Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:23])(=[O:22])[CH2:20][CH2:19][C:18]([C:24]([O:26]C)=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:29]=[CH:30][CH:31]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]2[S:21](=[O:22])(=[O:23])[CH2:20][CH2:19][C:18]([C:24]([OH:26])=[O:25])=[CH:17][C:16]=2[CH:28]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1cccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 77.4 %

Procedure:
To methyl 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.36 g) dissolved in THF (10.8 ml)/methanol (5.4 ml) was added a 1 N aqueous solution (2.4 ml) of sodium hydroxide, and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to the room temperature, the reaction mixture was concentrated under reduced pressure to remove a half of the solvent. A 1 N aqueous solution (3.0 ml) of sodium hydroxide was added to the resulting mixture, which was washed with ethyl acetate. After being adjusted to pH=about 5 with a 1 N aqueous solution of hydrochloric acid, the resulting aqueous layer was extracted with ethyl acetate, and the extract was washed with an aqueous saturated solution of sodium chloride and was then dried with magnesium sulfate. After evaporation to remove the solvent, the resulting residue was washed with hexane/ethyl acetate (=8/1) to obtain 7-[3-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.27 g).
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[CH2:18]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].OS(O)(=O)=O>CN(C)C=O.O>[C:3]([NH:6][C:7]([CH2:33][CH2:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc(CCBr)cc1
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60% NaH in oil (9.65 g) is added portionwise to a solution of diethyl acetamidomalonate (58.5 g) in dimethylformamide (240 ml) at such a rate to keep the temperature below 10° C. The resulting mixture is stirred for 90 min., the temperature being allowed to increase to room temperature. To this mixture is added dropwise within 15 min. a solution of 2-(4-octylphenyl)ethyl bromide (19) (40 g) in dimethylformamide (40 ml). The reaction mixture is heated to ca. 80° C. within ca. 25 min. and further stirred for ca. 3-5 hrs. After cooling to room temperature, water (280 ml) is added and the resulting mixture is further stirred until a beige precipitate is formed. The mixture is adjusted to pH 7 with 10% H2SO4. After cooling to ca. 2° C., the residue is filtered, washed with 200 ml water and then recrystallized in heptane to yield compound (8) as colorless crystals. The resulting compound (8) exhibits the same physico-chemical characteristics as indicated in Example 7.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:22])[N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[SH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH:10]1([N:9]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:8]([NH:7][C:5]2[S:6][C:2]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:3][N:4]=2)=[O:22])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Sc1ccccn1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCCCC1
Product: O=C(Nc1ncc(Sc2ccccn2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (E) using 3-(5-bromo-thiazol-2-yl)-1,1-dicyclohexyl-urea and 2-mercaptopyridine.
Reaction SMILES: [CH2:1](Cl)[C:2](=[CH2:4])[CH3:3].OS(O)(=O)=O.[C:11]1([CH3:18])[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1>>[CH3:3][C:2]1([CH3:4])[C:15]2[C:16](=[C:11]([CH3:18])[CH:12]=[C:13]([CH3:17])[CH:14]=2)[C:2]([CH3:4])([CH3:3])[CH2:1][CH2:1]1
Reactant: C=C(C)CCl
Reactant: Cc1cccc(C)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(C)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 20 °C
Reaction time: 3 h

Procedure:
The starting material 1,1,4,4,5,7-hexamethyl-1,2,3,4-tetrahydronaphthalene is prepared by substantially following the procedures of Fehr et al., U.S. Pat. No. 5,162,588. Specifically, in a 1 liter three-neck flask, equipped with a mechanical stirrer and kept under nitrogen, 150.0 g of methallyl chloride are slowly (2 hrs) added to a mixture of meta-xylene (490.9 g) and H2SO4 (30.0 g), while the temperature is maintained at 20° C. After 3 hrs, the H2SO4 is decanted and the organic phase is washed with, in succession, water, an aqueous solution saturated with NaHCO3, and an aqueous solution saturated with NaCl. The excess of meta-xylene is recovered through distillation, and the residue is distilled. A mixture of two isomers, 1-(2-chloro-1,1-dimethylethyl)-2,4-dimethylbenzene and 1-(2-chloro-1,1-dimethylethyl)-3,5-dimethylbenzene, is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH3:9])=[CH:4][C:3]=1[CH3:11].CC1C=CC([S:19]([NH:22][NH2:23])(=O)=O)=CC=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]=[N:22][S:19][CH:9]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: CC(=O)c1ccc(Br)c(C)c1
Solvent: CCO
Product: Cc1cc(-c2csnn2)ccc1Br
Reaction time: 5 h
Yield: 27.9 %

Procedure:
A mixture of 1-(4-bromo-3-methylphenyl)ethanone (500 mg) and 4-methylbenzenesulphonic acid hydrazide (437 mg) was heated to reflux in ethanol (15 ml) containing a few 4A molecular sieves for 5 h. On cooling, colourless needles were formed, which were collected by filtration (577 mg). 300 mg of this intermediate hydrazone were dissolved in thionyl chloride (2 ml) and was stirred at 20° for 5 h. The mixture was neutralised with 2N sodium carbonate (40 ml) and extracted with ethyl acetate (2×30 ml). The dried extracts were then evaporated to give a yellow solid. This material was chromatographed on silica eluting with dichloromethane;hexane (1:1) to give the title compound as pale yellow solid (167 mg). T.l.c. ethyl acetate:hexane (1:4) Rf 0.52.
Reaction SMILES: [C:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])(=[O:3])[CH3:2].[CH3:12][C:13](=[CH2:21])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([C:4]1[C:5]([OH:6])=[C:7]([C:13]([CH3:21])([CH3:12])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:8]=[CH:9][C:10]=1[OH:11])(=[O:3])[CH3:2]
Reactant: C=C(C)CCCC(=O)OC
Reactant: CC(=O)c1c(O)cccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(=O)CCCC(C)(C)c1ccc(O)c(C(C)=O)c1O
Temperature: 100 °C

Procedure:
1.5 Parts of 2-acetyl resorcinol, 1.4 parts of methyl 5-methyl-hex-5-enoate, and 0.1 parts of p-toluene sulphonic acid are sealed into a glass Carius tube and maintained at 100° C. for 48 hours. The reaction mixture is then washed free of the acid catalyst and chromatographed through silica to yield methyl 5-(3'-acetyl-2,4-dihydroxyphenyl)-5-methyl-hexanoate with m.p. 94°-7° after crystallisation from 40°-60° C. petroleum-ether.
Reaction SMILES: [S:1]([O-])(O)=O.[Na+].[CH2:6]([S:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8]>CN1CCCC1=O>[CH2:6]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:1])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)CS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)CS(=O)(=O)c1ccc(S)cc1
Temperature: 100 °C
Yield: 96 %

Procedure:
14.4 g (0.194 mol) of sodium hydrogen sulphite (NaSH·H2O) in 120 ml of N-methylpyrrolidone are introduced and the water is removed at 160° C. with nitrogen. The mixture is cooled to 100° C., 20 g (0.081 mol) of 4-(neopentylsul-phonyl)-chlorobenzene are added, and the mixture is further reacted at 125° C. for 5 hours and the solvent is distilled off under reduced pressure. The residue is dissolved in 150 ml of water and acidified at 10°-20° C. with half-concentrated hydrochloric acid. The mixture is extracted with 100 ml of methylene chloride, the organic phase is washed neutral with water, dried with magnesium sulphate, concentrated and, after addition of 50 ml of toluene, distilled at 0.1 mbar up to an inside temperature of 130° C. to give 19 g of 4-(neopentylsulphonyl)-thiophenol of boiling point: 130° C./0.1 mbar; purity by gas chromatography: 98.6%=95% of theory.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2].CI.[CH2:36](I)C>>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH3:36])[CH2:15][C:16]2[O:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)COc1c(C)cc(NCc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Solvent: CI
Product: CCOC(=O)COc1c(C)cc(N(C)Cc2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C

Procedure:
The title compound was prepared in analogy to example 15.4 from the above prepared (2,6-dimethyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester, but using methyl iodide as electrophile instead of ethyl iodide, as off-white solid, MS: 477.5 (MH)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[C:7]([CH3:14])=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:4]=2[O:3]1.[H][H]>[Ni].O1CCCC1>[NH2:11][C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[C:7]([CH3:14])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])c2c1CC(C)O2
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(N)c2c1CC(C)O2

Procedure:
A mixture of 24.3 g of 1C, 200 ml of tetrahydrofuran (THF) and 2 g of activated Raney nickel catalyst was treated with hydrogen (40 psig) in a Parr shaker three hours, then filtered. The solvent was evaporated from the filtrate to give 7-amino-2,3-dihydro-2,4-dimethylbenzofuran (1D), as an amber syrup.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)([O-:3])=[O:2].[Cl-:9].[Al+3].[Cl-:11].[Cl-]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[S:5][C:6]([Cl:11])=[C:7]([Cl:9])[CH:8]=1)([O-:3])=[O:2]
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1cccs1
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)s1

Procedure:
To a solution of 2-nitrothiophene (10.0 g, 77.5 mmol) in 60 ml of chloroform is added aluminum chloride (6.0 g, 45.0 mmol). The mixture is cooled to 10° and chlorine gas is bubbled through for 3 hours at 25°-30°. Nitrogen gas is then bubbled through the mixture for 10 min., after which the mixture is poured into ice water and extracted with chloroform. The combined chloroform layers are washed with water and with brine and dried to give 2-nitro-4,5-dichlorothiophene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([C:7]([O:10]C)=[CH:8][CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COc1ccc(Cl)c(F)c1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1c(O)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
To a solution of 3-chloro-2-fluoro-6-methoxy-benzaldehyde (10 g, 53.2 mmol,) in dichloromethane (200 mL) at −78° C. was added a dichloromethane solution (1 M) of BBr3 (159 mL, 159 mmol) dropwise. The mixture was gradually warmed to room temperature and stirred for 1 h, then quenched with water. The mixture was extracted with dichloromethane three times. The organic layer were combined, washed with brine, dried over MgSO4, concentrated to give a residue. The reside was triturated with dichloromethane and hexanes to afford 3-chloro-2-fluoro-6-hydroxy-benzaldehyde as a brown solid (Yield: 2.07 g, 22%)
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:10]4[C:14]5[C:19]([S:20][C:9]=4[CH:8]=[CH:7][C:6]=3[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:18][CH:17]=[CH:16][CH:15]=5.[H-].[Na+].Cl[C:24]1[N:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:27]=[C:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]=1>CN(C)C=O>[C:36]1([C:26]2[N:27]=[C:28]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:29]=[C:24]([N:12]3[C:11]4[C:10]5[C:14]6[C:19]([S:20][C:9]=5[CH:8]=[CH:7][C:6]=4[C:5]4[CH:4]=[CH:3][CH:2]=[CH:1][C:13]3=4)=[CH:18][CH:17]=[CH:16][CH:15]=6)[N:25]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: c1ccc2c(c1)[nH]c1c2ccc2sc3ccccc3c21
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(-c2nc(-c3ccccc3)nc(-n3c4ccccc4c4ccc5sc6ccccc6c5c43)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15.1 g (55.4 mmol) of 12H-7-thia-12-azaindeno[1,2-a]fluorene are dissolved in 315 ml of dimethylformamide under a protective-gas atmosphere, and 2.4 g of 60% NaH in mineral oil (61 mmol) are added. After 1 h at room temperature, a solution of 2-chloro-[4,6-bisphenyl]-1,3,5-triazine (17.8 g, 66.5 mmol) in 80 ml of dimethylformamide is added dropwise. The reaction mixture is stirred at room temperature for 12 h. After this time, the reaction mixture is poured onto ice and extracted three times with dichloromethane. The combined organic phases are dried over Na2SO4 and evaporated. The residue is recrystallised from toluene. The yield after sublimation is 23.8 g (47.1 mmol, 85%) with a purity of 99.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1.[C:19]([O-])(=O)/[CH:20]=[CH:21]/[C:22]([O-])=O>>[CH3:1][O:2][C:3]1[C:4]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH:20]3[CH2:6][C:7]4[C:22](=[CH:5][CH:4]=[CH:3][CH:12]=4)[CH2:21]3)[CH2:17][CH2:18]2)=[CH:5][C:6]2[O:11][CH2:10][CH2:9][O:8][C:7]=2[CH:12]=1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: COc1cc2c(cc1N1CCNCC1)OCCO2
Product: COc1cc2c(cc1N1CCN(CC3Cc4ccccc4C3)CC1)OCCO2

Procedure:
Prepared as described in Example 9, starting from 4-(2,3-dihydro-7-methoxybenzo-1,4-dioxin-6-yl)piperazine (Preparation 5). The fumarate of the title compound melts at 176°-178° C. (ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:14])[CH:8]=[C:9]2[O:13][CH:12]=[CH:11][C:10]=12)=[O:4].C(O)(=O)C>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:14])[CH:8]=[C:9]2[O:13][CH2:12][CH2:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cc(O)cc2occc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(O)cc2c1CCO2
Reaction time: 8 h

Procedure:
To a solution of 6-hydroxy-benzofuran-4-carboxylic acid methyl ester (6d) (354 mg, 1.82 mmol) in EtOAc was added acetic acid (1 mL) and Pd on carbon (40 mg). The reaction mixture was stirred under hydrogen gas balloon overnight. The mixture was filtered through Celite and concentrated to give a pale yellow solid which was used without further purification. LCMS and NMR showed it was a mixture of 6-hydroxy-benzofuran-4-carboxylic acid methyl ester and 6-hydroxy-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (2:1). 1H NMR (400 MHz, CDCl3) δ 7.02 (d, J=2.27 Hz, 2 H) 6.53 (d, J=2.27 Hz, 1 H) 4.61 (t, J=8.72 Hz, 2 H) 3.90 (s, 3 H) 3.44 (t, J=8.72 Hz, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[S:16][CH:17]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(c1csc(C(=O)O)c1)S(C)(=O)=O
Yield: 79.7 %

Procedure:
To a solution of ethyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-thiophene-2-carboxylate (Int. 43) (300 mg, 0.859 mmol) in THF/water 1/1 (20 ml), lithium hydroxide (61.7 mg, 2.58 mmol) was added, and the mixture was reacted overnight at RT. The organic solvent was evaporated and the aqueous residue was acidified with 1N HCl (pH=5); the resulting precipitate was collected by filtration yielding 4-(N-(tert-butoxycarbonyl)-methylsulfonamido)thiophene-2-carboxylic acid (Int. 44) (220 mg, 0.685 mmol, MS/ESI+343.7 [MNa]+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([C:14]#N)=[CH:4][CH:3]=1.C(O)=[O:17]>[Ni]>[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH:14]=[O:17])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: CN1CCc2c(Cl)ccc(C#N)c2CC1
Agent: [Ni]
Product: CN1CCc2c(Cl)ccc(C=O)c2CC1

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carbonitrile (3.1 g, 14 mmol) in 90% formic acid (40 ml) was treated with Raney® nickel (3.1 g), stirred and heated to reflux for 3 hours. Additional Raney® nickel (17 g) and 90% formic acid (85 ml) were added over the next 12 hours and the mixture was stirred for an additional 3 hours. The mixture was cooled, filtered and the filter cake washed with 45% formic acid. The filtrate was concentrated, basified with 10% sodium hydroxide, extracted with ethyl acetate and the organic phase was washed, dried and concentrated to give 3 g of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([OH:15])[CH2:10][CH2:11][O:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)OCCC2=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1ccc2c(c1)OCCC2O
Yield: 106.1 %

Procedure:
By a similar reaction operation as in Starting Material Synthetic Example 1 using 4-oxochromane-7-carboxylic acid methyl ester (1.4 g) synthesized according to a known method and sodium borohydride (0.26 g), the objective 4-hydroxychromane-7-carboxylic acid methyl ester (1.5 g) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][C:4](O)=[O:5].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[N:38][CH:39]=1)[N:36]=[C:35]([NH2:40])[CH:34]=[CH:33]2>C(Cl)Cl>[Br:29][C:30]1[CH:31]=[C:32]2[C:37](=[N:38][CH:39]=1)[N:36]=[C:35]([NH:40][C:4](=[O:5])[CH2:3][N:2]([CH3:7])[CH3:1])[CH:34]=[CH:33]2
Reactant: Nc1ccc2cc(Br)cnc2n1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN(C)CC(=O)Nc1ccc2cc(Br)cnc2n1
Yield: 59.5 %

Procedure:
Add N,N-dimethylglycine (0.28 g, 2.68 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.47 g, 2.45 mmol), 1-hydroxybenzotriazole (0.33 g, 2.45 mmol), and methylene chloride (111 mL) to 6-bromo-[1,8]naphthyridin-2-ylamine (Reichardt, C. et al, Tetrahedron Lett. 1977, 2087; 0.50 g, 2.23 mmol). Stir the reaction at room temperature for 19 h, concentrate in vacuo and purify by flash column chromatography to provide the subtitled compound (0.41 g, 60%) as an orange solid. MS ESI+ m/e 309/311 (M+1). 1H NMR (DMSO-d6) δ 10.52 (m, 1H), 8.96 (m, 1H), 8.71 (m, 1H), 8.35 (m, 2H), 3.15 (s, 2H), 2.25 (s, 6H). TLC (SiO2): Rf0.3 (1:4 [80:18:2 chloroform/methanol/concentrated aqueous ammonium hydroxide]/dichloromethane).
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]1[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2]
Reactant: CCOc1nc(C)cc(=O)[nH]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 2-ethoxy-6-methylpyrimidin-4(3H)-one (4.9 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (10.3 g) in acetonitrile (120 mL) was added potassium carbonate (5.24 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (6.15 g, 56%) as a colorless solid.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=O.Cl.[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH2:19][C:20]([NH2:22])=[S:21])[N:18]=1>>[CH3:13][C:14]1[NH:15][CH:16]=[C:17]([CH2:19][C:20]2[S:21][C:2]3[CH2:10][C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=4[C:3]=3[N:22]=2)[N:18]=1
Reactant: Cc1nc(CC(N)=S)c[nH]1
Reactant: O=C1c2ccccc2CC1Br
Agent: Cl
Product: Cc1nc(Cc2nc3c(s2)Cc2ccccc2-3)c[nH]1

Procedure:
Starting compounds: 2-bromo-1-indanone, (2-methyl-4-imidazolyl)thioacetamide hydrochloride
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]1=[O:20])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[CH2:6][CH2:5][C:4]1=[O:20])[CH3:2]
Reactant: CCn1c(=O)ccc2cnc(Nc3ccccc3)cc21
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCN1C(=O)CCc2cnc(Nc3ccccc3)cc21
Yield: 12.9 %

Procedure:
A suspension of 1-ethyl-7-phenylamino-1H-[1,6]naphthyridin-2-one from Example W (75 mg, 0.29 mmol), 0.6 g of Raney nickel, and 50 mL of ethanol was stirred under 50 psi of hydrogen at room temperature for 23 hours. The suspension was filtered and the filtrate was concentrated to a solid residue that was purified by preparative thin layer chromatography to give 1-ethyl-7-phenylamino-3,4-dihydro-1H-[1,6]naphthyridin-2-one (10 mg, 13% yield): mp 137-138° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[O:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: OCCc1c[nH]c2ccccc12
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(OCCc1c[nH]c2ccccc12)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
To a solution of 2-(1H-indol-3-yl)-ethanol (1600 mg, 9.92 mmol), in N-methyl morpholine (2000 m g, 19.84 mmol), was added p-nitrophenyl chloroformate (4000 mg, 19.84 mmol), and the mixture was stirred for 24 hours at room temperature. Water was added and the mixture extracted with dichloromethane. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography using a mixture of DCM/Hx (3:1) as eluent to produce 1034 mg (32%) of the title compound as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)/[N:5]=[C:6](\OCC)/[CH3:7])C.Cl.[CH:13]([NH:16][NH2:17])([CH3:15])[CH3:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:13]([N:16]1[C:4](=[O:3])[NH:5][C:6]([CH3:7])=[N:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)NN
Reactant: CCOC(=O)/N=C(/C)OCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)C)c(=O)[nH]1
Reaction time: 17 h

Procedure:
To a solution of [1-ethoxy-eth-(Z)-ylidene]-carbamic acid ethyl ester (834 mg, 5.24 mmol) in toluene (15 mL) was added isopropyl hydrazine hydrochloride (637 mg, 5.76 mmol) follwed by triethylamine (803 μL, 5.76 mmol). The reaction vessel was sealed and stirred at 45° C. for 45 minutes before the addition of triethylamine (803 μL, 5.76 mmol). The resultant mixture was heated to 90° C. and stirred for 17 hours, then cooled and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0% to 8% 2M NH3/MeOH in DCM) to give 2-Isopropyl-5-methyl-2,4-dihydro-[1,2,4]triazol-3-one as an off white solid (329 mg, 44%). LCMS: RT=2.16 min, [M+Na]+=164