Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:13](=[O:14])[N:12]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:17])[C:11]3[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=3[N:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:8]2=[O:40])[C:3]2[CH:41]=[CH:42][CH:43]=[CH:44][C:2]1=2.[CH3:45][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>CN(C=O)C.C1COCC1>[S:1]1[CH:5]=[C:4]([CH2:6][C:7]2([CH3:45])[C:13](=[O:14])[N:12]([CH2:15][C:16]([N:18]([CH:27]([CH3:29])[CH3:28])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:17])[C:11]3[CH:30]=[CH:31][CH:32]=[CH:33][C:10]=3[N:9]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:8]2=[O:40])[C:3]2[CH:41]=[CH:42][CH:43]=[CH:44][C:2]1=2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3csc4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 130 mg (0.22 mmol) of 2-(3-Benzo[b]thiophen-3-ylmethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Example 37, in 5 mL of DMF at 0° C. is added 0.43 mL (0.43 mmol, 2.0 equiv) of a 1.0M solution of NaN(TMS)2 in THF. The resulting solution is stirred 5 min, and 27 μL (0.43 mmol, 2.0 equiv) of methyl iodide is added. The resulting solution is stirred 4 h at RT, warmed to 50° C. for 16 h, and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of Et2O and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification of the material by silica gel MPLC on an Si60 column using hexane/EtOAc 3/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 106 mg of the title compound as a white amorphous solid: 1H NMR (DMSO-d6, 300 MHz) δ7.92 (m, 1H), 7.66-7.05 (m, 16H), 6.81 (d, 1H, J=8.1), 4.85 (m, 1H), 4.31 (s, br, 2H), 3.80 (s, 3H), 2.97 (d, 1H, J=15.2), 2.77 (d, 1H, J=15.2), 1.20 (s, 3H), 1.00 (m, 6H); low resolution MS (FAB)m/e 618 (MH+), 617 (M+), 453; Anal. (C37H35N3O4S) Calcd. C, 71.71; H, 5.74; N, 6.76; S, 5.26 Found C, 71.94; H, 5.71; N, 6.80; S, 5.19.
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Reactant: [H][H]
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 2.26 mg of [Ru(η5-2,4-DMP)((S)—(R)-(3,5-Me2-4-MeOPh)2PF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000) and 6 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of dichloromethane, 10 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (>99.9% conversion) and an enantiomeric purity of 87%.
Reaction SMILES: ON=[C:3]([CH3:18])[C:4](=[N:13][NH:14][C:15]([NH2:17])=[S:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[C:19](=O)([O-])[O-].[K+].[K+].C.CI>O>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]2[N:13]=[N:14][C:15]([S:16][CH3:19])=[N:17][C:3]=2[CH3:18])=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc(-c2nnc(SC)nc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
A mixture of 2-hydroxyimino-4'-methoxypropiophenone thiosemicarbazone (5.32 g), potassium carbonate (6.35 g) and water (50 ml) was treated in a similar manner to that of Example 25-(2), and then treated with activated charcoal. To the filtrate was added methyl iodide (6 g), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, treated with silica gel, and filtered. The filtrate was concentrated to dryness to give a residue, which was crystallized from diisopropyl ether. The resultant crystals were collected by filtration, washed with diisopropyl ether and dried to give 6-(4-methoxyphenyl)-5-methyl-3-methylthio-1,2,4,-triazine (2.42 g).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH2:9][CH2:10][CH2:11]/[C:12](=[CH:16]\[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[C:13]([OH:15])=O.Cl.[NH2:32][CH:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(Cl)CCl.CN(C=O)C>[CH2:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:41][CH:33]1[NH:32][C:13](=[O:15])/[C:12](=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1)/[CH2:11][CH2:10][CH2:9][Cl:8]
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)NC2Cc3ccccc3C2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
To a DMF solution (200 mL) of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (13 g) and 2-amino indan hydrochloride (7.8 g), IPEA (24.1 mL), HOBT (9.4 g) and EDC (13.3 g) were added one by one, and the reaction solution was agitated at room temperature. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution after 15 hours, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated sodium chloride solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 6.93 g of the title compound was obtained by purifying the residue by silica gel chromatography (elution solvent: ethyl acetate). The physical properties of the compound are as follows.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:13][N:14]([CH3:16])[CH3:15])[CH2:4][O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21](Cl)=[N:22][CH:23]=1>CO.C(O)CCC>[Br:17][C:18]1[C:19]([NH:25][C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[CH2:31][CH2:30][CH2:29]3)=[N:20][C:21]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([O:5][CH2:4][CH:3]([OH:2])[CH2:13][N:14]([CH3:16])[CH3:15])=[CH:7][CH:8]=2)=[N:22][CH:23]=1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Br)c(Nc2ccc3c(c2)CCC3)n1
Agent: Cl
Solvent: CO
Solvent: CCCCO
Product: CN(C)CC(O)COc1ccc(Nc2ncc(Br)c(Nc3ccc4c(c3)CCC4)n2)cc1
Temperature: 100 °C
Yield: 41.9 %

Procedure:
A hot solution of 4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]aniline hydrochloride (Method 89, 156 mg, 0.56 mmol) in methanol (2 ml) was added to a solution of 5-bromo-2-chloro-4-(indan-5-ylamino)pyrimidine (Method 15, 200 mg, 0.62 mmol) in n-butanol (20 ml). The mixture was heated at 100° C. for 18 hours and silica.(1 g) was added. Volatile material was removed by evaporation and the residue was purified by column chromatography, eluting with 0-10% 2.0M methanolic ammonia solution in DCM, to give the product as a colourless solid (117 mg, 42%). NMR: 2.03 (m, 2H), 2.18 (s, 6H), 2.32 (m, 2H), 2.83 (m, 4H), 3.80 (m, 3H), 4.76 (d, 1H), 6.70 (d, 2H), 7.17 (m, 1H), 7.23 (m, 1H), 7.41 (m, 3H), 8.10 (s, 1H), 8.35 (s, 1H), 9.03 (s, 1H); MS (MH+): 498.4, 500.4.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:39])[O:36][N:35]=4)=[CH:24][CH:23]=3)=[C:17]([CH2:40][CH2:41][CH3:42])[N:16]3[N:43]=[CH:44][N:45]=[C:15]23)[CH2:10][CH2:9]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[O:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[C:19](=[O:20])[C:18]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:39])[O:36][N:35]=4)=[CH:26][CH:27]=3)=[C:17]([CH2:40][CH2:41][CH3:42])[N:16]3[N:43]=[CH:44][N:45]=[C:15]23)[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](O[C@@H]3CCC[C@@H]3O)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC3CCCC3=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(trans-4-{[(1R,2S)-2-hydroxycyclopentyl]oxy}cyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.15 g), Dess-Martin reagent (0.2 g) and acetonitrile (10 mL) was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.09 g, 62%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=1)[CH2:14][CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(OCCCCl)cc1
Reactant: c1ccc(COc2ccc3c(c2)CCCN3)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)Oc1ccc(OCCCN2CCCc3cc(OCc4ccccc4)ccc32)cc1
Yield: 93.1 %

Procedure:
6-Benzyloxy-1,2,3,4-tetrahydro-quinoline (1.20 g, 5 mmol), 1-(3-chloropropoxy)-4-trifluoromethoxybenzene (1.42 g, 5.58 mmol), potassium carbonate (1.04 g, 7.5 mmol) and sodium iodide (0.90 g, 6 mmol) were heated and stirred at 90° C. in NMP (10 ml) overnight. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. The result was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=75:25) to afford the title compound as a yellow oil (2.13 g, 93%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[N:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:38]([N:36]1[CH:37]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[N:34]=[N:35]1)[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Reactant: CCn1cc(CCl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)nn1

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1.88 g; compound B50) is reacted with 4-(chloromethyl)-1-ethyl-1H-1,2,3-triazole (827 mg; compound D21) in the presence of potassium carbonate (1.22 mg) in DMF (30 ml). Using WU2 the title compound is obtained after flash column chromatography [silica gel, eluent: cyclohexane/EtOAc, 1/1 (v/v)] as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][OH:9].[C:10]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)#[N:11].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:9][CH2:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:16]1[CH:17]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:10]#[N:11]
Reactant: OCc1cnccc1Br
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1cccc(-c2ccncc2CO)c1

Procedure:
To a flask charged with (4-bromo-pyridin-3-yl)-methanol (90 mg, 0.48 mmol), 3-cyanophenylboronic acid (84.4 mg, 0.57 mmol) and tetrakis(triphenylphousphine)-palladium(0) (28 mg) was added 2 M Na2CO3 (2 mL) and toluene (3 mL). The reaction mixture was refluxed overnight and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and purified by column chromatography to yield 3-(3-Hydroxymethyl-pyridin-4-yl)-benzonitrile as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.[CH2:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:22](OCC)=[O:23])=[N:20][CH:21]=1)[CH3:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[CH:21][N:20]=1)=[O:23]
Reactant: CCOC(=O)c1ccc(OCC)cn1
Reactant: Nc1ccccc1Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)Nc2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of o-chloroaniline (0.68 g, 5.3 mmol) in 20 mL of PhMe was added 3 mL of AlMe3. The mixture was stirred at ambient temperature for 0.5 h and added into a solution of ethyl 5-ethoxypyridine-2-carboxylate 3 (0.26 g, 1.33 mmol) in 10 mL of PhMe. The mixture was stirred at ambient temperature for 15 h and quenched with 20 mL of 1N HCl. The mixture was extracted with ethyl acetate. The organic layer was separated and concentrated. The residue was purified by column (2:1 of hexane/ethyl acetate) to give N-(2-chlorophenyl)-5-ethoxypyridine-2-carboxamide 4 as a solid. Yield: 310 mg, 96%.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[Cl:15])(=[O:5])[CH3:4].[CH3:16]I.O>C1COCC1>[C:3]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH3:16])[C:7]=1[Cl:15])(=[O:5])[CH3:4]
Reactant: CC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1c(Cl)n(C)c2ccccc12
Reaction time: 72 h

Procedure:
To a slurry of 310 mg of NaH in 15 ml THF was added 1 g of (75), and then 625 μl of methyl iodide. The reaction was left with stirring for 3 days. Water was added, the product extracted with diethylether, and the ether phase dried and evaporated to dryness to give (76). Yield 870 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:19]([O-:21])=[O:20])=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccccc1CCCOC
Reactant: O=[N+]([O-])O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)COc1ccc([N+](=O)[O-])cc1CCCOC
Reaction time: 0.5 h

Procedure:
4.00 g (15.9 mmol) of the above prepared [2-(3-methoxy-propyl)-phenoxy]-acetic acid ethyl ester was dissolved in 5.0 ml of TFAA and added slowly and carefully via dropping funnel to a mixture of 5 ml of TFAA and 4 ml of conc. HNO3 (65%) kept at −10° C.; the reaction was then allowed to proceed for additional 30 min. Careful quenching with ice, twofold extraction with EtOAc, washing with NaHCO3 and brine, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/EtOAc=75/25) to deliver finally 3.00 g of the title compound as light brown oil, contaminated according to NMR with roughly 35% of the ortho-isomer which was separated after the next step, MS: 298.3 (MH+)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH:31]([C:33]1[S:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32]>C1COCC1.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>[CH3:24][O:23][C:21]([C:18]1[CH:19]=[N:20][C:15]([N:13]2[CH2:12][CH2:11][C:6]3[NH:7][C:8]4[CH:9]=[CH:10][C:2]([C:36]5[S:37][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=5)=[CH:3][C:4]=4[C:5]=3[CH2:14]2)=[N:16][CH:17]=1)=[O:22]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(Br)cc4c3C2)nc1
Reactant: O=Cc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)s5)cc4c3C2)nc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.5 %

Procedure:
To a solution of Example 33 (0.5 g, 1.29 mmol) in THF:H20 (4:1) were added Cs2CO3 (3.354 g, 10.32 mmol) and 5-formyl-2-thiopheneboronic acid (0.503 g, 3.22 mmol). The reaction mixture was thoroughly degassed and freshly prepared tetrakis(triphenylphosphine)palladium(0) (0.446 g, 0.38 mmol) was added under nitrogen atmosphere at room temperature. The reaction mixture temperature was raised to 80° C. and continued stirring for 12 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the THF was removed under reduced pressure. The mixture was partitioned between ethyl acetate (100 mL) and water (15 mL) and the organic layer was separated, dried over Na2SO4 filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[5-(formyl)-thien-2-yl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=O>O1CCCC1.[O-]CC.[Na+].C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])/[CH:11]=[CH:13]\[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: CC(=O)c1ccccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(/C=C\C(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
1-(2-Nitrophenyl)ethanone (1.04 g) and tert-butyl 4-formylpiperidine-1-carboxylate (1.47 g) were suspended in dry tetrahydrofuran (20 mL) and 20 drops of sodium ethoxide in ethanol (21% by weight) was added. The reaction mixture was stirred at room temperature for 18 hours and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 15% ethyl acetate/hexane) to furnish the title compound (1.30 g) with the following physical properties.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][C:15]=2[F:31])[CH2:10][CH2:9]1)=O)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[O:30]=[C:21]1[N:20]([C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[C:15]([F:31])[CH:16]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)c(F)c2)C(=O)O1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of (S)-(-)-4-[4-[5-[(acetylamino)methyl]-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 38, Step 1, 1.00 g) in dry methylene chloride (9.2 mL) at 0° C. under N2 is treated with trifluoroacetic acid (2.3 mL) over one minute, and the resulting mixture is stirred at 0° C. for three hours and added slowly to saturated aqueous potassium carbonate (30 mL) to neutralize excess trifluoroacetic acid. The resultant slurry is filtered and the precipitate is chromatographed on silica gel (70-230 mesh, 60 g), eluting with ammonium hydroxide/methanol/methylene chloride (0.25/19.75/80). Those fractions with an Rf =0.08 by TLC (methanol/chloroform, 20/80) are pooled and concentrated under reduced pressure to give the title compound, 1H NMR (MeOH-d4, 400 MHz) 7.47, 7.33, 7.25, 6.02, 4.80, 4.15, 3.83, 3.58, 3.47, 3.04, 2.46, 1.98 δ.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:6]=1.[CH3:20][O:21][CH:22]([O:33][CH3:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[NH4+]>CN(C)C=O>[CH3:34][O:33][CH:22]([O:21][CH3:20])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([NH:1][C:2]2[S:3][C:4]([C:17]([NH2:19])=[O:18])=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=3)[N:6]=2)[CH:24]=1
Reactant: COC(OC)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NC(=O)c1sc(N)nc1-c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(OC)c1ccc([N+](=O)[O-])c(Nc2nc(-c3cccc(C(F)(F)F)c3)c(C(N)=O)s2)c1
Yield: 87.3 %

Procedure:
A mixture of 0.5691 g (1.981 mmole) of 2-amino-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.48), 0.4515 g (2.098 mmole) of 4-dimethoxymethyl-2-fluoro-1-nitro-benzene 29 mL of dimethylformamide and 3.2215 g (9.877 mmole) of cesium carbonate was heated at 56 degrees for 4 hours. The cooled mixture was poured into dilute aqueous ammonium chloride solution. The precipitate was collected by filtration, washed with water, and dried to give 0.8344 g of 2-(5-dimethoxymethyl-2-nitro-phenylamino)-4-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.48a) as a brown-orange solid.