Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[C:13](=[O:20])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])N>C(O)CCC>[CH2:16]([O:15][C:13]([NH:11][CH:4]1[CH2:5][C:6]([CH3:8])([CH2:9][NH:10][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:20])[CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1)=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Reactant: CCCCOC(N)=O
Solvent: CCCCO
Product: CCCCOC(=O)NCC1(C)CC(NC(=O)OCCCC)CC(C)(C)C1
Reaction time: 4 h

Procedure:
766 g of isophorone diamine (3-aminomethyl-3,5,5-trimethyl-cyclohexylamine), 1054 g of n-butyl carbamate and 1000 g n-butanol were reacted in the apparatus described in Example 1 for 4.0 hours at 180° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography. A yield of 1350 g (81% of the theoretical yield) of 1-(n-butoxy-carbonylamino)-3,3,5-trimethyl-5-(n-butoxy carbonylamino-methyl)-cyclohexane was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.Cl.[O:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>CCOC(C)=O>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:37][CH:34]1[CH2:35][CH2:36][O:31][CH2:32][CH2:33]1)=[O:6]
Reactant: NC1CCOCC1
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)cccc1C(=O)NC1CCOCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52.4 %

Procedure:
A yellow mixture of 2-amino-3-bromobenzoic acid (Oakwood Products, Inc., West Columbia, S.C., 2.125 g, 9.83 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (6.37 mL, 10.82 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (Combi-Blocks, Inc., San Diego, Calif., 4.06 g, 29.5 mmol), and DIEA (5.15 mL, 29.5 mmol) was stirred at 0° C. for 5 min; the reaction mixture was then warmed to RT and stir for 30 min when product was observed via LCMS. The reaction mixture was diluted with EtOAc (150 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (4×100 mL); the organic layer was separated, dried over Na2SO4, and concentrated to give 2-amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)benzamide (515a, 1.54 g, 5.15 mmol, 52% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.49-1.63 (m, 2H) 2.00 (dd, J=12.52, 2.15 Hz, 2H) 3.53 (td, J=11.69, 2.05 Hz, 2H) 3.95-4.05 (m, 2H) 4.10-4.21 (m, 1H) 5.87 (d, J=7.24 Hz, 1H) 6.06 (br. s., 2H) 6.54 (t, J=7.92 Hz, 1H) 7.25-7.30 (m, 1H) 7.51 (dd, J=7.82, 1.17 Hz, 1H). MS (ESI, pos. ion) m/z: 299.0/301.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61]C(=O)C4C=CC(I)=CC=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:45][CH:46]([CH2:48][CH:42]([CH2:43]3)[CH2:41]1)[CH2:47]2.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)(C)C.ClCCCl>[C:40]12([CH2:50][NH:51][C:52]3[CH:57]=[CH:56][C:55]([S:58]([NH:61][C:11](=[O:13])[C:10]4[CH:9]=[CH:8][C:7]([C:6]5[CH:5]=[CH:4][S:3][C:2]=5[Cl:1])=[CH:15][CH:14]=4)(=[O:60])=[O:59])=[CH:54][C:53]=3[N+:71]([O-:73])=[O:72])[CH2:49][CH:44]3[CH2:43][CH:42]([CH2:48][CH:46]([CH2:45]3)[CH2:47]1)[CH2:41]2
Reactant: O=C(O)c1ccc(-c2ccsc2Cl)cc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(I)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: O=C(NS(=O)(=O)c1ccc(NCC23CC4CC(CC(C4)C2)C3)c([N+](=O)[O-])c1)c1ccc(-c2ccsc2Cl)cc1
Reaction time: 8 h

Procedure:
A room temperature mixture of Example 29A (39.4 mg, 0.17 mmol), resin-bound dicyclohexylcarbodiimide (225.0 mg, 1.83 mmol/g), and dimethylaminopyridine (60.0 mg, 4.95 mmol) was treated with a solution of Example 28A (40 mg, 0.11 mmol) in a 1:1 mixture of 1,2-dichloroethane and 2-methyl-2-propanol (3 mL), and agitated overnight on an Argonaut Technologies Quest 210. The mixture was treated with resin bound p-TsOH (990 mg, 1.44 mmol/g), agitated for 1 hour, decanted, and washed with dichloromethane. The combined extracts were concentrated and purified by HPLC using 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 586 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ12.50 (s, 1H), 8.66 (d, 1H), 8.57 (t, 1H), 7.96 (d, 2H), 7.95 (dd, 1H), 7.71 (d, 2H), 7.59 (d, 1H), 7.36 (d, 1H), 7.29 (d, 1H), 7.29 (d, 1H), 3.17 (d, 2H), 1.97 (s, 3H), 1.58 (m, 12H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:12]=3[S:11]2)=[CH:6][CH:5]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[ClH:28].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[C@@H:16]([O:17][C:29](=[O:31])[CH3:30])[C:15](=[O:18])[N:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:13]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:12]=3[S:11]2)=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride, 2 ml of acetic anhydride and 2 ml of acetic acid is stirred at 110° C. for 4 hours. Then, the reaction mixture is evaporated under reduced pressure to remove solvent. Ether is added to the residue, and the precipitated crystals are collected by filtration. 1.08 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride are thereby obtained. Recrystallization of the product from a mixture of chloroform, ethanol and ether gives crystals (needles) melting at 159°-161° C.
Reaction SMILES: FC(F)(S(O[C:17]1[CH:18]=[C:19]2[C:36](=[CH:37][CH:38]=1)[C:23]1=[N:24][O:25][C:26]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH3:35])=[CH:29][CH:28]=3)=[C:22]1[CH2:21][CH2:20]2)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[Cl-].[Li+].[CH2:42]([Sn](CCCC)(CCCC)C=C)[CH2:43]CC>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.O1CCOCC1>[CH2:33]([C:30]1[CH:31]=[CH:32][C:27]([C:26]2[O:25][N:24]=[C:23]3[C:36]4[C:19]([CH2:20][CH2:21][C:22]=23)=[CH:18][C:17]([CH:42]=[CH2:43])=[CH:38][CH:37]=4)=[CH:28][CH:29]=1)[CH2:34][CH3:35]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCCc1ccc(-c2onc3c2CCc2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2-3)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CCC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 3-(4-propylphenyl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (Preparation 11A, 160 mg, 0.272 mmol), anhydrous lithium chloride (34.6 mg, 0.817 mmol), tributyl(vinyl)tin (0.120 mL, 0.409 mmol), and anhydrous dioxane (1 mL) was bubbled nitrogen gas for 3 min before Pd(Ph3P)4 (62.9 mg, 0.054 mmol) was added. The reaction mixture was purged with nitrogen gas for an additional 3 min, stirred for 1 h at room temperature, and then at 110° C. for 4 h. The reaction mixture was cooled and treated with saturated aqueous sodium bicarbonate solution (1.5 mL). The biphasic mixture was extracted with ethyl acetate (2×2 mL). The combined ethyl acetate extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and filtered through a pad of silica gel and rinsed with dichloromethane. The filtrate was concentrated to give 3-(4-propylphenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (74 mg, 0.235 mmol, 86% yield) LC/MS M+1=316.17.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]2[N:13]=[C:14](Br)[S:15][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[S:15][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2nc(Br)sc2c(OC)c1OCc1ccccc1
Reactant: NCc1cccnc1
Solvent: O
Product: COc1cc2nc(NCc3cccnc3)sc2c(OC)c1OCc1ccccc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A mixture of 0.38 g of 6-benzyloxy-2-bromo-5,7-dimethoxybenzothiazole and 0.32 g of 3-aminomethylpyridine was heated and stirred at 120° C. for 4 hours. After adding water, the mixture was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. After distilling off the solvent, the obtained crude product was crystallized from ether. Thus 0.36 g of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH:6]([OH:11])[C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].[CH2:24](Br)[CH3:25]>O1CCOCC1>[CH2:24]([O:11][CH:6]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH:5]([O:4][C:3]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=1[Cl:1])[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)[CH3:25]
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1Cl)n1ccnc1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(C(Oc1ccc(Cl)cc1Cl)n1ccnc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
33 g (0.1 mol) of 1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-imidazol-1-yl-butan-2-ol were dissolved in 150 ml of dioxane and the solution was added dropwise to 3.5 g of 80% strength sodium hydride in 150 ml of dioxane. The mixture was stirred for 3 hours at room temperature. After addition of 13.1 g (0.12 mol) of ethyl bromide, the mixture was stirred under reflux for further 17 hours. After cooling, the solvent was distilled off in vacuo, the residue was taken up in 600 ml of methylene chloride and the methylene chloride solution was washed twice with 1,000 ml of water each time, dried over sodium sulphate and distilled under a high vacuum. 10 g (28% of theory) of 2-ethoxy-1-(2,4-dichlorophenoxy)-3,3-dimethyl-1-imidazol-1-yl-butane of boiling point 170°-175° C./0.2 mm Hg were obtained.
Reaction SMILES: [OH-].[K+].O.O.NN.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH:26]=1>C(O)COCCO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:13][C:12]=2[CH:26]=1
Reactant: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(Cc2cc3cc(Br)ccc3o2)cc1
Yield: 82.5 %

Procedure:
5.07 g of potassium hydroxide was added to 30 ml of diethylene glycol, and the mixture was stirred at room temperature during which 5.5 g of 80% hydrazine dihydrate.2H2O and 5.0 g of 5-bromo-2-(4-methoxybenzoyl)-benzofuran were further added. The thus prepared mixture was refluxed under heating. After cooling, the resulting reaction solution was adjusted to pH 4-5, extracted with benzene, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/isopropanol mixture as an elution solvent, thereby obtaining 3.95 g of 5-bromo-2-(4-methoxybenzyl)benzofuran as a brown oily material.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH2:20]([OH:22])C.C([O-])([O-])=O.[K+].[K+]>O>[OH:22][CH2:20][NH:13][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccccc1C(=O)c1ccccc1
Reactant: CCO
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(NCO)c1ccccc1C(=O)c1ccccc1

Procedure:
A mixture of 2.25g. (0.01 mole) of o-benzoylbenzamide, 4 ml. of aqueous formaldehyde solution (38%), 4 ml. of ethanol and 4 ml. of a solution of 1g. K2CO3 in 35 ml. water was refluxed for 20 hours. It was then allowed to cool and the crystalline product was filtered off and washed with water to yield 2.2g. (85%) of analytically pure material, m.p. 166/8°C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([SH:12])[CH:9]=[C:8]([CH3:13])[C:6]=1[NH2:7])([CH3:4])([CH3:3])[CH3:2].[C:14]1([N:20]2[C:24](=[O:25])[CH:23]=[CH:22][C:21]2=[O:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:14]1([N:20]2[C:24](=[O:25])[CH2:23][CH:22]([S:12][C:10]3[CH:9]=[C:8]([CH3:13])[C:6]([NH2:7])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=3)[C:21]2=[O:26])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: Cc1cc(S)cc(C(C)(C)C)c1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(SC2CC(=O)N(c3ccccc3)C2=O)cc(C(C)(C)C)c1N
Yield: 38 %

Procedure:
A stirred solution of 1.0 g (5 mmol) of 2-tert-butyl-4-mercapto-6-methylaniline, 0.9 g (5 mmol) of N-phenylmaleimide and 0.1 g (1 mmol) of triethylamine in 10 mL of toluene is heated at 50° C. for 18 hours. The solvent is removed in vacuo and the residue is purified by flash chromatography (silica gel, ethyl acetate eluent) to give 0.7 g (37%) of the title compound as a white solid melting at 126°-128° C.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])[CH:12]=[CH:13][C:14]=2[C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])[C:5]1=[O:37])(=O)C.CO.[OH-].[Na+].Cl>O>[CH3:29][C:28]1[C:23]([N:20]2[CH2:21][CH2:22][N:17]([C:15]([C:14]3[CH:13]=[CH:12][C:11]([N:31]4[CH2:35][CH2:34][O:33][C:32]4=[O:36])=[CH:10][C:9]=3[N:6]3[CH2:7][CH2:8][NH:4][C:5]3=[O:37])=[O:16])[CH2:18][CH2:19]2)=[N:24][CH:25]=[C:26]([CH3:30])[CH:27]=1
Reactant: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCNC3=O)CC2)c(C)c1
Temperature: 50 °C
Yield: 9.1 %

Procedure:
To 3-{3-(3-acetyl-2-oxoimidazolidin-1-yl)-4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (156 mg) described in Example 209 were added methanol (2 mL) and 1N aqueous sodium hydroxide solution (0.31 mL), and the mixture was stirred at 50° C. 1N hydrochloric acid (0.31 mL) and water were added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the residue was purified by column chromatography (ethyl acetate:methanol) to give the title compound (13 mg).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Cu]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]([O:8][CH3:9])=[O:7])([O-:17])=[O:16]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Cu]
Product: COC(=O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Reaction time: 4.5 h

Procedure:
A mixture of methyl 4-chloro-3,5-dinitrobenzoate (60 g), iodobenzene (36 ml) and copper powder (60 g) is stirred at 145°-155° C for 4-5 hours. After cooling, the resulting solids are extracted with three portions of boiling chloroform (each portion 150 ml), and the combined extracts are, after filtration, evaporated in vacuo. After trituration of the residue with methanol (150 ml) followed by recrystallization from 2-methoxyethanol, methyl 3,5-dinitro-4-phenylbenzoate is obtained with a melting point of 147.5°-148° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH2:11])[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1.Cl[C:15]1[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=1>C1COCC1>[CH3:3][O:4][C:5]1[N:10]=[C:9]([NH:11][C:15]2[S:16][C:17]([C:20]#[N:21])=[CH:18][N:19]=2)[CH:8]=[C:7]([O:12][CH3:13])[N:6]=1
Reactant: COc1cc(N)nc(OC)n1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C#N)s2)nc(OC)n1
Temperature: 40 °C

Procedure:
A flame dried flask under Ar was charged with sodium hydride (110 mg, 60% dispersion, 2.77 mmol) and 3 mL anhydrous THF. 2,6-Dimethoxy-pyrimidin-4-ylamine (118 mg, 0.76 mmol) was added slowly. After the resulting bubbling ceased, 2-chloro-thiazole-5-carbonitrile (100 mg, 0.69 mmol) was added and the reaction was heated to 40° C. After several hours the reaction was cooled to room temperature, the ThF was removed in vacuo, and the mixture was diluted with water and adjusted to pH 7 with 1M HCl (aq). The resulting precipitate was filtered, washed with water and air dried. The resulting solid was purified by flash column chromatography (eluted with 3:1 hexane/EtOAc) followed by purification by reverse phase HPLC. The product was free based with sat NaHCO3 (aq) and filtered to give a pure sample of the title compound. 1H-NMR (300 MHz, DMSO-d6) 12.36 (s, 1H), 8.29 (1H, s), 6.02 (1H, s), 4.02 (s, 3H), 3.87 (s, 3H). mp>250.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.CS[C:16]1[C:20]2[S:21][CH:22]=[CH:23][C:19]=2[S:18](=[O:25])(=[O:24])[N:17]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:16]2[C:20]3[S:21][CH:22]=[CH:23][C:19]=3[S:18](=[O:25])(=[O:24])[N:17]=2)=[N:6][CH:7]=1
Reactant: CSC1=NS(=O)(=O)c2ccsc21
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: CCO
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccsc21
Reaction time: 4 h

Procedure:
A mixture of 0.514 g (0.0021 mole) of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine and 0.463 g (0.0021 mole) of 3-(methylthio)thieno[2,3-d]isothiazole 1,1-dioxide in 35 ml of ethanol was heated under reflux with stirring for 4 hours. The reaction solution was cooled in ice giving a crystalline product which amounted to 0.71 g, m.p. 191°-193° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH3:18])[O:13]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[CH3:11][C:12]1([CH3:19])[C:16](=[O:17])[CH:15]=[C:14]([CH:18]=[CH:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])[O:13]1
Reactant: N#Cc1cccc(C=O)c1
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2cccc(C#N)c2)=CC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
A solution of 3-cyanobenzaldehyde (2.5 g, 19 mM) and 2,2,5-trimethyl-3(2H)-furanone (2.0 g, 15.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.6 mL, 1.6 mM). The reaction solution was stirred for one day at room temperature. After saturated aqueous sodium chloride (400 mL) was added, the aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a yellow solid. The product was recrystallized from hexane-ethyl acetate to afford an analytically pure sample (1.5 g, 43% yield), m.p. 155°-157° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:25][Si:26]([CH2:29][CH2:30][O:31][CH2:32]Cl)([CH3:28])[CH3:27]>CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[C:9]([C:11]3[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:22])[CH:12]=3)[N:8]([CH2:32][O:31][CH2:30][CH2:29][Si:26]([CH3:28])([CH3:27])[CH3:25])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3[nH]1)cn2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(-c1cc3nc(Br)cnc3n1COCC[Si](C)(C)C)cn2C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
2-Bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine (0.500 g, 1.40 mmol; Preparation #B.1) in DMF (15 mL) was cooled to about 0° C. and then treated with 60 wt % NaH (0.112 g, 2.80 mmol). The mixture was stirred for about 15 min at about 0° C. followed by the addition of SEMCl (0.372 mL, 2.10 mmol). The mixture was warmed to rt for about 15 min then was concentrated under reduced pressure and purified on a 40 g silica gel column eluting with DCM to provide 2-bromo-6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (0.61 g, 89%): LC/MS (Table 2, Method b) Rt=3.88 min; MS m/z 487 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH2:5][CH2:4][C:3]1=O.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[BH4-].[Na+].[ClH:22]>>[ClH:12].[ClH:22].[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH2:5][CH2:4][CH:3]1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC1C(=O)CCc2cccc(Cl)c21
Reactant: C1CNCCN1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC1c2c(Cl)cccc2CCC1N1CCNCC1

Procedure:
Using the method of Example 11, 1.94 g (10 mmol) of 1-methyl-8-chloro-2-tetralone were treated with piperazine followed by reduction with sodium borohydride and treatment with HCl to produce 0.67 g of the title compound as colorless crystals; m.p. >200° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:6]([O:8]CC)=[O:7].OS(O)(=O)=O.CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(OCCS(C)(=O)=O)c(OC)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C(=O)O)ccc1OCCS(C)(=O)=O
Temperature: 90 °C

Procedure:
Ethyl 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoate (30 mg, 0.099 mmol) was taken up in water (1.2 mL), H2SO4 (200 μL, 3.8 mmol), and AcOH (1300 μL, 23 mmol). The mixture was heated at 90° C. for 6 h before it was cooled to ambient temperature and was concentrated under vacuum. The residue was purified by column chromatography (1-40% MeOH/DCM) to give 3-methoxy-4-(2-(methylsulfonyl)ethoxy)benzoic acid. ESI-MS m/z talc. 274.1, found 275.1 (M+1)+; Retention time: 0.69 minutes (3 min run).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:20][C:21]1([F:29])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH2:28])[CH2:22]1>>[F:20][C:21]1([F:29])[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:22]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCN1CCC(F)(F)C1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCN3CCC(F)(F)C3)s2)c(C)[nH]c1=O
Yield: 43 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-(3,3-difluoro-pyrrolidin-1-yl)-ethylamine as described in Step 5, Example 24 to give the title compound (43% yield). LC/MS: RT 1.32 min; m/e 432 (M+H).