Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([N:12]([CH3:19])[CH2:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:25][C:26]1[CH:27]=[C:28]([S:33]C2C=C(Cl)C=C(Cl)C=2)[CH:29]=[C:30]([Cl:32])[CH:31]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:1]([O:8][CH2:9][C:10]([N:12]([CH:13]([S:33][C:28]1[CH:29]=[C:30]([Cl:32])[CH:31]=[C:26]([Cl:25])[CH:27]=1)[C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[CH3:19])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CN(C)C(=O)COCc1ccccc1
Reactant: Clc1cc(Cl)cc(Sc2cc(Cl)cc(Cl)c2)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)C(=O)C(Sc1cc(Cl)cc(Cl)c1)N(C)C(=O)COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
In 2 ml of dry tetrahydrofuran was dissolved 100 mg (0.4 mmol )of 2-benzyloxy-N-methyl-N-(3-methyl-2-oxobutyl)acetamide (18a'), and there was added 223 μl (0.4 mmol)of n-butyllithium (1.7 M hexane solution)with stirring at -78° C. over 10 minutes. After stirring at -78° C. for 1 hour, and a tetrahydrofuran solution (1 ml)of 135 mg (0.4 mmol)of 3,5-dichlorophenylsulfide was added thereto over 10 minutes. After 30 minutes, the temperature was raised up to room temperature, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate ester. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (hexane/ethyl acetate 5:1)to give 79 mg of 2-benzyloxy-N-[1-(3,5-dichlorophenylthio)-3-methyl-2-oxobutyl]-N-methylacetamide (20)(yield 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([O:21]C)=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:23])=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[NH:9][C:8]=2[CH3:23])=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2[nH]c(C)c(Cc3ccc(Cl)cc3)c2=O)sc1C(=O)O
Yield: 53 %

Procedure:
To a solution of methyl 2-(4-(4-chlorobenzyl)-3-methyl-5-oxo-2,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazole-5-carboxylate (0.22 g, 0.57 mmol) in a mixture of tetrahydrofuran (8 mL) and water (2 mL) was added lithium hydroxide monohydrate (0.12 g, 2.88 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue was neutralized to pH 4˜5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford the title compound in 53% yield (0.11 g): 1H NMR (300 MHz, DMSO-d6) δ 12.29 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 3.52 (s, 2H), 2.56 (s, 3H), 2.14 (s, 3H); MS (ES+) m/z 364.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]#[CH:20])[C:10]([O:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1.C(NCC)C>C(OCC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]#[C:19][CH2:18][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:11])=[CH:23][CH:24]=1
Reactant: Brc1ccc(I)cc1
Reactant: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H](CC#Cc1ccc(Br)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of cyclopentyl(2S)-2-[(tert-butoxycarbonyl)amino]pent-4-ynoate (2.45 g, 8.72 mmol) and 4-iodo-bromobenzene (2.96 g, 10.46 mmol) in diethyl ether (4 ml) was added copper iodide (0.166 g, 0.872 mmol) and PdCl2(PPh3)2 (0.306 g, 0.436 mmol). Diethylamine (5.43 ml, 52.3 mmol) was then added and the mixture stirred at RT. After 2 hrs, LCMS showed complete reaction. The mixture was poured onto water and extracted with diethyl ether. The combined organic layers were washed with water and brine, dried over magnesium sulphate, filtered and evaporated in vacuo. The crude residue was subjected to column chromatography eluting with 5 to 10% EtOAc in hexanes. Yield=2.9 g, 6.51 mmol, 75% yield. LCMS purity 98%: m/z 437 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[Cl:29]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([N:8]1[CH2:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:26]3[CH:25]=[CH:24][C:23]([Cl:22])=[C:28]([Cl:29])[CH:27]=3)[C:11]=2[O:10][CH2:9]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)N1COc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)N1COc2c(cccc2-c2ccc(Cl)c(Cl)c2)C1
Temperature: 58.5 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A mixture of 8-bromo-3-(tert-butyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.46 g, 1.71 mmol), potassium carbonate (0.945 g, 4.0 equiv), 3,4-dichlorophenylboronic acid (0.489 g, 1.5 equiv), and tetrakis(triphenylphosphine)Pd (0) (63 mg, 3.2 mol %) was heated at 53-64° C. for 3 hours, then at 80-87° C. for 2.5 hours. To the mixture was added additional 3,4-dichlorophenylboronic acid (0.2 g) and the resulting mixture was heated at 80-87° C. overnight. Upon cooling to room temperature, the reaction mixture was concentrated. The crude product was purified by column chromatography to give 3-(tert-butyl)-8-(3,4-dichlorophenyl)-3,4-dihydro-2H-benzo[e][1,3]oxazine (0.313 g) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C.O>CN(C)C=O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: Nc1ncnc2ccc(Cl)cc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2ccc(Cl)cc12)C(=O)OCC
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 79.6 %

Procedure:
A mixture of 4-amino-6-chloroquinazoline (8.7 g) and diethyl ethoxymethylenepropanedioate (11.53 g) in N,N-dimethylformamide (25 ml) was stirred for 2 hours and 40 minutes at 150° C. After the reaction mixture was cooled to ambient temperature, to the mixture was added water with stirring to give crystals, which were washed with water, dried under reduced pressure and dissolved in ethyl acetate under heating. Insoluble materials were filtered off. To the filtrate was added hexane and allowed to stand at ambient temperature to give crystals, which were separated by filtration and washed with a mixture of ethyl acetate and hexane to give a mixture (13.48 g) of crystalline diethyl [(6-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl 10-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20](Cl)=[O:21].Cl>[N+](C1C=CC=CC=1)([O-])=O.O>[CH3:17][CH:18]([CH2:23][CH3:24])[CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:2][CH:3]=1)=[O:21]
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: CCC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CCC(C)CC(=O)c1ccc(-c2ccccc2)cc1
Temperature: -7 °C
Reaction time: 18 h

Procedure:
To commercially available biphenyl (0.08 mole) and anhydrous aluminium trichloride (0.1 mole) dissolved in dry nitrobenzene (90ml), (+)-3-methylpentanoylchloride (0.1mole) the preparation of which is known and described in United Kingdom Patent Application No. 36211/75), is added in drops, the temperature being maintained at about -7° C. during the addition. The mixture is then stirred for about 18 hr. with cooling in an ice bath. It is then poured onto a mixture of ice, water and concentrated hydrochloric acid and stirred for 0.5 hr., and the nitrobenzene layer is separated. The nitrobenzene is removed by steam distillation and the residue is crystallised from a small volume of ethanol to constant melting point.
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>CO>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH2:30][CH2:29][C:28]#[N:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: COc1ccc(N2CCNC(Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(N2CCN(CCC#N)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C

Procedure:
Into a 25 mL screw-cap vial were added 3-benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (206 mg, 0.562 mmol), acrylonitrile (55 μL, 0.83 mmol), triethylamine (500 μL), and MeOH (5 mL). The reaction mixture was heated at 60° C. for 4 h then cooled to room temperature. The reaction mixture was concentrated and adsorbed onto silica gel then purified by silica gel flash chromatography with a 0-10% MeOH/CH2Cl2 gradient to afford the title compound as a yellow waxy solid (181 mg, 77%). LC/MS (Method B) 2.77 min, [M+1]+ 420.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C@H:8]1[N:18]2[C:19]3[N:10]([C:11](=[O:21])[CH:12]=[CH:13][C:14]=3[N:15]=[CH:16][C:17]2=[O:20])[CH2:9]1)(C)C>CO>[OH:6][CH2:7][C@H:8]1[N:18]2[C:19]3[N:10]([C:11](=[O:21])[CH:12]=[CH:13][C:14]=3[N:15]=[CH:16][C:17]2=[O:20])[CH2:9]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1Cn2c(=O)ccc3ncc(=O)n1c32
Solvent: CO
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.5 %

Procedure:
A suspension of (2S)-2-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (42.6 g, 128 mmol) and Dowex 50X2-200 ion exchange resin (50 g, 128 mmol) in MeOH (1000 mL) was stirred at room temperature for 15 h. The reaction mixture was filtered to give (2S)-2-(hydroxymethyl)-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (26.55 g, 121 mmol, 95%).
Reaction SMILES: O[CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1.S(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][CH2:2][C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[S:12][C:13]=2[CH3:14])=[C:5]([O:28][CH3:29])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1CCN(c2nc(COc3ccc(CO)cc3OC)c(C)s2)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2nc(COc3ccc(CCl)cc3OC)c(C)s2)CC1
Yield: 31.9 %

Procedure:
To a mixture of ethyl 1-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate (1.35 g) and toluene (50 mL) was added thionyl chloride (0.42 g), and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:4, v/v) to give ethyl 1-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-thiazol-2-yl}piperidine-4-carboxylate as colorless crystals (0.45 g, yield 32%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 98-99° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]12([CH2:22][CH2:23][N:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[O:26])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:12]12([CH2:22][CH2:23][N:24]([CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:25](=[O:26])[NH:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][N+:34]([O-:9])=[CH:35][CH:36]=3)[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCN(CCC12CC3CC(CC(C3)C1)C2)C(=O)NCCCc1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
m-Chloroperbenzoic acid (2.5 g, 15 mmol) was added to a solution of 1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea (Compound No. 1-1) (3.0 g, 7.3 mmol) at room temperature under a nitrogen atmosphere, and the mixture was stirred overnight. The reaction mixture was distributed with chloroform (20 ml) and a 1 N aqueous sodium hydroxide solution (60 ml). The organic layer was washed with water (10 ml) and a saturated aqueous sodium chloride solution (10 ml) successively and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 2.92 g (94.2%) of the titled compound.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:25])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH3:16])C1C=CC=CC=1.[Li].[Li+].[O-:28][O-]>C1COCC1.O>[Cl:24][C:18]1[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:15]([CH3:16])[C:14]([OH:25])=[O:28]
Reactant: CC(C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1cccc(Cl)c1Cl
Reactant: [O-][O-]
Agent: [Li+]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)c1cccc(Cl)c1Cl
Yield: 86.9 %

Procedure:
To a solution of compound 20 (160 mg, 0.42 mmol) in THF (5 mL) and water at 0° C., was added a solution of lithium peroxide (prepared by adding 30% hydrogen peroxide (2.9 mL, 2.10 mmol) to lithium hydroxide (17.6 mg, 0.41 mmol) in water (0.679 mL)) dropwise. The mixture was stirred for 0° C. for 1h, quenched with sat.Na2SO3 (1.28 mL), solvent was removed in vacuo. The mixture was diluted with water and aqueous solution was extracted with DCM twice. The aq.layer was acidified with Conc.HCl and extracted with EtOAc twice. Combined organic layers were washed with brine and dried over MgSO4, concentrated. Purified by column chromatography (EtOAc/n-Hexane 40:60) to afforded compound 21 (80 mg, 86.9%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.51 (d, J=7.2 Hz, 3H), 4.27 (q, J=6.8 Hz, 1H), 7.16-7.24 (m, 2H), 7.37 (d, J=7.6 Hz, 1H)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[N:20]=2)[N:10]=[N:9]1.[ClH:37]>CO>[ClH:37].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:20]=2)[N:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)CC1
Agent: Cl
Solvent: CO
Product: Fc1ccccc1-n1nnc(-c2nc(C3CCNCC3)no2)c1-c1ccncc1
Temperature: 50 °C
Yield: 96 %

Procedure:
To a suspension of tert-butyl 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate, obtained in Step 1, (601 mg; 1.22 mmol) in MeOH (30 mL) was added HCl (3 M, 30 mL) and the mixture was heated at 50° C. for 5 hours. The solvent was removed in vacuo affording the title compound as a white solid (462 mg; 96%). 1H NMR: (DMSO-d6, 400 MHz) δ 9.38-9.36 (1H, m), 9.26-9.24 (1H, m), 8.88 (2H, d, J=5.4 Hz), 7.94-7.84 (3H, m), 7.76-7.69 (1H, m), 7.55-7.46 (2H, m), 3.34-3.24 (3H, m), 3.06 (2H, q, J=11.1 Hz), 2.14 (2H, d, J=13.8 Hz), 2.04-1.90 (2H, m). LC/MS (Method C): 392 (M+H)+. HPLC (Method E) Rt 2.14 min (Purity: 97.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:19]2[C:23]([CH3:24])=[N:22][N:21]=[C:20]2[CH2:25][N:26]2C(=O)C3=CC=CC=C3C2=O)=[C:8]([CH:18]=1)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=O)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:19]3[C:23]([CH3:24])=[N:22][N:21]=[C:20]3[CH2:25][N:26]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:8]=2[CH:18]=1)([O-:3])=[O:2]
Reactant: Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 4, 5-nitro-2'-chloro-2-[3-(phthalimidomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 8-nitro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([OH:13])[CH:5]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Yield: 94 %

Procedure:
Methyl-3-hydroxy-4-nitrobenzoate Cmpd 1 (1.0 g, 1.0 eq) was dissolved in THF (6 mL) in a microwave vial. Benzyl alcohol (1.0 eq) and PPh3 (1.0 eq) were added to the vial. The reaction vial was put under nitrogen flow, and DIAD (1.0 eq) was added in the dark after stirring the reaction for 1.5 hours. The reaction was microwave irradiated at 100° C. for 6 min (Biotage Initiator™ Eight). The solution was concentrated, and purification of the resultant was performed on a SP1 flash chromatography system (Biotage™) starting with 6% EtOAc: 94% Hex to 60% EtOAc: 40% Hex. The recovered yellow solid was treated with MP-Carbonate resin (2 eq) in DCM and the mixture was shaken overnight at RT. The resin was filtered and multiply washed with DCM. The filtrate was concentrated under vacuum to give Cmpd 2 as a yellow solid (1.39 g, 94% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([O:14][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CN(C(=O)OC(C)(C)C)CC1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate (1-20 g) in dichloromethane (50 mL) at 0° C., triethylamine (0.61 mL) and methanesulfonyl chloride (0.31 mL) were added and the mixture stirred overnight at room temperature. The resulting solution was evaporated under reduced pressure and purified on Biotage Horizon® system (silica, gradient 10-20% ethyl acetate in dichloromethane) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([N:17]([CH2:25][C:26](N(OC)C)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:14]([N:17]([CH2:25][C:26]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=[CH2:16]
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCN(CC(=O)c1ccc(F)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 32.8 %

Procedure:
2-Bromo-5-fluoro-pyridine (2.46 g, 13.98 mmol) in tetrahydrofuran (20 mL) is added drop wise to isopropylmagnesium chloride (15 mL, 30.00 mmol of a 2M solution in tetrahydrofuran) with stirring under nitrogen at room temperature. The resulting reaction mixture is stirred at room temperature for 2 hours. tert-Butyl N-allyl-N-[2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (3.4 g, 13.16 mmol) in tetrahydrofuran (15 mL) is then added drop wise at room temperature and the resulting mixture is stirred overnight. Dilute aqueous hydrochloric acid is added followed by ethyl acetate. The layers are separated and the aqueous phase is re-extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-40% gradient of acetone in iso-hexane to give the title compound (1.27 g, 33%). ES/MS (m/e): 317 (M+23).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:27]([OH:29])=O.[NH2:30][CH2:31][CH2:32][CH2:33][OH:34].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:34][CH2:33][CH2:32][CH2:31][NH:30][C:27]([C:3]1[C:4]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[N:22]([CH3:26])[CH:23]=[CH:24][N:25]=5)[S:20][C:13]=34)=[CH:7][C:5]=2[S:6][C:2]=1[CH3:1])=[O:29]
Reactant: NCCCO
Reactant: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1sc2cc(Oc3ccnc4cc(-c5nccn5C)sc34)ccc2c1C(=O)NCCCO
Yield: 59.6 %

Procedure:
This material was prepared by the reaction of 2-methyl-6-{[2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl]oxy}benzo[b]thiophene-3-carboxylic acid 117b (85 mg, 0.20 mmole) with 3-amino-1-propanol (46 μL, 0.44 mmole), N,N-diisopropylethylamine (77 μL, 0.30 mmole), and HBTU (115 mg, 0.303 mmole) in a manner as previously described for example 117. The crude material was purified by silica gel chromatography (10:30:60% MeOH/CH2Cl2/EtOAc) to give a yellow solid (57 mg, 59%). 1H NMR (DMSO-d6, 300 MHz) δ8.52 (1H, d, J=5.27 Hz), 8.37 (1H, t, J=5.56 Hz), 7.95 (1H, d, J=2.26 Hz), 7.88 (1H, s), 7.82 (1H, d, J=8.85 Hz), 7.40 (1H, s), 7.33 (1H, dd, J=2.35, 8.76 Hz), 7.02 (1H, d, J=0.94 Hz), 6.70 (1H, d, J=5.46 Hz), 4.51 (1H, t, J=5.09 Hz), 3.98 (3H, s), 3.50 (2H, q, J=6.22 Hz), 3.35 (2H, m), 2.60 (3H, s), 1.71 (2H, m).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[C:19]([OH:21])=[O:20])=O)(C)(C)C>C(O)(=O)C>[NH2:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc2ccccc2c1C(=O)O
Solvent: CC(=O)O
Product: Nc1ccc2c(c1C(=O)O)CCCC2
Reaction time: 80 h
Yield: 86.4 %

Procedure:
A mixture of Example 128B (14.21 g, 49.46 mmol) and Pt2O (7.00 g, 30.8 mmol) in acetic acid (200 mL) was shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 80 hours, filtered, and concentrated. The concentrate was treated with dichloromethane (142 mL) and TFA (24 mL) and stirred for 3 hours. The organic layer was washed with NaOH (2×250 mL) and brine (200 mL), dried (MgSO4), filtered, and concentrated to provide the desired product (8.17 g, 86%). MS (ESI(+)) m/e 192 (M+H)+; MS (ESI(−)) m/e 190 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 6.83 (d, 1H), 6.53 (d, 1H), 2.72 (m, 2H), 2.57 (m, 2H), 1.64 (m, 4H).