Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=[O:15]>CO>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:1])=[O:15]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)Cc1ccccc1F
Solvent: CO
Product: COC(=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trimethylsilyl chloride (4.12 mL) was added to a solution of 2-fluorophenylacetic acid (2 g) in methanol (40 mL) in a nitrogen atmosphere, and the reaction solution was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.978 g of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 43.6 %

Procedure:
101 mg of (13E)-(8R,9R,11R,12R,15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-13,18-prostadienoic acid was stirred under argon at room temperature for 25 hours with 2 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was then concentrated under vacuum and the residue purified by column chromatography on silica gel with hexane/0-100% ethyl acetate as the eluent, thus producing 31 mg of the desired carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=O.[NH2:22][C:23](=[S:29])[CH2:24][C:25]([O:27][CH3:28])=[O:26].[CH3:30]CO>>[C:18]([N:8]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:5]([C:3]2[N:22]=[C:23]([CH2:24][C:25]([O:27][CH2:28][CH3:30])=[O:26])[S:29][CH:2]=2)[CH:6]=[N:7]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(-c2c(C(=O)CBr)cnn2C(C)(C)C)cc1
Reactant: CCO
Reactant: COC(=O)CC(N)=S
Product: CCOC(=O)Cc1nc(-c2cnn(C(C)(C)C)c2-c2ccc(OC)cc2)cs1

Procedure:
A solution of the compound (107 mg, 0.30 mmol) obtained in step 5 and methyl 3-amino-3-thioxopropanoate (48.7 mg, 0.37 mmol) in EtOH (3 mL) was stirred at 90° C. for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 5→80% ethyl acetate/hexane) to give a crude product ethyl 2-(4-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazol-2-yl)acetate as a colorless oil, which was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[C:13](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH3:13]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CN1C(=O)C(=O)c2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 4-chloroisatin (CAS#6344-05-4, 3.64 g, 20.0 mmol) in acetonitrile (150 mL) was added potassium carbonate (11.1 g, 80 mmol) followed by iodomethane (2.75 mL, 44.0 mmol). The reaction was then placed at 60° C. and stirred for 40 minutes. The reaction was then cooled to room temperature, filtered and concentrated to 10% of the original volume. The reaction was then diluted with dichloromethane, water, and brine. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate filtered, and concentrated to provide 4-chloro-1-methyl-1H-indole-2,3-dione as an orange solid without the need for further purification. The 4-chloro-1-methyl-1H-indole-2,3-dione (1.55 g, 7.92 mmol) was then treated with hydrazine hydrate (14.8 ml, 475 mmol). The reaction was then placed at 70° C. and heated to 130° C. over 20 minutes. The reaction was stirred at 130° C. for 45 minutes, at which time the reaction was placed at room temperature and cooled by the addition of ice. Once the reaction was cooled to room temperature it was diluted with dichloromethane and water and the layers were then separated. The aqueous layer was extracted an additional two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane 0 to 2%) to afford 4-chloro-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 182.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][NH:13]2)=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4].Br[CH2:25][CH2:26][F:27]>CN(C)C=O>[C:3]([C:6]1[C:15]([F:16])=[C:14]2[C:9]([C:10](=[O:22])[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][N:13]2[CH2:25][CH2:26][F:27])=[CH:8][C:7]=1[F:23])(=[O:5])[CH3:4]
Reactant: FCCBr
Reactant: CCOC(=O)c1c[nH]c2c(F)c(C(C)=O)c(F)cc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCF)c2c(F)c(C(C)=O)c(F)cc2c1=O
Reaction time: 2 h
Yield: 32.3 %

Procedure:
To 1.62 g (34.0 mmol) of sodium hydride (50% dispersion in oil, pentane washed) in 250 ml of dimethylformamide was added 10.0 g (34 mmol) of the ethyl 7-acetyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate dissolved in 100 ml of dimethylformamide at room temperature. The mixture was stirred for two hours, and 13.0 g (2.4 eq) of 1-bromo-2-fluoroethane was added. The mixture was stirred overnight at 50° C. It was concentrated, and partitioned between water and dichloromethane. The dichloromethane was then concentrated and the residue purified by column chromatography to give 3.75 g of ethyl 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3quinoline carboxylate, mp 155°-156° C. This material was hydrolyzed with 2 N hydrochloric acid and 2-propanol as co-solvent to give 2.95 g of the 7-acetyl-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, mp 215°-216° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][CH2:15][C:16]1[S:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH:17]=1)=O)(C)(C)C.C(N(CC)CC)C.[CH3:32][O:33][C:34]1[C:39]2[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=2[CH:37]=[C:36]([C:45](Cl)=[O:46])[CH:35]=1.[C:48]1(=O)[CH2:51]C[CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[S:20]1[C:16]([CH2:15][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH:6]2[CH2:51][CH2:48][CH2:49]2)[C:45]([C:36]2[CH:35]=[C:34]([O:33][CH3:32])[C:39]3[O:40][C:41]([CH3:44])([CH3:43])[O:42][C:38]=3[CH:37]=2)=[O:46])=[CH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]1=2
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNCc1cc2ccccc2s1
Reactant: COc1cc(C(=O)Cl)cc2c1OC(C)(C)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(Cc2cc3ccccc3s2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2
Reaction time: 2 h
Yield: 21.6 %

Procedure:
Experimental conditions were analogous to Example 58, from 0.29 g (0.84 mmol) of (S)-2-{[(benzo[b]thiophen-2-ylmethyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester, 10 mL dichloromethane, 141 μL (1.01 mmol) of triethylamine, and 0.22 mg (0.92 mmol) of 7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl chloride. The crude mixture was filtered through silica and the Boc-deprotection was conducted in 10 mL 10% trifluoroacetic acid/dichloromethane in 2 hours, followed by aqueous sodium bicarbonate quench. The crude material from organic layer was alkylated in 5 mL dichloromethane, with 0.2 g (2.5 mmol) of cyclobutanone and 0.53 mg (2.5 mmol) of sodium triacetoxyborohydride. After 2 days the reaction was quenched with aqueous sodium bicarbonate and di-tert-butyl dicarbonate. The residue from the organic layer was purified using reverse phase HPLC, mobile phase with a gradient 15-80% acetonitrile in 50 min., gave 92 mg of off-white solid as the free base. LC-MSD, m/z for C29H34N2O4S [M+H]+: 507.6. 1H NMR (400 MHz, CDCl3): δ 1.5-3.5 (m, 16 H), 1.7 (s, 6 H), 3.8 (bs, 3 H), 5.0 (bs, 2 H), 6.6 (s, 1 H), 6.7 (s, 1 H), 7.2 (bs, 1 H), 7.3-7.4 (m, 2 H), 7.7-7.8 (m, 1 H), 7.8-7.9 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH2:5]Br.C1N2CN3CN(C2)CN1C3.Cl.C(O)(=[O:24])C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH:5]=[O:24]
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cc(Br)cc(C=O)c1
Temperature: 25 °C

Procedure:
To 3-bromo-5-methylbenzyl bromide (Step A above) (5.49 g, 20 mmole) in glacial acetic acid (9.0 mL) and H2O` (9 mL) was added hexamethylenetetramine (4.50 g, 32 mmole) and the reaction was stirred at reflux for 2 hours. Concentrated HCl (7.0 mL) was added and the mixture was refluxed an additional 15 minutes. After cooling to room temperature, the reaction mixture was diluted with H2O (75 mL) and extracted with ether (150 mL). The ether layer was washed with H2O (3×25 mL), 10% NaHCO3 (2×50 mL) and dried over MgSO4. The ether was removed under vacuum and the residue was chromatographed on silica gel eluting with hexane and 10% Et2O/hexane to yield 3-bromo-5-methylbenzaldehyde (2.80 g) as a light yellow oil which solidified upon standing. MS and NMR were consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:15][CH:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)[C:4]=2[C:5](/[N:8]=C/N(C)C)=[N:6][CH:7]=1.ClC1C=CSC=1C(OC)=O.CS[C:49](=[O:51])[NH2:50].Cl.CNOC.C(N(CC)C(C)C)(C)C.[OH:66][CH2:67][CH2:68][N:69]1[CH2:74][CH2:73]N[CH2:71][CH2:70]1>N1C=CC=CC=1>[NH2:8][C:5]1[C:4]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]4[N:26]([CH3:34])[C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=3)=[CH:14][S:15][C:3]=2[C:2]([NH:1][C:49]([N:50]2[CH2:73][CH2:74][N:69]([CH2:68][CH2:67][OH:66])[CH2:70][CH2:71]2)=[O:51])=[CH:7][N:6]=1
Reactant: COc1cc(-c2csc3c(N)cnc(/N=C/N(C)C)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CSC(N)=O
Reactant: OCCN1CCNCC1
Agent: CNOC
Agent: COC(=O)c1sccc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2csc3c(NC(=O)N4CCN(CCO)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-[4-(7-Amino-4-{[(1E)-(dimethylamino)methylene]amino}thieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide (0.108 g, 0.217 mmol) was dissolved in pyridine (3 mL). Methyl chlorothiolformate (0.020 mL, 0.233 mmol) was added, and the solution was stirred at ambient temperature for 1.5 hours, at which point LCMS analysis indicated that a clean conversion of the 7-amino group to the thiocarbamic acid S-methyl ester had occurred. N,O-Dimethylhydroxylamine hydrochloride (0.106 g, 1.09 mmol) was added, and the solution was stirred at 50° C. for 4 h, at which point LCMS analysis indicated that the 4-(dimethylaminomethyleneamino) group had been cleaved. The reaction mixture was cooled to ambient temperature, and N,N-diisopropylethylamine (0.264 mL, 1.30 mmol) and 1-(2-hydroxyethyl)piperazine (0.057 mL, 1.52 mmol) were added. The mixture was stirred at 70° C. for 12 h, then was cooled to ambient temperature and concentrated. The residue was diluted with aqueous sodium carbonate (0.5 M, 10 mL), and the mixture was extracted with dichloromethane (3×20 mL). The organic fractions were combined, dried over magnesium sulfate, and concentrated. Purification of the residue on silica gel which had been deactivated with triethylamine (10% by volume of silica gel used) afforded the title compound as an off-white powder: 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (s, 1H), 8.48 (s, 1H), 7.99 (d, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.59 (d, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 7.33 (t, 1H), 7.20 (s, 1H), 7.15 (t, 1H), 7.08 (d, 1H), 5.40 (br, 2H), 4.47 (br, 1H), 4.04 (s, 3H), 3.91 (s, 3H), 3.55 (m, 2H), 3.46 (m, 4H), 2.45 (m, 6H); MS: (MH)+ 600.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2].CCO.[BH4-].[Na+].Cl>O.CCOC(C)=O>[C:1]([O:4][CH2:5][CH:6]([OH:20])[C@@H:7]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)OCC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a suitable reactor was added 3f (1.55 g, 1.0 equiv) and EtOH (30 mL) was added at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (132.1 mg, 0.8 equiv) in H2O (3.1 mL) was added at below −15° C. The reaction mixture was warmed to −5-5° C. and stirred for 1 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (13 mL) was added at below 10° C., and the mixture was warmed to 20-30° C. EtOAc (160 mL) was added at 20-30° C., and the mixture was stirred at this temperature for 30 min. The separated organic portion was concentrated at 40-50° C. under reduced pressure to afford crude 4f. The diastereomeric ratio of crude 4f was determined to be 58/42 by HPLC analysis. The residue was purified by flash column chromatography (EtOAc/n-heptane=1/2) to give a diastereomeric mixture of 4f (1.04 g, 78% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:12][CH2:11][CH2:10][C@H:9]([CH2:13][NH:14]C(=O)OC(C)(C)C)[CH2:8]1.[NH2:23][C:24]1[C:25]([C:31]([OH:33])=O)=[N:26][C:27](Br)=[CH:28][CH:29]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O>>[NH2:23][C:24]1[C:25]([C:31]([NH:1][C:2]2[CH:3]=[N:4][N:5]([CH3:22])[C:6]=2[N:7]2[CH2:12][CH2:11][CH2:10][C@@H:9]([CH2:13][NH2:14])[CH2:8]2)=[O:33])=[N:26][C:27]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[F:34])=[CH:28][CH:29]=1
Reactant: Cn1ncc(N)c1N1CCC[C@H](CNC(=O)OC(C)(C)C)C1
Reactant: OB(O)c1ccccc1F
Reactant: Nc1ccc(Br)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3F)ccc2N)c1N1CCC[C@@H](CN)C1
Yield: 15 %

Procedure:
Following the procedures for Example 141, (R)-tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-3-yl)methylcarbamate, 3-amino-6-bromopicolinic acid were coupled and the intermediate amide was reacted with 2-fluorophenylboronic acid under palladium catalyzed Suzuki conditions to give 128 as a white solid (27 mg, 15%) over three steps. 1H NMR (400 MHz, DMSO) δ 9.82 (s, 1H), 8.04 (t, J=8.0, 1H), 7.81-7.60 (m, 2H), 7.38 (ddd, J=22.0, 13.3, 7.2, 5H), 7.07 (s, 4H), 3.68 (s, 3H), 3.15-2.94 (m, 3H), 2.75 (dt, J=17.3, 10.2, 3H), 2.01-1.47 (m, 4H), 1.25-1.01 (m, 1H). ESIMS m/z=424.1 (M+1)
Reaction SMILES: [CH3:1][C:2]1([OH:7])[CH2:6][CH2:5][NH:4][CH2:3]1.O[C@H]1CCNC1.[OH:14][C:15]1([CH2:22][NH:23][C:24]([C:26]2[C:27]3[CH:28]=[CH:29][C:30](Cl)=[N:31][C:32]=3[CH:33]=[CH:34][C:35]=2[Cl:36])=[O:25])[CH2:20][CH2:19][CH2:18][CH:17]([CH3:21])[CH2:16]1.C(N(C(C)C)CC)(C)C>C(#N)C.C(N(CC)CC)C>[Cl:36][C:35]1[CH:34]=[CH:33][C:32]2[N:31]=[C:30]([N:4]3[CH2:5][CH2:6][C:2]([OH:7])([CH3:1])[CH2:3]3)[CH:29]=[CH:28][C:27]=2[C:26]=1[C:24]([NH:23][CH2:22][C@:15]1([OH:14])[CH2:20][CH2:19][CH2:18][C@H:17]([CH3:21])[CH2:16]1)=[O:25]
Reactant: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Reactant: CC1(O)CCNC1
Agent: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(C)(O)C4)ccc23)C1

Procedure:
The title compound was prepared by the method of Example 1, step e) by reacting 3-methylpyrrolidin-3-ol (0.42 g) (instead of (S)-3-hydroxypyrrolidine) with 2,6-dichloro-quinoline-5-carboxylic acid (1-hydroxy-3-methyl-cyclohexylmethyl)-amide (0.10 g) and triethylamine (0.38 ml) (instead of diisopropylethylamine) in acetonitrile (1 ml) to afford the title compound crude and as a 1:1 mixture of diastereomers. The reaction was concentrated in vacuo and the products isolated by flash column chromatography (SiO2, 4% methanol/dichloromethane as eluent) as a colourless solid (70 mg). The diastereomers were separated by supercritical fluid chromatography (SFC) on an OJ Daicel column using 25% ethanol/carbon dioxide as eluent to afford Isomer 1 as a colourless solid (18 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH2:23])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:24][CH2:25][CH2:26][CH3:27])[N:20]([CH2:21][CH2:22][NH:23][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: C/C=C/C(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Product: C/C=C/C(=O)NCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 81.1 %

Procedure:
Using the general method of Example 92, crotonyl chloride (68 μL, 0.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) to provide 0.2 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide as a white powder, m.p. 198-200° C. Analysis: Calculated for C19H24N6O: % C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N, 23.99. HRMS (EI) calcd for C19H24N6O (M+) 352.2011 found 352.1996
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9]>C(Cl)(Cl)Cl>[CH2:6]([O:5][C:1]([CH2:2][CH2:3][N:13]1[CH2:14][CH2:15][N:10]([CH:8]=[O:9])[CH2:11][CH2:12]1)=[O:4])[CH3:7]
Reactant: O=CN1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCN1CCN(C=O)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.6 %

Procedure:
Ethyl acrylate (326 g) and chloroform (2 l) were added to 1-formylpiperazine (320 g) and the mixture was stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure to give crude 4-ethoxycarbonylethyl-1-formylpiperazine (580 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1>C(#N)C>[Cl-:15].[Cl-:15].[C:1]([O:9][CH2:10][CH2:11][N+:12]([CH3:14])([CH3:13])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][N+:12]([CH2:11][CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([CH3:13])[CH3:14])=[CH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CN(C)CCOC(=O)c1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCOC(=O)c1ccccc1)Cc1ccc(C[N+](C)(C)CCOC(=O)c2ccccc2)cc1
Product: [Cl-]
Reaction time: 0.08 h

Procedure:
A solution of 38.64 grams (0.20 mol) of 2-(N,N-dimethylamino)ethyl benzoate prepared as described in Example 1, 17.51 grams (0.10 mol) of α,α'dichloro-p-xylene and 112 milliters of acetonitrile was heated at reflux for 10 minutes. Solid began to precipitate at this time. Acetonitrile (55 milliters) was added and heating was continued for another 5 minutes. The reaction set up to a solid mass and was cooled. The solid was collected with acetonitrile rinse. The solid was washed with ether and dried. The yield of product was 44.0 grams (78.4% of theory); mp=209° C. dec.
Reaction SMILES: [CH3:1][O:2][P:3](C1C=CC=CC=1)[O:4]C.CI.P([O-])[O-].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([CH2:23][PH:3](=[O:4])[O:2][CH3:1])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1
Reactant: COP(OC)c1ccccc1
Agent: [O-]P[O-]
Solvent: CI
Product: CO[PH](=O)Cc1ccccc1
Temperature: 110 °C
Yield: 96 %

Procedure:
To a suitable vessel equipped with a stirring means, a temperature measuring means and a material addition means was charged 11 parts dimethylphenylphosphonite, 2.5 parts methyl iodide and 9 parts toluene. The resultant solution was slowly heated. The reaction is exothermic and the temperature increases to about 110° C., the reaction mixture is maintained at a temperature of about 100°-120° C., and an additional 185 parts dimethylphenylphosphonite slowly added. Additional amounts of methyl iodide, in about 1 part increments, are occasionally added during the phosphonite addition. The reaction mixture was maintained at about 110° C. for an additional hour following the addition of components. The reaction mixture was then distilled collecting the portion boiling at 148°-149° C./17 mm. (96 percent yield of methyl phenylmethylphosphinate). [Harwood and Grisley J. Am. Chem. Soc., 82, 423 (1960)]. ##STR3##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:34][C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH:36]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: BrCc1ccc2ccccc2c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4ccccc4c3)C2)c1
Yield: 87 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (44.4 mg, 0.10 mmol) in CH3CN (5 ml) was added 2-Bromomethyl napthalene) (33 mg, 0.15 mmol) and diisopropylethylamine (35 μl, 0.20 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product as a clear oil, (51 mg, 87%). Calcd for C37H40F3NO2 (M+H) 587.71, Found 588.5.
Reaction SMILES: [C:1]([O-:5])(=O)[CH2:2][OH:3].C=C.[K+].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1Cl)([O-:11])=[O:10].O>C(O)CO>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:3][CH2:2][CH2:1][OH:5])([O-:11])=[O:10]
Reactant: O=C([O-])CO
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: C=C
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(OCCO)c([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
200 ml of ethylene glycol and 40 ml of the mono-potassium ethylene glycolate solution prepared under Example 3 were introduced initially under nitrogen and were heated to 65° C. in a 2 l reaction vessel fitted with a stirrer. Over the course of 5 h, 162 g of molten 2,4-dinitro-chloro-benzene and the remainder of the mono-potassium ethylene glycolate solution in ethylene glycol were simultaneously metered in. The mixture was then stirred for one hour at 65° C., and then 600 ml of water were added. The precipitate which formed was filtered off and washed with 1000 ml of water and dried, giving 169.7 g of 2-(2′,4′-dinitrophenoxy)-ethanol in a purity of 92%. Hence, a yield of 92% is achieved based on 2,4-dinitrochlorobenzene.