Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4[C:28](O)=[O:29])[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([NH2:37])[CH2:33]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:37][C@@H:34]1[CH2:35][CH2:36][N:32]([C:28]([C:16]2[C:15]3[C:20](=[CH:21][CH:22]=[C:13]([C:11]4[CH:12]=[C:7]([CH:8]=[CH:9][C:10]=4[CH3:31])[C:5]([NH:4][CH:1]4[CH2:2][CH2:3]4)=[O:6])[CH:14]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=2)=[O:29])[CH2:33]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)O)c2c1
Reactant: N[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C(=O)N3CC[C@@H](N)C3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the product of step v) (100 mg), (R)-pyrrolidin-3-amine (20 mg) and N,N-diisopropylethylamine (0.13 mL) in DMF (2 mL) was added HATU (140 mg) and the reaction stirred at room temperature for 10 minutes. The reaction mixture was filtered and purified by HPLC to yield the title compound as a solid (65 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][CH2:30][N:31]1[CH2:37][CH:36]2[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]2)[CH2:32]1>>[CH:36]12[CH2:38][CH2:39][CH:33]([CH2:34][CH2:35]1)[CH2:32][N:31]([CH2:30][CH2:29][N:14]1[CH2:15][CH2:16][C:11]3[C:5]4[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([CH3:1])=[CH:3][C:4]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]1)[CH2:37]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1[N+](=O)[O-])CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 50.7 %

Procedure:
Prepared by the method described for Example 1 from 1,2,3,4-tetrahydro-8-methyl-9-nitro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (8.9 g, 0.034 moles), triethylamine (9.5 ml, 0.069 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (7.7 g, 0.034 moles). The product was triturated with 10% aqueous potassium carbonate, filtered off, rinsed with water, and dried to afford the free base. Recrystallization from N,N-dimethylformamide gave the product (7.1 g), mp 187°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].[NH4+].[Cl-].CO>[Fe].O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cnn(-c2ccc([N+](=O)[O-])cc2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cnn(-c2ccc(N)cc2)c1
Temperature: 100 °C
Yield: 57.6 %

Procedure:
A mixture of 1-(4-nitrophenyl)-1H-pyrazol-4-carboxylic acid methyl ester (19.44 g), Fe powder, NH4Cl, methanol and H2O was heated for 30 minutes at 80° C. for 3 hours at 100° C. The reaction mixture was concentrated by evaporation, added into dichloromethane, and was filtered. The filtrate was extracted with water, dried over magnesium sulfate and concentrated by evaporation to give 1-(4-aminophenyl)-1H-pyrazol-4-carboxylic acid methyl ester (9.84 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:1][C:2]1[N:11]=[C:10]([CH3:14])[C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(C)nc1Cl
Temperature: 110 °C
Yield: 25.2 %

Procedure:
A mixture of methyl 2,6-dichloro-5-fluoronicotinate (17) (3.5 g 15.62 mmol), trimethylboroxin (1.96 g, 15.62 mmol), 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (1.276 g, 1.562 mmol) and cesium carbonate 15.27 g, 46.86 mmol) was heated at 110° C. overnight. The mixture is cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic phase is washed with water followed by brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography using a gradient of 0-30% EtOAc/heptanes to provide methyl 2-chloro-5-fluoro-6-methylnicotinate (18) 0.8 g as a colorless solid (0.8 g 25%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[Cl:13][CH2:14][C:15](=O)[CH2:16][C:17](OCC)=[O:18]>>[Cl:13][CH2:14][C:15]1[N:1]=[C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][N:6]2[C:17](=[O:18])[CH:16]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1nnc(-c2ccccc2)s1
Product: O=c1cc(CCl)nc2sc(-c3ccccc3)nn12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-5-phenyl-1,3,4-thiadiazole (10 g) was reacted with ethyl 4-chloro-acetoacetate (18.6 g) in polyphosphoric acid (100 g) under stirring at 100° C. for 1 hour. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water until neutral: crystallization from methanol gave 7-chloromethyl-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 201°-202° C. (11.6 g), which was reacted with triphenylphosphine (12.4 g) in acetonitrile (500 ml) under stirring at reflux temperature for 48 hours. After cooling the precipitate was filtered and washed with isopropyl ether to give (5-oxo-2-phenyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride, m.p. 295°-300° C. (20 g), which was suspended in dimethylsulphoxide (100 ml) and treated dropwise with potassium terbutoxide (5 g) dissolved in dimethylsulphoxide (100 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (4.55 g) at room temperature for 90 minutes. After dilution with ice water the precipitate was filtered and washed with water: crystallization from methanol gave 5.1 g of 2-phenyl-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 217°-219° C., N.M.R. (CDCl3) δp.p.m.: 6.34 (s) (1H, C-6-proton), 6.82 (d) (1H, β-ethenyl proton), 7.58 (d) (1H,α-ethenyl proton), 7.12-7.98 (m) (10H, phenyl protons); JHαHβ =16 Hz.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:29])[C@H:15]([CH3:28])[CH2:16]/[CH:17]=[CH:18]/[CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1.OO.O.[OH-].[Li+].S([O-])([O-])(=[O:37])=S.[Na+].[Na+]>O.O1CCCC1>[CH2:21]([O:20][CH2:19]/[CH:18]=[CH:17]/[CH2:16][C@@H:15]([CH3:28])[C:14]([OH:29])=[O:37])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=S([O-])([O-])=S
Reactant: C[C@H](C/C=C/COCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](C/C=C/COCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 18.7 g of (S)-4-benzyl-3-[(2R,4E)-6-benzyloxy-2-methylhex-4-enoyl]oxazolidin-2-one (47.5 mmol) obtained in Example (76a) in a mixed solvent of tetrahydrofuran (700 ml) and water (230 ml) was cooled in an ice bath, and then 30.0 ml of a 30% hydrogen peroxide aqueous solution and 4.15 g of lithium hydroxide monohydrate (95.3 mmol) were added thereto. The mixture was stirred at the same temperature for 30 minutes, and then raised to room temperature and further stirred for 16 hours. After cooling in an ice bath, 250 ml of a 1.5 M sodium thiosulfate aqueous solution was added to the reaction mixture. The mixture was further stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure, diluted with 500 ml of water and washed with ethyl acetate. Then, the aqueous layer was made acidic with 30 g of sodium dihydrogenphosphate, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to obtain 11.0 g of the crude title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]=1[CH3:32])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:26][C:25]([CH3:27])=[C:24]([CH2:28][C:29]([OH:31])=[O:30])[C:23]=4[CH3:32])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 38 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), (5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid (54.3 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 1 day. The reaction was concentrated, the residue was suspended in 1N HCl. The precipitate was filtered, washed with water, suspended in hot ethyl acetate, filtered and dried to give 42 mg (38%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.21 (br s, 1H, NH), 12.17 (br s, 1H, COOH), 11.65 (s, 1H, NH), 9.13 (s, 1H), 8.26 (s, 1H), 7.71 (m, 1H), 7.3-7.4 (m, 3H), 3.37 (s, 2H, CH2), 2.3 (s, 3H, CH3), 2.10 (s, 3H, CH3). MS 442 [M++1].
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]2[CH2:30][O:29]2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:28]([OH:29])[CH2:30][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C2CO2)cc1OC
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1OC
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
To a solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.2 g, 6.0 mmol) in 6 mL DMF, was added sodium hydride (720 mg, 12 mmol) under nitrogen at 0° C. and stirred for 5 min. 2-(3,4-Dimethoxy-phenyl)-oxirane (2.16 g, 18 mmol) was diluted in DMF (2 mL) and added dropwise to the reaction mixture under nitrogen atmosphere. The reaction mixture was stirred at RT for 5 h. After consumption of starting material (TLC and LCMS), the reaction mixture was poured in ice-cold water and extracted with EtOAc (3×50 mL). The combined organic layer was washed with water (5×30 mL) and dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel 100-200 mesh, eluent: 6% MeOH in DCM) to obtain 590 mg of 1-(3,4-dimethoxy-phenyl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 7.19 (m, 2H), 6.98 (d, 1H), 6.83 (m, 2H), 6.78 (s, 1H), 4.98 (t, 1H), 4.1 (m, 2H), 4.83 (s, 3H), 4.8 (s, 3H), 3.6 (dd, 2H), 2.68-2.88 (m, 3H), 2.53 (m, 1H), 2.5 (s, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers 66a and 66b.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])(C(OCC)=O)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCC1(C(=O)OCC)N=C(c2ccc(Cl)cc2)c2cc(CC)sc2-n2c(C)nnc21
Agent: [Ba+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCCC(=O)O)N=C2c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (10 g) is dissolved in diethyl carbonate (150 ml) in a nitrogen stream, and 60% sodium hydride (2.0 g) is added with stirring at room temperature. The mixture is refluxed under heating for 2 hours and cooled to 50° C. with ice water. Ethyl bromovalerate (7.9 ml) is added. After stirring at 100° C. for 2 hours, the reaction mixture is poured on ice water (1 l) and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=100:l) and crystallized from isopropyl ether and ethyl acetate to give 8.3 g of (±)-ethyl 5-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl) valerate as white powdery crystals. (±)-Ethyl 5-(4-(4-chlorophenyl)-6-ethoxycarbonyl-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)valerate (8.2 g) is dissolved in a mixture of ethanol (90 ml) and water (30 ml), and barium hydroxide 8 hydrate (19 g) is added. The mixture is refluxed under heating for 4 hours. After the completion of the reaction, ethanol is distilled away under reduced pressure and adjusted to pH 1 with 6N hydrochloric acid. The mixture is stirred for 30 minutes and adjusted to pH 4 with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The organic layer is washed with a saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is crystallized from ethyl acetate and isopropyl ether and recrystallized from chloroform and methanol to give 3.2 g of (±)-5-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)valeric acid as white powdery crystals, melting point 257°-260° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:3][CH2:2]1.Cl[CH2:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:22]1=[O:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[BrH:39]>CC(CC(=O)C)C.C(O)C>[BrH:39].[Cl:16][C:14]1[CH:13]=[CH:12][C:11]2[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([CH2:18][CH2:19][CH2:20][N:21]4[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[NH:23][C:22]4=[O:30])[CH2:6][CH2:5]3)=[N:8][O:9][C:10]=2[CH:15]=1
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Reactant: Clc1ccc2c(C3CCNCC3)noc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: CCO
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(c2noc3cc(Cl)ccc23)CC1
Reaction time: 1 h
Yield: 53 %

Procedure:
A stirred mixture, under nitrogen, of 18.9 g of 3-(4-piperidyl)-6-chloro-1,2-benzisoxazole, 16.9 g of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 17.0 g of anhydrous sodium carbonate and 1.33 g of pulverized potassium iodide in 1000 ml of 2-methyl-4-pentanone was heated under reflux for 6 hrs. The solvent was removed and the residue was partitioned between 500 ml of dichloromethane and 250 ml of water. The organic phase was separated, washed three times with brine, dried under anhydrous sodium sulfate and concentrated, first at aspirator pressure in a 100° bath, then with the high-vacuum pump attached to yield an oil. The oil was dissolved in 150 ml of ethanol. The solution was cooled and stirred, while 50 ml of ethanol, freshly saturated with gaseous hydrogen bromide, was added over a 5-min period. After stirring 1 hr more in the cold, the salt was collected, filtered, washed twice with ethanol and dried to afford 16.0 g (53%) of product, mp 231°-237° dec.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.C(N(CC)CC)C.[CH3:39][C:40]1([CH3:47])[C:44]([CH3:46])([CH3:45])[O:43][BH:42][O:41]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([N:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=4)[CH:18]=[C:13]3[C:12]([B:42]3[O:43][C:44]([CH3:46])([CH3:45])[C:40]([CH3:47])([CH3:39])[O:41]3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)c1ccc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccccc2)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(-c2cnc3c(c2)c(B2OC(C)(C)C(C)(C)O2)cn3S(=O)(=O)c2ccccc2)cc1
Yield: 115.6 %

Procedure:
A mixture of 3 (0.50 g, 0.99 mmol), [1,1′-bis(diphenylphosphino) ferrocene dichloropalladium(II).dichloromethane complex [PdCl2(dppf)2.CH2Cl2] (24.3 mg, 0.0298 mmol), triethylamine (415 μL, 2.98 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (221 μL, 1.52 mmol) in dioxane (5.0 mL) was microwaved at 120° C. for 0.5 h. The reaction mixture was cooled, poured onto water (100 mL), extracted with ethyl acetate (4×30 mL), the combined organic extracts washed with brine (30 mL), dried (MgSO4) and concentrated. This gave the product 16 as a brown foam (576 mg, 113%) which was used in the next step without further purification; 1H NMR (400 MHz, CDCl3) δ 1.38 (s, 12H), 3.02 (s, 6H), 6.86 (d, J=8.8 Hz, 2H), 7.65-7.45 (m, 5H), 8.16 (s, 1H), 8.26 (d, J=7.4 Hz, 2H), 8.30 (d, J=2.2 Hz, 1H), 8.63 (d, J=2.2 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]2=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:32]([O:37]C)(OC)[O:33]C.S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:32]([OH:37])[OH:33])=[CH:7][CH:6]=3)[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[C:11]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COB(OC)OC
Reactant: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Ten point zero (10.0) grams (22.5 mmol) of 9-(4-iodophenyl)tribenz[b,d,f]azepin was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to −78° C. Fourteen point one (14.1) ml (22.5 mmol) of a 1.6 M hexane solution containing n-butyl lithium was dropwise added thereinto. After completion of the addition, the solution was stirred for 30 minutes, and then a tetrahydrofuran solution containing 2.8 g (22.5 mmol) of trimethyl borate was dropwise added thereto over about one hour. After completion of the addition, the solution was stirred for 1 hour, then the temperature was gradually raised to room temperature, and the solution was allowed to react for further two hours. Subsequently, a dilute sulfuric acid (3 ml of sulfuric acid and 50 ml of water) was added at 0° C. and hydrolysis was performed. The reaction solution was extracted with ethyl acetate, concentrated under reduced pressure, the obtained solid of boronic acid was recrystallized with toluene and purified, thereby 6.1 g of 4-(tribenz[b,d,f]azepin-9-yl)phenyl boronic acid was obtained (yield: 75%).
Reaction SMILES: CON(C)[C:4](=[O:12])[CH2:5][CH:6]([CH3:11])[CH2:7][C:8]([OH:10])=[O:9].[CH3:14][Li].Cl>C1COCC1>[CH3:11][CH:6]([CH2:5][C:4](=[O:12])[CH3:14])[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CON(C)C(=O)CC(C)CC(=O)O
Reactant: [Li]C
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)CC(C)CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(methoxy(methyl)amino)-3-methyl-5-oxopentanoic acid (10 mmol) in THF (50 mL) and cooled to −78° C. and treated dropwise with methyllithium (1.4 M in diethyl ether, 2 equivalents). The resulting mixture was warmed to rt where it stirred overnight. After this time, the mixture was cooled to 0° C. and then treated with ice cold water. After stirring for 10 min at 0° C., the mixture was acidified with cold 1 M aqueous HCl. The acidified mixture was extracted three times with ethyl acetate, and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under vacuum to provide 3-methyl-5-oxohexanoic acid (quantitative yield). Mass spectrum m/z 143.22 (M−H−).
Reaction SMILES: [CH2:1]([NH:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH2:20][CH2:21][CH3:22])=[C:18]([C:23]([OH:25])=O)[N:17]=[N:16]2)=[CH:11][CH:10]=1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1C=C[C:29]2N(O)N=[N:32][C:30]=2[CH:31]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:30]1([NH:32][C:23]([C:18]2[N:17]=[N:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8])=[CH:14][CH:13]=3)[C:19]=2[CH2:20][CH2:21][CH3:22])=[O:25])[CH2:31][CH2:29]1
Reactant: On1nnc2ccccc21
Reactant: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
1-{4-[(Pentylamino)carbonyl]phenyl}-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (487 mg, 1.41 mmol) obtained in Example 57b), HOBt (193 mg, 1.41 mmol, 1.0 eq.) and cyclopropylamine (0.131 ml, 1.84 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (1:1, 7.5 ml), WSC (332 mg, 1.70 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (40 ml), and washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous ammonium chloride solution and saturated brine. The aqueous layers were each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give a white powder. This was crystallized from methanol-ethyl acetate to give the title compound as a white powder (298 mg, 0.777 mmol, 55.1%). The mother liquor was concentrated, and crystallized from diethyl ether to give the title compound as a white powder (225 mg, 0.587 mmol, 41.6%).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+]>CO>[OH:11][CH2:10][CH2:9][O:8][C:7]1[C:2]([O:13][CH3:12])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCCOc1cccnc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1OCCO
Yield: 44.7 %

Procedure:
A mixture of the product obtained in Step 1 (2.33 g, 10.7 mmol) and NaOMe (0.634 mg, 11.8 mmol) in MeOH (50 mL) was refluxed overnight. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography on silica, using CH2Cl2/MeOH/heptane (4:1:5) as eluent, to give 0.81 g (45%) of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([O:26]C)=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1.[OH-].[K+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]([OH:26])=[O:25])(=[O:17])=[O:16])=[O:13])[N:4]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
N-[(4,6-Dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide (15 g) was added to a warm solution of 7.5 g of potassium hydroxide in 7.5 ml of water and 60 ml of ethanol. The mixture was stirred at room temperature overnight and then poured into dilute hydrochloric acid. The solid was filtered, washed with water and dried to afford 12.5 g of the desired product: m.p. 155°-157° C.