Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCC.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[Cl:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][N:26]1[CH2:25][CH2:24][N:23]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: ClCCCBr
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Pentane (10 mL) was added to sodium hydride (0.50 g, 11 mmol of 50% suspension in mineral oil) and the mixture was stirred under nitrogen. The pentane was decanted. Anhydrous DMF (12 mL) was added and the suspension was cooled to 0° C. [Bis(4-fluorophenyl)methylpiperazine (2.9 g, 10 mmol) in anhydrous DMF (14 mL) was added at 0° C. within 10 min. The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled to 0° C. and to the light green solution 1-chloro-3-bromopropane (5 mL, 50 mmol) in anhydrous DMF (5 mL) was added over a period of 10 min. The mixture was stirred under nitrogen at room temperature for 72 h. The solvents were evaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated in methylene chloride and filtered through celite. The filtrate was washed with water (2× 100 mL), dried (sodium sulfate), filtered, and the filtrate was evaporated in vacuo to give crude chloro-propyl compound (3.65 g). Pentane (50 mL) was added, and on the next day the pentane insoluble solid was removed by filtration. The filtrate was evaporated in vacuo to give the title compound (2.3 g, 75%) as a clear, colorless oil. 100 MHz 1H NMR (CDCl3) δ: 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.57 (m, 2H), 2.2-2.6 (m, 10H), 1.9 (m, 2H). DCI/MS (M+1) 361.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1.I[CH2:16][CH2:17][CH3:18].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH:14]=1
Reactant: CCCI
Reactant: Clc1cccc(-c2ccncc2)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCN1CC=C(c2cccc(Cl)c2Cl)CC1

Procedure:
Preparation according to preparation 10: 4-(2,3-dichlorophenyl)pyridine (1.0 g, 4.46 mmol), 1-iodopropane (6 ml), ethanol (60 ml), sodium borohydride (1.5 g, 44 mmol). Yield: 0.45 g. MS m/z (rel. intensity, 70 eV) 271 (M+, 16), 269 (M+, 28), 242 (62), 240 (bp), 127 (11).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>O1CCOCC1.C(OCC)(=O)C.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>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([C:19]([NH:21][C@@H:22]3[C@@H:27]([OH:28])[CH2:26][O:25][CH2:24][CH2:23]3)=[O:20])[CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2c(n1)CCCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCOC[C@@H]1O)c1cc(Cc2ccc(-c3cnccn3)nc2)c2c(n1)CCCC2
Temperature: 25 °C

Procedure:
To a solution of 1,5-anhydro-3-[({4-[(6-chloropyridin-3-yl)methyl]-5,6,7,8-tetrahydroquinolin-2-yl}carbonyl)amino]-2,3-dideoxy-L-threo-pentitol (Example 1, 0.038 g, 0.095 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.060 mL g, 0.19 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0095 mmol). The mixture was irradiated in a microwave reactor at 130° C. for 1.5 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-6% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 446.0 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.52 (s, 1H), 8.74-8.70 (m, 2H), 8.64 (s, 1H), 8.34-8.30 (m, 2H), 7.77-7.66 (m, 1H), 7.63 (s, 1H), 4.16 (s, 2H), 3.82-3.72 (m, 3H), 3.69-3.53 (m, 1H), 3.04-2.99 (m, 1H), 2.92 (br s, 2H), 2.75 (br s, 2H), 1.96-1.66 (m, 4H), 1.65-1.55 (m, 2H), 1.13-1.09 (m, 1H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[C:53]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:54]=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cccc3[nH]ccc23)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 50.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.013 g of product in 52% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [C:1]([NH:9][C:10]([NH:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:35]I>C(O)(=O)C>[C:1]([NH:9][C:10]([NH:12][C:13]1[N:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:16]=[N:15][C:14]=1[C:30]([NH2:32])=[O:31])=[SH:11][CH3:35])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ncn(OCCCOCc2ccccc2)c1NC(=S)NC(=O)c1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C[SH]=C(NC(=O)c1ccccc1)Nc1c(C(N)=O)ncn1OCCCOCc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 5-(N'-benzoylthiocarbamoyl)amino-1-(3-benzyloxyprop-1-oxy)imidazole-4-carboxamide (2.9 g, 6.4 mmol), 0.1N sodium hydroxide solution (100 ml) and methyl iodide (0.64 ml; 10.3 mmol) was stirred at 20° C. for 16 hours and then the solution adjusted to pH 5 with glacial acetic acid. After several extractions with chloroform, the combined extracts were dried (magnesium sulphate) and evaporated to a syrup. Column chromatography on silica gel (eluted with chloroformethanol, 30:1) afforded the title compound (2.7 g, 88.7%).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]=[C:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1.O>C1C=CC=CC=1>[Br:1][C:2]1[C:3]([O:23][CH3:24])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:34]([CH:31]3[CH2:33][CH2:32]3)=[O:35])[C:8]([CH3:21])=[CH:7][C:6]=2[CH:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(cc1Br)CC(C)=NN=C2c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: COc1cc2c(cc1Br)C=C(C)N(C(=O)C1CC1)N=C2c1ccc([N+](=O)[O-])cc1

Procedure:
0.5 g of 7-bromo-1-(4-nitrophenyl)-4-methyl-8-methoxy-5H-2,3-benzodiazepine (Example 3, Step C) is suspended in 15 ml of benzene, mixed with 0.53 g of potassium carbonate and 0.17 ml of cyclopropylcarboxylic acid chloride and then refluxed for 5 hours. Then, the mixture is stirred with water, the organic phase is separated, washed in succession with soda solution and water, dried, filtered and concentrated by evaporation. The residue is purified by absorptive precipitation in ethanol, and 0.38 g of 7-bromo-3-cyclopropylcarbonyl-1-(4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepine of the title compound with a melting point of 231-223° C. is obtained.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[Na+]>CO>[Cl:7][CH2:8][CH2:9][CH2:10][S:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:2]
Reactant: CCOC(=O)CSCCCCl
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CS(=O)CCCCl
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 95.6 %

Procedure:
To 4 ml of an aqueous solution of 0.39 g of sodium metaperiodate was added 3 ml of a methanol solution of 0.30 g of ethyl [(3-chloropropyl)thio]acetate obtained in Reference Example 1. The mixture was stirred at room temperature for 100 minutes To the reaction mixture was added 30 ml of a saturated aqueous sodium chloride solution followed by extraction with ethyl acetate The extract was dried over anhydrous magnesium sulfate The solvent was then distilled off. The residue was applied to silica gel column chromatography. Elution with a solvent mixture of hexaneethyl acetate (1:3) gave 0.31 g of ethyl (3-chloropropylsulfinyl)acetate.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][CH:34]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:36]([O:35][C:32]1[N:31]=[N:30][C:29]([N:14]2[CH2:13][C:12]3[CH2:8][N:9]([C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=3[CH2:15]2)=[CH:34][CH:33]=1)[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: Clc1ccc(OCCc2ccccc2)nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCCc3ccccc3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol), 3-chloro-6-phenethyloxypyridazine (example 4a) (296 mg, 1.26 mmol), tris(dibenzylideneacetone)dipalladium(0)chloroform adduct (67.9 mg, 65.6 μmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (81.7 mg, 131 μmol) and cesium carbonate (1.645 g, 5.048 mmol) were stirred in 5 ml of dioxane under an argon atmosphere at 80° C. for 4 h. The reaction mixture was concentrated and admixed with ethyl acetate and water, and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 104 mg (14%), M+H+: 481.2.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH2:30])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]>ClC(Cl)Cl>[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH:30][C:10](=[O:12])[CH3:11])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC)cc12
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(C)=O)c(OC)cc12
Reaction time: 1 h
Yield: 87 %

Procedure:
Diisopropylethylamine (83.2 μL, 477 μmol), followed by acetic anhydride (239 μmol) were added to a solution of 6-amino-2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 17 (75 mg, 239 μmol) in dry trichloromethane (3 mL). After one hour, the reaction was quenched with water (3 mL). After concentration to dryness, the crude oil was purified by HPLC (reverse phase, C18, acetonitrile/water with 0.1% acetic acid) to provide 73 mg (87%) of the title compound.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C(N(CC)CC)C.[N:19]1([CH2:24][CH2:25][OH:26])[CH:23]=[CH:22][N:21]=[N:20]1.Cl>CN(C1C=CN=CC=1)C.ClCCl>[N:19]1([CH2:24][CH2:25][O:26][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: OCCn1ccnn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCn2ccnn2)cc1
Temperature: -4 °C
Reaction time: 8 h

Procedure:
A solution of 12.9 g (66.3 mmol) p-toluenesulfonic acid chloride, 2.03 g (16.6 mmol) 4-(N,N-dimethylamino)-pyridine and 11.2 ml (80.2 mmol) triethylamine in 150 ml dichloromethane was cooled to −10° C. A solution of 7.50 g (66.3 mmol) 2-(1H-[1,2,3]triazol-1-yl)-ethanol in 150 ml dichloromethane was added dropwise and the mixture stirred overnight at −4° C. 170 ml Ice and 170 ml dichloromethane were added and stirring continued for 10 min. followed by addition of 3.9 ml conc. HCl. The organic phase was separated, washed with sat. NaHCO3-solution and brine, dried over Na2SO4 and solvents distilled off. Yield 15.3 g (86%) orange crystals.
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][CH:4]=1>C(Cl)Cl>[Br:1][C:5]1[CH:4]=[N:3][C:8]2[NH:9][C:10](=[O:14])[CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: O=C1CCCc2cccnc2N1
Solvent: ClCCl
Product: O=C1CCCc2cc(Br)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A 10% solution of bromine (0.57 mL, 11.1 mmole) in CH2Cl2 was added dropwise over 1 hr to a solution of 5,6,7,9-tetrahydro-pyrido[2,3-b]azepin-8-one (1.20 g, 7.4 mmole) in CH2Cl2 at RT. The mixture was stirred at RT overnight, then was concentrated in vacuo. The residue was diluted with 10% Na2CO3 and extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (EtOAc) gave the title compound (1.00 g, 56%) as a light yellow solid after drying in vacuo: MS (ES) m/e 241/243.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C(N(CC)C(C)C)(C)C.[C:22]([O:25][CH2:26]Br)(=[O:24])[CH3:23].CCC(OBr)=O>C(#N)C>[C:22]([O:25][CH2:26][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])(=[O:24])[CH3:23]
Reactant: CC(=O)OCBr
Reactant: O=C(O)Cc1ccc(I)cc1F
Agent: CCC(=O)OBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(=O)OCOC(=O)Cc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 2-fluoro-4-iodo phenyl acetic acid (described in U.S. Pat. No. 6,252,090, incorporated herein by reference; 0.82 g, 2.93 mmol) in anhydrous acetonitrile (10 mL) was treated with N,N-diisopropyl ethyl amine (1.27 mL, 7.32 mmol) followed by acetoxy methyl bromide/bromo methylacetate (0.896 g, 5.86 mmol) and the resulting reaction mixture was stirred overnight at ambient temperature. The volatiles were evaporated in vacuo and the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil that was subjected to flash column chromatography over silica gel (230–400 mesh) using 10–20% ethyl acetate in hexane as the eluent to afford the title compound as an oil (0.75 g, 72%). 1H NMR (300 MHz, CDCl3): 7.42 (m, 2H), 6.97 (dd, J=8.0 & 8.0 Hz, 1H), 5.73 (s, 2H), 3.65 (s, 2H), 2.08 (s, 3H).
Reaction SMILES: N1CCCCC1.O[CH:8]1[CH2:13]SC(O)C[S:9]1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]>>[NH2:16][C:15]1[S:9][CH:8]=[CH:13][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: OC1CSC(O)CS1
Reactant: CCOC(=O)CC#N
Solvent: C1CCNCC1
Product: CCOC(=O)c1ccsc1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Piperidine (20.7 ml) was added dropwise with stirring to a mixture of 2,5-dihydroxy-1,4-dithiane (17.5 g) and ethyl cyanoacetate (23.7 g). The mixture was stirred at room temperature for 4 hours and then allowed to stand overnight. It was filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, filered and evaporated to dryness. The residue was triturated with light petroleum (b.p. 60-80° C.) containing a small amount of ethyl acetate. The gummy solid obtained was purified by silica gel column chromatography and the semi-solid product was triturated with water, filtered and washed with light petroleum (b.p. 60-80° C.) and dried to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.I[CH2:31][C:32]([NH2:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][C:32]([NH2:34])=[O:33])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: NC(=O)CI
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CC(N)=O)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with 2-iodoacetamide in the presence of potassium carbonate to give the title compound as a light yellow solid, MS (ESI+): m/z=487.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH2:29])[CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][NH:29][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: NCCc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCc1cccc(F)c1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 2-(3-fluoro-phenyl)ethylamine (0.051 mL, 0.389 mmol) and triethylamine (0.135 mL, 0.972 mmol) in acetonitrile (10 mL). The reaction mixture stirred for 1 hr at room temperature, concentrated and crude product purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [2-(3-fluoro-phenyl)-ethyl]-amide. LCMS m/z=412.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH3:12]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Br)ccc1C(=O)O
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-methylbenzoic acid (5.11 g, 23.8 mmol, 1.0 equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes (mildly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched into saturated aqueous NaHCO3 (100 mL) (note—significant gas evolution) and extracted with dichloromethane (200 mL×1 then 50 mL×1). The combined organic phases were washed with a mixture of brine/saturated NaHCO3 (9:1)(50 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain the title compound as a colorless oil (5.28 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.78 (d, J=8.0 Hz, 1H), 7.42 (d, J=1.6 Hz, 1H), 7.38 (dd, J=1.6 Hz, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>ClCCl>[CH2:1]([N:8]=[C:16]1[CH2:17][CH2:18][C:13]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: c1ccc(CN=C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4 Å molecular sieve (20 g) and benzylamine (8.90 g, 83 mmol) were added to a solution of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g, 64 mmol) in dichloromethane (100 ml), and the reaction mixture was stirred for 16 h at room temperature. The suspension was then filtered and the filtrate was concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([OH:12])=[O:11])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([O:12][CH3:17])=[O:11])[CH:3]=1
Reactant: CO
Reactant: Nc1cc(C(=O)O)nc(Cl)c1F
Solvent: O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(N)c(F)c(Cl)n1
Temperature: 50 °C
Yield: 86 %

Procedure:
To a solution of 4-amino-6-chloro-5-fluoropicolinic acid (23.8 g, 125 mmol) in MeOH (400 ml), cooled in an ice water bath, thionyl chloride (11.78 ml, 162 mmol) was added. The reaction mixture was heated to an internal temperature of 50° C., for 8 hours. The reaction mixture was then diluted with H2O, and extracted with EtOAC (3×100 mL). The combined organics were washed with Sat. NaCl, dried over Mg Sulfate, filtered and concentrated under vacuum to give methyl 4-amino-6-chloro-5-fluoropicolinate (21.9 g, 107 mmol, 86% yield).