Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]([CH3:71])[N:68]=[N:69][CH:70]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.Cl.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[N:67]([CH3:71])[N:68]=[N:69][CH:70]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: Cn1nncc1SCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Solvent: O
Product: Cn1nncc1SCC1=C(C(O)=S)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 82.2 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (900 mg: 0.869 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) is added a solution of aluminum chloride (924 mg: 6.95 mMol.) in anisole (2 ml) at -40° C., and the mixture is stirred for 1 hour at -40°--30° C. The reaction mixture is diluted with 1N-hydrochloric acid (7 ml) and water and washed with ethyl acetate. The aqueous layer is concentrated under reduced pressure to remove organic solvent and passed through a column of styrene-divinylbenzene copolymer adsorbent. The product is eluted with methanol-water (4:1) to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(3-methyl-1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid as pale yellow powder (366 mg). Yield: 80%.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(N)(=O)C1C=CC=NC=1>>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)nc1
Agent: NC(=O)c1cccnc1
Product: CC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(Cl)c([N+](=O)[O-])c3)cn2)CC1

Procedure:
6-chloro-N-(4-chloro-3-nitrophenyl)nicotinamide (1.6 mmol) was used in general procedure 3 with 1-acetylpiperazine (4.8 mmol to give 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-nitrophenyl))-nicotinamide. MS (Q1) 404.4 (M)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[N:20]=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[N:18]=1>>[Cl:16][C:17]1[N:18]=[C:19]([O:24][CH:25]([CH3:27])[CH3:26])[N:20]=[C:21]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([N:9]3[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:22]=1
Reactant: CC(C)Oc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(Cl)nc(OC(C)C)n2)ccc1-n1cnc(C)c1
Yield: 41 %

Procedure:
The title compound was prepared from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2,4-dichloro-6-isopropoxy-[1,3,5]triazine (Synth. Commun. 24, 2153 (1994)) in analogy to example 2a. The compound crystallized from methanol as a slightly brownish solid in 41% yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1.Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]([N:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]1[N:17]=[CH:16][S:15][CH:19]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCCOCc1ccccc1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCCOCc1ccccc1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
32.2 G. (150 mmoles) of 2-benzyloxyethylchloroformate is added dropwise with protection from moisture to a stirred suspension of 30.1 g. (150 mmoles) of 2(4-thiazolyl)-benzimidazole in 200 ml. of pyridine. The addition is complete in 30 minutes whereupon all of the starting material is dissolved and pyridine hydrochloride begins to precipitate. The reaction mixture is stirred at room temperature for 15 1/2 hours and filtered to remove pyridine hydrochloride. The solid material is washed with a small volume of pyridine and the combined filtrate and washing are evaporated to dryness in vacuo. The residual oil is dissolved in 300 ml. of methylene chloride and allowed to stand during which time a substantial amount of solid material precipitates. The solid is removed by filtration and the filtrate washed twice with 250 ml. of 0.25 N HCl containing ice followed by 200 ml. of saturated sodium bicarbonate solution containing 50 ml. of ice. The methylene chloride fraction is dried with magnesium sulfate, treated with charcoal, filtered and evaporated to dryness in vacuo affording 38.9 g. of a yellow-orange oil which begins to solidify on standing. The material is recrystallized from toluenecyclohexane affording 23.8 g. of 1-(2-benzyloxyethoxycarbonyl)-2-(4-thiazolyl)-benzimidazole, m.p. 93°-95° C.
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]([C:10]2[C:11](=[CH:13][C:14](=[CH:16][C:17]=2[OH:18])[OH:15])[OH:12])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.O>[OH:1][CH:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([C:10]2[C:17](=[CH:16][C:14](=[CH:13][C:11]=2[OH:12])[OH:15])[OH:18])=[O:9])=[CH:19][CH2:20]1
Reactant: O=C(CCc1ccc(O)cc1)c1c(O)cc(O)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(CCC1=CCC(O)C=C1)c1c(O)cc(O)cc1O
Yield: 67.5 %

Procedure:
Phloretin (25 mg) is dissolved in the minimum amount of methanol, diluted with water (3 ml) and treated with a slight excess of NaBH4. After 5 minutes the solution is carefully acidified, with ethyl acetate. The Organic phase is dried over Na2SO4 and evaporated to dryness to give 17 mg of dihydrophloretin as white powder, homogeneous on TLC analysis (silica gel, CHCl3 /MeOH/H2O 70:28:2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][CH2:27][O:28][Si](C(C)(C)C)(C)C)([C:14]2[NH:18][N:17]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:26][CH2:27][OH:28])([C:14]2[NH:18][N:17]=[C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO[Si](C)(C)C(C)(C)C)(c2cc(Cc3ccccc3)n[nH]2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCO)(c2cc(Cc3ccccc3)n[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-tert-butyldimethylsilyloxyeth-1-yl)-4-(3-benzyl-(1H)-pyrazol-5-yl)piperidine (243 mg, 0.49 mmol) from Step H in THF (5 mL) was added 1M tetrabutylammonium fluoride in THF (0.63 mL, 0.63 mmol). The reaction was stirred at room temperature for 1 h and was then diluted with ethyl acetate, poured into 1N HCl, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 5% methanol in methylene chloride to afford the title compound (125 mg).
Reaction SMILES: O1CCOCC1.[Cl:7][C:8]1[C:13](B(O)O)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][N:9]=1.Cl[C:20]1[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:7][C:8]1[C:13]([C:20]2[N:25]=[C:24]([CH3:26])[N:23]=[C:22]([NH2:27])[N:21]=2)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][N:9]=1
Reactant: COc1cnc(Cl)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)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
Solvent: O
Product: COc1cnc(Cl)c(-c2nc(C)nc(N)n2)c1
Temperature: 90 °C
Yield: 51.4 %

Procedure:
1,4-dioxane (10.00 mL) and water (2.5 mL) were added to a stirred mixture of 2-chloro-5-methoxypyridin-3-ylboronic acid (1.03 g, 5.48 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (0.72 g, 4.98 mmol), Na2CO3 (1.32 g, 12.5 mmol), and Pd(PPh3)4 (0.576 g, 0.1 eq) and the mixture was sealed and heated at 90° C. overnight. After cooling, the mixture was concentrated. Flash column chromatographic purification (short column, SiO2, pure DCM to 5% MeOH in DCM) provided 4-(2-chloro-5-methoxypyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.644 g, 51%) as a white solid. LCMS (API-ES) m/z 252 (M+H)+; 1H NMR (400 MHz, d6-DMSO) δ 8.24 (d, J=1.17 Hz, 1H) 7.68 (br. s., 2H) 7.65 (d, J=1.17 Hz, 1H) 3.87 (s, 3H) 2.36 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([CH3:23])[CH:14]=3)[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4ccc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.48) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.084 g, 36%). MS (ISP) 465.3 [(M+H)+]; mp 290° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[Li+].[CH3:12][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[Br:2][C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[NH2:10])[CH:6]=[CH:7][CH:8]=1
Reactant: NNc1cccc(Br)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN(N)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To a solution of 3-bromophenylhydrazine hydrochloride (15 g, 67 mmol) in anhydrous THF (360 mL) was added LiHMDS (1.0 M solution in THF, 127 mL, 127 mmol) dropwise over a period of 1 h at 0° C. The reaction mixture was stirred for 30 min while warming to room temperature. The flask was recooled to −78° C., and MeI (4.1 mL, 67 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. and then was quenched with water (600 mL). The aqueous layer was extracted with methylene chloride (3×200 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 60:40) gave the title compound (10.2 g, 76%) as yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.18 (t, J=3.5 Hz, 1H), 7.08 (t, J=13.5 Hz, 1H), 6.91-6.86 (m, 2H), 3.69 (br s, 2H), 3.11 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][C:15]4[CH:20]([CH2:23][C:24]([O:26]CC)=[O:25])[CH2:21][CH2:22][C:14]=4[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li+].[OH-]>O1CCOCC1>[CH3:1][S:2]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[NH:16][C:15]4[CH:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][CH2:22][C:14]=4[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(S(C)(=O)=O)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.2 %

Procedure:
To the stirred solution of ethyl 2-(7-(4-(methylsulfonyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (40 mg, 0.094 mmol) in dioxane was added 1M LiOH aqueous solution (0.47 mL, 0.47 mmol). The reaction mixture was stirred at room temperature for 24 h. The solvent was partly removed, diluted with water, and acidified with HCl solution. The pinkish solid was collected and dried to give the title compound (26 mg). LCMS m/z=400.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.04-2.08 (m, 1H), 2.35 (dd, J=16.0 and 9.0 Hz, 1H), 2.63-2.75 (m, 4H), 3.20 (s, 3H), 3.45-3.50 (m, 1H), 5.21 (s, 2H), 6.73 (dd, J=8.7 and 2.4 Hz, 1H), 6.92 (d, J=2.4 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.3 Hz, 2H), 10.47 (s, 1H), 12.18 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]3)=[CH:9][CH:8]=2)=[N:3]1.[C-:21]#[N:22].[Na+]>>[OH:20][C:17]1([C:21]#[N:22])[CH2:18][CH2:19][N:14]([CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:4]3[N:5]=[N:6][N:2]([CH3:1])[N:3]=3)=[CH:12][CH:11]=2)[CH2:15][CH2:16]1
Reactant: Cn1nnc(-c2ccc(CN3CCC(=O)CC3)cc2)n1
Reactant: [C-]#N
Agent: [Na+]
Product: Cn1nnc(-c2ccc(CN3CCC(O)(C#N)CC3)cc2)n1

Procedure:
In a first step as depicted in Scheme 2, an appropriately substituted phenyl derivative, for example, the known compound 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole, is brominated with, for example N-bromosuccinimide and light, to afford the corresponding 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole (A1). Intermediate (A1) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one (B1). Intermediate (B1) is then reacted under acidic conditions with, for example sodium cyanide, to afford the corresponding nitrile compound, 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile (C1). Intermediate (C1) is esterified under acidic conditions with, for example ethanol, to afford the corresponding ethyl 4-hydroxy-1-{[4-(2-methyl-(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate (D1). The Grignard of an appropriately substituted halophenyl derivative, for example 4-trifluoromethoxybromobenzene, is reacted with intermediate (D1) to provide compounds of formula I-B, wherein X and Y are, for example hydroxyl. Example 2, set forth below, provides detailed methods to how compounds of formula I (-B) shown in Scheme 2 were prepared.
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.[OH:43][CH2:44][CH2:45][NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53](B2OC(C)(C)C(C)(C)O2)=[CH:52][CH:51]=1)=[O:48]>>[OH:43][CH2:44][CH2:45][NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:24]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[CH:27]=[C:26]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:25]=2)=[CH:52][CH:51]=1)=[O:48]
Reactant: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCO)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(-c2ccc(NC(=O)NCCO)cc2)n1
Yield: 64 %

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(pyridin-2-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 21) and 1-(2-hydroxyethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 18). Material was purified by prep HPLC (low pH) to afford a grey solid. Further purification was achieved using an SCX-2 cartridge to afford a grey solid (122 mg, 64%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:14]([N:26]2[C:30]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[N:29][N:28]=[C:27]2[CH2:37][O:38][CH3:39])=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17](=[O:25])[NH:16]2>CC(C)=O>[Cl:12][C:13]1[C:14]([N:26]2[C:30]([C:31]3[CH:32]=[N+:33]([O-:6])[CH:34]=[CH:35][CH:36]=3)=[N:29][N:28]=[C:27]2[CH2:37][O:38][CH3:39])=[C:15]2[C:20](=[CH:21][C:22]=1[Cl:23])[NH:19][C:18](=[O:24])[C:17](=[O:25])[NH:16]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Solvent: CC(C)=O
Product: COCc1nnc(-c2ccc[n+]([O-])c2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 16.4 %

Procedure:
A solution of 3-chloroperoxybenzoic acid (0.85 g, 4.93 mmol) in acetone (20 ml) was added in one portion to a suspension of (−)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (see Example 111) (1.0 g, 2.24 mmol) in acetone (40 ml) which caused all the solid to dissolve. The reaction was stirred at room temperature for 40 minutes after which time a white solid began to form. The reaction mixture was allowed to stir at room temperature for 3 days. The white solid was collected by filtration and purified by flash chromatography on silica gel using dichloromethane:methanol:glacial acetic acid (90:10:1, by volume) as eluent, to give after combination and concentration of the appropriate fractions, the title compound (0.16 g, 17%) as a white solid, m.p. >310° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[NH4+].[OH-]>Cl.C(OCC)(=O)C>[F:8][C:5]1[CH:6]=[C:7]2[C:2](=[C:3]([OH:9])[CH:4]=1)[N:1]=[C:12]([CH3:13])[CH:11]=[CH:10]2
Reactant: C/C=C/C=O
Reactant: Nc1ccc(F)cc1O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(F)cc(O)c2n1
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
2-amino-5-fluorophenol (13.0 g, 102 mmol) was dissolved in 6N HCl (78 mL) and heated to reflux. The solution was treated with (E)-but-2-enal (8.8 mL, 107 mmol) in 1 mL portions over 1 hour. The reaction was heated at reflux for 13 hours. The reaction mixture was cooled and adjusted to pH 8 with concentrated NH4OH. The reaction was diluted with ethyl acetate, stirred for 30 minutes then filtered through a nylon membrane (0.45 μM). The filtrate was separated and the aqueous was washed with ethyl acetate then the combined organics were washed with saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo to provide the product as a thick dark oil (19 g). MS APCI (+) m/z 178.1 (M+1) detected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]([O:16]CC)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1ncc(C(=O)O)c1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 102.9 %

Procedure:
To a solution of the compound (14.2 g, 57.4 mmol) obtained in step 1 in ethanol (50 mL) was added 2N aqueous sodium hydroxide solution (63.2 mL, 126 mmol) at room temperature, and the mixture was heated under reflux for 1 hr. The reaction mixture was cooled to room temperature, and 2N hydrochloric acid was added until the mixture became pH 6. The precipitate was collected by filtration with ethyl acetate to give a mixture (3:2.2 (mol/mol), 13.0 g, 100%) of 5-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxylic acid and 3-(4-fluorophenyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25]O)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a solution of benzenethiol (11.16 ml, 108.65 mmol), (R)-methyl 3-(benzyloxycarbonylamino)-4-hydroxybutanoate (INTERMEDIATE 4, 26.4 g, 98.77 mmol) and tributylphosphine (34.5 ml, 138.28 mmol) in anhydrous THF (350 ml) under nitrogen atmosphere was added. A solution of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (34.9 g, 138.22 mmol) in anhydrous THF (350 ml) was added dropwise over a 30 minute period. During the addition a white precipitate was formed and stirring was continued for 2 hours after the addition was complete. The white precipitate was filtered off and evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, eluting with 0→100% EtOAc/hexanes) to give the title product (25.0 g, yield: 70%).
Reaction SMILES: O1CCCC1.[CH:6]([N:9]1[C:14](=O)[CH2:13][O:12][CH:11]([C:16]([O:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[CH2:24][CH2:23][CH:22]3[CH3:28])=[O:17])[CH2:10]1)([CH3:8])[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[OH:17][CH:16]([O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH2:24][CH2:23][CH:22]2[CH3:28])[CH:11]1[O:12][CH2:13][CH2:14][N:9]([CH:6]([CH3:8])[CH3:7])[CH2:10]1
Reactant: CC1CCc2ccc(OC(=O)C3CN(C(C)C)C(=O)CO3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1CCc2ccc(OC(O)C3CN(C(C)C)CCO3)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.8 %

Procedure:
In 10 ml. of tetrahydrofuran was dissolved 3.17 g. of 4-isopropyl-2-(3-methyl-1-oxo-5-indanyloxymethyl)-5-oxomorpholine and the solution was added dropwise to the suspension of 0.4 g. of lithium aluminum hydride in 20 ml. of tetrahydrofuran followed by stirring for 5 hours at room temperature. Thereafter, 0.4 ml. of water, 0.4 ml. of aqueous 15% sodium hydroxide solution, and then 1.2 ml. of water were added successively to the mixture followed by stirring for 30 minutes and then the filtrate obtained was concentrated under reduced pressure to provide 2.1 g. (yield 68.8%) of 2-(1-hydroxy-3-methyl-5-indanyloxymethyl)-4-isopropylmorpholine having a boiling point of 174°-178° C./0.5 mm.Hg was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])[CH3:2].Cl.[NH2:35]O.O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:10]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][N:35]=1)=[O:33])[CH3:2]
Reactant: NO
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1

Procedure:
69.3 g of 4-(2,4-Bis-benzyloxy-5-bromo-phenyl)-2,4-dioxo-butyric acid ethyl ester (0.135 mol, 1 eq) were dissolved in 750 ml ethanol. 14.11 g hydroxylamine hydrochloride (0.203 mol, 1.5 eq) were added. The mixture was refluxed for 2.5 hours and cooled down. It was then poured onto 1000 ml water, the precipitate was filtered off. The filter cake was washed with 500 ml of water followed by 75 ml diethyl ether and dried.