Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])[CH:6]=1)C.[OH-].[Na+]>CO>[F:19][C:18]([F:20])([F:21])[O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:22])=[O:3]
Reactant: CCOC(=O)c1cccc(-c2ccccc2OC(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccc2OC(F)(F)F)c1

Procedure:
A solution of 0.3 g (4.19 mmol) of ethyl-3-(2-trifluoromethoxyphenyl)-benzoate and 8.3 mL (8.3 mmol) of a 1N solution of NaOH in 12.5 mL of methanol was stirred 18 h at RT. The reaction mixture was concentrated and the pH was adjusted to pH of 2 with 1 N HCl solution. The mixture was extracted with ethyl acetate (EtOAc) and the organic fraction was dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound as a white solid that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]3[O:31][CH2:30][CH2:29][O:28][C:25]=3[CH:26]=2)[N:21]=[CH:20][N:19]=1>CC(O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:18]2[C:27]3[C:22](=[CH:23][C:24]4[O:31][CH2:30][CH2:29][O:28][C:25]=4[CH:26]=3)[N:21]=[CH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cc3c(cc12)OCCO3
Reactant: Clc1ccc2c(c1)NCC2
Solvent: CC(C)O
Solvent: c1ccncc1
Product: Clc1ccc2c(c1)N(c1ncnc3cc4c(cc13)OCCO4)CC2
Yield: 87 %

Procedure:
To 6-chloroindoline (52 mg, 0.339 mmol) and pyridine (23.3 mg, 0.294 mmol) in i-PrOH (3 mL) was added 4-chloro-6,7-(ethylenedioxy)quinazoline (65 mg, 0.284 mmol). The mixture was heated to reflux under dry N2(g) for 16 hours and then concentrated in vacuo. The residue was partitioned between CHCl3 and saturated aqueous NaHCO3, and the organic phase was washed with brine, dried over Na2SO4(s), and concentrated in vacuo. The residue was flash chromatographed on silica using 30% acetone/hexanes to afford 84 mg of 4-(6-chloro-2,3-dihydro-indol-1-yl)-7,8-dihydro-[1,4]dioxino [2,3-g]quinazoline as its free-base (M.P. 209°-211° C.; GC/MS: 339 (M+); anal. RP18-HPLC RT: 5.02 min).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2.[C-:12]#[N:13].[Na+]>CS(C)=O>[CH2:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][C:12]#[N:13])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1
Reactant: [C-]#N
Reactant: ClCc1ccc2c(c1)CCC2
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a stirred solution of 5-(chloromethyl)-2,3-dihydro-1H-indene (90.0 g, 0.54 mol) in DMSO (500 ml) was added sodium cyanide (54.0 g, 1.08 mol) at 0° C. portion wise. The reaction mixture was then stirred at room temperature for 3 hours. The reaction was quenched with water (1000 ml), extracted with ethyl acetate (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4 and evaporated in vacuo to afford 2-(2,3-dihydro-1H-inden-5-yl)acetonitrile (82.2 g, 97%), that was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:27]([O:34][C:35]1[C:36]([C:46](Cl)=[O:47])=[CH:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[C:40](=[O:45])[C:39]=12)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]([C:46]([C:36]2[C:35]([O:34][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:39]3[C:40](=[O:45])[N:41]([CH3:44])[CH2:42][CH2:43][N:38]3[CH:37]=2)=[O:47])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CN1CCn2cc(C(=O)Cl)c(OCc3ccccc3)c2C1=O
Reactant: CC(C)(C)OC(=O)NNCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCn2cc(C(=O)N(Cc3ccc(F)cc3)NC(=O)OC(C)(C)C)c(OCc3ccccc3)c2C1=O

Procedure:
To a cold (0° C.) solution of tert-butyl 2-(4-fluorobenzyl)hydrazinecarboxylate (7.30 g, 30.37 mmol; see Fassler et al., J. Med Chem. 1996, 3203) and diisopropylethylamine (10.70 g, 82.82 mmol) in dichloromethane (200 mL), a solution of 8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carbonyl chloride (8.80 g, 27.61 mmol; derived from treatment of the corresponding acid with oxalyl chloride in dichloromethane in the presence of catalytic amount of DMF at room temperature) in dichloromethane was added. The resultant mixture was stirred at room temperature overnight. The resultant mixture was washed with aqueous ammonium chloride, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the titled amide. This was used with no further purification.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH3:26])[CH:17]=1
Reactant: CC(Oc1cc(Cl)ccc1CO)c1ccccc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: CC(Oc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1)c1ccccc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-chloro-2-(1-phenylethoxy)phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C24H19ClN4O2, 431. Found, 431.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-])=O)[CH:10]=1)[N:7]([C:14]([C:16]([O:18]CC)=O)=[O:15])[CH2:6][CH2:5]2.O.C(O)(=O)C>C1COCC1.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:14](=[O:15])[C:16](=[O:18])[NH:11][C:9]([CH:10]=1)=[C:8]23
Reactant: CCOC(=O)C(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)cc3c2n(c1=O)CC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.6 %

Procedure:
To a solution of 5-bromo-7-nitro-N-ethoxalylindoline (2.0 g, 5.83 mmol) in a mixture of THF (50 mL), water (10 mL), and acetic acid (10 mL) was added aqueous 20% titanium trichloride (31 mL, 40.8 mmol) and the mixture was stirred for 4 h at room temperature. The precipitates formed were collected by filtration, washed with diluted aqueous hydrochloric acid and then distilled water, and dried in vacuo to give 772 mg of the title compound (50%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ11.91 (bs, 1H), 7.21 (d, 1H, J=1 Hz), 7.02 (d, 1H, J=1 Hz), 4.22 (t, 2H, J=7 Hz), 3.32 (t, 2H, J=7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[OH-].[K+].N#N.[C:31]1(=[O:37])[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32]1>CCOC(C)=O.C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].O1CCOCC1>[Cl:1][C:2]1[C:7]([CH:33]2[CH2:34][CH2:35][CH2:36][C:31](=[O:37])[CH2:32]2)=[CH:6][C:5]([C:17]#[N:18])=[CH:4][C:3]=1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(B2OC(C)(C)C(C)(C)O2)c1Cl
Reactant: O=C1C=CCCC1
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: N#N
Solvent: C1=CCCC=CCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CCCC(=O)C2)c1Cl
Temperature: 80 °C
Yield: 41.6 %

Procedure:
To a 20 gram dram vial was charged with tert-butyl (2-chloro-5-cyano-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate (Example 573A)(379 mg, 1 mmol) and chloro(1,5-cyclooctadiene)rhodium(I) dimer (9.86 mg, 0.020 mmol). Dioxane (10 mL) was then added, followed by aq. KOH (2 M, 1 mL). The resulting solution was then evacuated and refilled with N2 before cyclohex-2-enone (144 mg, 1.500 mmol) was added via a syringe. The resulting reaction was heated at 80° C. for 1 h before it was cooled to room temperature. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (0-60% EtOAc/Hexane) to give tert-butyl (2-chloro-5-cyano-3-(3-oxocyclohexyl) phenyl)carbamate (145 mg) as white foam.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:28]Cl>C(O)(=O)C.O>[F:22][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([I:28])=[C:7]2[N:6]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:4]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2cncn12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 112 %

Procedure:
To a stirred solution of 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.56 g, 4.98 mmol) in acetic acid (9 ml) was added at room temperature sodium acetate (0.46 g, 5.63 mmol) and drop wise a solution of iodine monochloride (0.91 g, 5.63 mmol) in acetic acid (4 ml). The reaction mixture was stirred at room temperature for 17 h, diluted slowly with water (150 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 100%) as a yellow solid. MS (EI) 439.0 [(M)+]; mp 159° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O>>[OH:8][C:7]1[C@@H:5]([C@@H:3]([OH:4])[CH2:2][OH:1])[O:6][C:11](=[O:12])[C:9]=1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
A series of resting cell reactions (0.5 ml reaction mixture in 5 ml reaction tube) was carried out with 2% D-sorbitol or with 2% L-sorbose, and all reaction mixtures further contained 0.3% NaCl, 1% CaCO3 and cells at a final concentration of 5 absorbance units at 600 nanometers (OD600). After 20 h incubation time, G. oxydans DSM 17078 produced 270 mg/l or 670 mg/l of Vitamin C, respectively from 2% D-sorbitol or 2% L-sorbose, respectively. In comparison, strain G. oxydans DSM 17078-SMS 05::Km produced 1540 mg/l or 1990 g/l of Vitamin C, respectively.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([NH:25][C:26]([NH:15][C:11]1[CH:10]=[C:9]([CH2:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:16])[CH:14]=[CH:13][N:12]=1)=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccccc1CCc1ccnc(N)c1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1CCc1ccnc(NC(=O)NC(=O)c2ccccc2)c1
Temperature: 65 °C

Procedure:
4-(2-o-Tolyl-ethyl)-pyridin-2-ylamine (100 mg, 0.47 mmol) is dissolved in methylene chloride (3 mL). Then benzoyl isocynate (100 mg, 0.71 mmol) is added. The resulting mixture is sealed and heated at 65° C. for 1 hour. The solvent is then removed to give 225 mg of crude which is used in the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CN(C)C=O>O>[CH2:41]([O:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][N:4]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:19][CH:20]=2)[N:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (500 mg), potassium carbonate (165 mg), benzyl bromide (205 mg), and N,N-dimethylformamide (10 ml) was stirred at 80° C. for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (385 mg, yield: 64%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:32])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:32][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:33])=[O:2])[C:14]([CH3:15])=[C:13]2[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:24])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NC(=O)Nc3ccccc3)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(NC(=O)Nc2ccccc2)cc1
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid methyl ester (40 mg, 0.09 mmol) in ethanol (2 mL) and THF (3 mL) was added a solution of sodium hydroxide (262 uL, 1.0 N) at room temperature. The resulting mixture was stirred for 5 hours. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL) and acidified with 1.0 N hydrochloric acid. The mixture was allowed to stand for 3 h, then the solid was filtered off and air-dried to afford {6-chloro-3-methyl-4-[4-(3-phenyl-ureido)-phenyl]-naphthalen-2-yl}-acetic acid (37 mg, 95%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.50 (s, 1 H), 8.86 (s, 1 H), 8.77 (s, 1 H), 7.94 (d, J=8.8 Hz, 1 H), 7.84 (s, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.41-7.58 (m, 3 H), 7.30 (t, J=7.8 Hz, 2 H), 7.19 (d, J=1.2 Hz, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 6.99 (t, J=7.2 Hz, 1 H), 3.85 (s, 2 H), 2.12 (s, 3 H). HRMS calcd. for C26H22ClN2O3 [(M+H)+] 445.1314, obsd. 445.1311.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18].C([O-])([O-])=O.[K+].[K+].C1([CH:31]([B-](F)(F)F)[N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1.[K+]>O1CCOCC1.CN(C=O)C.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>[C:11]1([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([CH2:31][N:32]4[CH2:33][CH2:34][CH:35]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:36][CH2:37]4)=[C:3]([C:17]#[N:18])[C:4]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N#Cc1c(Cl)ccn2c(-c3ccccc3)cnc12
Reactant: F[B-](F)(F)C(c1ccccc1)N1CCCCC1
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: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1c(CN2CCC(c3ccccc3)CC2)ccn2c(-c3ccccc3)cnc12
Temperature: 150 °C
Yield: 61.9 %

Procedure:
To a mixture of compound D6 (0.15 g, 0.593 mmol) and K2CO3 (0.35 g, 2.55 mmol) in 1,4-dioxane (4 ml) and DMF (1.5 ml) was added compound D7 (0.237 g, 0.85 mmol). The resulting mixture was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.098 g, 0.085 mmol). The reaction mixture was then subjected to microwave heating in a sealed tube at 150° C. for 10 min. The reaction mixture was cooled to room temperature and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo. The residue thus obtained was purified by preparative reverse phase HPLC to yield compound E1 (0.072 g, 31%).
Reaction SMILES: [ClH:1].[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]1([C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19](=O)[C:18](=[CH:27]N(C)C)[CH2:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>CO.C(Cl)Cl>[ClH:1].[ClH:1].[CH3:3][C:2]1[N:4]=[CH:27][C:18]2[CH2:17][N:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[C:19]=2[N:5]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2)c2ccccc2C1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccccc1C(c1ccccc1)=NC2

Procedure:
In five equal portions 9.0 g (95 mmole) of acetamidine hydrochloride and 22.5 ml (0.1 mole) of a 4.46M methanol solution of sodium methoxide was added over 3 hr to a solution of 4.5 g (15 mmole) of 1-phenyl-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to give an oil. The oil was dissolved in an excess of 6% methanolic hydrogen chloride and the solvent was removed at reduced pressure to dryness. The residue was crystallized from a mixture of ether and methylene chloride to give a white solid mp 211°-221° C. Recrystallization from a mixture of methanol and ether gave white flakes, mp 217°-227° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH3:20])[C:18]([C:21]34[CH2:28][CH2:27][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:25][CH2:26]3)[CH2:23][CH2:22]4)=[N:17][N:16]=2)=[C:11]([O:34][CH3:35])[CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[CH3:35][O:34][C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[C:15]1[N:19]([CH3:20])[C:18]([C:21]23[CH2:26][CH2:25][C:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH2:27][CH2:28]2)[CH2:23][CH2:22]3)=[N:17][N:16]=1
Reactant: CCCCCC12CCC(c3nnc(-c4ccc(OCc5ccccc5)cc4OC)n3C)(CC1)CC2
Agent: [Pd]
Solvent: CO
Product: CCCCCC12CCC(c3nnc(-c4ccc(O)cc4OC)n3C)(CC1)CC2

Procedure:
A solution of 3-[4-(benzyloxy)-2-methoxyphenyl]-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (1-E) (272 mg, 0.572 mmol) in MeOH (8 mL) was hydrogenated for 19 h with 10% Pd/C catalyst (27 mg) at room temperature and atmospheric pressure. The catalyst was filtered and washed with MeOH. The MeOH was removed in vacuo to afford 3-methoxy-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazol-3-yl]phenol (1-F). MS: m/z 384 (M+1); 1H NMR (500 MHz, DMSO-d6): δ 9.94 (s 1H), 7.09 (d, 1H, J=8.3), 6.53 (d, 1H, J=1.6 Hz), 6.46 (dd, 1H, J=2.2, 8.2 Hz), 3.72 (s, 3H), 3.40 (s, 3H), 1.95 (m, 6H), 1.44 (m, 6H), 1.07-1.33 (m, 8H), 0.86 (t, 3H, J=7.2).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:14])[C:3]=1[C:15](=O)[CH3:16].[OH:18][C:19]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:20]=1[C:21]([NH:23][NH2:24])=[O:22]>CS(C)=O>[CH3:14][C:4]1[C:3](=[C:15]([NH:24][NH:23][C:21](=[O:22])[C:20]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:19]=2[OH:18])[CH3:16])[C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=2)[N:5]=1
Reactant: CC(=O)c1c(C)nn(-c2ccc(I)cc2)c1O
Reactant: NNC(=O)c1ccc(O)cc1O
Solvent: CS(C)=O
Product: CC1=NN(c2ccc(I)cc2)C(=O)C1=C(C)NNC(=O)c1ccc(O)cc1O
Temperature: 85 °C
Yield: 94.1 %

Procedure:
1.03 g (3 mmol) of 1-(5-hydroxy-1-(4-iodophenyl)-3-methyl-1H-pyrazol-4-yl)-ethanone and 505 mg (3 mmol) of 2,4-dihydroxybenzoic hydrazide were dissolved in 50 ml of DMSO and heated at 85° C. for 9 hours with stirring. After cooling and evaporation of the solvent, the crude product was recrystallized from chloroform/ether to give 1.39 g of the desired product as a pale brown solid (yield 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.I[C:38]1[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=1>>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:34])[CH3:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:38]4[CH:43]=[CH:42][N:41]([CH3:44])[C:40](=[O:45])[CH:39]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(I)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2cccc(F)c2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn(C)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2cccc(F)c2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 23 Step 9. LC-MS Method 2 tR=1.57 min, m/z=501, 479, 421.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12.[Li]CCCC.C1(S(N([F:52])S(C2C=CC=CC=2)(=O)=O)(=O)=O)C=CC=CC=1>C1COCC1>[F:52][C:2]1[CH:3]=[C:4]([C:24]([F:27])([F:26])[F:25])[N:5]2[CH2:22][CH2:21][N:20]([CH3:23])[C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[C:6]=12
Reactant: CN1CCn2c(C(F)(F)F)cc(Br)c2C12CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCn2c(C(F)(F)F)cc(F)c2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 42.5 %

Procedure:
A solution of tert-butyl 8-bromo-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (15.0 g, 33.2 mmol) in THF (200 mL) was purged with Argon for 5 min. The mixture was cooled to −78° C. before nBuLi (42.5 mL of 1.6 M, 68 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min before a solution of N-(benzenesulfonyl)-N-fluoro-benzenesulfonamide (20.9 g, 66.3 mmol) in THF (100 mL) was added dropwise. The mixture was allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. aq. NH4Cl. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated to dryness. CH2Cl2 was added and the solid was removed via filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography (10-20% EtOAc-Hex) to provide tert-butyl 8-fluoro-2-methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (5.52 g, 43%) as a light brown oil that solidified upon standing. ESI-MS m/z calc. 391.4, found 392.5 (M+1)+; Retention time: 1.35 minutes (3 minute run).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.C([OH:25])(C)C>>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]2[C:13]3[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=3[O:11][C:10]([CH3:21])([CH3:20])[CH2:9]2)[N+:7]=1[O-:25]
Reactant: CC1(C)CC(c2cccc(N)n2)c2cc(C#N)ccc2O1
Reactant: CC(C)O
Product: CC1(C)CC(c2cccc(N)[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 4-(6-amino-2-pyridyl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 2-amino-6-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 210°-212° C. (from isopropanol).