Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:27][CH:28]=O)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]([CH2:40][OH:41])[NH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH2:27][CH2:28][N:31]1[C@H:32]([CH2:40][OH:41])[CH2:33][C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:30]1)([CH2:14][CH2:15][CH2:16][CH2:17][B:18]1[O:19][C:20]([CH3:26])([CH3:25])[C:21]([CH3:24])([CH3:23])[O:22]1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: COC(=O)[C@](CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1Cc2ccccc2C[C@H]1CO)NC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 93.2 %

Procedure:
A solution of (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (0.148 g, 0.358 mmol, 1.0 equiv.) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (0.088 g, 0.54 mmol, 1.5 equiv.) in 1,2-dichloroethane (0.34 mL, 0.5 M) was treated with sodium triacetoxyborohydride (0.19 g, 0.90 mmol, 2.5 equiv) in one portion. After stirring for 1.5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and stirred for an additional 5 min. The resulting mixture was added to a separatory funnel, diluted with saturated aqueous NaCl (5 mL) and extracted with dichloromethane (2×10 mL). The organic layer was dried over MgSO4, filtered and concentration under reduced pressure. Purification by flash column chromatography eluting with 5% methanol in chloroform gave (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-((S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a pale yellow oil (0.187 g, 93%). Rf 0.52 (10% methanol in dichloromethane); 1H NMR (CDCl3, 300 MHz) δ 7.15-7.08 (m, 2H), 7.07-6.98 (m, 2H), 5.90 (s, 1H), 3.78 (d, J=16.2 Hz, 1H), 3.70 (s, 3H), 3.60-3.47 (m, 2H), 3.04-2.93 (m, 1H), 2.92-2.82 (m, 1H), 2.71-2.60 (m, 1H), 2.56-2.38 (m, 2H), 2.37-2.23 (m, 1H), 2.21-2.10 (m, 1H), 1.77-1.63 (m, 1H), 1.42 (s, 9H), 1.43-1.26 (m, 3H), 1.23 (s, 12H), 1.22-1.16 (m, 1H), 0.99-0.82 (m, 2H), 0.74 (t, J=7.5 Hz, 2H); ESI-LCMS m/z calcd for C30H49BN2O7: expected 560.4. found 561.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]23[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:28](Cl)([Cl:30])=[O:29].N1C=CC=CC=1>C(Cl)Cl>[Cl:30][C:28]([O:27][CH:24]1[CH2:23][CH:12]2[CH2:13][O:14][C:15]3[C:20]([C:11]2([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[CH2:26][CH2:25]1)=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[O:29]
Reactant: O=C(Cl)Cl
Reactant: O=S(=O)(c1ccc(Cl)cc1)C12CCC(O)CC1COc1c(F)ccc(F)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Cl)OC1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
10a-(4-chloro-benzenesulfonyl)-1,4-difluoro-6a,7,8,9,10,10a-hexahydro-6H-benzo[c]chromen-8-ol (0.46 g, 1.11 mmole) was dissolved in 30 ml DCM. Phosgene (20% in toluene, 4 ml) and pyridine (1 ml) were added and the reaction was stirred at room temperature for 10 minutes. 20 ml DCM was added and the reaction was quenched by slowly adding 10 ml water. The organic layer washed with 50 ml 1N HCl solution, dried over sodium sulfate. After the solvent was removed, the residue was purified by column using EtOAc/Hex. as the solvent (gradient from 0/100 to 25/75 in 25 minutes). Yield: 0.37 g, 70%. 1H NMR (CDCl3 400 MHz) δ 7.62 (d, 2H, J=8.8 Hz), 7.50 (d, 2H, J=8.8 Hz), 7.06-7.13 (m, 1H), 6.40-6.47 (m, 1H), 5.28 (dd, 1H, J=11.7 and 2.9 Hz), 5.05 (s, 1H), 4.14 (d, 1H, J=11.7 Hz), 3.02 (dt, J=13.2 and 2.9 Hz, 1H), 2.31-2.49 (m, 2H), 2.01-2.16 (m, 2H), 1.66-1.75 (m, 1H), 1.30-1.40 (m, 1H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:23]2[CH2:25][CH2:24]2)(O)[CH:20]=[CH2:21])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:23]2[CH2:25][CH2:24]2)=[CH:20][CH:21]=[O:2])=[CH:15][CH:14]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: C=CC(O)(c1ccc(Cl)cc1)C1CC1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC=C(c1ccc(Cl)cc1)C1CC1
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a stirred solution of 40.3 grams (0.192 mole) of pyridinium chlorochromate in 210 mL of methylene chloride was added a solution of 20.0 grams (0.096 mole) of 1-(4-chlorophenyl)-1-cyclopropyl-2-propen-1-ol in 25 mL of methylene chloride in one portion. Upon completion of addition, the reaction mixture was stirred for two hours. A supernatent layer was decanted from a residue, and the residue was extracted with diethyl ether. The supernatent layer was combined with the ether extracts, and the combination was washed with two 100 mL portions of an aqueous 5% sodium hydroxide solution, 100 mL of an aqueous 5% hydrochloric acid solution, and then with 50 mL of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished using 5% diethyl ether in hexane. The appropriate fractions were combined and concentrated under reduced pressure, yielding 6.8 grams of 3-(4-chlorophenyl)-3-cyclopropylpropenal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1.CN.[CH3:33][N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[C:14]1[S:30][C:17]2[C:18]3[CH:26]=[CH:25][C:24]([C:27]([NH:34][CH3:33])=[O:28])=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)OCCc1cc(-c3n[nH]c(=O)n3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(2-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with methylamine, HATU and DIPEA in THF to give 330 as a colorless solid after reverse phase HPLC. MS: (ESI+) 453.0
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[CH2:17]([NH2:25])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:25][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Solvent: C1COCCO1
Product: Nc1nc(NCCc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and phenethylamine in dioxane. ES-MS m/e (%): 317 (M{37Cl}+H+, 30), 315 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:7]([F:19])=[CH:8][C:9]([Cl:18])=[C:10]([NH:12][S:13]([CH2:16][Cl:17])(=[O:15])=[O:14])[CH:11]=1>C1(C)C=CC=CC=1>[Cl:17][CH2:16][S:13]([NH:12][C:10]1[CH:11]=[C:6]([N:5]=[C:1]=[O:2])[C:7]([F:19])=[CH:8][C:9]=1[Cl:18])(=[O:15])=[O:14]
Reactant: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
To a stirred solution of phosgene (68 mmol) in 35 mL toluene was added the title compound of Step D (4.2 g, 15.4 mmol) in 80 mL toluene at 0° C. and the reaction was stirred at room temperature overnight. The temperature was then raised to 70° C. for 4 h. After cooling to room temperature, the reaction mixture was filtrated and the solvent was removed under reduced pressure. Drying of the white precipitate under reduced pressure yielded the title compound of Step E (4.4 g, 95%) melting at 101.5-102.5° C. 1H NMR (CDCl3) δ 7.5 (d, 1H), 7.3 (d, 1H), 7.0-6.9 (br s, 1H), 4.64.5 (s, 2H).
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.[C:18](C#N)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[O:25]=[C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: N#CC(=O)c1ccccc1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (6.0 g, 24.3 mmole) and benzoyl cyanide (6.36 g, 48.5 mmole) in 80 mL of dichloromethane was stirred at room temperature for 24 h. The precipitate was filtered and washed with dichloromethane. The crude product was recrystallized from acetone to give 6.48 g (96%) of 3-(oxophenylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as yellow crystals: mp 190°-191° C.; 1H NMR (CDCl3) δ8.35 (d, 3H), 7.82 (d, 1H), 7.73 (t, 1H), 7.59 (t, 2H), 7.50 (t, 1H), 7.36 (t, 1H) ppm; 13C NMR (CDCl3) δ180.86, 163.69, 150.82, 146.70, 134.79, 134.34, 131.22 (2C), 129.46 (2C), 128.74, 125.82, 122.27, 119.49, 115.23 ppm; IR (KBr) ν1671 cm-1 ; HRMS calcd for C15H9N3OS: 279.0466, found: 279.0475. Anal. Calcd for C15H9N3OS: C, 64.50; H, 3.25; N, 15.04. Found: C, 63.93; H, 3.10; N, 14.53.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[NH2:3].C(N(CC)CC)C.C[O:21][C:22](=O)[N:23]=[C:24](SC)[C:25](=[N:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[C:39]([F:45])[CH:38]=1)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1>CN(C=O)C>[C:43]([C:40]1[CH:41]=[CH:42][C:37]([NH:36][CH:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:24]2[NH:23][C:22](=[O:21])[N:2]([C:4]3[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=3[C:6]([OH:8])=[O:7])[N:3]=2)=[CH:38][C:39]=1[F:45])#[N:44]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)c(F)c1)c1ccc(OC)c(OC)c1
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(Nc2ccc(C#N)c(F)c2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 16 h
Yield: 70.7 %

Procedure:
After adding 55 mg of 2-hydrazinobenzoic acid hydrochloride and 101 μl of triethylamine to a solution of 120 mg of [2-(4-cyano-3-fluorophenylimino)-2-(3,4-dimethoxyphenyl)-1-methylsulfanylethylidene]carbamic acid methyl ester in 3 ml of DMF, the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=1:1 mixed solvent. After adding 58 μl of acetic acid and 91 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 15 hours. Ethyl acetate was then added to the reaction mixture. The organic layer was washed with dilute hydrochloric acid and saturated brine and then dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (100 mg) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCc1ccccc1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCc5ccccc5)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared according to Method E from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and benzyl alcohol. Yellow solid, 193 mg. ES-MS m/z 510 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[N:7][CH:6]=[C:5]2[OH:12].Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:14]([O:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=[N:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1cnnc2ccc(I)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Ic1ccc2nncc(OCc3ccccc3)c2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 6-iodocinnolin-4-ol (as prepared in the previous step, 6.5 g, 23.90 mmol, 1.00 equiv) in N,N-dimethylformamide (120 mL), 1-(bromomethyl)benzene (4.4 g, 25.88 mmol, 1.10 equiv) and Cs2CO3 (5.47 g, 16.78 mmol, 0.70 equiv). The reaction mixture was stirred for 3 h at 60° C. in an oil bath. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 ml, of ethyl acetate, and the combined organic layers washed with 2×100 mL of sodium chloride, dried (Na2SO4), and concentrated under vacuum. The title compound was obtained as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Br:14][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cc(CO)ccc1F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(CBr)ccc1F
Temperature: 25 °C
Yield: 81 %

Procedure:
(4-Fluoro-3-nitro-phenyl)-methanol (100 mg, 0.58 mmol) was dissolved in toluene (1 ml) under nitrogen. PBr3 (225 mg, 0.83 mmol) was added and the reaction was allowed to stir at room temperature. The solvent was removed under vacuum. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was washed with brine two additional times, dried over MgSO4, and the solvent removed to yield the title product as a yellow oil (110 mg (81%), 0.47 mmol). 1H NMR (DMSO-d6): δ=8.04 (s, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.38 (d, J=7.5 Hz, 1H), 3.85 (d, J=4.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4[C:17]([CH:29]=3)=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:19][N:20]=4)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1>C1COCC1.[Pd]>[CH3:28][O:27][C:23]1[CH:22]=[C:21]([C:18]([C:17]2[CH:29]=[C:13]([C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:12][CH2:11][CH2:10][O:9]3)[CH:14]=[CH:15][C:16]=2[NH2:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2onc3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)c2cc(C3(c4ccc(Cl)cc4)OCCO3)ccc2N)c1
Yield: 103.5 %

Procedure:
Interm. (5-b) (30 g) in THF (250 ml) was hydrogenated with palladium on carbon (3 g) as a catalyst at room temperature for 12 hours under a 2.6 105 Pa pressure in a Parr apparatus. After uptake of H2 (1 equivalent), the catalyst was filtered through celite and the filtrate was evaporated till dryness. The product was used without further purification, yielding 31.2g (100%) of (3-methoxyphenyl)[2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl]methanone (interm. 5-c).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:9]=2[CH2:15]O)=[C:4]([CH2:17][OH:18])[CH:3]=1>P(=O)(O)(O)O.O>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[CH2:17][O:18][CH2:15][C:9]=2[CH:10]=1
Reactant: OCc1cc(Br)ccc1-c1ccc(Br)cc1CO
Agent: O=P(O)(O)O
Solvent: O
Product: Brc1ccc2c(c1)COCc1cc(Br)ccc1-2
Temperature: 160 °C
Yield: 95 %

Procedure:
The suspension of (4,4′-dibromo-2′-hydroxymethyl-biphenyl-2-yl)-methanol (460 mg) in phosphoric acid (25 ml) was heated at 160° C. for 4 hours. The mixture was cooled and diluted with water (100 ml), and was extracted with EtOAC. The organic phase was washed with water, saturated sodium bicarbonate, and brine, and was dried with sodium sulfate. Concentration yielded 3,9-dibromo-5,7-dihydro-dibenzo[c,e]oxepine (416 mg).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].F[B-](F)(F)F.[CH3:18][O+](C)C>>[CH3:18][O:12][C:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:1]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCc2ccccc2N1
Agent: F[B-](F)(F)F
Product: COC1=Nc2ccccc2CCC1

Procedure:
A sample of the title compound of EXAMPLE 165 (3.2 g, 20.0 mmol) was reacted with trimethyloxonium tetrafluoroborate (4.4 g, 30.0 mmol) by the method of EXAMPLE 26 to yield, after chromatography, 2.5 g (73%) of the title material.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].Cl.O.[NH2:15][NH2:16]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:15][NH2:16])=[O:8])([O-:3])=[O:2]
Reactant: NN
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Solvent: O
Product: NNC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 167g (1 mole) of m-nitrobenzoic acid and 160g (5 moles) of methanol was refluxed with stirring for 3 hours while a stream of dry HCl was bubbled in. A precipitate which formed on cooling to room temperature was filtered off, and dissolved in hot methanol. The solution was boiled for 10 minutes with a mixture of sodium carbonate and anhydrous calcium sulfate and was then filtered. The filtrate was stirred and refluxed while 118g (2 moles) of 85% hydrazine hydrate was added. The mixture was refluxed for 90 minutes and allowed to cool. The solid product was filtered off and recrystallized from water to give 258 g of m-nitrobenzhydrazide, m.p. 155°-155.5°C.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[O-]CC.[Na+].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1=[CH:26]N(C)C>C(O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2[N:6]=[CH:5][N:7]=[CH:26][C:14]=2[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: N=CN
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2ncncc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Formamidine acetate (472 mg, 4.52 mmol) in 15.0 mL of absolute ethanol was treated with sodium ethoxide (21 wt % solution in ethanol; 1.7 mL). After 30 min, a solution of the product from Step A above (1.15 g) in 8 mL of absolute ethanol was added, and the mixture was warmed at reflux for 18 h. The dark solution was cooled to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to an orange oil. Purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a light yellow gum.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+]>C(O)C.C(OCC)C.Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under argon 2.16 g (0.010 mole) of 4-fluoro-3-phenoxybenzaldehyde was dissolved in 50 ml of absolute ethanol. To this solution was added with stirring 0.28 g (0.0074 mole) of sodium borohydride. After stirring at room temperature for 24 hours, 3 ml of 10% hydrochloric acid was added to the reaction mixture. The solvent was then evaporated under reduced pressure, leaving a milky-white residue. This residue was dissolved in 100 ml of diethyl ether and 5% hydrochloric acid. The organic phase was separated, washed in succession twice with 25 ml of 5% hydrochloric acid and twice with 10 ml of a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, leaving 1.98 g of (4-fluoro-3-phenoxyphenyl)methyl alcohol as a clear, colorless liquid. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][C:3]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.C([Li])CCC.CCCCCC.[CH2:32]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH2:32]([O:34][CH2:35][C:36]([C:2]1[S:6][C:5]([N:7]([CH3:15])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][C:3]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=[O:37])[CH3:33]
Reactant: CN(C(=O)OC(C)(C)C)c1nc(-c2ccco2)c(Br)s1
Reactant: CCOCC(=O)N(C)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOCC(=O)c1sc(N(C)C(=O)OC(C)(C)C)nc1-c1ccco1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
tert-Butyl N-[5-bromo-4-(2-furyl)thiazol-2-yl]-N-methylcarbamate (1.41 g, 3.93 mmol) obtained in Step 1 was dissolved in THF (19 mL), and a 1.57 mol/L solution of n-butyllithium in n-hexane (2.75 mL, 4.32 mmol) was added thereto in a stream of argon at −78° C., followed by stirring at −78° C. for 15 minutes. 2-Ethoxy-N-methoxy-N-methylacetamide (1.74 g, 11.8 mmol) was added to the reaction mixture, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 623 (550 mg, 38%).
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([C:28]2[NH:29][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)=[CH:30][CH:31]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc(C(C)(C)C)cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1
Yield: 31.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate (47.8 g) and 4-tert-butylbenzylamine (35.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 10 to give ethyl 2-(4-tert-butylphenyl)-5-(4-nitrophenyl)imidazole-4-carboxylate (22.5 g), melting point 190-191° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[CH3:20])=[O:11])[CH2:3]1.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:29]([N:7]2[C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[CH3:20])=[O:11])[CH2:5][C@H:6]2[CH3:8])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N[C@@H](C)C1
Product: Cc1c(F)cccc1NC(=O)CN1C[C@@H](C)N(S(=O)(=O)c2cccc(C#N)c2)[C@@H](C)C1

Procedure:
The title compound was prepared from the product of step (i) (0.503 mmol) and 3-cyanobenzenesulphonyl chloride (0.503 mmol) by the method of Example 58 step (ii) as a white solid. Yield: 44 mg