Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][C:28]1[N:29]=[C:25]([NH:24][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])[S:26][CH:27]=1)[CH3:35]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1cccc(Cl)c1)CCO2
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=492.0 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3-chlorobenzenesulfonyl chloride, furnishing 4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][N:2]1[CH2:16][CH2:15][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=1)=[CH2:18].[OH-].[K+]>CN1C(=O)CCC1>[OH:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:18][CH2:17][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[N:23][CH:24]=3)[C:5]3[CH2:15][CH2:16][N:2]([CH3:1])[CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: CN1CCc2[nH]c3ccc(CO)cc3c2C1
Reactant: C=Cc1ccc(CO)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(CO)ccc3n2CCc2ccc(CO)nc2)C1

Procedure:
The title compound is prepared from a mixture of (2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indol-8-yl)methanol, (5-vinylpyridin-2-yl)methanol and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [I-:1].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13]OS(C)(=O)=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20])([CH3:6])([CH3:5])[CH3:4]>CC(C)=O>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][I:1])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc(COS(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc(CI)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
1.65 g (11 mmol) of sodium iodide were added to a solution of 2.00 g (6.96 mmol) of 2-t-butyl-5-(methanesulfonyloxymethyl)-1-nitrobenzene [prepared as described in step (i) above] in 40 ml of acetone, and the mixture was stirred at 50° C. for 20 minutes. At the end of this time, the reaction mixture was cooled to room temperature, and filtered. The precipitate was washed with ethyl acetate, and the combined filtrate and washings were concentrated by evaporation under reduced pressure. The concentrate was dissolved in ethyl acetate, and the resulting solution was washed with water, with an aqueous solution of sodium thiosulfate, and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to give 2.18 g (yield 98%) of the title compound as crystals, melting at 98°-99° C. (after recrystallization from a mixture of methylene chloride, diethyl ether and hexane).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:3][CH2:2]1.O[CH2:25][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([F:12])=[CH:10][C:9]([C:13]3[O:14][C:15]4[CH:21]=[C:20]([O:22][CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH3:25])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:8][C:7]=2[F:23])[CH2:2][CH2:3]1
Reactant: Oc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[C@@H](COc1ccc2nc(-c3cc(F)c(OCC4CC4)c(F)c3)oc2c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 2-(4-(cyclopropylmethoxy)-3,5-difluorophenyl)-1,3-benzoxazol-6-ol (1.92 g), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (1.59 g) and triphenylphosphine (2.38 g) in THF (15 mL) was added dropwise diisopropyl azodicarboxylate toluene solution (1.9 M, 4.78 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to give the title compound (2.60 g). 1H NMR (300 MHz, CDCl3) δ 0.29-0.37 (2H, m), 0.56-0.67 (2H, m), 1.17-1.36 (4H, m), 1.46 (9H, s), 3.94-4.19 (5H, m), 4.67-4.82 (1H, m), 6.97 (1H, dd, J=8.7, 2.3 Hz), 7.10 (1H, d, J=2.3 Hz), 7.62 (1H, d, J=8.7 Hz), 7.68-7.81 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13](OC)=[O:14]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]([CH3:11])=[C:5]2[CH2:12][CH2:13][OH:14]
Reactant: COC(=O)CC1=C(C)Cc2ccc(F)cc21
Solvent: C1CCOC1
Product: CC1=C(CCO)c2cc(F)ccc2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63 %

Procedure:
To a solution of methyl 5-fluoro-2-methyl-3-indenyl-acetate (24 g) in dry THF (300 ml) lithiumaluminum hydride (6.9 g) is added. The mixture is stirred at room temperature for 1.5 hours. Excess LiAlH4 is destroyed with saturated aqueous NaHSO4 solution. The organic phase is concentrated in vacuo, and the crude product is purified via silica gel column chromatography elution with methylene chloride. The residue is recrystallized from hexane to give 5-fluoro-2-methyl-1H-3-indenyl-(2-hydroxy) ethane (yield 63%; m.p. 65°-66.5° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[CH:16])[CH:5]=[CH:4][C:3]1=2.I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: C#CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.4 g (32.7 mmol) of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propyne, 8.2 g (29.7 mmol) of ethyl 4-iodobenzoate and 50 ml of triethylamine are introduced into a three-necked flask under a stream of nitrogen. The reaction medium is degassed by bubbling nitrogen through, 360 mg (0.5 mmol) of bis(triphenylphosphine)palladium(II) chloride and 130 mg of copper iodide are introduced and the mixture is stirred at room temperature for eight hours. The reaction medium is evaporated to dryness, the residue is taken up in ethyl acetate and hydrochloric acid (1 N) and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (70/30). After evaporation of the solvents, a solid is collected which is triturated from heptane, filtered and dried. 9.3 g (84%) of the expected ethyl ester are collected, with a melting point of 59-60° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]([Mg]Br)=[CH2:12]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:12]=[CH:11][NH:8][C:7]=12
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: Clc1nccc2cc[nH]c12
Temperature: -20 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 2-chloro-3-nitropyridine (5 g, 31.5 mmol)) in THF (200 mL) at −78° C., was added vinylmagnesium bromide (100 mL, 1.0M in THF) The reaction mixture was stirred at −20° C. for 8 hours, quenched with NH4Cl solution (20%, 150 mL), extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography, eluent EtOAc/hexane (1:5), to afford the title compound 259 (1.23 g, 26% yield) as a white solid [Z. Zhang, et al., J. Org. Chem., 2002, 67, 2345-23471]. MS (m/z): 153.1 (M+H) (found).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27](O)=[O:28])[CH2:26][CH2:25]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.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>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][C:24]5([C:27]([N:35]6[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]6)=[O:28])[CH2:25][CH2:26]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)O)CC4)cc2OCC3)n(C(C)C)n1
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC4(C(=O)N5CCN(C)CC5)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropanecarboxylic acid (90 mg, 0.22 mmol), 1-methylpiperazine (29 uL, 0.26 mmol), HATU (108 mg, 0.29 mmol) and DIPEA (52 uL, 0.31 mmol) in DMF (3 mL) was stirred at RT for 2 h. Volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, followed by brine, then dried (MgSO4) and concentrated in vacuo affording {1-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]cyclopropyl}-(4-methylpiperazin-1-yl)methanone (quantitative). LCMS: RT 2.08 min [M+H]+ 492.2
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][CH:13]=[N:12][C:11]=2[N:10]=[C:9]1[Cl:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1[nH]cnc2ncn(Cc3ccccc3)c12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2nc(Cl)n(Cc3ccccc3)c12
Reaction time: 8 h
Yield: 41.5 %

Procedure:
12.748 g of 7-benzyl-1,7-dihydropurin-6-one was dissolved in 150 ml of N,N-dimethylformamide, and 7.9 g of N-chlorosuccinimide was added thereto. The reaction solution was stirred overnight, and then diluted with ethyl acetate. The solution was washed with water and 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. The solution was filtered, and the filtrate was concentrated to give 6.103 g of 7-benzyl-8-chloro-1,7-dihydropurin-6-one. This compound was combined with 20 g of t-butyl piperazine-1-carboxylate, and the mixture was heated at 150° C. After being stirred for one hour, the reaction mixture was combined with ethyl acetate and water, and partitioned. The organic layer was washed with 1N hydrochloric acid, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography. Thus, 1.539 g of the title compound was obtained from the fraction eluted with ethyl acetate-methanol (10:1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[CH3:25][CH:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:33][CH:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:25])=[O:21]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Reactant: CC(N)c1ccccc1
Product: CC(NC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O)c1ccccc1

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and α-methylbenzylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.40 (1H, br), 10.80 (1H, br), 8.35 (1H, br), 7.35-7.24 (1H, m), 5.14 (1H, m), 4.05 (2H, br s), 1.46 (3H, br); HRMS calcd for C24H21N3O3+H+: 400.1661. Found: 400.1670.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:14]([CH3:15])[C:6]2=[N:7][CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:5]2[N:4]=1.[H][H]>[Pd]>[NH2:11][C:9]1[CH:10]=[C:5]2[N:4]=[C:3]([CH2:2][OH:1])[N:14]([CH3:15])[C:6]2=[N:7][CH:8]=1
Reactant: Cn1c(CO)nc2cc([N+](=O)[O-])cnc21
Reactant: [H][H]
Agent: [Pd]
Product: Cn1c(CO)nc2cc(N)cnc21
Yield: 0.1 %

Procedure:
A suspension of 0.5 g (2.4 mol) of 2-hydroxymethyl-6-nitro-3-methyl-3H-imidazo[4,5-b]pyridine, prepared in the preceding step, and 0.3 g of 10% palladium-on-charcoal is stirred for 3 hours under 2.5 atm. of hydrogen. After this time, the suspension is filtered through a pad of Celite and the filtrate is concentrated under reduced pressure. 0.4 g of the expected product is thus isolated, and is used without further purification in the rest of the synthesis.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[CH:6]=[C:7]([SH:11])[CH:8]=[CH:9][CH:10]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:2][CH3:3])[CH:6]=1
Reactant: CCI
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
Iodoethane (0.46 mL, 0.0058 mol) was added to a suspension of 3-bromothiophenol (0.50 mL, 0.0048 mol), ACN (7.11 mL, 0.136 mol) and potassium carbonate (2.0 g, 0.014 mol). The reaction was stirred for 2 h at rt, was diluted with ethyl acetate and filtered to remove the solids. The reaction was concentrated in vacuo to give 1-bromo-3-(ethylthio)benzene as a colorless oil 1.0 gm, 100%
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].CO[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]>>[CH3:2][N:3]([CH3:4])[C:7]([C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][C:17]2[C:22]3[CH2:23][C:24]([CH3:27])([CH3:26])[O:25][C:21]=3[CH:20]=[C:19]([C:28](=[O:36])[NH:29][C:30]3[CH:34]=[CH:33][N:32]([CH3:35])[N:31]=3)[CH:18]=2)=[CH:11][N:10]=1)=[O:8]
Reactant: CNC
Reactant: COC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F
Agent: Cl
Product: CN(C)C(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from dimethyl amine hydrochloride (278 mg, 3.41 mmol) and 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid methyl ester (175b) (150 mg, 0.341 mmol) to give a white solid (74 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1 H) 8.22 (d, J=1.77 Hz, 1 H) 7.27-7.31 (m, 1 H) 7.01-7.13 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.81 (s, 3 H) 3.16 (s, 3 H) 3.00 (s, 3 H) 2.92 (s, 2 H) 1.50 (s, 6 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4: C, 60.92; H, 5.33; N, 15.44; Found: C, 60.66; H, 5.37; N, 15.26.
Reaction SMILES: [F:1][CH:2]([F:11])[P:3]([O:8][CH2:9][CH3:10])(=[O:7])[O:4][CH2:5][CH3:6].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C1COCC1>[CH2:5]([O:4][P:3]([C:2]([F:1])([F:11])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])(=[O:7])[O:8][CH2:9][CH3:10])[CH3:6]
Reactant: CCOP(=O)(OCC)C(F)F
Reactant: CCCCCCCCCCCCCCBr
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(F)(F)P(=O)(OCC)OCC
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a solution of diethyl difluoromethanephosphonate (1.0 g, 5.316 mmol) in THF (50 mL) 2 M LDA (626 mg, 5.847 mmol) was added at −78° C. and stirred for 30 min. Tetradecyl bromide (1.474 g, 5.316 mmol) in THF (10 mL) was added to the mixture at −78° C. and the reaction mixture was stirred overnight. THF was evaporated and the residual oil was purified by flash chromatography using 30% ethyl acetate in hexane as eluent to give 817 mg (40%) of compound 10 as colorless oil. 1H NMR (CDCl3): δ 4.26 (m, 4H), 2.05 (m, 2H), 1.56 (m, 2H), 1.37 (t, J=6.9 Hz, 6H), 1.25 (br s, 22H), 0.87 (t, J=6.6 Hz, 3H); MS: [M+23Na] at m/z 407.2.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>>[O:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:15]3([OH:22])[C:14]4[C:18](=[CH:19][CH:20]=[C:12]([I:11])[CH:13]=4)[NH:17][C:16]3=[O:21])[C:10]=2[O:9][CH2:8]1
Reactant: Brc1cccc2c1OCO2
Reactant: O=C1Nc2ccc(I)cc2C1=O
Product: O=C1Nc2ccc(I)cc2C1(O)c1cccc2c1OCO2
Yield: 64.8 %

Procedure:
With 2.70 g of 4-bromo-1,3-benzodioxol and 9.00 g of 5-iodoisatin as starting materials, 3.44 g of the title compound (orange color solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[Cl:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:14]([C:12]1[S:13][C:9]([S:8][C:7]2[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=2[Cl:20])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=1)=[O:15]
Reactant: Nc1ccccc1Cl
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccccc1Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2-chloro-aniline (49 mg, 0.39 mmol). The title compound was obtained as a solid (42 mg, 28% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.53 (1H, s), 8.99 (2H, s), 8.61 (1H, s), 7.55 (1H, m), 7.47 (1H, m), 7.38 (2H, m), 7.32 (1H, m). MS m/z: 458.07, 460.05 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8].C(N(CC)CC)C>C(O)C.[Pd]>[CH3:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[C:4]=1[NH:5][C:6](=[O:9])[CH2:7][Cl:8]
Reactant: O=C(CCl)Nc1c(CCl)cccc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)F)c1NC(=O)CCl
Yield: 105 %

Procedure:
A solution of 8.01 g (0.0262 mol based on 93.5% assay) of 2'-(chloromethyl)-6'-(trifluoromethyl)-2-chloroacetanilide (prepared as in example 6) and 4.0 ml (0.029 mol) of triethylamine in 60 ml of ethanol was shaken with 0.160 g of 10% Pd/C under 20-50 psi of H2 pressure at room temperature. When H2 uptake was complete (4.0 hr.), the mixture was filtered to remove catalyst and partitioned between 100 ml of methylene chloride and 50 ml of water. The organic phase, combined with a small methylene chloride wash of the aqueous phase, was washed with two 50 ml portions of water and was dried using magnesium sulfate. Solvent removal in vacuo provided 6.92 g of white 2'-methyl-6'-(trifluoromethyl)-2-chloroacetanilide assaying 92.1% for a yield of 96.7%.
Reaction SMILES: [Na].[CH3:2][OH:3].[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.[OH-].[Na+]>CS(C)=O>[Br:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:3][CH3:2])[CH:10]=1
Reactant: Brc1cncc(Br)c1
Reactant: CO
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cncc(Br)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Sodium (2.33 g, 101.3 mmol) was added to methanol (50 ml) and was allowed to react, the mixture was evaporated. 3.5-Dibromopyridine (20.0 g, 84.4 mmol) and dimethyl sulfoxide (100 ml) were added. The mixture was stirred at 90° C. for 2 h. Sodium hydroxide (400 ml, 1 M) was added and the mixture was extracted twice with diethyl ether (200 ml). Chromatography on silica gel with dichloromethane and 3% ethanol as solvent gave the title compound. Yield 10.6 g, 67%. Mp 30-32° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:14]([O:13][C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:27][CH3:28])=[O:24])[CH2:10]1)([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.9 %

Procedure:
To a solution of 3-((2S,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-pyrrolidin-2-yl)acrylic acid (40 g, 0.107 mol) in dry DMF (250 ml) was added iodoethane (17.3 ml, 0.23 mol), followed by K2CO3 (29 g, 0.22 mol). After stirring at RT for 4 h, K2CO3 was filtered off and solvent removed under vacuum. The residue was taken in dichloromethane, washed with brine and dried. The solvent was removed under vacuum to give tert-butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]pyrrolidine-1-carboxylate (35 g) as pale yellow liquid. Yield: 82%
Reaction SMILES: C(N(CC)CC)C.[F:8]N1N=C(F)C=C(F)N1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:19]=1>ClCCl>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([F:8])=[O:23])=[C:20]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:19]=1
Reactant: O=C(O)c1ccc(Cl)nc1NCc1ccccn1
Reactant: FC1=CC(F)=NN(F)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(F)c1ccc(Cl)nc1NCc1ccccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
2.27 ml of triethylamine (16.31 mmol) and 1.65 ml of 2,4,6-trifluorotriazine (19.57 mmol) are added successively to a suspension of 4.3 g of 6-chloro-2-[(pyridin-2-ylmethyl)amino]nicotinic acid (16.31 mmol) in 90 ml of dichloromethane. The mixture is stirred for 1 hour at ambient temperature and then a dichloromethane/ice-cold water mixture is added. The organic phase is washed 3 times with ice-cold NaHCO3aq and then dried over Na2SO4, filtered, and concentrated under vacuum. 3.97 g of expected product are obtained in the form of an orange solid. Yield=92%.