Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C(C2C=CC=C(F)N=2)=CC(N[C@H]2CC[C@H](O)CC2)=NC=1.NC1CCN(C(OC(C)(C)C)=O)CC1.[Cl:37][C:38]1[C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([NH:58][CH:59]3[CH2:64][CH2:63][N:62](C(OC(C)(C)C)=O)[CH2:61][CH2:60]3)[N:53]=2)=[CH:40][C:41]([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]2)=[N:42][CH:43]=1>CS(C)=O>[Cl:37][C:38]1[C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([NH:58][CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[N:53]=2)=[CH:40][C:41]([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([OH:51])[CH2:47][CH2:46]2)=[N:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc(-c3cc(N[C@H]4CC[C@H](O)CC4)ncc3Cl)n2)CC1
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O[C@H]1CC[C@H](Nc2cc(-c3cccc(F)n3)c(Cl)cn2)CC1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cccc(NC4CCNCC4)n3)c(Cl)cn2)CC1
Temperature: 105 °C
Reaction time: 40 h

Procedure:
A mixture of trans-4-(5′-chloro-6-fluoro-2,4′-bipyridin-2′-yl-amino)cyclohexanol (15.5 mg, 0.048 mmol), DMSO (0.4 ml), and tert-butyl 4-aminopiperidine-1-carboxylate (48.2 mg, 0.241 mmol) reaction mixture was stirred at 105° C. for 40 hr. LCMS indicated formation of the intermediate tert-butyl 4-(5′-chloro-2′-(trans-4-hydroxycyclohexylamino)-2,4′-bipyridin-6-yl-amino)piperidine-1-carboxylate (LCMS (m/z): 502.4 (MH+), retention time=0.70 min.). The Boc protecting group was removed from the intermediate by adding HCL 6M aq (140 μl, 0.840 mmol) to the crude reaction mixture mixture, followed by stirring the mixture at 90° C. for 45 minutes. The reaction mixture was cooled, 0.5 ml of DMSO was added, filtered and purified by prep LC. Lypholization of the material yielded 9.8 mg of the title compound, as a TFA salt. LCMS (m/z): 402.3 (MH+), retention time=0.41 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.32-1.52 (m, 4 H) 1.71-1.87 (m, 2 H) 1.96-2.12 (m, 4 H) 2.27 (dd, J=14.21, 3.37 Hz, 2 H) 3.06-3.18 (m, 2 H) 3.39-3.50 (m, 2 H) 3.54-3.68 (m, 2 H) 4.05-4.17 (m, 1 H) 6.72 (d, J=8.50 Hz, 1 H) 6.90 (d, J=7.33 Hz, 1 H) 7.00 (s, 1 H) 7.56-7.64 (m, 1 H) 8.01 (s, 1 H)
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)=[CH:11][C:6]=2[C:5](=O)[O:4][C:3]1=[O:24].[NH2:25][C@H:26](C(O)=O)[CH2:27][CH2:28][OH:29]>C(O)(=O)C>[OH:29][CH2:28][CH2:27][C@H:26]1[C:3](=[O:24])[N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:14][CH:13]=3)=[CH:11][C:6]=2[C:5](=[O:4])[NH:25]1
Reactant: Cn1c(=O)oc(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Reactant: N[C@@H](CCO)C(=O)O
Solvent: CC(=O)O
Product: CN1C(=O)[C@H](CCO)NC(=O)c2cc(-c3ccc(OC(F)(F)F)cc3)ccc21
Temperature: 130 °C
Yield: 10.8 %

Procedure:
1-Methyl-6-(4-(trifluoromethoxy)phenyl)-1H-benzo[d][1,3]oxazine-2,4-dione (60 mg, 0.178 mmol) and L-homoserine (23.3 mg, 0.196 mmol, 1.1 equiv.) were added to a magnetically stirred 0.5-2 mL Smith process vial containing 0.75 mL glacial acetic acid. Reaction mixture was then heated for 2 hours at 130° C. Excess acetic acid was then removed en vacuo, residue was dissolved into a minimal amount of acetonitrile and purified by reverse-phase preparative HPLC to give the title compound (7.6 mg) following removal of solvent as a clear yellow film.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[CH3:42][Si:43]([C:46]#[CH:47])([CH3:45])[CH3:44]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3=[C:11]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:47]#[C:46][Si:43]([CH3:45])([CH3:44])[CH3:42])=[CH:21][C:20]=4[F:26])[N:12]([CH3:17])[C:13](=[O:16])[C:14]([CH3:15])=[C:7]3[N:6]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:36])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[C:5]2=[O:37])[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(I)cc4F)n(C)c(=O)c(C)c32)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(-n2c(=O)n(C3CC3)c(=O)c3c(Nc4ccc(C#C[Si](C)(C)C)cc4F)n(C)c(=O)c(C)c32)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
Under a nitrogen atmosphere, to N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 59 (14.5 g) obtained in Example 4-1 were added chloroform (145 ml), trimethylsilylacetylene 60 (4.99 ml) and triethylamine (13.1 ml). Copper(I) iodide (22 mg) and bis(triphenylphosphine)palladium(II)chloride (83 mg) were added, and the mixture was stirred at room temperature for 20 hrs. The mixture was concentrated under reduced pressure, activated carbon (435 mg) and methanol (435 ml) were added to the residue, and the mixture was stirred with heating at reflux for 2 hrs. Activated carbon was filtered off while it was hot, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=10:1→4:1) and toluene-acetone [5:1 (volume ratio), 87 ml] was added to the obtained crystals. The mixture was stirred at 80° C. for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-5-(2-fluoro-4-trimethylsilanylethynylphenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide 61 (12.9 g, yield 93%) as pale-yellow crystals.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]/[C:20](=[C:27]2\[C:28](=[O:36])[NH:29][C:30]3[C:35]\2=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:43]>ClCCl>[ClH:43].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19]/[C:20](=[C:27]2\[C:28](=[O:36])[NH:29][C:30]3[C:35]\2=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone and ethyl acetate/hydrogen chloride in dichloromethane.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:14]#[C:15][Si](C)(C)C)=[N:10][CH:11]=[CH:12][CH:13]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(OCC)C>[NH:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1cnc2cc[nH]c2c1
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A mixture of (2-trimethylsilanylethynylpyridin-3-yl)carbamic acid tert-butyl ester (500 mg, 1.72 mmol) in 5 mL of THF was treated with TBAF (1 M in THF, 10.3 mL) at room temperature. The mixture was heated at reflux for 8 hours, cooled to room temperature, diluted with 100 mL of diethyl ether, and quenched with 100 mL of water. The aqueous layer was extracted with three 50 mL portions of diethyl ether, and the combined organic layers were washed with 500 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (100% CH2Cl2 to 10% MeOH in CH2Cl2, gradient) gave 160 mg of the title product as tan solid (79% yield).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:14](=[S:16])[NH2:15])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.Br[CH2:18][C:19](=O)[CH2:20][CH:21]([CH3:23])[CH3:22]>CCO>[Br:1][C:2]1[C:3]([C:14]2[S:16][CH:18]=[C:19]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:15]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1
Reactant: CC(C)CC(=O)CBr
Reactant: CCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CCO
Product: CCNC(=O)Nc1cc(-c2nc(CC(C)C)cs2)c(Br)cn1
Temperature: 80 °C

Procedure:
In a 100 mL round-bottomed flask 5-bromo-2-(3-ethylureido)pyridine-4-carbothioamide (Intermediate 6, 0.95 g, 3.13 mmol) and 1-bromo-4-methylpentan-2-one (0.561 g, 3.13 mmol, Chem. Pharm. Bull., 2001, 49(8), 988-998) were mixed in EtOH (10 mL) to give a yellow suspension. The reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. ACN was added, and the residue solid was azeotroped with ACN (3×). The crude mass obtained, 1.02 g, was taken forward without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.Br[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCCC1.[Zn].[Cu]Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(c1)CCC2=O
Agent: Cl[Cu]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCc2cc(OC)ccc21

Procedure:
To a solution of 5-methoxyindanone (150 g, 0.91 mol) in anhydrous tetrahydrofuran (4.5 L), was added zinc (30 mesh, 103.64 g, 1.59 mol) and copper(I) chloride (4.53 g, 0.045 mol). The suspension was stirred under argon atmosphere and refluxed for 15 min; approximately a 25% portion of ethyl bromoacetate (133 mL, 1.18 mol) was added to the refluxing mixture in a slow dropwise fashion. After allowing to cool and stirring for 12 h at rt; TLC showed the presence of desired product. The remainder of ethyl bromoacetate was added dropwise; an exotherm was observed (internal temperature increased to 35° C.). After 4 h, TLC showed complete reaction. After the solids settled to the bottom of the flask, the liquid was siphoned off leaving a small amount behind to cover the solids. The flask was re-charged with 5-methoxyindanone (157.6 g, 1.86 mol total), anhydrous tetrahydrofuran (4.5 L), and zinc (80.92 g, 2.73 mol total). Ethyl bromoacetate (140 mL, 2.36 mol) was added dropwise. An exotherm was observed (internal temperature increased to 35° C.). When the stirred mixture was cooled to rt, TLC showed the reaction to be complete. The solids were allowed to settle and the liquid was siphoned off. The combined reaction solutions were concentrated under reduced pressure to a volume of about 2 L. The liquid was then poured into HCl (1 N aqueous solution, cooled in ice water) to bring the pH to 1. The product was extracted with ethyl acetate (2×1 L, 1×500 mL). The combined extracts were washed with water (1 L), brine (1 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a dark red oil which solidified gradually (438.3 g; theoretical yield=432 g). 1H NMR (CDCl3): δ 7.5 (d, 1H), 6.8 (m, 2H), 6.2 (t, 1H), 4.2 (q, 2H), 3.8 (s, 3H), 3.3 (m, 2H), 3.0 (t, 2H), 1.3 (t, 3H). MS (Cl) m/z 233 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>C(O)C>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][C:2]2[CH:13]=[CH:12][C:5]([CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: Oc1ccc(CN2CCCC2)cc1
Solvent: CCO
Product: Brc1ccc(COc2ccc(CN3CCCC3)cc2)cc1
Yield: 57.9 %

Procedure:
The mixture of 4-hydroxybenzyl-pyrrolidine (177 mg), 4-bromo-benzylchloride (205 mg), and t-Bu3ONa (192 mg) in ethanol (10 mL) was heated at 80° C. for overnight. Concentration and preparative TLC provided the title compound (200 mg). 1H NMR (400 MHz, CDCI3)δ7.50 (d, J=6.5 Hz, 2 H), 7.32 (d, J=6.5 Hz, 2 H), 7.25 (d, J=6.5 Hz, 2 H), 6.90 (d, J=6.5 Hz, 2 H), 2.84 (s, 2 H), 2.50 (m, 4 H), 1.42 (m, 4 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[NH2:33])[C:27]([OH:29])=[O:28]>CC(O)C.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:33][C:32]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:23][CH3:22])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
A mixture of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (98 g, 0.31 mol), 3-methoxy-4-aminobenzoic acid (57 g, 0.341 mol) in i-PrOH (1.05 L) and conc. HCl (30 mL) was heated to reflux for a day. The mixture was cooled to room temperature and the solid was filtered, washed with isopropanol and dried to give 96.5 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:37][CH2:38][CH:39]([CH2:44][O:45][C:46](=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:40][C:41](O)=[O:42])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C1C=CC=CN=1)C.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(O)(=O)C.ClCCl>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:41](=[O:42])[CH2:40][CH:39]([CH2:38][O:37][C:35](=[O:36])[C@H:31]([CH:32]([CH3:33])[CH3:34])[NH:30][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:29])[CH2:44][O:45][C:46](=[O:64])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Reaction time: 48 h

Procedure:
To a solution of 2′,3′-dideoxy-3′-fluoroguanosine (113 mg, 0.42 mmol) and 3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid (140 mg, 0.21 mmol) in DMF (2 ml) were added dimethylaminopyridine (3 mg, 0.02 mmol) and DCC (52 mg, 0.25 mmol). After two days, dichloromethane (10 ml) and a few drops of acetic acid were added and the organic phase was filtered through Celite. The filtrate was washed with aqueous sodium hydrogen carbonate solution and the product 2′,3′-dideoxy-3′-fluoro-5′-O-[3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butanoyl]guanosine was isolated by silica gel column chromatography to yield 51 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9].Cl[CH2:26][C:27](Cl)=[O:28].[N:30]1[CH:35]=[CH:34]C=[CH:32][CH:31]=1.C(NCC)C>C(Cl)Cl.C(OCC)(=O)C>[CH2:31]([N:30]([CH2:35][CH3:34])[CH2:26][C:27]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[C:13]=1[C:22]([OH:24])=[O:23])(=[O:10])=[O:9])=[O:28])[CH3:32]
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Reactant: c1ccncc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: CCN(CC)CC(=O)Nc1ccccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 11.1 %

Procedure:
A solution of Example 294 (0.0590 g, 0.17 mmol) in CH2Cl2 (3.0 mL) was treated with chloroacetyl chloride (16 μL, 0.20 mmol) and pyridine (69 μL, 0.85 mmol), stirred 4 hours at room temperature, then quenched with 1N HCl (10 mL). The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to a residue (45.0 mg). The residue was dissolved in acetone (0.4 mL), treated with diethylamine (50 μL, 0.48 mmol), heated to 60° C. for 2 hours, cooled to room temperature, diluted with ethyl acetate (10 mL), and washed with 1N HCl (10 mL). The organic layer was dried (MgSO4), filtered and concentrated. The concentrate was purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (8.7 mg, 18%). MS (ESI(+)) m/e 460 (M+H)+; MS (ESI(−)) m/e 458 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.79 (m, 2H), 7.56 (m, 1H), 7.23 (m, 2H), 6.90 (m, 1H), 3.30 (m, 4H), 2.80 (m, 2H), 2.73 (s, 2H), 2.59 (m, 2H), 1.61 (m, 4H), 1.06 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6](OC)[C:5](SC)=[CH:4][N:3]=1.[CH2:13]([S:19]([OH:22])(=[O:21])=[O:20])[CH2:14][S:15]([OH:18])(=[O:17])=[O:16].[OH2:23]>>[CH2:13]([S:19]([O-:22])(=[O:21])=[O:20])[CH2:14][S:15]([O-:18])(=[O:17])=[O:16].[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:5][OH:23])[C:14]([CH2:13][SH:19])=[CH:4][NH+:3]=1.[CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:5][OH:23])[C:14]([CH2:13][SH:19])=[CH:4][NH+:3]=1
Reactant: O
Reactant: COc1c(SC)cnc(C)c1O
Reactant: O=S(=O)(O)CCS(=O)(=O)O
Product: Cc1[nH+]cc(CS)c(CO)c1O
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]

Procedure:
A mixture of 9.25 gm. (0.05 m) 5-mercaptopyridoxine, 4.75 gm. (0.025 m) of ethane-1,2-disulfonic acid, and 40 ml. of water is heated briefly until solution occurs. The solution is cooled and the precipitate collected by filtration. Recrystallization from methanol gives bis(2-methyl-3-hydroxy-4-hydroxymethyl-5-mercaptomethylpyridinium) ethane-1,2-disulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[NH2:13]C(N)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[NH:13][C:9]2=[O:8]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NC(N)=O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2cc(F)ccc21
Temperature: 25 °C
Yield: 100.6 %

Procedure:
To 4-fluorophthalic anhydride (5.0 g, 30.10 mmol) in toluene (15 mL) is added urea (2.1 g). The reaction mixture is stirred at refluxed for 16 h. The reaction mixture is allowed to cool to room temperature, concentrated under reduced pressure and triturated with H2O (250 mL) to afford 5-fluoro-isoindole-1,3-dione (5.0 g, 100%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([OH:16])=[CH:15][C:9]=2[CH:8]=1)=[O:6].Cl[CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.O>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[CH:12]=[CH:13][C:14]([O:16][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:9]=2[CH:8]=1)=[O:6]
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1cc2cc(O)ccc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2cc(OCc3cccnc3)ccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
Sodium hydride (0.24 g. of 50% dispersion in mineral oil) was added portionwise to a solution of 5-hydroxybenzo[b]thiophene-2-carboxylic acid methyl ester (1.04 g.) in dry N,N-dimethylformamide (10 ml.) and the mixture was stirred at room temperature for 30 minutes. 3-Chloromethylpyridine (0.65 g.) in dry N,N-dimethylformamide (5 ml.) was then added and the mixture was stirred at room temperature for 1 hour, and then poured into water. The mixture was extracted several times with ethyl acetate and the combined extracts were washed well with water and dried (Na2SO4). Evaporation of the solvent gave a solid which was washed with petrol and crystallized from isopropanol to give 5-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylic acid methyl ester (0.80 g.), m.p. 126°-127° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH:20]1([NH:25][C:26](=O)[O:27]C2C=CC=CC=2)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C)C=O>[CH:20]1([NH:25][C:26]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([O:10][C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=4)=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(NC1CCCC1)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NC3CCCC3)c2)ccn1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (2.50 g, 11.1 mmol, CAS No. 417722-11-3), which was described in WO 02/32872, was dissolved in N,N-dimethylformamide (30 ml); sodium hydride (0.530 g, 13.3 mmol) was added thereto at room temperature; and the reaction mixture was stirred for 30 minutes. Phenyl N-cyclopentylcarbamate (2.50 g, 12.2 mmol) was added thereto at room temperature while stirring; and the reaction mixture was stirred for 30 minutes. Water was added to the reaction mixture; and the precipitated crystals were filtered off, and washed with water. This crystals were dissolved in methanol, and purified by silica gel column chromatography (Fuji Silysia NH; hexane:ethyl acetate=1:1, ethyl acetate, ethyl acetate:methanol=98:2 in this order). The obtained crystals were suspended in hexane: ethanol=10:1, filtered off, washed with hexane, and dried under aeration to yield the title compound as colorless crystals (2.08 g, 6.18 mmol, 55.7%).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=O)[CH:15]=1>O1CCCC1.C(OCC)(=O)C>[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2([CH3:31])[C:25](=[C:26]=[S:27])[C:24](=[C:28]=[S:29])[CH2:23][CH2:22][C:21]2=[CH:3][C:1]#[N:2])[CH:15]=1
Reactant: CC1(c2cccnc2)C(=O)CCC(=C=S)C1=C=S
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(c2cccnc2)C(=C=S)C(=C=S)CCC1=CC#N
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of diethyl cyanomethylphosphonate (18.2 g, 0.1 mol) in dry tetrahydrofuran (200 ml) at 25° C. was treated with sodium hydride (4.5 g of a 60% oil dispersion). After 30 mins at 25° C. the mixture was treated with 2-(pyrid-3-yl)-2-methyldithiocarbonylcyclohexanone (24.7 g, 0.93 mol) in dry tetrahydrofuran (100 ml). After 3 hrs at reflux the mixture was cooled to 25° C. over 30 mins, diluted with ethyl acetate (500 ml) and then washed with water (500 ml). The organic phase was removed and dried over magnesium sulphate and then filtered. Concentration in-vacuo (50° C.; 20 mm Hg) afforded a crude oil which wa purified by flash chromatography over silica gel, eluting with ethyl acetate/n-hexane (25:75) to give 2-(pyrid-3-yl)-2-methyldithiocarbonyl-1-cyanomethylenecyclohexane (7.4 g, 0.026 mol) as an orange gum.