Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][NH:6][CH2:5]1)=[N+:2]=[N-:3].CCN(C(C)C)C(C)C.[C:19](Cl)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl>[N:1]([C@H:4]1[C@H:8]([F:9])[CH2:7][N:6]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [N-]=[N+]=N[C@@H]1CNC[C@H]1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a stirred mixture of (trans)-3-azido-4-fluoropyrrolidine (18 g) in CH2Cl2 (120 mL) was added DIPEA (35 g, 0.27 mol, 2.5 eq), then CBZ-Cl (22 g, 0.13 mol) was added dropwise at 0-5° C. After addition, the resulting mixture was stirred at rt overnight. The mixture was washed with sat. aq. NH4Cl (150 mL), sat. aq. NaHCO3 (3×40 mL) and brine (40 mL). The organic layer was concentrated and purified by column (petroleum ether/EtOAc=10:1˜5:1) to give the title compound (30 g, ˜100% yield in two steps, containing residual EtOAc and DCM) as a light yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=2[Cl:24])=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])([O-:3])=[O:2].[OH-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(Oc2c(Cl)cc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
The product from paragraph (a) (6.86 g) in ethanol (50 ml) was heated and stirred with a solution of sodium hydroxide (0.8 g) in water (10 ml) at 60°-70° C. for 4 hours. The mixture was then cooled and the ethanol removed under reduced pressure. The residue was diluted to 100 ml with water and brought to pH 2 with concentrated hydrochloric acid. The solid which separated was collected and recrystallised from toluene to give the required benzoic acid derivative (4.26 g) with a melting point of 192°-192.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6](O)[C:7](=[CH2:11])[CH2:8][CH2:9][F:10])[CH3:2].S(Br)([Br:19])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([NH:13][CH:14]=[O:15])[CH:6]=[C:7]([CH2:11][Br:19])[CH2:8][CH2:9][F:10])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCF)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C(C=C(CBr)CCF)NC=O
Reaction time: 0.75 h

Procedure:
1.40 g (6.0 mmol) of 6-fluoro-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 14 ml of 1,2-dichloroethane, and 0.56 ml (7.2 mmol) of thionyl bromide is added dropwise at room temperature. After 45 minutes, 12 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with water, 1N potassium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated by evaporation. 4-bromomethyl-6-fluoro-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[CH:7]2.C1C(=O)N([Br:19])C(=O)C1>>[Br:19][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[N:8][CH:9]=[N:10]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Oc1cccc2cncnc12
Product: Oc1ccc(Br)c2cncnc12

Procedure:
Bromination of 8-hydroxy-quinazoline (A1) with N-bromosuccimide, according to the method previously described by Gerson and McNeil,15 gave 5-bromo-8-hydroxy-quinazoline (A139).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]4[CH2:20][O:21][C:22](=[O:23])[C:12]3=4)[CH:9]=2)[NH:4][N:3]=1.[CH3:24][CH:25]([O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)[CH3:26].C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[CH3:19][C:15]1[NH:14][C:13]2[CH2:20][O:21][C:22](=[O:23])[C:12]=2[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[C:31]2[CH:32]=[N:33][C:28]([O:27][CH:25]([CH3:26])[CH3:24])=[CH:29][CH:30]=2)[C:16]=1[C:17]#[N:18]
Reactant: CC(C)Oc1ccc(B(O)O)cn1
Reactant: CC1=C(C#N)C(c2ccc3[nH]nc(Br)c3c2)C2=C(COC2=O)N1
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: [Na+]
Solvent: C1COCCO1
Product: CC1=C(C#N)C(c2ccc3[nH]nc(-c4ccc(OC(C)C)nc4)c3c2)C2=C(COC2=O)N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 19.6 %

Procedure:
To a degassed solution of 120 mg (0.323 mmol) 4-(3-bromo-1H-indazol-5-yl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine-3-carbonitrile (Example 24) and 70.2 mg (0.388 mmol) [6-(propan-2-yloxy)pyridin-3-yl]boronic acid in anhydrous 1,4-dioxane (3.5 ml) were added under inert gas atmosphere 37.4 mg (0.032 mmol) tetrakis(triphenylphosphine)palladium(0) and aqueous sodium bicarbonate solution (2 M, 0.77 ml). The resulting mixture was stirred at 100° C. for 12 h. After cooling to room temperature and concentration under reduced pressure, the remaining solid was dissolved in ethyl acetate (20 ml). The solution was subsequently washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (acetonitrile/water gradient, final mixture 95:5 v/v) to yield the title compound as a white solid (27 mg, 19% of th.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reaction time: 72 h
Yield: 80 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperidine-4-ethanol (5.0 g, 22 mmol) in methylene chloride (100 mL) was treated with pyridinium chlorochromate (5.2 g, 24 mmol), and diatomaceous earth (5 g). After 3 days, the mixture was filtered through diatomaceous earth, concentrated, and the residue purified by column chromatography (SiO2: 20 to 30% EtOAc:hexanes) affording 4.0 g (81%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:25]([OH:26])=[CH:24][C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[C:9]([F:31])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:35])(=O)=O.C(OCC)C>ClCCl>[F:1][C:2]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:25]([OH:26])=[C:24]([Cl:35])[C:23]3[C:22]([CH3:28])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:30])([CH3:29])[C:18]=3[CH:17]=2)=[O:15])[CH:10]=[C:9]([F:31])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1F
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1c(F)cc(NC(=O)c2cc3c(c(Cl)c2O)C(C)(C)CCC3(C)C)cc1F

Procedure:
To a solution ethyl 2,6-difluoro-4-[(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-benzoate (Compound C, 227 mg, 0.52 mmol) in 10 ml of anhydrous dichloromethane under nitrogen at 25° C. was added sulfuryl chloride (0.0413 ml, 0.57 mmol) and anhydrous ethyl ether (0.054 ml, 0.52 mmol). Reaction was instantaneous at 25° C. as monitored by 1H NMR. The reaction mixture was quenched with saturated NaHCO3 then extracted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The title compound was obtained as a white solid after column chromatography with ethyl acetate:hexane (1:9).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[NH3:12]>>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: N
Reactant: FC(F)(F)c1cccc(Cl)n1
Product: Nc1cccc(C(F)(F)F)n1
Temperature: 170 °C

Procedure:
A mixture of 2-chloro-6-trifluoromethylpyridine (20.0 g), cuprous chloride (0.2 g) and ammonia (specific gravity 0.88, 75 ml) was heated at 170° C. in a pressure vessel for 18 hours. After cooling to ambient temperature, the mixture was extracted with dichloromethane (300 ml). The organic extract was dried and evaporated to give 6-trifluoromethylpyridin-2-amine, m.p. 74°-79° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:43])[CH:31]=[CH:32][C:33]=1[O:34][CH2:35][CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:30]2[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:7]=1
Reactant: COc1cc(N)ccc1OCC1CCN(C)CC1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Nc2nccc(N(c3nc4ccccc4[nH]3)c3c(C)cccc3C)n2)ccc1OCC1CCN(C)CC1
Temperature: 80 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), from Example 155 Step F, 3-methoxy-4-(1-methylpiperidin-4-ylmethoxy)-phenylamine (36 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 80° C. for 18 h. The reaction was cooled to RT then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 9:1, containing TEA [1%]) to afford a brown solid, which was further purified by column chromatography (silica; CH2Cl2:MeOH; 9:1; containing TEA [0.5%]) to afford a light brown solid. MS m/z=564 (M+H). Calc'd for C33H37N7O2=563.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[C:43]2[CH:42]=[CH:41][CH:40]=[C:39]([C:44]#[N:45])[C:38]=2[CH2:37][CH2:36]1.O>C1COCC1>[CH3:12][O:13]/[CH:14]=[C:35]1\[CH2:36][CH2:37][C:38]2[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][C:43]\1=2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1cccc2c1CCC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C1\CCc2c(C#N)cccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium bis(trimethylsilyl)amide (2 mL, 4 mmol, 2M in THF) was added to a stirred suspension of (methoxy methyl)triphenylphosphonium chloride (1.47 g, 4.29 mmol) in dry THF (20 mL) at 0° C. for 35 min and a solution of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.86 mmol) in THF (10 mL) added over 10 min. The mixture was stirred at 0° C. for 2 h and at room temperature for 1 h. Water was added and the mixture was partitioned between EtOAc and brine. The organic layer was dried and concentrated. The crude product was purified via prep-TLC (PE:EtOAc=10:1) to afford (1E)-1-[(methyloxy)methylidene]-2,3-dihydro-1H-indene-4-carbonitrile. 1H-NMR (400 MHz, CDCl3) δ ppm 8.00 (d, J=8.3 Hz, 0.4H), 7.42 (d, J=8.3 Hz, 0.6H), 7.30-7.40 (m, 1H), 7.18-7.22 (m, 1H), 6.70 (s, 0.6H), 6.22 (s, 0.4H), 3.72 (s, 3H), 3.15 (t, J=5.7 Hz, 2H), 2.70-2.82 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[C:6](=[N:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:10]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCCCC1=O
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Product: O=[N+]([O-])c1ccc2nc3c(nc2c1)CCCC3
Reaction time: 8 h

Procedure:
A mixture of 4-nitro-o-phenylenediamine (33.7 g, 0.22 mole) and 25.0 g (0.22 mole) of 1,2-cyclohexanedione in 500 ml of SDA#32 was heated at reflux for 24 hours. The reaction mixture was then stored overnight at room temperature and then filtered. The brown crystalline solid was then washed with ether, air dried, and dried to a consistent weight at 60°, m.p. 175°-178°. Yield: 22 g (96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]3([CH3:15])[CH2:13][CH2:12][C:9]([CH3:14])([C:10]=2[CH:11]=1)[CH2:8][CH2:7]3.[C:17](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[C:6]3([CH3:15])[CH2:13][CH2:12][C:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CC12CCC(C)(CC1)c1cc(Br)c(O)cc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc2c(cc1Br)C1(C)CCC2(C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-1,8-dimethyl-tricyclo[6.2.2.02,7]dodeca-2(7),3,5-trien-4-ol (Compound 3, 0.825 g, 2.94 mmol) in 10 mL of anhydrous acetone was added potassium carbonate (0.128 g, 8.82 mmol) and iodomethane (0.1 mL, 8.82 mmol). The reaction mixture was stirred at 25° C. for 12 hours and filtered. The filtrate was concentrated, and then it was diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate:hexane (5:95) to yield the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8]O.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)[CH2:8][Cl:33]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CO
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1CCl
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
34.8 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl alcohol were suspended in 200 parts by volume of absolute toluene, 8 parts by weight of pyridine were added, and 13.1 parts by weight of thionyl chloride were added dropwise at 0° C. Thereafter the reaction mixture was stirred for a further 2 hours at 110° C., was cooled, and was extracted with 75 parts by volume of 3N hydrochloric acid and with five times 250 parts by volume of water. The organic phase was separated off, dried with magnesium sulfate and concentrated under reduced pressure. 32 parts by weight (88% of theory) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzyl chloride were obtained in the form of an initially oily residue which crystallized when triturated with pentane, to give crystals of melting point 55°-60° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:2].[CH3:15][C:16](=O)[CH2:17][C:18](=O)[CH3:19].N1CCCCC1>>[CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][N:5]1[C:16]([CH3:15])=[CH:17][C:18]([CH3:19])=[C:7]([C:8]#[N:9])[C:6]1=[O:10])[CH3:2]
Reactant: CCCCC(CC)CNC(=O)CC#N
Reactant: CC(=O)CC(C)=O
Solvent: C1CCNCC1
Product: CCCCC(CC)Cn1c(C)cc(C)c(C#N)c1=O
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of N-(2-ethylhexyl)cyanoacetamide (201.5 g., 1.0 mole), 2,4-pentanedione (100 g., 1.0 mole), piperidine (10 g.) and 2-B-ethanol 300 ml. is refluxed for 24 hours, cooled to room temperature and the solid precipitate is collected by filtration to give 155 g. (60% yield), mp. 84°-89° C. The solid when recrystallized from petroleum ether/benzene has a mp. 89°-90° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[C:10]([CH2:18][CH2:19][CH3:20])=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([NH2:16])=[O:15])=O)[CH3:2].[OH-].[Na+].OO.C(O)C>O>[CH2:1]([O:3][C:4]1[CH:24]=[CH:23][CH:22]=[CH:21][C:5]=1[C:6]1[NH:16][C:14](=[O:15])[C:13]2[N:12]([CH3:17])[N:11]=[C:10]([CH2:18][CH2:19][CH3:20])[C:9]=2[N:8]=1)[CH3:2]
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1ccccc1OCC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12

Procedure:
4-(2-Ethoxybenzamido)-1-methyl-3-n-propylpyrazole-5-carboxamide (223 g, 0.676 mol) was added portionwise to a solution of sodium hydroxide (54 g, 1.35 mol) and 30% hydrogen peroxide solution (224 ml) in water (2000 ml). Ethanol (700 ml) was added and the resulting mixture heated under reflux for 2.5 hours, cooled, then evaporated under vacuum. The resulting solid was treated with 2N hydrochloric acid (380 ml), with external cooling, and the mixture was extracted with dichloromethane (1×700 ml, 3×200 ml). The combined organic extracts were washed successively with saturated aqueous sodium carbonate solution (3×400 ml) and brine (300 ml), then dried (Na2SO4) and evaporated under vacuum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[N+:29]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>[Fe]>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])=[CH:17][C:16]=2[NH2:29])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cccs3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)c3cccs3)cc2N)cc1
Yield: 65 %

Procedure:
The product from Example 256b was reduced with Fe and NH4Cl using the conditions of Example 9E to provide the title compound (1.25 g, 65%).
Reaction SMILES: [CH2:1]([C:4]1[C:9]2[O:10][C@@H:11]([CH2:14][O:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][O:13][C:8]=2[CH:7]=[CH:6][C:5]=1[N+:26]([O-])=O)[CH:2]=[CH2:3].O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([O:15][CH2:14][CH:11]2[O:10][C:9]3[C:4]([CH2:1][CH:2]=[CH2:3])=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=3[O:13][CH2:12]2)(=[O:18])=[O:17])=[CH:20][CH:21]=1
Reactant: C=CCc1c([N+](=O)[O-])ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(N)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C

Procedure:
(2R)-Toluene-4-sulfonic acid 8-allyl-7-nitro-2,3-dihydro-benzo(1,4)dioxin-2-ylmethyl ester (5.3 g, 13 mmole) and tin (II) chloride dihydrate (14.7 g, 65 mmole) were combined in 500 mL of ethyl acetate and the mixture refluxed for 3 hours under nitrogen. The reaction was allowed to cool to room temperature and was quenched by the addition of 300 mL of saturated aqueous sodium bicarbonate. The biphasic mixture was filtered through celite, the phases separated and the aqueous back-extracted with 200 mL of ethyl acetate. The combined organic phases were washed with 250 mL portions of water and saturated brine, dried over sodium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 2.2 g of the (R)-enantiomer of the title compound as an orange oil. 1H-NMR (CDCl3): doublet 7.8 δ (2H); doublet 7.35 δ (2H); doublet 6.6 δ (1H); doublet 6.25 δ (1H); multiplet 5.8 δ (1H); singlet 5.05 δ (1H); doublet 5.0 δ (1H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); doublet of doublets 4.0 δ (1H); doublet 3.25 δ (2H); singlet 2.45 δ (3H).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH:19]=[CH:20][CH2:21][CH2:22][O:23]CC2C=CC=CC=2)[C:10]=1[CH3:31])C1C=CC=CC=1.C1CCCCC=1>C(O)C.[OH-].[Pd+2].[OH-]>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][C:11]1[NH:12][C:13]2[C:18]([C:9](=[O:8])[C:10]=1[CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: Cc1c(C=CCCOCc2ccccc2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1c(CCCCO)[nH]c2ccccc2c1=O
Yield: 75.8 %

Procedure:
To a solution of 4-(benzyloxy)-2-[4-(benzyloxy)-1-buten-1-yl]-3-methylquinoline (2.57 g) in ethanol (26 mL) were added cyclohexene (13 mL) and 20% palladium hydroxide-activated carbon powder (1.5 g), followed by stirring under reflux for 2 hours. The catalyst was removed by filtration, and then the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=93/7) to obtain 2-(4-hydroxybutyl)-3-methylquinolin-4(1H)-one (1.10 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([O:4][C:2]([O:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1)=[O:3])[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: On1nnc2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)On1nnc2ccc(Cl)cc21
Reaction time: 8 h
Yield: 45.7 %

Procedure:
A solution of ethyl chloroformate (2.17 g.) in benzene (10 ml.) was added dropwise to a solution of 1-hydroxy-6-chloro-1H-benzotriazole (3.38 g.) and triethylamine (2.80 ml.) in benzene (30 ml.) under ice-cooling and stirring. Benzene (30 ml.) was further added to the mixture and the reaction temperature was slowly elevated to room temperature the mixture was allowed to stand overnight. Precipitated crystals were filtered off and the filtrate was concentrated. Benzene was added to the residue and an insoluble material was filtered off. The filtrate was concentrated to give 1-ethoxycarbonyloxy-6-chloro1H-benzotriazole (2.2 g.), crystals. The precipitated crystals filtered off and the insoluble material in benzene were mixed and then washed with water, a sodium bicarbonate aqueous solution, 1 N hydrochloric acid and water, and recrystallized from methanol (75 ml.) to give the desired compound (3.5 g.), white needles, mp 160° to 162° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:20])[F:21])[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2ccc(C(F)(F)F)c(F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)c(F)c2)C1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)isonicotinate (8.26 g, 26.37 mmol) in acetic acid (50 mL) was added platinum(IV) oxide (0.44 g, 1.94 mmol) and the resulting mixture hydrogenated at 5 bar in a Büchi hydrogenator for 8 h. The reaction mixture was filtered through a diatomeous earth filter carton and the catalyst washed with methanol. The solvents were evaporated, the residue dissolved in DCM and washed with 10% Na2CO3. After phase separation the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4 and evaporated. Methyl 2-(3-fluoro-4-(trifluoromethyl)-benzyl)piperidine-4-carboxylate (8.4 g, 100%) was isolated as a pale yellow oil that partially solidified upon standing. MS m/z 320 (M+H)+