Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]1[O:24][C@@H:23]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])[S:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:29]([O:28][P:26]([CH2:25][C@H:23]1[S:22][CH2:21][C@H:20]([CH2:19][OH:18])[O:24]1)([O:31][CH2:32][CH3:33])=[O:27])[CH3:30]
Reactant: CCOP(=O)(C[C@@H]1O[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CS1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(C[C@@H]1O[C@@H](CO)CS1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
To a solution of cis and trans 5-(t-butyldiphenylsilyloxy methyl)-2-(diethyloxyphosphinoylmethyl)-1,3-oxathiolane (example 129) (15.68 g, 31.83 mmol) in THF (280 mL) was added tetrabutylammoniumfluoride (1 M solution in THF) (38.2 mL, 38.19 mmol, 1.2 eq.) at 0° C. The mixture was stirred at room temperature for 30 min. after which it was evaporated under reduced pressure. The residue was purified by flash chromatography with ethyl acetate: MeOH (95:5 to 93:7) to give 7.39 g of the compound in a 86% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:19])[C:9]2[N:14]=[C:13]([C:15]([O:17]C)=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:19])[C:9]2[N:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(C(O)c2ccc(F)cc2)n1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1cccc(C(O)c2ccc(F)cc2)n1

Procedure:
In analogy to the procedure described in Example 5 c), methyl 6-((4-fluorophenyl)(hydroxy)methyl)picolinate was saponified with lithium hydroxide to obtain the title compound. MS (EI): m/e=246.1 [M−H]−.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([N+:23]([O-])=O)=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[C:8]([O:26][CH3:27])=[C:9]([NH:11][C:12]([C:14]2[S:18][C:17]3[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:16]=3[CH:15]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(NC(=O)c2cc3cccc([N+](=O)[O-])c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2cc3cccc(N)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
To a solution of 7-nitro-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (1.2 g) in EtOAc (60 mL) was added 600 mg of 10% Pd/C. The reaction mixture was degassed and charged with H2 two times. The reaction was then stirred at room temperature under the H2 balloon. After 5 h, the reaction was diluted with EtOAc, filtered through a pad of diatomaceous earth and rinsed with EtOAc. The combined organics were concentrated to give 7-amino-benzo[b]thiophene-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (1.1 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)=[O:19])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
2-(6-Chloropyridin-3-yl)-1H-benzo[d]imidazole-4-carboxylic acid (6; 340 mg, 1.24 mmol) was taken up in DMF (5 mL) along with thiazol-2-amine (4; 125 mg, 1.24 mmol) and HATU (943 mg, 2.48 mmol). DIEA (0.41 mL, 2.48 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and the resulting solids were collected by filtration. Purification by silica gel chromatography (pentane/EtOAc) afforded 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide 7 as a pale yellow solid (215 mg, yield: 52%). MS (ESI) calcd for C16H10ClN5OS: 355.03; found: 356 [M+H].
Reaction SMILES: [CH2:1](OCC)C.C[Li].O1CCCC1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=4[C:38]=3[CH3:39])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(OCC)(=O)C.O>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[C:28]([CH3:41])=[C:29]([CH3:40])[C:30]4[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:1])([OH:37])[C:31]=4[C:38]=3[CH3:39])[CH2:25][CH2:26]2)=[CH:19][CH:20]=1
Reactant: CCOCC
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Li]C
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A diethylether solution (5.60 mL, 6.38 mmol) containing 1.14 M methyl lithium was added dropwise to a solution of tetrahydrofuran (20 mL) containing 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-1-benzofuran-3(2H)-one (2.00 g, 5.06 mmol) synthesized in Reference Example 42 under ice-cooling condition, and the mixture was stirred for 10 minutes. Water was added to the reaction solution, and extraction was performed using ethyl acetate. The organic layer was washed with water and saturated saline, and then dried using anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the obtained residue was crystallized using hexane to give 2.00 g of the title compound (yield: 96%).
Reaction SMILES: C([NH:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH2:15][CH:16]([C:18]3[CH:39]=[CH:38][C:21]([C:22]([NH:24][C@H:25]([C:33]([O:35]CC)=[O:34])[CH2:26][CH2:27][C:28]([O:30]CC)=[O:29])=[O:23])=[CH:20][CH:19]=3)[CH3:17])[CH2:12][NH:11][C:9]=2[N:10]=1)(=O)C>[OH-].[Na+]>[NH2:4][C:5]1[N:6]=[C:7]([OH:40])[C:8]2[CH2:14][CH:13]([CH2:15][CH:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23])=[CH:38][CH:39]=3)[CH3:17])[CH2:12][NH:11][C:9]=2[N:10]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(C)CC2CNc3nc(NC(C)=O)nc(O)c3C2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CC(CC1CNc2nc(N)nc(O)c2C1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Reaction time: 72 h
Yield: 67.3 %

Procedure:
A homogeneous solution of 17.5 mg of diethyl N-(4-[1-(2-acetamido-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl]benzoyl)-L-glutamate in 2 mL of methanolic sodium hydroxide solution was allowed to stand at room temperature for 72 hours. Most of the solvent was then removed under reduced pressure and the mixture was diluted with water and acidified with acetic acid. The precipitate was collected by filtration, washed with water, and dried under reduced pressure (0.1 mm) for 48 hours to give 9.7 mg (67%) of the title compound, which may be alternatively named as 5,10-dideaza-10-methyl-5,6,7,8-tetrahydrofolic acid. mp >250° C., NMR delta 0.87-0.88 (brs, 1H each), 1-2.8 (m, 11H), 3.13 (m, 1H), 4.59 (m, 1H), 6.96 (d, 2H, J=9 Hz), 7.34 (d, 2H, J=9 Hz).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]2[N:17]=[C:16]([NH2:18])[N:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:14]=2)[CH:5]=1.C1COCC1.[OH-].[Na+].Cl>O.CO>[NH2:18][C:16]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:14]=[C:13]([NH:12][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:25])=[O:2])[N:17]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2nc(N)n(-c3ccccn3)n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1Nc1nc(N)n(-c2ccccn2)n1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
A suspension of 3-(5-Amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-4-methoxy-benzoic acid methyl ester (1.31 g, 3.85 mmol) in a mixed solvent of THF (40 mL), MeOH (5 mL) and water (10 mL) was treated with 2N NaOH (8 mL) at 50° C. for 1 h. The reaction mixture was cooled to room temperature, neutralized with 6N HCl. Precipitate came out and collected by filtration to give the title compound (1.20 g) in 95% yield. Small amount was further purified by HPLC. FIA-MS: m/e=327.1 (M+H), 325.0 (M−H). Rt=3.09 min (Method A). 1H-NMR (500 MHz, DMSO(d6)): 12.53 (s, 1H), 8.81 (d, 1H), 8.43 (dd, 1H), 8.01 (td, 1H), 7.78 (s, 2H), 7.65 (d, 1H), 7.56 (s, 1H), 7.353 (dd, 1H), 7.23 (dd, 1H), 7.07 (dd, 1H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH3:23]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-But-3-yn-2-ol (189 mg, 2.71 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (30 mg, 0.03 mmol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and trituration with Et2O. (Yield 40 mg, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(=O)oc2c1
Agent: [Pd]
Product: COc1ccc2c(c1)OC(=O)CC2
Yield: 96 %

Procedure:
Compound 14A was prepared by hydrogenation of 7-methoxy-chromen-2-one catalyzed by 10% Pd/C in 96% yield. MS: 179 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:24][CH2:25][CH:26]([F:28])[F:27])[N:3]=1.[CH3:29][NH2:30]>C1COCC1>[F:27][CH:26]([F:28])[CH2:25][O:24][C:4]1[N:3]=[C:2]([NH:30][CH3:29])[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][C:5]=1[C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([F:18])([F:17])[F:16])[CH2:11][CH2:10]1)=[O:7]
Reactant: CN
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Solvent: C1CCOC1
Product: CNc1nc(OCC(F)F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The subtitle compound is prepared from 6-chloro-2-(2,2-difluoro-ethoxy)-5-nitro-N-(trans-4-trifluoromethyl-cyclohexyl)-nicotinamide (2.5 g, 5.8 mmol) and CH3NH2 (2 M in THF; 6.0 mL, 12.0 mmol) in THF (25 mL) in analogy with example 1d.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O-:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2].[Na+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1>CN(C)C=O.[Cl-].[Na+].O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:43][CH2:44][CH2:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:23])=[CH:17][CH:16]=1)#[N:2]
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc([O-])c(C#N)cc34)cc2)cc1
Reactant: ClCCCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCc5ccncc5)c(C#N)cc34)cc2)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
The sodium 6-cyano-4-(4-((4-methoxyanilino)carbonyl)aminophenoxy)-7-quinolinolate (200 mg) synthesized in Example 87 was dissolved in dimethylformamide (4 ml), and then potassium carbonate (130 mg, 0.9400 mmol), potassium iodide (3 mg) and 1-chloro-3-(4-pyridyl)propane (80 mg, 0.5159 mmol) were added and the mixture was heated and stirred at 80° C. for 5 hours and 30 minutes. After allowing the mixture to stand and adding saturated brine, it was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system). The obtained crystals were suspended in ethanol, the suspension was diluted with diethyl ether, and the crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (60 mg) as light yellow crystals.
Reaction SMILES: O[C:2]1[CH:12]=[CH:11][C:5]([C:6](OCC)=O)=[CH:4][CH:3]=1.O[C:14]1C=CC(C(OCCC)=O)=C[CH:15]=1.[Na].C(O)(=O)C1C=CC=CC=1>>[CH:14]([C:4]1[CH:3]=[CH:2][CH:12]=[CH:11][C:5]=1[CH3:6])=[CH2:15]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C(O)c1ccccc1
Agent: [Na]
Product: C=Cc1ccccc1C

Procedure:
Ethyl para-hydroxybenzoate (E 214) and propyl para-hydroxybenzoate (E 216) and their sodium compounds (E 2 15 and E 2 17) up to 5 grams per kilogram of product calculated as benzoic acid on a dry weight basis
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:32]C1C=CC=CC=1CCl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CC(O)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1
Reactant: ClCc1ccccc1Cl
Product: OC(Cc1ccccc1Cl)(c1cccc(F)c1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of 4a, 1-(4-Benzyl-morpholin-2-yl)-1-(3-fluoro-phenyl)-2-(2-methoxy-phenyl)-ethanol was followed using 2-chorobenzyl chloride (available from Aldrich Chemical Company) as starting material, and making non-critical variations, to yield the title compound which was taken without further purification in the next step. LCMS (6 minutes method) [M+H]+=426 @ Rt 2.85 min. major peak.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]1([CH2:13][C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([O-])(O)=O.[Na+].[CH2:22]([S:24][C:25]1[C:34]([NH2:35])=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1)[CH3:23]>C(Cl)Cl.CC(=O)OCC.CCCCCC.CC(=O)OCC.CN(C=O)C>[CH:7]1([CH2:13][C:14]([NH:35][C:34]2[C:25]([S:24][CH2:22][CH3:23])=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:16])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)CC1CCCCC1
Reactant: CCSc1nc2ccccc2cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CCSc1nc2ccccc2cc1NC(=O)CC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
760 mg (6 mmol) of oxalyl chloride and a catalytic amount of DMF (100 μl) were added at 0° C. to a suspension of 427 mg (3 mmol) of 2-cyclohexylacetic acid in DCM (45 ml). After stirring for 4 h at RT, the mixture was concentrated in vacuo. The residue was taken up in dioxane (30 ml), and 670 mg (8 mmol) of NaHCO3 were added. After stirring for 5 min at RT, 408 mg (2 mmol) of 2-(ethylthio)quinolin-3-amine (VC04) were added. After stirring for 16 h at RT, the reaction solution was diluted with EA and washed with a sat. aq. NaHCO3 soln. and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 19:1) of the residue yielded 397 mg (1.0 mmol, 51%) of 2-cyclohexyl-N-(2-ethylsulfanyl-quinolin-3-yl)-acetamide. MS: m/z 329.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Br.[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)P(=O)(N(C)C)N(C)C>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]1
Reactant: CC1CCc2c(Br)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC1CCNCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCC4C)CC1
Reaction time: 6.5 h
Yield: 2.7 %

Procedure:
In a 100 ml flask were placed 7 g of 9-fluoro-8-bromo-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 10.2 g of 4-methylpiperidine and 60 ml of hexamethylphosphoric triamide and the mixture was stirred at 160° C. in nitrogen gas atmosphere. After 6.5 hours, disappearance of the starting materials was confirmed by thin layer chromatography, and hexamethylphosphoric triamide was removed using a vacuum pump. To the residue was added several drops of concentrated hydrochloric acid and then ethyl acetate to separate oily substances from crystals. The crystals were collected by filtration and recrystallized from dimethylformamide-water to give 200 mg of 9-fluoro-8-(4-methyl-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 266° to 268° C., white rhombic crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C=C[S:42]C=3CCC2C)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[CH:18]=[CH:17][S:42][C:14]=3[CH2:15][CH2:16][CH:12]2[CH3:13])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2c3ccsc3CCC2C)n1
Product: CCc1nc(NC2c3ccsc3CCC2C)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(5-methyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.08, 6.87, 6.80, 5.55, 5.08, 4.45, 4.40, 2.91–2.78, 2.58, 2.22, 2.05–1.98, 1.79, 1.28, 1.10, 1.00.
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH2:36]([O:43][C:44]1[CH:45]=[C:46]([Cl:53])[C:47]([CH2:51]Br)=[C:48]([Cl:50])[CH:49]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[CH2:36]([O:43][C:44]1[CH:45]=[C:46]([Cl:53])[C:47]([CH2:51][N:15]2[CH2:16][CH2:17][CH:13]([N:10]3[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:12][CH2:11]3)[C:14]2=[O:18])=[C:48]([Cl:50])[CH:49]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)[Si](OC1CCN(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CCN(C2CCN(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
Treat a −78° C. solution of 3-[4-(tert-butyl-diphenyl-silanyloxy)-piperidin-1-yl]-pyrrolidin-2-one (0.25 g, 0.59 mmol) in THF (6 mL) with a 1.6 M n-butyl lithium in hexanes (0.37 mL, 0.59 mmol) and stir at −78° C. for 10 minutes under N2. Treat the reaction with 5-benzyloxy-2-bromomethyl-1,3-dichloro-benzene (0.204 g, 0.59 mmol), warm to room temperature, and stir for 16 hours under N2. Re-cool the reaction to −78° C., treat with 1.6 M n-butyl lithium in hexanes (0.37 mL, 0.59 mmol), warm to room temperature, and stir for 2 hours. Quench the reaction with water and extract with ethyl acetate. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 50 to 100% ethyl acetate in hexanes gradient to afford 0.263 g (65%) of the titled product. Rf=0.18 (3/1 ethyl acetate/hexanes). ES MS (m/z): 687 (M+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]2[CH2:28][CH2:27][O:26][CH2:25]2)[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12].[N:29]1([C:33]([C:35]2[S:39][C:38](Br)=[N:37][C:36]=2[CH3:41])=[O:34])[CH2:32][CH2:31][CH2:30]1>C(#N)C>[N:29]1([C:33]([C:35]2[S:39][C:38]([O:7][C:8]3[CH:9]=[C:10]([CH:20]=[C:21]([O:23][C@H:24]4[CH2:28][CH2:27][O:26][CH2:25]4)[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[N:37][C:36]=2[CH3:41])=[O:34])[CH2:30][CH2:31][CH2:32]1
Reactant: Cc1nc(Br)sc1C(=O)N1CCC1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc(Oc2cc(O[C@H]3CCOC3)cc(C(=O)Nc3ccn(C)n3)c2)sc1C(=O)N1CCC1
Temperature: 120 °C

Procedure:
Cesium carbonate (489 mg, 1.5 mmol) was added to a solution of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (152 mg, 0.5 mmol) and 5-(azetidin-1-ylcarbonyl)-2-bromo-4-methyl-1,3-thiazole (144 mg, 0.55 mmol) in acetonitrile (5 mL) and the stirred mixture heated at 120° C. in a microwave reactor for 2 hours. The mixture was allowed to cool, the acetonitrile evaporated in vacuo, and the residue partitioned between water (25 mL) and ethyl acetate (50 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with ethyl acetate, to give the desired compound as a solid which was further crystallised from an ethyl acetate/isohexane mixture (122 mg).
Reaction SMILES: F[C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[CH2:19]([OH:23])[CH2:20][CH2:21][CH3:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>>[CH2:19]([O:23][C:2]1[N:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCO
Reactant: O=C(NCCc1ccccc1)c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCCOc1ncccc1C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.5 %

Procedure:
2-Fluoro-N-phenethyl-nicotinamide (196 mg, 0.802 mmol), n-butanol (700 μL, 7.65 mmol) and potassium bis(trimethylsilyl)amide (2.5 mL, 0.5 M in toluene) were combined and stirred for 5 minutes at room temperature. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a colorless oil (207 mg, 0.694 mmol, 86.5%). ESI-MS m/z calc. 298.2, found 299.2 (M+1)+. Retention time of 3.46 minutes. H NMR (400 MHz, CD3CN) δ, 0.95 (t, J=7.4 Hz, 3H), 1.34-1.44 (m, 2H), 1.63-1.70 (m, 2H), 2.91 (t, J=7.0 Hz, 2H), 3.65-3.73 (m, 2H), 4.41 (t, J=6.7 Hz, 2H), 7.08 (dd, J=7.5, 4.8 Hz, 1H), 7.23-7.37 (m, 5H), 8.01 (s, 1H), 8.25 (dd, J=4.8, 2.0 Hz, 1H), 8.39 (dd, J=7.5, 2.0 Hz, 1H).