Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[CH2:35]([NH:37][C:38]([NH:40][C:41]1[CH:46]=[C:45]([C:47]2[S:48][CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[N:51]=2)[C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][N:42]=1)=[O:39])[CH3:36].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:44]3[CH:43]=[N:42][C:41]([NH:40][C:38](=[O:39])[NH:37][CH2:35][CH3:36])=[CH:46][C:45]=3[C:47]3[S:48][CH:49]=[C:50]([C:52]([F:55])([F:53])[F:54])[N:51]=3)=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cn3C(COC)COC)cn1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
A solution of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate (Intermediate 79, 400 mg, 0.68 mmol) in dimethylformamide (15 mL) was purged argon gas, then tetrakis(triphenylphosphine)palladium (69.25 mg, 0.06 mmol) followed by 1-ethyl-3-{5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-2-yl}urea (Intermediate 17, 360 mg, 0.82 mmol) was added. The mixture was stirred at room temperature and sodium carbonate (217 mg, 2.05 mmol) which was dissolved in minimum amount of water was added and the reaction mixture was heated to 95° C. for 3 h. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was poured into water (200 mL) and stirred for 30 min. The obtained solid was filtered and dried to give the crude compound. The crude was purified by column chromatography eluting with a gradient of 30% ethyl acetate/petroleum ether to 60% ethyl acetate/petroleum ether to afford 260 mg (49%) of tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-{6-[(ethylcarbamoyl)amino]-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]pyridin-3-yl}-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[C@H:31]([CH2:32][OH:33])[CH2:30][O:29][C:28]5=[O:34])=[N:25][CH:26]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[CH3:35]I>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[C@H:31]([CH2:32][O:33][CH3:35])[CH2:30][O:29][C:28]5=[O:34])=[N:25][CH:26]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CI
Reactant: O=C(c1ccc(N2C(=O)OC[C@H]2CO)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{5-[4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-hydroxymethyloxazolidin-2-one (310 mg) described in Example 252 and methyl iodide (50 μL), the title compound (85 mg) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.CC(OC(/N=N/C(O[CH:27]([CH3:29])[CH3:28])=O)=O)C.[Cl:30][C:31]1[CH2:36][C:35]([Cl:40])(OCC)C=[CH:33][C:32]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:40][C:35]1[CH:36]=[C:31]([Cl:30])[CH:32]=[CH:33][C:29]=1[CH2:27][CH2:28][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Sc1ccc(O)cc1
Reactant: CCOC1(Cl)C=CC(O)=C(Cl)C1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Sc1ccc(OCCc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The title product was prepared according to the procedure described in Method B starting from methyl 2-(4-hydroxyphenylthio)iso-butyrate (prepared as described in example 3) (0.280 g, 1.24 mmol) and DIAD (0.325 g, 1.61 mmol) dissolved in 3 mL of anhydrous THF and added dropwise to a solution of 2,4-dichlorophenetylalcohol (0.260 g, 1.36 mmol) and triphenylphosphine (0.422 g, 1.61 mmol) in 4 mL of anhydrous THF at 0° C. The reaction was left overnight under magnetic stirring at room temperature After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/AcOEt 9.6/0.4 as eluent. 0.346 g of product were obtained (yield: 70%); Mp: 73-74° C.; TLC: silica gel, eluent hexane/AcOEt 9/1, Fr: 0.26; 1H NMR (CDCl3, 300 MHz) δ: 7.35 (m, 3H), 7.22 (m, 2H), 6.83 (d, 2H), 4.18 (t, 2H), 3.65 (s, 3H), 3.20 (t, 2H), 1.45 (s, 6H); HPLC: Column: Inertisil ODS—3 (5 μm) 4.6×250 mm, T: room temperature, mobile phase CH3CN/H2O. 85/15 (v/v), pH: as is, flow rate: 1 mL/min, 205 nm UV detector, retention time 12.58 min; KF: 0.4% H2O; E.A. conforming for C19H20Cl2O3S.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16](Cl)[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1.[C-:38]#[N:39].[K+].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:6][C:7]1[C:12]2[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH:16]([C:38]#[N:39])[CH3:17])[O:15][C:11]=2[C:10]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[C:9]([F:37])[CH:8]=1
Reactant: CCOC(=O)c1c(C(C)Cl)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Reactant: [C-]#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(C)C#N)oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.3 %

Procedure:
20 ml of N,N-dimethylformamide was added to 0.8 g (1.6 mmol) of 3-[4-chloro-2-(1-chloroethyl)-3-ethoxycarbonyl-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil, 0.16 g (2.5 mmol) of potassium cyanide and 0.40 g (2.9 mmol) of potassium carbonate, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.58 g (yield: 74%) of the desired product as a yellow glassy substance. Refractive index: 1.5348 (20° C.).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[C:4]([C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: Cn1c(=O)c(C(=O)O)cc2cccnc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(=O)c(C(=O)Cl)cc2cccnc21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
1.0 g (4.9 mmol) of 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid was dissolved in dichloromethane (50 mL), and 1.0 mL (12 mmol) of oxalyl chloride was added thereto. Three droplets of N,N-dimethylformamide were added to the above mixture, and the resulting mixture was stirred for one hour at 40° C. The reaction solution was concentrated under reduced pressure, and thus 1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-carboxylic acid chloride was obtained. The acid chloride thus obtained was dissolved in acetonitrile (30 mL), and this solution was added to an acetonitrile (50 mL) solution of 0.60 g (5.4 mmol) of 1,3-cyclohexanedione and 0.82 mL (5.9 mmol) of triethylamine under ice cooling. The resulting mixture was stirred for one hour at room temperature. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic phase was washed with water, an aqueous solution of sodium hydrogen carbonate, and water in this order, and then was dried and concentrated. The residue was washed with diisopropyl ether, and thus 0.83 g of the title compound was obtained as a light yellow solid (yield: 57%).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=2)[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH2:51][C:52]3[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=3)[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: COc1ccc(CNc2nc(N)c(F)cc2F)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 18 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 2.52 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 2.65 g of 2-amino-3,5-difluoro-6-(p-methoxybenzylamino)pyridine. The solution was concentrated under reduced pressure, and to the residue were added 2.5 g of anhydrous potassium carbonate and 6 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 50 ml of chloroform and 500 ml of distilled water, and the chloroform layer was washed twice with 500 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol to obtain 3.20 g of the title compound as a yellow powder.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:35]=[CH:36][CH:37]=1)[C:11]([NH:13][CH:14]([C:16]1[N:21]=[N:20][C:19]([NH:22][C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=2)=[N:18][CH:17]=1)[CH3:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:15][C:14]1[N:13]=[C:11]([C:10]2[CH:35]=[CH:36][CH:37]=[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:9]=2)[N:21]2[C:16]=1[CH:17]=[N:18][C:19]([NH:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1)=[N:20]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Oc4ccccc4)c3)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2ncc3c(C)nc(-c4cccc(Oc5ccccc5)c4)n3n2)cc(OC)c1OC
Yield: 50.8 %

Procedure:
In a similar manner as described for Example 9, 3-phenoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 31) (58 mg, 0.11 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave 5-methyl-7-(3-phenoxyphenyl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (27 mg, 49%) as a tan-yellow solid. 1H NMR (CD3OD): δ8.99 (s, 1H), 8.08 (d, J=7.87 Hz, 1H), 7.96 (t, J=1.92 Hz), 7.44 (t, J=8.06 Hz, 1H), 7.31 (t, J=7.87 Hz, 2H), 7.00-7.11 (m, 6H), 3.77 (s, 6H), 3.72 (s, 3H), 2.54 (s, 3H). MS m/z 448 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1.C1(C)C=CC=CC=1.CC([O-])(C)C.[Na+]>CCOC(C)=O.O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Cl)nc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(F)cn2)CC1
Temperature: 75 °C
Yield: 65.2 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid ethyl ester (14.3 g, 0.091 mol) and 2-chloro-5-fluoro-pyridine (10 g, 0.076 mol) in toluene (100 mol) was added NaOtBu (8.77 g, 0.091 mol), BINAP (1.42 g, 2.28 mmol) and tris(dibenilideneacetone)dipalladium(0) (1.39 g, 1.52 mmol). The reaction mixture was heated at 75° C. for 2 hours, cooled down to RT, and diluted with AcOEt (100 mL) and H2O (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated under vacuo. Column chromatography (SiO2, EtOAc/heptane, 1:9 to 1:1) yielded 12.5 g (65%) of 5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester as a yellow oil. ES-MS m/e: 253.3 (M+H+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[O:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1.C(O)(=O)C>C(#N)C.ClCCl>[F:52][C:16]([F:51])([F:15])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=1)[CH2:20][N:21]([C@H:22]1[CH2:28][CH2:27][CH2:26][N:25]([CH:56]2[CH2:57][CH2:58][O:53][CH2:54][CH2:55]2)[C:24]2[CH:29]=[C:30]([C:34]([F:35])([F:36])[F:37])[C:31]([CH3:33])=[CH:32][C:23]1=2)[C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCOCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.100 g, 0.181 mmol), tetrahydro-4-pyranone (0.054 g, 0.543 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white solid (0.070 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 0.87-0.95 (m, 1H), 1.24-1.34 (m, 1H), 1.61-2.10 (m, 6 H), 2.30 (s, 3H), 2.75-2.90 (m, 1H), 3.15-3.22 (m, 1H), 3.41-3.62 (m, 3H), 3.96-4.10 (m, 2H), 4.14 (s, 3H), 4.75-4.95 (m, 2H), 5.37-5.50 (m, 1H), 6.96 (s, 1H), 7.20 (s, 1H), 7.30 (s, 1H), 7.65 (s, 1H), 7.72 (s, 1H); ESI MS m/z 637 [C28H29F9N6O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21]O)[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS([Cl:40])(=O)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:23])[CH:15]=[C:16]([CH2:21][Cl:40])[CH:17]=3)[N:12]([CH3:24])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CO)cc(I)c21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)cc(I)c21
Temperature: 65 °C
Yield: 93 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(hydroxymethyl)-8-iodo-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide (4.89 g), DMAP (209 mg) and collidine (1.59 mL) in 173 mL anhydrous DMF is heated to 65° C. to solubilize the starting material. To this solution is added methanesulfonyl chloride (2.77 mL) at room temperature. The reaction is heated at 65° C. for 2 h, then allowed to cool to room temperature. The reaction is poured into H20 (300 mL) to precipitate the product. The solid is filtered and recrystallized from CH2Cl2/hexanes to afford 4.74 g (93%) of the desired product as a white solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([O:13]COCC)=[CH:11][CH:10]=[CH:9][N:8]=1.[Br:18][C:19]1[CH:20]=[C:21]2[C:31](=[CH:32][CH:33]=1)[O:30][C:24]1[CH:25]=[N:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:22]2=[N:34]S(C(C)(C)C)=O>C1COCC1>[NH2:34][C:22]1([C:7]2[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[C:23]2[CH:28]=[C:27]([Cl:29])[N:26]=[CH:25][C:24]=2[O:30][C:31]2[C:21]1=[CH:20][C:19]([Br:18])=[CH:33][CH:32]=2
Reactant: CC(C)(C)S(=O)N=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Reactant: CCOCOc1cccnc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NC1(c2ncccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 71.3 %

Procedure:
Butyllithium solution, 2.5m in hexanes (1.70 mL, 4.24 mmol) was added dropwise to a solution of 2-bromo-3-(ethoxymethoxy)pyridine (0.98 g, 4.24 mmol) in THF 25 mL at −78° C. The reaction was stirred for 25 min. Then N-(7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-ylidene)-2-methylpropane-2-sulfinamide (1.35 g, 3.26 mmol, prepared as in Example 18b) in THF was added. The reaction was warmed up to RT and stirred for 1 h. The reaction was quenched with aq. ammonium chloride and extracted with EtOAc. The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography with 25-60% EtOAc/Hexane to give 0.94 g of desired product. The resulting material was dissolved in dry MeOH 10 mL and cooled in an ice bath. Hydrochloric acid, 4.0M solution in 1,4-dioxane (20 mL, 80 mmol) was added and mixture was stirred at RT for 4 h. The reaction was quenched with 10% sodium carbonate solution and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated to give the desired product which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.Cl.[CH:20]12[CH2:26][CH:23]([NH:24][CH2:25]1)[CH2:22][N:21]2[C:27](=[O:30])[CH2:28][OH:29].CCN(CC)CC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CN1CCCC1=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][N:21]3[C:27](=[O:30])[CH2:28][OH:29])=[CH:13][CH:12]=1
Reactant: O=C(CO)N1CC2CC1CN2
Reactant: O=Cc1ccc(Oc2nc3ccccc3s2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(Cl)Cl
Product: O=C(CO)N1C[C@@H]2C[C@H]1CN2Cc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A mixture of 4-(benzothiazol-2-yloxy)-benzaldehyde (67 g, 0.26 mol), 1-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2-hydroxy-ethanone hydrochloride (40.61 g, 0.26 mol), Et3N (183 mL, 1.31 mol), and N-methylpyrrolidinone (150 mL) in dichloroethane (750 mL) was stirred at rt for 1 h. Sodium triacetoxyborohydride (66.63 g, 0.314 mol) was then added in four equal portions over a 4 h period. After stirring overnight, the mixture was quenched with 3 N HCl(aq) (250 mL) and then 6 N HCl(aq) (3×50 mL) to a final pH of 0.54. The layers were separated and the organic was extracted again with 3 N HCl(aq) (250 mL). The combined aqueous layers were basified with Na2CO3 (50 g) and then 50% NaOH(aq) (130 mL) to a final pH of 13.2. After stirring for 1 h, isopropyl acetate (200 mL) was added and the mixture was stirred for 20 min. After separation of layers, the aqueous was extracted with additional isopropyl acetate (2×200 mL) and the organic layers were combined with an interstitial oil and concentrated. The resulting brown oil was purified by flash chromatography (0-5% MeOH in CH2Cl2) to provide the product as a clear oil (93.84 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.B(Cl)(Cl)Cl.[CH3:19][S:20][C:21]#N.C(=O)([O-])[O-:24].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][S:20][C:21](=[O:24])[C:10]1[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CSC#N
Reactant: O=C([O-])[O-]
Reactant: CN1CCC(Nc2ccccc2)CC1
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CSC(=O)c1ccccc1NC1CCN(C)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 1.14 g of N-(1-methyl-4-piperidinyl)aniline in 20 ml of toluene was added 3.6 ml of a solution of 2.04M boron trichloride--toluene and the mixture was refluxed with heating on an oil bath for 2 hr. After cooling, the reaction mixture was mixed with 0.49 ml of methyl thiocyanate and refluxed with heating on an oil bath for 2 hr. After cooling, 20 ml of water was added and the mixture was stirred at 110° C. on an oil bath for 1 hr. The rection mixture was turned to basic conditions with aqueous 2N sodium carbonate and extracted with toluene. The toluene layer was dried over anhydrous magnesium sulfate, chromatographed on a column of 20 g of aluminium oxide for purification, eluted with methylene chloride and concentrated. The crystalline residue (1.35 g) was recrystallized from ether--petroleum ether to give 1.21 g of N-(1-methyl-4-piperidinyl)thioanthranilic acid S-methyl ester melting at 64°-65° C. as yellow crystals.
Reaction SMILES: OC1C([NH2:11])=CC=CC=1C(O)=O.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19][C:20](=[O:21])[NH2:11]
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: O=C=Nc1ccccc1Br
Product: NC(=O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 3-amino benzoic acid (300 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the DMF solution with methylene chloride and precipitation with hexane (0.287 g. 41%). EI-MS m/z 351 (M+H)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:3]1([N:8]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:26]=[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: CCCCCCCCCCCCCc1nc2ccccc2n1-c1ccccc1
Yield: 69 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and myristanilide (182 mg, 0.6 mmol) yielded the title compound as colorless oil (130 mg, 69%). 1H NMR (DMSO) δ 0.74 (t, J=6.9Hz, 3H), 1.14-1.28 (m, 20H), 1.68 (p, J=7.6Hz, 2H), 2.83 (t, J=7.6Hz, 2H), 7.14 (d, J=8.1Hz, 1H), 7.29 (dd, J=8.1, 7.7Hz, 1H), 7.47 (dd, J=8.1, 7.7Hz, 1H), 7.56-7.68 (m, 5H), 7.74 (d, J=7.7Hz, 1H); 13C NMR δ 13.9, 22.0, 26.3, 26.4, 28.3, 28.4, 28.7, 28.8, 28.9, 29.9, 31.2, 110.7, 116.9, 123.5, 123.7, 127.2, 129.6, 130.1, 134.2, 135.0, 137.6, 154.7. HRMS (FAB): cal. for C26H36N2 [M+H+]: 377.2957; found: 377.2953. Method C afforded 149 mg of the title compound (79% yield).