Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CN1CCCCC1>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:25][CH:26]=1)(=[O:19])=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][S:14]([CH3:17])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CN1CCCCC1
Product: CS(=O)(=O)CCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(N2CCOCC2)cc1
Reaction time: 24 h
Yield: 92.6 %

Procedure:
To a dimethylsulfoxide (0.5 ml) solution of the 1,4-difluoro-2-[1-[(4-fluorophenyl)sulfonyl]-5-(methylsulfonyl)pentyl]benzene (40 mg, 0.095 mmol) obtained in Example 160 were successively added morpholine (0.012 ml, 0.14 mmol) and 1-methylpiperidine (0.017 ml, 0.14 mmol). The resulting mixture was allowed to stand at 80° C. for 24 hours. The reaction mixture was purified by preparative high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid). The resulting solid was washed with diethyl ether and collected by filtration, whereby the title compound (43 mg, 0.088 mmol, 92%) was obtained as a white powder.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][CH2:5][C:6]1([CH3:16])[CH2:15][CH2:14][CH2:13][CH2:12][C:7]21[O:11][CH2:10][CH2:9][O:8]2.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Mg].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Cl-].[NH4+]>CCOCC.CI.C1C=CC=CC=1>[CH3:16][C:6]1([CH2:5][CH2:4][C:3]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH2:15][CH2:14][CH2:13][CH2:12][C:7]21[O:8][CH2:9][CH2:10][O:11]2
Reactant: Br[Mg]c1ccccc1
Reactant: COC(=O)CCC1(C)CCCCC12OCCO2
Reactant: Brc1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CI
Product: CC1(CCC(O)(c2ccccc2)c2ccccc2)CCCCC12OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-methyl-1,4-dioxaspiro[4.5]decane-6-propionic acid methyl ester (52.5 g, 0.21 mole), described in Example 7, in anhydrous ether (500 ml) and dry benzene (100 ml) is added dropwise under nitrogen to a cooled (0°-5° C.) stirred solution of phenyl magnesium bromide in ether prepared from magnesium turnings (15.9 g, 0.65 mole), bromobenzene (75 ml, 0.72 mole) and anhydrous ether (500 ml). (Note: Only about 75 ml of ether is used to start the reaction with 15 drops methyl iodide and 2-3 ml bromobenzene). The mixture is stirred overnight at room temperature. Following the careful addition of saturated ammonium chloride solution (114 ml) with cooling, the resulting yellow ether layer is decanted and the precipitated magnesium salts are rinsed thoroughly with ether. The combined ether layers are steam distilled and methanol (100 ml) and 25% aqueous sodium hydroxide (150 ml) is added to the residue. The mixture is heated at reflux for 2 hr to saponify any unreacted ester. The methanol is evaporated and the residue is extracted with ether (4×). The ether extracts are dried (MgSO4) and concentrated to give 6-methyl-α,α-diphenyl-1,4-dioxaspiro[4.5]decane-6-propanol, mp 115°-117° C. after recrystallization from chloroformhexane, νmaxCHCl3 3620, 3500, 1092 cm-1.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][O:47][Si](C(C)(C)C)(C)C)[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[N:16][N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH2:19][CH2:20][CH2:21][CH3:22])=[C:10]([C:34]([N:36]2[C@H:45]([CH2:46][OH:47])[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[CH:9]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO[Si](C)(C)C(C)(C)C)c(C(=O)OCC)nn1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C(=O)OCC)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-((tert-butyldimethylsilyloxy)methyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (Intermediate 259E, 207 mg, 0.275 mmol) in THF (2.0 mL) at room temperature was added TBAF (0.413 mL, 0.413 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with EtOAc, washed with sat. aq. sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting with 0-70% EtOAc/hexanes) to give ethyl 4-(4-(tert-butoxycarbonyl)-2-((S)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-5-butyl-1-phenyl-1H-pyrazole-3-carboxylate (113 mg, 0.177 mmol, 64%) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[SH:6][C:7]1[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=1[NH2:9].O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[O:4]=[C:3]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[S:6][CH2:2]1
Reactant: Nc1ccccc1S
Reactant: O=C(Br)CBr
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C1CSc2ccccc2N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of bromo acetylbromide in toluene (20 ml) was added dropwise to an ice-cooled stirred solution of o-mercaptoaniline (10 mmol, 2.5 g) in a mixture of pyridine and toluene (50 ml, 30 ml). The mixture was allowed to heat to room temperature and stirring was continued for 2 hours followed by reflux for 30 min., whereafter water (100 ml) was added. The organic phase was separated, dried (MgSO4) and evaporated to give 3,4-dihydro-3-oxo-2H-1,4-benzothiazine.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:9]([OH:10])[C@@H:8]([CH2:11][OH:12])[O:7][CH:5]([OH:6])[C@@H:4]1[OH:13].F[C:15](F)(F)S(O)(=O)=O.C(N([CH2:27][CH3:28])CC)C>FC(F)(F)C(O)=O.C(O)C=C>[CH2:15]([C:5]1([O:7][C@H:8]([CH2:11][OH:12])[C@@H:9]([OH:10])[C@H:3]([O:2][CH3:1])[C@H:4]1[OH:13])[OH:6])[CH:27]=[CH2:28]
Reactant: CO[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1O
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C=CCO
Product: C=CCC1(O)O[C@H](CO)[C@@H](O)[C@H](OC)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
3-O-methyl-1,2:5,6-di-O-isopropylidine-glucopyranose (10.2 g) was dissolved in 90% aqueous trifluoroacetic acid (30 mL) and stirred for 1 hour at room temperature. The reaction mixture was evaporated and then coevaporated with toluene followed by ethanol coevaporation to provide the product which was directly used for further allyl glycosylation. 7.9 g of 3-O-methyl-glucopyranose was dissolved in 50 mL of dry allyl alcohol and 120 μL of trifluoromethanesulfonic acid was added. The mixture was heated for 51/2 h at 80° C. Triethylamine (1 mL) was added to destroy excess trifluoromethanesulfonic acid, evaporated and coevaporated with water to remove allyl alcohol. The material was purified by chromatography on silica gel using dichloromethane-methanol (20:1) as eluent to yield allyl-3-O-methyl-glucopyranose (4.85 g, 50.8%).
Reaction SMILES: C([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)=[CH:11][C:10]=1[N+:23]([O-])=O)C1C=CC=CC=1.CO.Cl>[Pd].O>[NH2:23][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]([CH3:22])[CH2:17][C:18](=[O:21])[NH:19][N:20]=2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC1CC(=O)NN=C1c1ccc(NCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CC1CC(=O)NN=C1c1ccc(N)c(N)c1

Procedure:
6-(4-Benzylamino-3-nitrophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one was mixed with methanol and a separately prepared mixture of Pd/C catalyst, water and hydrochloric acid. After hydrogenation, the reaction mixture was filtered and the filtrate was alkalined with a sodium hydroxide solution. The precipitate was filtered, rinsed with water and methanol, filtered and dried, to obtain 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: C([Li])CCC.O1CCCC1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1>O>[Cl:20][C:21]1[N:26]=[C:25]([O:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OCc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(COc2ccnc(Cl)n2)cc1
Reaction time: 0.5 h
Yield: 68 %

Procedure:
n-Butyl lithium (2.6 M n-hexane solution, 10.1 mL) was added to tetrahydrofuran solution (12 mL) of 4-fluorobenzyl alcohol (3.08 mL) at −78° C., and stirred at the same temperature for 30 minutes. This reaction liquid was gradually added to tetrahydrofuran suspension (24 mL) of 2,4-dichloropyrimidine (4.0 g) and stirred at room temperature for 2 hours. After addition of water, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the residue was crystallized from mixed solvent of chloroform and hexane to provide the title compound (4.36 g, 68%).
Reaction SMILES: [Mg].[CH3:2][Ge:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:11]=[C:12](Br)[CH:13]=1>O1CCCC1>[CH3:2][Ge:3]([CH3:5])([CH3:4])[C:8]1[CH:9]=[C:10]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:11]=[C:12]([Ge:3]([CH3:5])([CH3:4])[CH3:2])[CH:13]=1.[CH3:2][Ge:3]([CH3:5])([CH3:4])[C:8]1[CH:9]=[C:10]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC1(c2cc(Br)cc(Br)c2)OCCO1
Reactant: C[Ge](C)(C)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2cc([Ge](C)(C)C)cc([Ge](C)(C)C)c2)OCCO1
Product: CC1(c2cccc([Ge](C)(C)C)c2)OCCO1
Yield: 65 %
Yield: 11 %

Procedure:
To a suspension of 108 mg (4.44 mmol) of magnesium and 765 mg (5.00 mmol) of trimethylgermyl chloride was added a solution of 644 mg (2.00mmol) of 2-(3,5-dibromophenyl)-2-methyl-1,3-dioxolane in 10 ml of tetrahydrofuran at 40° C., stirred in an atmosphere of argon. The mixture was stirred at 70° C. for 4.5hr. and at room temperature overnight. The reaction mixture was poured into ice-aqueous sodium bicarbonate solution and extracted with methylene chloride. The solvent was removed to give pale brown crystals, which were purified by column chromatography on silica gel [eluent: methylene chloride-n-hexane (1:1)] to give 514 mg (yield 65%) of 2-(3,5-bis(trimethylgermyl)phenyl]-2-methyl-1,3-dioxolane, m.p.54° C., and 61 mg (yield 11%) of 2-(3-trimethylgermylphenyl)-2-methyl-1,3-dioxolane and 75 mg of the mixture, in which the ratio was 3:2 (by NMR).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1.CCN(C(C)C)C(C)C.Cl[CH2:44][CH2:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.O>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([S:46]([CH:45]=[CH2:44])(=[O:48])=[O:47])[CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[C:30]([O:31][CH3:32])[C:5]=2[N:4]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(OC2CCNCC2)nc(N2CCOCC2)n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 65 %

Procedure:
To a solution of 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyloxy)-1,3,5-triazin-2-yl]-1H-benzimidazole (Example 16) (1.52 g, 3.29 mmol) and DIPEA (2.3 ml, 4 eq.) in CH2Cl2 (30 mL) at 0° C. was added 2-chloroethanesulfonyl chloride (1 mL, excess). The reaction mixture was stirred at 20° C. for 20 hrs and diluted with water (50 mL). The CH2Cl2 layer was separated and the aqueous layer was further extracted with CH2Cl2 (3×20 mL). The combined organic fractions were washed successively with aq. HOAc, aq. K2CO3, and water, and dried (MgSO4). Evaporation of the solvent and chromatography of the residue on silica, eluting with CH2Cl2/EtOAc (9:1) gave 2-(difluoromethyl)-4-methoxy-1-(4-(4-morpholinyl)-6-{[1-(vinylsulfonyl)-4-piperidinyl]oxy}-1,3,5-triazin-2-yl)-1H-benzimidazole (1.17 g, 65% yield): mp (CH2Cl2/MeOH) 266-269° C.; 1H NMR (DMSO-d6) δ7.95 (d, J=7.9 Hz, 1H), 7.70 (t, JHF=52.8 Hz, 1H), 7.44 (t, J=8.2 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.88 (dd, J=16.5, 10.0 Hz, 1H), 6.19 (d, J=10.0 Hz, 1H), 6.15 (d, J=16.5 Hz, 1H), 5.26-5.20 (m, 1H), 3.98 (s, 3H), 3.84 (m, 4H), 3.74-3.32 (m, 4H), 3.39-3.32 (m, 2H), 3.14-3.08 (m, 2H), 2.14-2.09 (m, 2H), 1.90-1.18 (m, 2H); Anal. Calcd. for C23H27F2N7O5S.0.5CH2Cl2: C, 47.7; H, 4.7; N, 16.5. Found: C, 47.8; H, 4.7; N, 16.8%.
Reaction SMILES: [CH2:1](O)C.Br[C:5]1[CH:6]=[CH:7][C:8]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)[CH2:13][CH2:12][C:11]([C:24]([OH:26])=[O:25])=[CH:10][C:9]=2[CH:27]=1.B([O-])([O-])O[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:1][CH:13]1[CH2:12][C:11]([C:24]([OH:26])=[O:25])=[CH:10][C:9]2[CH:27]=[C:5]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:32][CH:31]=3)[CH:6]=[CH:7][C:8]=2[N:14]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: CCO
Reactant: CCCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COc1cccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CC(C)N3Cc2cccc(OC)c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended 7-bromo-1-(3-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (320 mg), 4-butoxyethoxyphenyl borate (246 mg) and potassium carbonate (285 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (64 mg), and the mixture was heated at 100° C. for 8 hours under argon atmosphere. After allowing to cool, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=5:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (207 mg) as yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=O.[CH3:8][CH:9]([CH3:13])[CH2:10][CH2:11][NH2:12].[S-:14][C:15]#[N:16].[K+].II>C(#N)C>[C:2]([C:3]1[S:14][C:15](=[NH:16])[N:12]([CH2:11][CH2:10][CH:9]([CH3:13])[CH3:8])[CH:4]=1)([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)CCN
Reactant: N#C[S-]
Reactant: CC(C)(C)CC=O
Agent: II
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCn1cc(C(C)(C)C)sc1=N
Yield: 104545.5 %

Procedure:
A mixture of 3,3-dimethylbutanal (3.0 mL, 24 mmol), 3-methylbutan-1-amine (2.5 mL, 22 mmol), 4 Å molecular sieves (3 g, 8-12 mesh beads), potassium thiocyanate (2.8 g, 29 mmol) and iodine (11 g, 44 mmol) in acetonitrile (40 mL) were processed as described in Example 18A to provide the title compound (4.9 g, 23 mol, 99% yield). MS (DCI/NH3) m/z 227 (M+H)+.
Reaction SMILES: Cl[O-].[Na+].[OH-].[Na+].[C:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:19])[CH:15]=2)[CH:10]=1)(=[O:8])C.CC1(C)CC=C(C2C=CC(C)=CC=2)C2C=C(C#CC3C=CC(C(OCC)=[O:45])=CC=3)C=CC1=2>O.O1CCOCC1>[Br:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]([OH:8])=[O:45])[CH:18]=[CH:17]2
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc2cc(Br)ccc2c1
Temperature: 70 °C
Yield: 232.7 %

Procedure:
To a solution of sodium hypochlorite (62 ml, 5.25% in water (w/w), 3.6 g, 48.18 mmol) and sodium hydroxide (6.4 g, 160.6 mmol) in 50 ml of water was added a solution of 2-acetyl-6-bromonaphthalene (Compound L) 4 g, (1 6.06 mmol) in 50 ml of 1,4-dioxane. The yellow solution was heated to 70° C. in an oil bath for 2 hours, cooled to ambient temperature, and extracted with ethyl ether (2×50 ml). The aqueous layers were diluted with NaHSO3 solution (until KI indicator solution remained colorless) and then acidified (pH <2) with 1N sulfuric acid to give a white precipitate. The mixture was extracted with ethyl ether, and the combined organic phase washed with saturated aqueous NaCl, dried (MgSO4) and concentrated to give 3.54 g (88%) of the title compound as a solid. 1H NMR (DMSO-d6): δ8.63 (1H, br s), 8.32 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 8.00-8.05 (2H, m), 7.74 (1H, dd, J=2.0, 8.8 Hz).
Reaction SMILES: [C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.C([CH:12]=[C:13]([C:17]#[N:18])[C:14]([OH:16])=[O:15])C(C)C.[OH-].[K+]>O>[C:1]12[CH2:7][C:4]([CH2:5][CH2:6]1)=[CH:3][CH:2]=2.[C:17]([C:13](=[CH2:12])[C:14]([OH:16])=[O:15])#[N:18]
Reactant: CC(C)CC=C(C#N)C(=O)O
Agent: C1=C2CCC(=C1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C=C(C#N)C(=O)O
Temperature: 25 °C

Procedure:
Into a flask fitted with a condenser and magnetic stirring bar is charged 12.3 g (0.05 mole) norbornadiene/isobutyl 2-cyanoacrylic acid adduct and a solution of 4.9 g 86% potassium hydroxide (0.075 mole) in 75 ml. of water. After heating at reflux for 1.5 hours, the solution is cooled to room temperature and extracted with 2 × 25 ml. of hexane to remove any nonsaponified adduct. The aqueous phase is acidified to pH 2 with 6 N hydrochloric acid and the liberated oily product is taken up in 100 ml. ethyl acetate. The extract is filtered to remove some white insoluble solids (0.9 g., m.p. 182° C.) and the filtrate washed with 3 × 25 ml. water, 1 × 25 ml. saturated sodium chloride solution, and solvent stripped in vacuo to a pale yellow, viscous oil (8.7 g.). Crystallization of the oily product from benzene/hexane in the cold affords 4.2 g of the norbornadiene/2-cyanoacrylic acid adduct, white crystals, m.p. 83°-86° C. Another 3.0 g. of adduct, m.p. 81°-84° C., is obtained on concentration of the mother liquors and cooling. The combined crops and adduct are recrystallized from 1:2 benzene/hexane to afford 5.9 g of pure adduct, white crystals, m.p. 81°-83 ° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)=[O:14]>O1CCCC1>[Cl:22][C:18]1[CH:17]=[C:16]([N:15]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1cccc(Cl)c1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2cccc(Cl)c2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
3-Methylphenyl isocyanate (0.6 g) is added at a temperature in the region of 20° C. to a solution of tert-butyl 2-[2-amino-N-(3-chlorophenyl)acetamido]-acetate (1.25 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 4 hours at a temperature in the region of 20° C and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2 cm in diameter [eluent: ethyl cyclohexaneacetane [sic] (75:25 by volume)], collecting 20 cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After crystallisation in diisopropyl ether, tert-butyl 2-{N-(3-chlorophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.8 g), m.p. 110° C. is obtained
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:38]5[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]5)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(C(=O)c2ccc3c(n2)CCC2C3=NN(c3ccc(C#N)c(Cl)c3)C2C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), 1-methylsulfonylpiperazine (0.214 g, 1.303 mmol), DIEA (0.2 mL, 1.15 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 2 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellowish-green solid, which was washed with methanol to produce a purified product (0.325 g) in 57.3% yield.
Reaction SMILES: [C:1]1(=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[N:10]O.O1CCOCC1>CCO>[NH2:10][C@@H:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C@H:1]1[OH:12]
Reactant: O=C1C(=NO)Cc2ccccc21
Solvent: CCO
Solvent: C1COCCO1
Product: N[C@@H]1Cc2ccccc2[C@H]1O
Yield: 171.9 %

Procedure:
A solution of indan-1,2-dione-2-oxime (6.2g, 39mmol) in EtOH (470 ml) and 4MHCl/Dioxane (36 ml) was hydrogenated at room temperature and 40 psi. The reaction mixture was filtered through celite, washed with EtOH (30 ml) and concentrated under reduced pressure to give 10 g of an off-white solid which was recrystallised from EtOH to give the title compound (5 g, 86%) as a white solid.
Reaction SMILES: O1CCN(C(CCC(O)=O)=O)CC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[O:31]1[CH2:36][CH2:35][N:34]([C:37]([CH2:39][CH2:40][N:41]=[C:42]=[O:43])=[O:38])[CH2:33][CH2:32]1.[F:44][C:45]1[C:46](=[O:52])[NH:47][C:48](=[O:51])[NH:49][CH:50]=1>C1C=CC=CC=1.C(N(CC)CC)C>[O:31]1[CH2:32][CH2:33][N:34]([C:37]([CH2:39][CH2:40][NH:41][C:42]([N:49]2[CH:50]=[C:45]([F:44])[C:46](=[O:52])[NH:47][C:48]2=[O:51])=[O:43])=[O:38])[CH2:35][CH2:36]1
Reactant: O=C=NCCC(=O)N1CCOCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C(O)CCC(=O)N1CCOCC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCNC(=O)n1cc(F)c(=O)[nH]c1=O)N1CCOCC1

Procedure:
The reaction of 3-morpholinocarbonylpropionic acid and diphenylphosphoryl azide in a solution of triethyl amine and benzene provided a solution comprising 2-morpholinocarbonylethyl isocyanate, which was reacted with 5-fluorouracil to provide 1-[N-(2-morpholinocarbonylethyl)carbamoyl]-5-fluorouracil substantially in the similar method to that of Example 4.