Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[C:4](=[O:13])[C:3]=1[C:14]1[NH:19][C:18]2[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=2[S:16](=[O:30])(=[O:29])[N:15]=1.[Br:31]N1C(C)(C)C(=O)N(Br)C1=O>O1CCCC1>[Br:31][C:7]1[C:2]([OH:1])=[C:3]([C:14]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][C:17]=3[S:16](=[O:30])(=[O:29])[N:15]=2)[C:4](=[O:13])[N:5]([CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:6]=1
Reactant: CC(C)CCn1ccc(O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c1=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)CCn1cc(Br)c(O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c1=O
Yield: 42.8 %

Procedure:
A solution of the product of Example 470A (0.258 g, 0.57 mmol) in tetrahydrofuran (10 mL) was treated with 1,3-dibromo-5,5-dimethyl hydantoin (0.24 g, 0.84 mmol) at 25° C. for 18 hours. The solvent was under a warm stream of nitrogen and the residue was chromatographed on silica gel eluting with dichloromethane to provide the title compound (0.13 g, 43%). 1H NMR (300 MHz, DMSO-d6) δ 0.94 (d, J=6.25 Hz, 6 H) 1.61 (m, 3 H) 3.08 (s, 3 H) 4.00 (m, 2 H) 7.56 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=2.21 Hz, 1 H) 7.70 (m, 1 H) 8.59 (s, 1 H) 10.26 (s, 1 H) 14.29 (s, 1 H). MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C.O1CCCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:25]2[CH:26]=[CH:27][C:28]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(C=O)cc1)c1ccc(C(C)C)cc1)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(CO)cc1)c1ccc(C(C)C)cc1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
N-[(4-Formylphenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.42 g) was dissolved in a mixed solvent (10 mL) of ethanol: tetrahydrofuran (2:1), and sodium borohydride (0.15 g) was added under ice-cooling. The mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-{[4-(hydroxymethyl)phenyl]methyl}-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.25 g). melting point: 143.2° C.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[N:57]=[CH:56][C:55]([NH2:58])=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:58][C:55]4[CH:56]=[N:57][C:52]([N:49]5[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(N6CCN(C)CC6)nc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 6-(4-methylpiperazino)-3-pyridinamine as the aniline component. (15%, MS=682.4 (M+H))
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH:27]=1)[CH2:7][CH2:8][O:9][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[C:30](=[O:33])([O-])[O-:31].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:7][C:6]1[C:27]([C:2]2[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([CH2:7][CH2:8][OH:9])[CH:27]=2)=[CH:2][CH:3]=[CH:4][C:5]=1[C:30]([OH:31])=[O:33]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Br)cc1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccc(C(=O)O)c2C)cc1CCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
1.013 g of [(5-bromo-2-methoxyphenethyl)oxy](t-butyl)diphenyl silane, 580 mg of 3-carboxymethylboronic acid, 170 mg of tetrakistriphenyl phosphine palladium and 1.01 g of potassium carbonate were dissolved in 12 ml of toluene, and the mixture was stirred overnight at 90° C. in a nitrogen atmosphere. The reaction mixture was filtered through Celite, the filtrate was concentrated, and then the residue was dissolved in 15 ml of tetrahydrofuran. To this reaction mixture was added 5 ml of tetrabutyl ammonium fluoride solution (1M) in tetrahydrofuran, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and successively washed with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by a silica gel column, and 197 mg methyl 3-[3-(2-hydroxyethyl)-4-methoxyphenyl]benzoic acid was obtained from a fraction eluted with hexane-ethyl acetate (2:1).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)=[O:20])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:40]([O-:42])=[O:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>ClCCl.C([SiH](CC)CC)C>[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46].[CH:1]1([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19](=[O:20])[C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:40]([O-:42])=[O:41])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(NCC4CCCCC4)c([N+](=O)[O-])c3)cc2)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NS(=O)(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1)c1ccc(N2CCNCC2)cc1

Procedure:
A solution of EXAMPLE 22C (0.85 g, 1.4 mmol) in dichloromethane (10 mL), trifluoroacetic acid (10 mL) and triethylsilane (1 mL) was stirred for 24 hours. The mixture was concentrated to afford the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>C1COCC1.CCO>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[N:12]=[N:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(-n2cc(-c3ccccn3)nn2)cc1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2cc(-c3ccccn3)nn2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 31.4 %

Procedure:
To a stirred solution of 2-[1-(4-nitro-phenyl)-1H-[1,2,3]triazol-4-yl]-pyridine (0.149 g, 0.556 mmol) in 1:1 THF/EtOH (8 mL) is added tin (II) dichloride dihydrate (0.439 g, 1.95 mmol) and the mixture is stirred at room temperature for 22 hours. The solvent is removed in vacuo and 2N NaOH (3 mL) added to the residue. The mixture is stirred for 1 hour, diluted with water and extracted with DCM (3×40 mL). The organic layers are dried over Na2SO4, filtered and evaporated to give a crude product purified by Isolute FlashSilicaII Cartridge chromatography, eluting with 98:2 DCM:MeOH. The fractions containing the title compound are combined and evaporated to afford the desired compound as a yellow solid (41.4 mg, 31%).
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1>C1C=CC=CC=1.CCCCC>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:27])=[CH:23][CH:24]=1
Reactant: FC(F)(F)Oc1ccc(N=C=S)cc1
Reactant: CCCCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCCCC(=N)NC(=S)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Following a procedure similar to that described in Example 1 but using 2.3 g. sodium in 300 ml. dry acetone, 16.4 g. heptanamidine hydrochloride, and 21.9 g. 4-(trifluoromethoxy)phenyl isothiocyanate [b.p. 88° C./7 mm.; prepared from 4-(trifluoromethoxy)aniline] in 120 ml. dry acetone there was obtained 1-[4-(trifluoromethoxy)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 90°-91° C. (from benzene-n-pentane); hydrochloride (25.3 g.), m.p. 171°-172° C. (from acetonitrile).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.Br[CH2:23][C:24]([O:26]CC)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:20]=2)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)Cc2cc(F)cc(CCc3ccc(O)cc3)c2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)Cc2cc(F)cc(CCc3ccc(OCC(=O)O)cc3)c2O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenol (650) (164.1 mg, 0.573 mmol), ethyl bromoacetate (95.7 mg, 0.573 mmol), cesium carbonate (265 mg, 0.688 mmol) and acetonitrile (5 mL) was heated at 50° C. for 18 hours. The reaction was concentrated in vacuo and then purified by flash column chromatography with hexanes and EtOAc (30%). The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 2-(4-(2-(5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)phenoxy)acetic acid (99). 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=7.8 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.56 (d, J=8.4 Hz, 1H), 4.65 (s, 2H), 2.96 (s, 2H), 2.88-2.73 (m, 4H), 1.43 (s, 6H). LC-MS ESI m/z: found 343.4 [M−H]−.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:36]1[C:37]([O:47][CH3:48])=[C:38]([O:45][CH3:46])[CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[CH:41]=1)#[N:35]>O1CCCC1>[Br:1][CH2:43][C:42]([C:40]1[CH:39]=[C:38]([O:45][CH3:46])[C:37]([O:47][CH3:48])=[C:36]([CH:41]=1)[C:34]#[N:35])=[O:44]
Reactant: COc1cc(C(C)=O)cc(C#N)c1OC
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(C#N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.48 g of phenyltrimethylammonium bromide dibromide dissolved in 30 ml of tetrahydrofuran are added dropwise at room temperature within 45 minutes to 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30 ml of tetrahydrofuran, whereupon the mixture is stirred for 30 minutes. Thereupon, the reaction mixture is poured into 120 ml of ice-water and extracted three times with 70 ml of methylene chloride. The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulfate and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane there is obtained 5-(bromoacetyl)-2,3-dimethoxybenzonitrile of m.p. 138°-141°.
Reaction SMILES: [Cl-].[C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S+:13]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[Pb+2].[CH2:41]([S:45]([OH:48])(=[O:47])=[O:46])[CH2:42][CH2:43][CH3:44]>CO>[CH2:41]([S:45]([O-:48])(=[O:47])=[O:46])[CH2:42][CH2:43][CH3:44].[C:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([S+:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:8][CH:9]=2)[C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)([CH3:22])([CH3:23])[CH3:24]
Reactant: CCCCS(=O)(=O)O
Agent: CC(C)(C)Oc1ccc([S+](c2ccc(OC(C)(C)C)cc2)c2ccc(OC(C)(C)C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Product: CCCCS(=O)(=O)[O-]
Temperature: 50 °C

Procedure:
In 93 g of methanol was dissolved 9.3 g (0.018 mol) of tris(4-tert-butoxyphenyl)sulfonium chloride. 3.5 g (0.013 mol) of lead carbonate and 3.0 g (0.022 mol) of butanesulfonic acid were added to the solution, which was heated at 50 ° C. After cooling, the precipitate was filtered off and the filtrate was evaporated. Then 100 g of chloroform was added to the residue, the solution was washed with 100 g of water, and the solution was evaporated again, obtaining 9.2 g (two-steps yield 29%) of tris(4-tert-butoxyphenyl)sulfonium butanesulfonate with 97% purity.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[O:17]1[CH:19]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1>>[C:5]1([N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:1][CH2:18][CH:19]([OH:17])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: NCCN(c1ccccc1)c1ccccc1
Product: OC(CNCCN(c1ccccc1)c1ccccc1)COc1ccccc1

Procedure:
A mixture of 6.4 g. N-(2-aminoethyl)-diphenylamine and 4.7 g. 1,2-epoxy-3-phenoxy-propane was heated for 10 minutes at 160° C. The reaction product was triturated with ether and then recrystallized from isopropanol. 4.7 g. (43% of theory) of colorless crystals of 1-(2-diphenylaminoethylamino)-2-hydroxy-3-phenoxy-propane were obtained; m.p. 95°-96° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([O:37]C)=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:17]2[CH:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[CH:24]3[C:19]([C:20]4[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][C:21]=4[CH2:22][CH2:23]3)=[N:18]2)[CH:12]=[CH:13][C:14]=1[C:15]#[N:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCC1C2=NN(c2ccc(C#N)c(OCc3ccccc3)c2)C1C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1OCc1ccccc1
Yield: 93 %

Procedure:
A mixture of methyl 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 30, (100 mg, 0.20 mmol), tetrahydrofuran (3 mL), and methanol (1 mL) was treated with 2.5 N sodium hydroxide (1 mL) at room temperature. After 18 hours the mixture was concentrated to one-third of its original volume, diluted with water (3 mL) and treated with 2 N hydrogen chloride (2 mL). The mixture was extracted three times with ethyl acetate, dried over magnesium sulfate, filtered and concentrated to give 2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid (yellow/orange solid, 90 mg, 0.18 mmol, 93% yield). The title compound was largely present as (±)-(3RS,3aSR)-2-(3-(benzyloxy)-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.51 (m, 7H), 1.57-1.69 (m, 1H), 1.74-1.89 (m, 1H), 1.95-2.07 (m, 1H), 2.18-2.29 (m, 1H), 2.82-2.96 (m, 1H), 3.03-3.14 (m, 1H), 3.57 (ddd, J=13.70, 9.40, 4.30 Hz, 1H), 4.91 (dd, J=9.53, 5.50 Hz, 1H), 5.31 (q, J=12.35 Hz, 2H), 6.84 (d, J=8.86 Hz, 1H), 6.96 (s, 1H), 7.35 (t, J=7.25 Hz, 1H), 7.40-7.53 (m, 5H), 7.81-7.88 (m, 2H), 8.09 (d, J=8.06 Hz, 1H), 13.03 (s, 1H). ES-MS m/z 492 (M+H).
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)C.O=[S:29](Cl)Cl>>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([C:5]2[N:4]=[N:3][S:29][C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=S(Cl)Cl
Reactant: CCN(N=C(Cc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Product: O=[N+]([O-])c1ccc(-c2nnsc2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Yield: 60.3 %

Procedure:
Acylhydrazone 35 (21 g, 58.7 mmol) was added to SOCl2 (80 ml) at 0° C. The temperature was increased to 50° C., and the reaction was complete (by TLC) after 4 hours. SOCl2 was removed under reduced pressure. The crude solid was recrystallized from ETOAc/MeOH to afford 36 (11.6 g, 60.3%) m.p. 185°-186.5° C.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[OH:21])([CH3:10])([CH3:9])[CH3:8]>>[CH:1]1([C:4]([C:15]2[CH:14]=[C:13]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:12]([OH:21])=[C:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:16]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C(Cl)C1CC1
Product: CC(C)(C)c1cc(C(=O)C2CC2)cc(C(C)(C)C)c1O

Procedure:
Reacting cyclopropanecarbonyl chloride with 2,6-di(t-butyl)phenol by the method of Example 1, white, solid 3,5-di(t-butyl)-4-hydroxyphenyl cyclopropyl ketone, m.p. 140.5°-142.5° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]=[O:27])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][Mg]I.C(OCC)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23](=[O:25])[NH:24][C:10]([C:11]=34)=[C:9]([CH:26]([OH:27])[CH3:29])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(C=O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Reactant: C[Mg]I
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(C)O)c2[nH]c(=O)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (4S)-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-9-carbaldehyde (1.30 g, 3.45 mmol) (single enantiomer from Example 137, step 3) in tetrahydrofuran (30.0 mL) was treated with 3.0 M methylmagnesium iodide in diethyl ether (4.03 mL, 12.1 mmol) and stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product as a mixture of diastereoisomers. The diastereoisomers were separated by chiral HPLC (Chiracel AD-H column, 20×250 mm, 5 micron particle size, eluting with 50% ethanol in hexanes at 12 mL/min, 45 mg per injection) to give Peak 1 (Diastereoisomer 1, RT=10.2 min) and Peak 2 (Diastereoisomer 2, RT=12.6 min).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17]Cl)[N:16]=2)[CH:7]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].[O:26]=[CH:27][C:28]1[CH:36]=[CH:35][C:33]([OH:34])=[C:30]([O:31][CH3:32])[CH:29]=1.CN(C)C=O>O>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]([CH3:19])=[C:15]([CH2:17][O:34][C:33]3[CH:35]=[CH:36][C:28]([CH:27]=[O:26])=[CH:29][C:30]=3[O:31][CH3:32])[N:16]=2)[CH:7]=1)(=[O:4])=[O:3]
Reactant: COc1cc(C=O)ccc1O
Reactant: Cc1oc(-c2cccc(OS(C)(=O)=O)c2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccc(OS(C)(=O)=O)c2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl methanesulfonate (8.35 g), potassium carbonate (3.65 g), vanillin (4.02 g) and N,N-dimethylformamide (100 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl methanesulfonate as colorless crystals (7.95 g, 72%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 136-137° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[N:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1)=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ncc([N+](=O)[O-])cn1
Solvent: c1ccncc1
Product: O=C(Nc1ncc([N+](=O)[O-])cn1)c1ccccc1Cl
Yield: 43782.3 %

Procedure:
2-chlorobenzoyl chloride (577 mg, 3.3 mmol) was added dropwise to a stirred suspension of 2-amino-5-nitropyrimidine (420 mg, 3 mmol) in pyridine (5 ml) and the reaction was heated at reflux for 4 hours under an inert atmosphere followed by solvent removed in vacuo. Purification by flash chromatography on silica gel, eluting with 10–60% ethyl acetate in hexane yielded 2-(N-2-chlorobenzoyl)amino-5-nitropyrimidine (366 g, 44% yield) as a beige solid:
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.NC1N=CC(C)=CN=1.C[O:34][C:35]1[CH:36]=[C:37]([C:41]2[C:42]3[CH2:55][CH2:54][N:53]([C:56]4[CH:61]=[CH:60][C:59]([CH3:62])=[CH:58][N:57]=4)[C:43]=3[N:44]=[C:45]([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[N:46]=2)[CH:38]=[CH:39][CH:40]=1>>[CH3:62][C:59]1[CH:60]=[CH:61][C:56]([N:53]2[C:43]3[N:44]=[C:45]([N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[N:46]=[C:41]([C:37]4[CH:36]=[C:35]([OH:34])[CH:40]=[CH:39][CH:38]=4)[C:42]=3[CH2:55][CH2:54]2)=[N:57][CH:58]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(C)cn2)c1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Agent: Cc1cnc(N)nc1
Product: Cc1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)nc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 2-amino-5-methylpyrimidine, 4-(3-methoxy-phenyl)-7-(5-methyl-pyridin-2-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[C:13]#[N:14])([O-])=O.[H][H]>ClCCCl.[Pd]>[NH2:1][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[C:13]#[N:14]
Reactant: [H][H]
Reactant: N#Cc1c([N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: ClCCCl
Product: N#Cc1c(N)sc2ccccc12
Reaction time: 8 h
Yield: 73 %

Procedure:
Combine in a 500 mL schlenk flask, 2-nitro-benzo[b]thiophene-3-carbonitrile (5.8 g, 28.4 mmol) and Pd/C (3.0 g, 10% w/w, 2.84 mmol) in 1,2-dichloroethane (120 ml), the reaction mixture is charged with a balloon of hydrogen. After overnight stirring, release the hydrogen, remove the catalyst by filtration, and wash the catalyst by 1,2-dichloroethane several times. Concentrate down to a residue, which purified by flash chromatography on silica gel, gradient (100% hexane to 100% of Hexane:CH2Cl2:EtOAc=50:50:2.5), afford brownish solid 3.6 g of title compound (yield 73%). Mass spectrum: ES(+)(m/e): 175(M+1); 1H NMR (300 MHz, DMSO-d6, ppm): δ 7.81 (br, 2H), 7.65-7.62 (m, 1H), 7.28-7.24 (m, 2H), 7.11-7.01 (m, 1H).