Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:4]=2[O:3]1.[C:13]([O:17][C:18](=[O:26])[N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)([CH3:16])([CH3:15])[CH3:14].[H-].[Na+]>CN(C=O)C>[C:13]([O:17][C:18]([N:19]1[CH2:23][CH2:24][N:11]([C:10]2[C:4]3[O:3][C:2]([F:1])([F:12])[O:6][C:5]=3[CH:7]=[CH:8][CH:9]=2)[CH2:21][CH2:20]1)=[O:26])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Nc1cccc2c1OC(F)(F)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OC(F)(F)O3)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
An intermediate compound, 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-piperazine, was produced as follows: To the mixture of 2,2-difluoro-benzo[1,3]dioxol-4-ylamine (27 g, 0.156 mol) and bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester (75.5 g, 0.31 mol) in DMF (500 mL) was added NaH (15.6 g, 60% oil dispersion, 0.39 mol) at 0° C. and the resulting mixture was stirred at room temperature for 24 h until LCMS indicated the starting material disappeared. The reaction was quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried and concentrated. The residue was purified by flash chromatography (Et3N:EtOAc:heptane/1:10:100) to afford 4-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (12.0 g, 22%) as colorless crystals.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[NH:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8].[CH3:26][S:27]([O:30][C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:43])[NH2:42])[CH:37]=2)[CH:32]=1)(=[O:29])=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:26][S:27]([OH:30])(=[O:29])=[O:28].[NH:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]([O:25][C:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[C:36]([C:41](=[NH:42])[NH2:43])[CH:37]=4)[CH:32]=3)=[O:24])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)[C:7]([NH2:9])=[NH:8]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: N=C(N)Nc1ccc(CCc2ccc(C(=O)O)o2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)Nc1ccc(CCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To 2.9 g of 5-(p-guanidinophenylethyl)-furan-2-carboxylic acid methanesulfonate, 2.2 g of 6-amidino-2-naphthol methanesulfonate and 1.9 g of DCC was added 15 ml of anhydrous pyridine. The reaction mixture was stirred overnight at room temperature. The insolubles were filtered off and the filtrate was added to 100 ml of ethyl ether with stirring. Decantation is conducted to remove the ethyl ether. After repeating the procedure several times, the filtrate was dissolved in a small amount of methanol and the resulting solution was added to a saturated aqueous sodium hydrogencarbonate solution while stirring. The insolubles which were precipitated were collected by filtration and washed with water and acetone. The precipitate was suspended in a small amount of methanol and methanesulfonic acid was added to the resulting suspension. The insolubles were filtered off and the filtrate was added with stirring to 100 ml of ethyl ether. The ethyl ether was removed by decantation. After repeating the procedure several times, acetone was added to the filtrate. The mixture was stirred and decanted to remove the acetone. To the resulting mixture was added a small amount of ethanol and isopropanol and stirred. A pale yellow solid which was precipitated was collected by filtration to give 2.5 g of 6-amidino-2-naphthyl 5-(p-guanidinophenylethyl)-furan-2-carboxylate dimethanesulfonate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].Cl.[CH2:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[CH2:2]([O:4][C:5]([C:7]1([NH:13][C:28]([C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:20][CH2:19][N:18]([CH2:15][CH2:16][CH3:17])[CH2:23][CH2:22]3)=[CH:32][CH:31]=2)=[O:29])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1(N)CCCCC1
Reactant: CCCN1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)OCC)CCCCC3)cc2)CC1
Yield: 64.7 %

Procedure:
741 mg (3.57 mmol) of 1-aminocyclohexanecarboxylic acid ethyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, and 1.00 g (3.57 mmol) of 4-(4-propylpiperazin-1-yl)benzoic acid hydrochloride was used instead of 3-furancarboxylic acid in the process according to Reference Example 15 to obtain 928 mg (65%) of the title compound.
Reaction SMILES: [N:1]1([C:5]2[CH:6]=[CH:7][C:8]([N+:11]([O-])=O)=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[N:1]1([C:5]2[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCC2)cn1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC2)cn1

Procedure:
The 5-(azetidin-1-yl)-2-nitropyridine obtained above is taken up in 10 ml of ethanol and hydrogenated in the presence of 65 mg of 10% palladium-on-charcoal at 30° C. under a pressure of 1 bar. The reaction mixture is filtered and the filtrate is diluted with 7N ammoniacal methanol and then concentrated to dryness at 30° C. under reduced pressure. The residue is taken up in dichloromethane, an insoluble material is removed and the residue obtained after evaporation to dryness is chromatographed on a silica cartridge, elution being carried out with a mixture of dichloromethane and 7N ammoniacal methanol (90/10). The fractions comprising the expected product are combined and concentrated to give 185 mg of 5-(azetidin-1-yl)pyridine-2-amine in the form of a red oil.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]1[NH:17][C:18](=[O:25])[C:19]([CH:22]([CH3:24])[CH3:23])([CH3:21])[N:20]=1)[C:10]([C:26]([OH:28])=[O:27])=[CH:9]2>CO>[CH:22]([C:19]1([CH3:21])[C:18](=[O:25])[NH:17][C:16]([C:11]2[C:10]([C:26]([OH:28])=[O:27])=[CH:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([N:5]=[C:1]=[S:2])[CH:7]=3)[N:12]=2)=[N:20]1)([CH3:24])[CH3:23]
Reactant: CC(C)C1(C)N=C(c2nc3ccc(N)cc3cc2C(=O)O)NC1=O
Reactant: S=C(Cl)Cl
Solvent: CO
Product: CC(C)C1(C)N=C(c2nc3ccc(N=C=S)cc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
Thiophosgene (0.12 mL, 1.56 mmol) is added to a solution of the above prepared formula III 6-amino-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-3-quinolinecarboxylic acid (170 mg, 0.521 mmol) and methanol (25 mL). The reaction mixture is stirred for five minutes at room temperature and then concentrated in vacuo. The residue is redissolved into a small amount of methanol, filtered and the filtrate is added to 25 mL of ether. The resulting precipitate is collected, washed with ether and dried under reduced pressure to give 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl) -6-isothiocyano-3-quinolinecarboxylic acid as a brown powder (190 mg). The product is obtained in the form of a tricyclic anhydride which hydrolyses to the acid in water or during subsequent reaction in aqueous media. The purity of this material is determined by TLC on silica gel with chloroform, methanol and acetic acid (220:30:6) elution.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+].FSI.[Cl-].[NH4+].[OH-].[NH4+]>CN(C)C=O.CO.C(OCC)(=O)C.[Cu]I.[Cu]Br.O>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Cu]I
Agent: FSI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc2[nH]ccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 5-bromo-7-azaindole (1, 500.0 mg, 2.53 mmol) in N,N-dimethylformamide (8 mL) were added copper(I) iodide (966 mg, 5.08 mmol) and sodium methoxide in methanol (3 M, 5 mL). The reaction was stirred overnight at 120° C. under an atmosphere of Argon. The reaction was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated and purified with silica gel column chromatograph eluting with 20% ethyl acetate in hexane to give white solid (2, 140 mg, 28%). MS (FSI) [M+H+]+=149.1. In an alternative method, 2.3 g (11.7 mmol) 5-bromo-7-azaindole (1, 2.3 g, 11.7 mmol) was dissolved in 75 mL N,N-dimethylformamide and 50 mL methanol (50 mL), adding sodium methoxide (32 g, 0.6 mol) and copper-(I) bromide (3.2 g, 22.4 mmol) at room temperature. The reaction was stirred for three hours at 100° C. under an atmosphere of argon. The mixture was diluted with ethyl acetate and poured into a solution of ammonium chloride:ammonium hydroxide (4:1). The organic layer was extracted with ammonium chloride:ammonium hydroxide (4:1), washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 30% to 70% ethyl acetate in hexanes to give a yellow solid (2, 0.27 g, 15.6%). MS (ESI) [M+H+]+=149.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[S:18]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH:11][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Yield: 70 %

Procedure:
4-nitro-o-phenylenediamine (15.4 grams, 100 mmol) was dissolved in anhydrous pyridine (70 mL) at 45° C. p-Toluenesulfonyl chloride was added to the reaction mixture in 5 gram portions over the period of 30 minutes. The reaction was then heated to 100° C. for 4 hours. After cooling to room temperature, the mixture was poured into ice/water and this was extracted 3 times with methylene chloride. The combined organic portions were washed with water and brine and dried over anydrous sodium sulfate. Filtration and concentration afforded crude product, which was triturated with hot ethanol to give 32.5 grams of product as yellow powder (70%). M+462.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Rh]>[OH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: O=C(O)CCCCCc1ccc(O)cc1
Agent: [Rh]
Solvent: CCO
Product: O=C(O)CCCCC[C@H]1CC[C@@H](O)CC1

Procedure:
6-(4-Hydroxyphenyl)hexanoic acid (2 g) is subjected to catalytic reduction in the presence of 5% rhodium-carbon (500 mg) in ethanol (100 ml) at an initial hydrogen pressure of 10.1 kg/cm2. The catalyst is filtered off and the filtrate is concentrated under reduced pressure and subjected to silica gel column chromatography. Elution is carried out with 4% ethanol-chloroform to give three fractions. The first fraction is recrystallized from ether-ligroin to give 392 mg of cis-6-(4-hydroxycyclohexyl)hexanoic acid, m.p. 83°-85° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([NH:10][C:11](=[O:27])[CH:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:28])[NH:7]1)(=O)=O.[I-:36].[Na+]>CC(C)=O>[C:23]([O:22][C:20]([NH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([NH:10][C@H:9]1[C:8](=[O:28])[NH:7][C@H:6]1[CH2:5][I:36])=[O:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: [I-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N[C@H]1CI)c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 2 g (3.98 mmol) of product from Example 20, 6 g (40 mmol) of sodium iodide and 150 ml of acetone is thoroughly degassed with argon and then heated at 55°-60° for seven hours. The mixture is cooled to room temperature and the acetone is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is separated and washed with aqueous sodium thiosulfate and saline. The dried solution is evaporated to give 1.48 g (81%) of the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:14]([Si:17]([O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[CH:8]=1)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Reaction time: 3 h
Yield: 96.3 %

Procedure:
To a solution of 6-bromo-2-naphthol (13.68 g, 61.33 mmol) and TBDMS-Cl (11.09 g, 73.6 mmol) in DMF (50 mL) was added imidazole (10.2 g, 150 mmol). The solution was stirred for 3 hr, mixed with sodium bicarbonate solution (250 mL), and extracted with 50% ethyl acetate-hexanes (3×250 mL). The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporation of the solvent yielded a tan oil which was dried under vacuum to yield 19.92 g (97%) of the title compound as a white solid:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:31])[CH3:6])[CH3:2]
Reactant: CCOC(=O)[C@@H](C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 148.3 %

Procedure:
A mixture of (R)-2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (80.0 g, 272.0 mmol) and Lawesson's Reagent (66 g, 163.0 mmol) in toluene (1 L) was heated at 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluting with 3% EtOAc in petroleum ether) to give (R)-2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.0 g, 89%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.06 (dd, J=2.4, 8.8 Hz, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 6.71 (m, 1H), 5.06 (d, J=15.6 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H), 1.76 (d, J=7.6 Hz, 3H), 1.28-1.21 (t, J=7.2 Hz, 3H). SFC (Table 2, Method 3) Rt=4.04 min.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][S:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:25][S:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: CSc1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methylthiophenyl isocyanate (0.168 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 168 mg (50.3%) of the desired product as a solid.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=1[OH:14])=[O:4].C(=O)([O-])[O-].[K+].[K+].CC#N.O.FC(F)(F)C(O)=O>CN(C)C=O.C(OCC)(=O)C>[CH3:13][O:12][C:10]1[CH:9]=[CH:8][C:7]2[O:14][CH2:2][C:3](=[O:4])[NH:5][C:6]=2[CH:11]=1
Reactant: COc1ccc(O)c(NC(=O)CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1ccc2c(c1)NC(=O)CO2
Temperature: 85 °C
Yield: 88.5 %

Procedure:
2-bromo-N-[2-hydroxy-5-(methyloxy)phenyl]acetamide (3.42 g, 13.1 mmol), was dissolved in 120 mL of anhydrous dimethylformamide under argon. Potassium carbonate was added and suspended in the solution at room temperature. The mixture was warmed to 85° C. and refluxed for one hour before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=1.1 min and m/e 180 [M+1]+. The mixture was allowed to cool to room temperature before it was diluted with 600 mL of ethyl acetate and washed with water (2×150 mL) and brine (2×150 mL). The organic phase was dried over Na2SO4, filtered and concentrated to give 6-(methyloxy)-2H-1,4-benzoxazin-3(4H)-one (2.08 g, 11.6 mmol, 88%) as a brown amorphous solid. MS (ES) m/e 180 [M+H]+.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][C:16]=3[S:15](=[O:32])(=[O:31])[N:14]=2)[C:3]1=[O:33].C(O[CH:37](OCC)[CH2:38][CH3:39])C>CN(C)C(=O)C>[CH2:24]([O:23][C:21]1[CH:20]=[CH:19][C:17]2[NH:18][C:13]([C:4]3[C:3](=[O:33])[N:2]([N:1]=[CH:37][CH2:38][CH3:39])[C:11]4[C:6]([C:5]=3[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=4)=[N:14][S:15](=[O:32])(=[O:31])[C:16]=2[CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(CC)OCC
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Solvent: CC(=O)N(C)C
Product: CCC=Nn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Temperature: 25 °C
Yield: 40.7 %

Procedure:
The product of Example 304F (0.1 g, 0.22 mmol) in N,N-dimethylacetamide (1 mL) was reacted with propionaldehyde diethylacetal (0.34 mL, 2.2 mmol) in a sealed tube in a microwave reactor at 100° C. for 60 minutes. The reaction was cooled to 25° C., concentrated under a stream of nitrogen warmed through a manifold heated to 165° C. and the resulting residue was triturated with diethyl ether to give the title compound (0.045 g, 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.FC1C=CC(OC2C=CC(S(NCCC3C=CC=CC=3OC)(=O)=O)=CC=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccccc1CCN
Agent: COc1ccccc1CCNS(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COc1ccccc1CCNS(=O)(=O)c1ccc(C)cc1

Procedure:
5.0 g (33 mmol) of ortho-methoxyphenethylamine are reacted with 1.2 equivalents of para-toluenesulfonyl chloride in analogy to the method described under 19A, resulting in the title compound in virtually quantitative yield.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[C:29]([C:30](O)=[O:31])=[C:28]([CH3:33])[O:27][N:26]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[C:25]([CH3:24])=[N:26][O:27][C:28]=2[CH3:33])=[O:31])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1noc(C)c1C(=O)O
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)noc2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-isoxazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=451.3.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5](=[O:15])[C:4]2[CH2:16][S:17][CH2:18][C:3]1=2.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][N:2]1[C:8]2[CH:9]=[C:10]([CH3:14])[C:11]([CH3:13])=[CH:12][C:7]=2[NH:6][C:5](=[O:15])[C:4]2=[CH:16][S:17][CH:18]=[C:3]12
Reactant: Cc1cc2c(cc1C)N(C)C1=C(CSC1)C(=O)N2
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C)N(C)c1cscc1C(=O)N2

Procedure:
To a suspension of 0.40 g. of 1,3,4,9-tetrahydro-4,6,7-trimethyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 3 ml. of dry pyridine is added, in portions, a total of 0.21 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid which separates is collected and recrystallized from methanol to give yellow crystals, m.p. 260°-262° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([O:26]CC)=[O:25])[CH:21]=[N:20]1)[NH:12][C:11]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([N:19]1[CH:23]=[C:22]([C:24]([OH:26])=[O:25])[CH:21]=[N:20]1)[N:12]=[C:11]2[N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(Cc4ccccc4)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: O=C(O)c1cnn(-c2nc(N3CCOCC3)c3cc(Cc4ccccc4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C23H20ClN5O3, 449.9
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Br:15]N1C(=O)CCC1=O>CS(C)=O.O>[Br:15][C:9]1[N:10]=[CH:11][C:12]([NH2:14])=[N:13][C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cncc(-c2cccc(F)c2)n1
Solvent: CS(C)=O
Solvent: O
Product: Nc1cnc(Br)c(-c2cccc(F)c2)n1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a 0° C. cooled stirred solution of 6-(3-fluorophenyl)pyrazin-2-ylamine (0.5 g, 2.64 mmol) in a mixture of DMSO (10 mL) and water (0.25 mL), was added N-bromosuccinimide (0.518 g, 2.90 mmol) in portions. After stirring for 5 h, the mixture was poured into water, the precipitate collected by filtration, washed with water and dried to give the title compound as a yellow solid (0.60 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:24][CH:25]=[CH2:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:26][CH:25]=[CH2:24])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: C=CCC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
Step AB (1): 2-(2,4-Dichlorophenyl)acetic acid was deprotonated with NaHMDS and reacted with 3-bromoprop-1-ene using a procedure analogous to Step AA (1) to afford 2-(2,4-dichlorophenyl)pent-4-enoic acid as a clear viscous oil. LC-MS (M−H)− 243.1. 1H NMR (500 MHz, chloroform-d) δ ppm 7.42 (d, J=2.14 Hz, 1 H) 7.31-7.36 (m, 1 H) 7.25 (dd, J=8.24, 2.14 Hz, 1 H) 5.67-5.77 (m, J=17.05, 10.19, 6.83, 6.83 Hz, 1 H) 5.07 (dd, J=17.09, 1.53 Hz, 1 H) 5.04 (d, J=10.38 Hz, 1 H) 4.26 (t, J=7.48 Hz, 1 H) 2.81 (dt, J=14.34, 7.17 Hz, 1 H) 2.55 (dt, J=14.57, 7.21 Hz, 1 H).