Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:15]3[C:11]([CH2:12][CH2:13][CH2:14]3)=[C:10]([CH2:16]O)[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.I.[I-].C([O-])([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:15]3[C:11](=[C:10]([CH3:16])[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13][CH2:14]3)=[CH:6][CH:7]=1
Reactant: OCc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Agent: I
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1c(-c2ccncc2)c(-c2ccc(F)cc2)n2c1CCC2
Yield: 46.9 %

Procedure:
[3-(4-Fluorophenyl)-2-(4-pyridyl)-6,7-dihydro-5H-pyrrolizin-1-yl]methanol (3.08 g, 10 mmol) is heated with hydriodic acid (57%, 18 ml, 134 mmol HI) in an oil bath at 120° C. (reflux). The initially undissolved substance has dispersed in the batch after 45 min, and starting material (rf=0.05) is no longer detectable (product rf=0.9, iodide rf=0.6) by tlc (ether, Al2O3). After cooling (1 h), the solution is diluted with 50 ml of water and covered with a layer of 100 ml of ethyl acetate. The water phase is carefully neutralized with sat. Na2CO3 soln (30 ml) and the phases are separated. The water phase again extracted with ethyl acetate (50 ml), the combined ethyl acetate extracts decolorized using sodium thiosulfate solution (Na2S2O3, 2% strength, 40 ml) and, after washing again with water (50 ml), dried over Na2SO4 sicc. After evaporating the solvent in vacuo, 2.28 g of residue remain, which solidifies from CH2Cl2/ethyl acetate to give a resinous mass. The substance is purified by CC (Al2O3/ether) and the substance obtained from the fractions by evaporating the solvent (fractions 1-17, 1.74 g) is crystallized from diisopropyl ether. 1.37 g of pure compound are obtained.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=O)[CH:18]([CH3:20])[CH3:19])[C:3]=1[O:22][CH2:23][CH3:24].[CH3:25][CH2:26][O:27][C:28]([CH:30](P(OCC)(OCC)=O)[F:31])=[O:29].C([Li])CCC>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:15])[CH3:16])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH:18]([CH3:19])[CH3:20])=[C:30](/[F:31])\[C:28]([O:27][CH2:26][CH3:25])=[O:29])[C:3]=1[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: CCOc1c(C(=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(F)=C(\c1cc2c(c(Br)c1OCC)C(C)(C)CC=C2C(C)C)C(C)C

Procedure:
As described in General Procedure F-1, 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-methyl-propan-1-one (Compound A-111, 234 mg, 0.60 mmol) and triethyl 2-fluoro-2-phosphonoacetate (576 mg, 2.38 mmol) were reacted with n-butyllithium (1.6 M in hexanes, 1.48 mL, 2.38 mmol) in THF to produce the title compound as a clear oil after purification by flash column chromatography (silica gel, 2% ethyl acetate in hexane).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[N:20]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(C)=O.Cl.[CH2:34]([N:41]([CH2:43][CH2:44]Cl)[CH3:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl.O.[Cl-].[Na+].O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[N:17]([CH2:44][CH2:43][N:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH3:42])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([Cl:28])[CH:22]=3)[N:20]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CN(CCCl)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(Cl)c3)c[nH]2)CC1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)Cc1ccccc1
Yield: 78.9 %

Procedure:
Add powdered KOH (283 mg; 5.05 mmol) and 4-[4-(3-chloro-4-fluoro-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (2.02 mmol; 768 mg) to DMSO (6 mL). Then add benzyl-(2-chloro-ethyl)-methylamine hydrochloride (2.22 mmol; 0.49 mL) in one portion and heat to 40° C. for 18 h. Cool, dilute with DCM/water, add brine and separate layers. Wash the organic phase with water, brine, dry over MgSO4, filter and evaporate. Purify on 120 g silica gel with 1% MeOH/DCM to provide the title compound (840.5 mg; 79%). MS (ES): m/z=527 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][S:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30]([OH:32])=O)[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[I-].ClC1C=CC=C[N+:36]=1C.C(N(CC)CC)C.N>ClCCl.C(#N)C.CCOCC>[C:30]([CH2:29][CH2:28][S:27][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([S:13][CH2:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:32])[NH2:36]
Reactant: C[n+]1ccccc1Cl
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(SCc2ccc3ccc(Cl)cc3n2)c1
Agent: N
Agent: [I-]
Solvent: CC#N
Solvent: CCOCC
Solvent: ClCCl
Product: NC(=O)CCSC(SCCC(=O)O)c1cccc(SCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 mg of diacid (Example 20, Step 4) in dichloromethane (39 mL) and acetonitrile (9.9 mL) at 0° C. was added 2-chloro-1-methylpyridinium iodide (315 mg). After 15 min triethylamine (170 μL) and 10 mL of a saturated solution of ammonia in ether were added. The solution was stirred 1 hr at room temperature then it was washed with acidified 25% ammonium acetate, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated to dryness. Purification by chromatography afforded the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C@@H:15](/[CH:16]=[CH:17]/[C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]>CC#N.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.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.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.[Cu].[Cu].[Cu].[Cu].[Cu].[Cu]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][N:10]1[C@@H:15]([CH2:16][CH2:17][C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13][CH2:12][C:11]1=[O:27]
Reactant: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Agent: [Cu]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)COC/C=C\CN1C(=O)CCC[C@@H]1CCC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of {(Z)-4-[(R)-2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-but-2-enyloxy}-acetic acid methyl ester (24.6 mg, 0.064 mmol) in CH3CN (1.5 mL) was added via cannula to hydrido(triphenylphosphine)copper(I) hexamer (125 mg, 0.064 mmol) at −40° C. After 1 h at −40° C., the reaction was allowed to warm to rt. After 3 h at rt, the reaction was quenched by addition of a solution of NH4OH and saturated aqueous NH4Cl (1:1, 6 mL). The mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→70% EtOAc/CH2Cl2, gradient) afforded 19.6 mg (79%) of the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:28])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([C:21]([OH:24])([CH3:23])[CH3:22])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:25]([NH2:27])=[O:26])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH2:35][NH:34][C:33](=[O:36])[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:24][C:21]([C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:34]5[CH2:35][C:31]([O:30][CH3:29])=[CH:32][C:33]5=[O:36])[C:3]=4[CH3:28])=[CH:9][CH:10]=[C:11]([C:25]([NH2:27])=[O:26])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1)([CH3:22])[CH3:23]
Reactant: COC1=CC(=O)NC1
Reactant: Cc1c(Br)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C(C)(C)O)ccc3c12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC1=CC(=O)N(c2cccc(-c3ccc(C(N)=O)c4[nH]c5cc(C(C)(C)O)ccc5c34)c2C)C1
Temperature: 100 °C
Yield: 26.6 %

Procedure:
A mixture of 4-(3-bromo-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (Intermediate 81-25, 70 mg, 0.160 mmol), 4-methoxy-1H-pyrrol-2(5H)-one (362 mg, 3.20 mmol), cesium carbonate (78 mg, 0.24 mmol), tris(dibenzylideneacetone)dipalladium (14.7 mg, 0.016 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos, 27.8 mg, 0.048 mmol) in 1,4-dioxane (2 mL) was purged with nitrogen and heated via microwave irradiation in a sealed tube at 100° C. for 1 h. The mixture was diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by preparative HPLC, and the appropriate effluent fractions were treated with NaHCO3 (aq) and extracted with DCM. The combined organic phases were washed with water, dried and concentrated to provide as a white solid (20 mg, 27%). 1H NMR (400 MHz, methanol-d4) δ 7.91 (1H, d, J=7.70 Hz), 7.73 (1H, d, J=0.88 Hz), 7.39-7.46 (2H, m), 7.31-7.34 (1H, m), 7.09 (1H, dd, J=8.47, 1.65 Hz), 7.01 (1H, d, J=7.70 Hz), 6.98 (1H, d, J=8.36 Hz), 5.29 (1H, s), 4.37-4.49 (2H, m), 3.91 (3H, s), 1.90 (3H, s), 1.58 (3H, s), 1.57 (3H, s). Mass spectrum m/z 492.0 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:40])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:39][CH2:38][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][N:17]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([O:32]C)=[O:31])[C:16]3=[O:37])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:40])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:39][CH2:38][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][N:17]([CH2:26][C:27]4[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=4)[C:30]([OH:32])=[O:31])[C:16]3=[O:37])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(=O)c4ccc(F)cc4)CC3)C2=O)c1
Temperature: 35 °C
Reaction time: 24 h
Yield: 22.8 %

Procedure:
A solution of methyl 3-((8-(4-(4-fluorophenyl)-4-oxobutyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (450 mg, 0.828 mmol, 1 equiv) and lithium hydroxide (34.7 mg, 1.656 mmol, 2.0 equiv) in a 3:1 mixture of methanol and water (5 ml t/v) was stirred at 35° C. for 24 hrs. The reaction was concentrated in vacuo and purified using preparatory high performance liquid chromatography. The combined pure fractions were lyophilized to afford the acetate salt of the title compound as a white solid (100 mg, 25%); 1H NMR (400 MHz, DMSO-d6): δ 1.59 (d, 2H, J=13.6 Hz), 1.84 (t, 2H, J=7.2 and 6.8 Hz); 2.45-2.46 (m, 4H); 2.72-2.78 (m, 4H); 3.05 (t, 2H, J=6.8 and 7.2 Hz); 4.57 (s, 2H); 4.60 (s, 2H); 6.72-6.78 (m, 3H); 7.12-7.16 (m, 2H); 7.32-7.36 (m, 2H); 7.47-7.53 (m, 2H); 7.86-7.88 (m, 2H); 8.04-8.08 (m, 2H); 10.82 (s, 1H); 12.9 (bs, 1H); MS for C31H32FN3O4 m/z 529.99 (M+H)+.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]([NH:9][NH2:10])([NH2:8])=[NH:7].Cl.[Na+].[Cl-].O=[C:15]([CH3:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[NH2:7][C:6]1[N:9]([NH2:10])[C:17](=[O:18])[CH:16]=[C:15]([CH3:22])[N:8]=1
Reactant: N=C(N)NN
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: Cc1cc(=O)n(N)c(N)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a stirring solution of NaOEt prepared from sodium (FLUKA, 9.19 g, 400 mmol) and ethanol (350 mL) was added aminoguanidine hydrochloride (ALDRICH, 44.2 g, 400 mmol). The reaction mixture was heated at 50° C. for 30 min. Then, the mixture was filtered to remove NaCl, and ethyl 3-oxobutanoate (ALDRICH, 25.3 mL, 200 mmol) was added to the filtrate. The reaction mixture was heated under reflux for 5 h and, then, stirred at room temperature overnight. The precipitate obtained was filtered and dried under vacuum to afford Intermediate 1 as a pale pink solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:10]([N:11]2[CH:15]=[N:14][N:13]=[CH:12]2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1ccc(Nn2cnnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(Br)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
8 Milliliters of acetonitrile was added to 0.63 g of 4-[N-(4-nitrophenyl)amino]-4H-1,2,4-triazole, 0.82 g of 4-bromobenzyl bromide and 0.62 g of anhydrous potassium carbonate and the mixture was stirred for 3 hours at room temperature. The solvent was removed by distillation under reduced pressure, and water was added to the residue obtained, which was then extracted with chloroform. The chloroform layer separated was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography to give crude crystals from the chloroform/methanol (100/1) eluate. The crude crystals were recrystallized from acetone to give 0.71 g of 4-[N-(4-bromobenzyl)-N-(4-nitrophenyl)amino]-4H-1,2,4-triazole.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([C:8]([C:20]#[N:21])([CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)C(OCC)=O)[N:7]=1.Cl.[NH4+].[OH-]>[OH-].[Na+]>[NH2:1][C:2]1[NH:3][C:4](=[O:25])[C:5]([N+:22]([O-:24])=[O:23])=[C:6]([CH:8]([CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[C:20]#[N:21])[N:7]=1
Reactant: CCOC(=O)C(C#N)(Cc1ccsc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Product: N#CC(Cc1ccsc1)c1nc(N)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 45 °C

Procedure:
A solution of 2-Amino-α-cyano-1,6-dihydro-5-nitro-6-oxo-α-(3-thienyl-methyl)-4-pyrimidineacetic acid, ethyl ester in 1N NaOH (200 mL) is stirred for 2 h at room temperature and then acidified to pH 1 by the dropwise addition of conc HCl. The resulting suspension is warmed (45° C.) for 2 min and then cooled. The pH is adjusted to pH=3 with NH4OH. The solid is collected by filtration, washed with water, and dried under vacuum to give 2-Amino-l,6-dihydro-5-nitro-6-oxo-α-(3-thienylmethyl)-4-pyrimidineacetonitrile (3.03 g). ##STR18##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH3:19][S:20]([O:8][CH2:7][CH2:6][C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:22])=[O:21]
Reactant: COc1cccc(CCO)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCOS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
To a flask under argon was added 10.1 g (0.0661 mole) 3-methoxyphenethyl alcohol, 150 mL methylene chloride and 9.2 ml (0.0661 mole) triethylamine. The solution was cooled to 0° C. and 5.1 ml (0.0661 mole) methanesulfonyl chloride was added slowly. The reaction mixture was warmed to room temperature. After 24 hr, the reaction was washed with water and brine, and dried with MgSO4. The solvent was evaporated in vacuo to give 15.0 g of the product as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([N:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:9](=[O:10])[CH2:8]1)=[O:6])[CH3:3].C(S([O-])(=O)=[O:35])CCCCCCCCCCC.[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+].C(=O)([O-])[O-].[Ca+2]>>[CH3:3][CH:2]([NH:4][C:5]([N:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:9](=[O:10])[CH2:8]1)=[O:6])[CH3:1].[OH2:35]
Reactant: CCCCCCCCCCCCS(=O)(=O)[O-]
Agent: CC(C)NC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Product: O

Procedure:
60% benziothiazolinone, 2% iprodione, 2% sodium dodecyl sulfonate, 2% sodium alkyl naphthalene sulfonate, 3% ammonium sulfate, complemented to 100% with light calcium carbonate.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][C:9](=[O:13])[O:10][C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])cc2c(=O)oc(=O)[nH]c12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a flask charged with 8-methyl-1H-benzo[d][1,3]oxazine-2,4-dione ((Example 295: step a) 9.27 g, 52.4 mmol) in an ice-water bath was added concentrated H2SO4 (90 mL) over 5 minutes period. After stirring for 10 minutes, fuming HNO3 (2.9 mL) was added over 15 minutes. The reaction mixture was stirred for further 30 minutes in the ice-water bath, 30 minutes at ambient temperature, then slowly poured into ice with stirring. The solid was collected, washed with H2O (3×50 mL), and dried in high vacuum to give the title compound (10.4 g, 89% yield) as a yellow solid. 1H NMR (DMSO) δ 11.65 (br s, 1H), 8.46–8.43 (m, 2H), 2.44 (s, 3H).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:5]=1[NH:6][C:7](=[O:30])[C:8]1[C:9](=[C:11]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([S:16][C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[Cl:25])[C:14]=1[CH3:15])[OH:10]>C(O)(=O)C>[Cl:3][C:4]1[CH:34]=[C:33]([N+:35]([O-:37])=[O:36])[CH:32]=[CH:31][C:5]=1[NH:6][C:7](=[O:30])[C:8]1[C:9](=[C:11]([C:26]([CH3:29])([CH3:27])[CH3:28])[CH:12]=[C:13]([S:16]([C:17]2[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=2[Cl:25])=[O:1])[C:14]=1[CH3:15])[OH:10]
Reactant: Cc1c(Sc2cc(Cl)c(Cl)cc2Cl)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: OO
Solvent: CC(=O)O
Product: Cc1c(S(=O)c2cc(Cl)c(Cl)cc2Cl)cc(C(C)(C)C)c(O)c1C(=O)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 0 °C

Procedure:
30% w/v Aqueous hydrogen peroxide solution (1.5 ml.) is added to a solution of 2'-chloro-4'-nitro-5-(2,4,5-trichlorophenylthio)-3-t-butyl-6-methylsalicylanilide (0.4 g.) in acetic acid (15 ml.) at 50°-60° C. The mixture is heated at 95°-100° C. for 30 minutes and is then poured into ice cold water (200 ml.). The precipitated solid thus obtained is crystallised twice from acetic acid to give 2'-chloro-4'-nitro-5-(2,4,5-trichlorophenylsulphinyl)-3-t-butyl-6-methylsalicylanilide, m.p. 245°-246° C.
Reaction SMILES: [N:1]1[N:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][CH2:7]3)[N:3]=[N:4][CH:5]=1.[Br:14]C1NN=NN=1>>[Br:14][C:5]1[N:4]=[N:3][N:2]([C:6]23[CH2:13][N:10]([CH2:11][CH2:12]2)[CH2:9][CH2:8][CH2:7]3)[N:1]=1
Reactant: c1nnn(C23CCCN(CC2)C3)n1
Reactant: Brc1nnn[nH]1
Product: Brc1nnn(C23CCCN(CC2)C3)n1
Yield: 56 %

Procedure:
5-(Tetrazol-2-yl)-1-azabicyclo[3.2.1]octane (the free base of E29) (0.2 g, 1.12 mmol) was converted to the 5-bromotetrazole according to the method of Example 40. Chromatography on silica using 4% methanol/chloroform afforded the title compound (E50) as a white crystalline solid (0.16 g, 56%) m.p. 108-110° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH:23]=[O:24])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH4+].[Cl-:26].Cl>CCO>[ClH:26].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:22][CH2:23][OH:24])[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(CC=O)cc2OCc2ccccc2)n1
Reactant: [Cl-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: Cc1csc(Nc2ncc(CCO)cc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A 20 mL vial was charged with 2-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-yl)acetaldehyde (50 mg, 0.15 mmol), NaBH (11 mg, 0.29 mmol), and EtOH (2 mL). The reaction was stirred at room temperature for 10 minutes and aqueous NH4Cl was added. The mixture was extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel (1:1 EtOAc:Hexanes) to afford the title compound (37 mg, 66% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 11.03 (bs, 1H), 7.85 (d, 1H), 7.59 (t, 3H), 7.45-7.33 (m, 3H), 6.83 (s, 1H), 5.31 (s, 2H), 3.61 (t, 2H), 2.72 (t, 2H), 2.32 (s, 3H). Mass spectrum (apci) m/z=342.1 (M+H-HCl).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][N:17]=1>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:4][CH2:3]2)=[N:17][CH:18]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC2CCN(Cc3ccccc3)CC2)nc1
Temperature: 75 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
4-Amino-1-benzylpiperidine (30 mL, 150 mmol) and N,N'-diisopropylethyl amine (25 mL, 150 mmol) were added sequentially to a solution of methyl 2-chloropyridine-5-carboxylate (5 g, 29.1 mmol) in DMF (20 mL) at 25° C. The mixture was stirred at 75° C. for 12 h. The reaction mixture was then evaporated and diluted with a mixture of sat. NaCl (aq)/EtOAc (100 mL, v/v, 50:50). The aqueous layer was extracted with more EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuc to give a yellow oily residue. Purification of the residue by flash column chromatography (gradient elution 70 to 80% EtOAc/hexanes) provided the title compound (4.3 g, 45.4%): TLC (Rf =0.20; 60% EtOAc/hexanes); 1H NMR (CDCl3) δ 8.73 (d, 1H, J=2.1), 7.95 (m, 1H), 7.30 (m, 5H), 6.32 (d, 1H, J=8.8), 5.01 (d, 1H, J=7.8), 3.85 (s, 3H), 3.71 (m, 1H), 3.52 (s, 2H), 2.85 (m, 2H), 2.18 (m, 2H), 1.20 (m, 2H), 1.57 (m, 2H); 13C NMR (CDCl3) δ 166.4, 160.1, 151.6, 138.3, 129.0, 128.1, 127.6, 127.0, 115.0, 105.8, 63.0, 52.0, 51.4, 48.4, 32.3; HRMS (FAR) m/z 326.1879 (M+H)+ (C19H23N3O2 requires 326.1869).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:17]([O:19]CC)=[O:18])=[CH:7][N:8]([CH2:13][CH2:14][CH2:15][OH:16])[C:9]2=[O:12])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[C:17]([C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH2:13][CH2:14][CH2:15][OH:16])[CH:7]=1)([OH:19])=[O:18]
Reactant: CCOC(=O)c1cn(CCCO)c(=O)c2cc(Cl)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn(CCCO)c(=O)c2cc(Cl)ccc12
Temperature: 0 °C
Yield: 89.7 %

Procedure:
Then, 20.1 g of 7-chloro-4-ethoxycarbonyl-2-(3-hydroxypropyl)-1(2H)-isoquinolone was dissolved in 50 ml of ethanol, and 100 ml of an ethanolic solution of 5.5 g of potassium hydroxide was added to the resulting solution, followed by thoroughly stirring. The resulting solution was then poured into ice-water and the mixture was filtered. The filtrate was rendered neutral with dilute acetic acid and the precipitated crystals were filtered and washed with water. Recrystallization from a mixture of ethanol and petroleum ether gave 16.4 g of 4-carboxy-7-chloro-2-(3-hydroxypropyl)-1(2H)-isoquinolone having a melting point of 193° C. as colorless prisms.