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:19]=2[CH3:36])[C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]([CH3:14])([CH3:15])[CH2:9]2)=[N:6][CH:7]=1
Reactant: CC1(C)CN(c2ncc(Br)cc2N)CCO1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(Br)cnc1N1CCOC(C)(C)C1
Reaction time: 2 h

Procedure:
5-Bromo-2-(2,2-dimethylmorpholino)pyridin-3-amine (0.087 g, 0.31 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.071 g, 0.25 mmol), and hydrochloric acid, 4.0M in 1,4-dioxane (0.07 mL, 0.28 mmol) were stirred in NMP (0.5 mL) then microwaved at 150° C. After 2 h, the reaction was diluted with EtOAc and washed once with satd aq. sodium bicarbonate and once with brine. After drying over anhydrous sodium sulfate, filtration, and concentration, the brown residue was purified with silica gel chromatography (0-40% EtOAc in hexanes) to yield mostly N-(5-bromo-2-(2,2-dimethylmorpholino)pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. Mass Spectrum (ESI) m/e=540.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:37][CH:38]([OH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:44][CH:38]([CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCCCCC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(C)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 68.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-heptanol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 65%).
Reaction SMILES: [C:1]1([C:7]23[CH2:16][CH:11]4[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]4)[CH2:8]2)[CH2:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=[O:19])C>C(OC(=O)C)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[OH:19][C:11]12[CH2:12][CH:13]3[CH2:15][CH:9]([CH2:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([CH2:14]3)[CH2:16]1)[CH2:10]2
Reactant: CC(=O)O
Reactant: c1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: OC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Temperature: 4 °C
Reaction time: 24 h
Yield: 50 %

Procedure:
To a solution of 0.03 mol chromiumtrioxide in 20 ml glacial acetic acid and 20 ml acetic anhydride, add 0.0095 mol of 1-phenyl adamantane at 0° C. and stir for 24 hours at 4° C. Pour the reaction mixture onto water and extract with three portions of pentane. Wash the organic phase with saturated sodium chloride solution, dry over magnesium sulfate, filter and evaporate to dryness under vacuum. Hydrolize the residue with 20 ml of 2N NaOH and 50 ml of methanol. Subsequently, remove the methanol under vacuum and dilute the residue with water. Then extract with three portions of ether. Dry the organic phase, filter and evaporate to dryness under vacuum. Recrystallize the residue from cyclohexane. (Yield: 50%).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:7][C:8]([CH2:11]O)=[N:9][CH:10]=1.C(Br)(Br)(Br)[Br:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[Br:31][CH2:11][C:8]1[CH:7]=[C:6]([CH:13]([S:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[C:5]([Cl:4])=[CH:10][N:9]=1
Reactant: OCc1cc(C(Sc2ccc(Cl)cc2)c2cc(F)ccc2F)c(Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(CBr)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 77.3 %

Procedure:
To a dichloromethane (15 ml) solution of the [5-chloro-4-[(4-chlorophenylthio)(2,5-difluorophenyl)methyl]pyridin-2-yl]methanol (582 mg, 1.41 mmol) obtained in Example 256 were sequentially added carbon tetrabromide (936 mg, 2.82 mmol) and triphenylphosphine (407 mg, 1.55 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=20:1 eluate was concentrated under reduced pressure to give the title compound (518 mg, 1.09 mmol, 77%) as a colorless oil.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.[CH3:18][Sn:19](Cl)([CH3:21])[CH3:20]>O1CCCC1>[CH3:6][O:7][C:8]1[C:9]([Sn:19]([CH3:21])([CH3:20])[CH3:18])=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=1
Reactant: COc1ccc(C(F)(F)F)nc1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)nc1[Sn](C)(C)C
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of t-butyllithium (1.7M in pentane; 8.5 ml, 14.45 mmol) was added dropwise to a stirred solution of 3-methoxy-6-trifluoromethylpyridine (1.57 g, 8.87 mmol) in dry tetrahydrofuran (20 ml) at −78° C. over 5 min. After stirring for 10 min at −78° C. a solution of trimethyltin chloride in tetrahydrofuran (18 ml, 1 M in THF, 18 mmol) was added over 5 min. The reaction mixture was allowed to warm up to room temperature over 5 hour and then quenched with water (50 ml) and extraxted with hexane (3×30 ml). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (100 g, hexane:diethyl ether 0-10%) to afford 3-methoxy-6-trifluoromethyl-2-trimethystannylpyridine (0.7 g, 23%) H1 NMR δ(250 MHz, CDCl3): 7.50 (1H, d, J 8.7 Hz), 7.02 (1H, d, J 8.7 Hz), 3.85 (3H, s), 0.35 (9H, s); and afford 3-methoxy-6-trifluoromethyl-4-trimethylstannylpyridine (1.7 g, 57%) H1 NMR δ(250 MHz, CDCl3): 8.38 (1H, s), 7.65 (1H, s), 3.95 (3H, s) 0.35 (9H, s).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1.C(N(CC)CC)C>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:5]1[N:6]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[C:7]2[C:3]([N:4]=1)=[C:2]([NH:25][C@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)[N:10]=[CH:9][N:8]=2
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)C1
Temperature: 80 °C
Yield: 95.1 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (100 mg, 0.267 mmol, 1 eq.) in 3 mL of ethanol was added tert-butyl (3S)-3-aminopiperidine-1-carboxylate (64 mg, 0.32 mmol, 1.2 eq.) and triethylamine (0.06 mL, 0.4 mmol, 1.5 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 137 mg (95%) of tert-butyl (3S)-3-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.43 (br. s., 9 H) 1.60-1.76 (m, 2 H) 1.77-1.93 (m, 1 H) 2.08-2.22 (m, 1 H) 3.30 (br. s., 2 H) 3.60 (br. s., 1 H) 3.98 (br. s., 1 H) 4.42 (br. s., 1 H) 5.96 (d, J=7.54 Hz, 1 H) 7.14-7.68 (m, 8 H) 8.48 (s, 1 H), [M+H]+ 539.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>ClCCCl>[Cl:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH:24][CH:21]1[CH2:23][CH2:22]1)=[O:6]
Reactant: NC1CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=C(NC1CC1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2-Chloro-4,5-dinitrobenzoic acid (known from WO-A-2009/47558) (8.0 g, 32.5 mmol) was dissolved in 1,2-dichloroethane (80 ml), and thionyl chloride (20 ml) was added under nitrogen. The reaction mixture was heated under reflux for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (80 ml) and, at 0° C., cyclopropylamine (2.4 ml, 39 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then the solvent was removed under reduced pressure. The residue was stirred with diethyl ether (50 ml) for 30 min and then filtered off with suction. The residue was washed with water (100 ml) and dried. 7.5 g (81% of theory) of 2-chloro-N-cyclopropyl-4,5-dinitrobenzamide were thus obtained.
Reaction SMILES: [I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[O:7][Si](CC)(CC)CC)[CH3:3]>C(O)(=O)C.C1COCC1.O>[I:1][C:2](=[CH:4][CH2:5][C@H:6]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[OH:7])[CH3:3]
Reactant: CC[Si](CC)(CC)O[C@H](CC=C(C)I)c1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(I)=CC[C@@H](O)c1ccc2ncccc2c1

Procedure:
A solution of (5R)-2-iodo-5-(6-quinolyl)-5-(triethylsilyloxy)-2-pentene (2.26 g) in 50 mL of 3:1:1 acetic acid/THF/water is stirred at ambient temperature for 8 hours, then concentrated. The residue is dissolved in ethyl acetate, washed sequentially with sat. NaHCO3 and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([CH3:29])=[C:15]([NH:21][C@H:22]([C@H:26]([OH:28])[CH3:27])[C:23](O)=[O:24])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[C:6]([NH:8][NH2:9])(=[O:7])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1.[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:23](=[O:24])[C@H:22]([NH:21][C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[C:13]([Cl:12])[C:14]=2[CH3:29])[C@H:26]([OH:28])[CH3:27])=[O:7])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Cl)cc2)[C@@H](C)O)ccc(C#N)c1Cl
Product: NNC(=O)c1ccccc1
Yield: 168.6 %

Procedure:
4-Chloro-N′(2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide was prepared using 4-chlorobenzoic hydrazide (4.42 mmol, 1.1 equiv.) and (2R,3R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (4.02 mmol, 1.0 equiv.) according to the procedure as described for intermediate 5a. The crude off-white solid was recrystallized using hot methylene chloride to provide the desired product as a white solid (1.57 g, 93% yield). Other data: 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.94 (br. s, 1H), 9.48 (br. s, 1H), 7.95 (d, J=8.5 Hz, 2H), 7.55 (m, 3H), 6.73 (d, J=8.5 Hz, 1H), 5.59 (br. d., J=7.1 Hz, 1H), 4.25 (m, 1H), 4.13 (m, 1H), 2.35 (s, 3H), 1.37 (d, J=6.4 Hz, 3H); LRMS (ESI+) exact mass calcd for C19H18Cl2N4O3 [M]+ 421.28, found 421.3; TLC Rf=0.32, 100% EtOAc, vanillin stain.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1.[OH:26][CH2:27][CH:28]([CH2:30]O)[OH:29]>ClCCl.O1CCCC1>[OH:29][CH:28]([CH2:27][OH:26])[CH2:30][O:23][C:22](=[O:24])[C:21](=[O:25])[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:16][CH:17]=1
Reactant: OCC(O)CO
Reactant: O=C(O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCC(O)CO)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The acid chloride, prepared from 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzene-acetic acid (0.5 g) as described in Example 6, was dissolved in dichloromethane (10 mL) and added dropwise to a stirred, cold (<-50° C.) mixture of glycerine (0.9 mL) in tetrahydrofuran (10 mL). The cooling bath was removed and the mixture stirred for 1 hour at room temperature. The mixture was diluted with dichloromethane and washed once with saturated aqueous sodium bicarbonate, once with water, and the organic solution was dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (ethyl acetate) to provide, after crystallization from ethyl acetate-hexane, 0.25 g of rac.-4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid 2,3-dihydroxypropyl ester as a colorless solid, mp 124°-125° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][N:9]2[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[CH:5][CH:4]=1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc2cnn(C3CCCCO3)c2c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 90 °C
Yield: 80.8 %

Procedure:
To a solution of 6-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (4.0 g, 14 mmol) (100) in DMF (30 mL) was added sodium azide (6 g, 92 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution was formed. After cooling down to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine then dried (MgSO4). Evaporation of solvent gave an yellow oil which was purified by column chromatography to yield title compound (2.91 g, 83%). TLC Rf 0.31 (70:30 of hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ1.75 (m, 3H), 2.10 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.01 (m, 1H), 4.48 (s, 2H), 5.73 (dd, 1H, J=8.2, 2.8 Hz), 7.12 (dd, 1H, J=8.2, 0.8 Hz), 7.55 (s, 1H), 7.71 (d, 1H, J=8.2 Hz), 8.02 (s, 1H).
Reaction SMILES: [C:1]1(NN)[CH:6]=[CH:5]C=CC=1.N1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:15]1([C:21](Cl)=[O:22])CCCCC1>CN(C=O)C>[CH:11]([O:22][CH:6]([CH3:5])[CH3:1])([CH3:12])[CH3:10].[CH2:21]([O:22][CH2:13][CH3:14])[CH3:15]
Reactant: O=C(Cl)C1CCCCC1
Reactant: NNc1ccccc1
Reactant: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)OC(C)C
Product: CCOCC

Procedure:
To a cooled (0-5° C.) solution of 43.2 g (0.4mol) phenylhydrazine and 35.2 g (0.44 mol) pyridine in 300 ml DMF were added slowly 51 g (0.35 mol) cyclohexane carboxylic acid chloride. The solution was stirred 30 mn more after the end of the addition and concentrated under vacuum. The residue was poured in 300 ml water and stirred 30 mn. Filtration, washing with water and drying led to 74.5 g (98%) of the desired compound. The compound contained traces of starting material and was used without further purification. An analytical sample was obtained from isopropyl ether/ethyl ether
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[CH:9][S:8][C:7]=1[CH3:12])[CH2:3][CH2:4][CH3:5].[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH3:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O.CO>[CH2:2]([N:6]1[C:10]([CH3:11])=[CH:9][S:8]/[C:7]/1=[CH:12]\[C:19]([C:18]1[CH:22]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=1[CH3:23])=[O:20])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)csc1C
Reactant: Cc1ccc(F)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [I-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CO
Product: CCCCN1C(C)=CS/C1=C\C(=O)c1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial a solution of 3-butyl-2,4-dimethylthiazol-3-ium iodide (47.92 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL) was added, followed by the addition of DMAP (49.24 mg, 0.40 mmol) dissolved in CH2Cl2 (0.8 mL). Then, to the solution was added 5-fluoro-2-methylbenzoyl chloride (27.6 mg, 0.16 mmol) dissolved in CH2Cl2 (0.5 mL). The vial was capped and shaken overnight at room temperature. The residue was dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.28-1.41 (m, 2 H) 1.57-1.68 (m, 2 H) 2.28-2.31 (m, 3 H) 2.33-2.36 (m, 3 H) 3.92-4.03 (m, 2 H) 6.09-6.15 (m, 1 H) 6.54-6.59 (m, 1 H) 7.05-7.14 (m, 1 H) 7.19-7.27 (m, 2 H);); MS (ESI) positive ion 306 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:17](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-hydroxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D6) (1.20 g, 5.43 mmol) and cesium carbonate (1.77 g, 5.43 mmol) in DMF (10 ml) was sonicated for 15 minutes. Iodomethane (0.372 ml, 5.97 mmol) was added and the mixture was stirred at room temperature. After 1 hr more iodomethane (0.05 ml) was added and stirring was continued for a further 30 minutes. The solvent was evaporated, ethyl acetate and 2N HCl were added and the product was extracted into ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by trituration with ethyl acetate and/or chromatography on silica gel (elution with ethyl acetate) gave the title compound (D41). (1.042 g).
Reaction SMILES: C([O:3][C:4](=[O:8])[CH:5]=[N+:6]=[N-:7])C.[CH3:9]O[C:11](C)(C)[CH3:12]>>[NH:6]1[C:5]([C:4]([OH:3])=[O:8])=[CH:12][CH:11]=[N:7]1.[NH:7]1[CH2:9][CH:4]=[CH:5][NH:6]1
Reactant: COC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Product: C1=CNNC1
Product: O=C(O)c1ccn[nH]1
Reaction time: 8 h

Procedure:
The reaction of trimethylphosphonoacrylate and ethyldiazoacetate was carded out as follows. Trimethylphosphonoacrylate (1.0 g, 5.15 mmol) was dissolved in methyl-t-butyl ether followed by ethyl diazoacetate (0.60 g, 5.26 mmol). After stirring overnight, the reaction was filtered and the resultant solid (880 mg, 55%) recrystallized from acetone-hexane to afford off-white granules of the pyrazoline 1H-Pyrazole-5-carboxylic-acid, 3-carboethoxy-5-(dimethoxyphosphinyl)-4,5-dihydro, methyl ester (699 mg) mp 100°-102°.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13](Cl)=[O:14])[N:5]=1)(=[O:3])[CH3:2].Cl.[CH3:17][NH:18][CH3:19].N1C=CC=CC=1>ClCCl>[C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH2:11][O:12][C:13]([N:18]([CH3:19])[CH3:17])=[O:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)c1cc(C)n(CCOC(=O)Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cc(C)n(CCOC(=O)N(C)C)n1
Reaction time: 1.5 h

Procedure:
3-Acetyl-1-[2-(chlorocarbonyloxy)ethyl]-5-methylpyrazole (prepared in Example 22, Preparation 1) in dry dichloromethane (20 ml) was treated with dimethylamine hydrochloride (367 mg) and pyridine (712 mg) and the mixture stirred for 1.5 h. The mixture was then partitioned between ethyl acetate and 1M aqueous HCl. The organic phase was separated, washed with 1M aqueous HCl, saturated aqueous NaHCO3 and brine then dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give 3-acetyl-1-[2-(N,N-dimethylaminocarbonyloxy)ethyl]-5-methylpyrazole (222 mg); νmax (KBr) 1697 and 1683 cm−1; δH (CDCl3) 2.31 (3H,s), 2.53 (3H,s), 2.82 (3H,s), 2.91 (3H,s), 4.4 (4H,m); Found m/z 239.1273 C11H17N3O3 requires 239.127.