Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]N(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2.CI.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:1][O:19][C:18]([CH:15]1[CH2:14][CH2:13][C:12]2[C:17](=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=2)[CH2:16]1)=[O:20]
Reactant: CN(C)C=O
Reactant: COc1cccc2c1CC(C(=O)O)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C1CCc2cccc(OC)c2C1
Reaction time: 8 h

Procedure:
To a DMF solution (30 mL) of 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (5.0 g, 24 mmol) was added MeI (7.1 g, 50 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was allowed to stir overnight and ethyl acetate (200 mL) was added. The resulting solution was washed with water (3×50 mL) and brine (50 mL) to provide 8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid methyl ester (6.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([Cl:21])[C:13]=1[CH:14]=[O:15].[OH-].[K+].Cl>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:14]([C:13]3[C:16]([Cl:21])=[CH:17][CH:18]=[C:19]([F:20])[C:12]=3[Cl:11])[OH:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c(Cl)ccc(F)c1Cl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C

Procedure:
To a stirred mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (0.100 g, 0.508 mmol) and 2,6-dichloro-3-fluorobenzaldehyde (0.107 g, 0.558 mmol) in MeOH (5 mL) was added potassium hydroxide (0.199 g, 3.553 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was then stirred at rt. overnight. The mixture was then poured into water (50 mL), acidified with 2N HCl and extracted with ethyl acetate (50 mL×3). The organics were combined, dried (Na2SO4) and concentrated under reduced pressure to give a crude residue which was then purified by chromatography (eluent: 20% ethyl acetate in hexane). MS (ES+): m/z=388.85, 390.84, 392.83 [MH+]. HPLC: tR=3.29 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2[CH2:25][CH3:26])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:33]Br>C(O)(=O)C.O>[Br:33][CH:25]([C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1)[CH3:26]
Reactant: BrBr
Reactant: CCc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(C(C)Br)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
In a 100 mL round bottom flask combined 4-[(3-chloro-2-methylphenyl)methyl]-5-ethyl-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.1 g, 10.13 mmol) (Example 75) and sodium acetate (1.246 g, 15.19 mmol) in acetic acid (30 mL). Bromine (0.782 mL, 15.19 mmol) in acetic acid (5 mL) was added dropwise over ˜3 min. The red colored reaction was stirred at room temperature for 16 hr. LC/MS indicated complete conversion to product. This reaction mixture was diluted with water (150 mL), producing a gummy yellow residue. The mixture was extracted with chloroform (100 mL), then concentrated to a thick yellow oil. This oil was triturated from ether (150 mL), to provide, after sonication a yellow solid that is consistent with 5-(1-bromoethyl)-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (4.52 g, 9.34 mmol, 92% yield). The proton NMR is consistent for the desired product. LC/MS m/z MH+=484 (theoretical), found=484.9, 1H NMR (400 MHz, CHLOROFORM-d) S ppm 1.97 (d, J=6.57 Hz, 3H) 2.51 (s, 3H) 3.52-3.64 (m, 4H) 3.71-3.84 (m, 4H) 4.53-4.65 (m, 1H) 5.43 (d, J=17.43 Hz, 1H) 5.95 (d, J=17.43 Hz, 1H) 6.38 (d, J=7.83 Hz, 1H) 7.06 (t, J=8.08 Hz, 1H) 7.34 (d, J=7.83 Hz, 1H)
Reaction SMILES: Cl[C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][C@H:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])=[O:7])=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[CH2:24]([OH:26])[CH3:25]>O>[N:18]1([C:2]2[CH:17]=[CH:16][C:25]([C:24]([O:8][C@H:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])=[O:26])=[CH:4][N:3]=2)[CH2:23][CH2:22][N:21]([C:2]2[CH:17]=[CH:16][C:5]([C:6]([O:8][C@H:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:10])=[O:7])=[CH:4][N:3]=2)[CH2:20][CH2:19]1
Reactant: C1CNCCN1
Reactant: CCOC(=O)[C@H](C)OC(=O)c1ccc(Cl)nc1
Reactant: CCO
Solvent: O
Product: CCOC(=O)[C@H](C)OC(=O)c1ccc(N2CCN(c3ccc(C(=O)O[C@@H](C)C(=O)OCC)cn3)CC2)nc1
Temperature: 80 °C

Procedure:
A mixture of 1.4 g of (S)-1-(ethoxycarbonyl)ethyl 6-chloronicotinate, 0.2 g of piperazine and 25 ml of ethanol was heated at 80° C. for 2 days. The reaction mixture was treated with 500 ml of water and then extracted three times with 100 ml of diethyl ether each time. The combined organic phases were washed twice with 500 ml of concentrated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. The residue was chromatographed on silica gel with toluene/ethyl acetate (vol. 4:1). Recrystallization from ethanol gave pure bis-[(S)-1-(ethoxycarbonyl)ethyl] 6,6'-(1,4-piperazinediyl)dinicotinate with m.p. (C-I) 143° C., [α]20 589 =+68.3 °.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6](O)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].C([N:13](CC)CC)C.CS([Cl:22])(=O)=O.[N-]=[N+]=[N-].[Na+].[NH4+]=S>C1C=CC=CC=1>[ClH:22].[ClH:22].[CH3:2][CH:1]([N:4]1[CH2:7][CH:6]([NH2:13])[CH2:5]1)[CH3:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC(O)C1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CC(C)N1CC(N)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The hydrochloride salt of 1-isopropyl-3-azetidinol (168 g; 1 mole) was partitioned between dilute sodium hydroxide and 700 ml of benzene. The benzene solution was dried over anhydrous sodium sulfate and concentrated to one half volume. The volume was made back to 700 ml with dry benzene and 110 g (1.1 mole) of triethylamine added. To this was added dropwise 115 g (1 mole) of methanesulfonyl chloride while cooling with an ice bath. The mixture was stirred at room temperature for one hour and filtered. The filter cake was washed twice with 100 ml of benzene and all the benzene filtrates combined. The benzene filtrate was extracted with 300 ml of 4N hydrochloric acid followed by 100 ml of water. The aqueous extracts were combined and the pH adjusted to 7 with sodium hydroxide. The solution was treated with 65 g (1 mole) of sodium azide and heated to reflux for 20 hr and cooled to room temperature with an ice bath. A solution (673 ml) of 23% aqueous ammonium sulfide was added while cooling with an ice bath to 30° C. and the solution was stirred at room temperature for 6 hr. The solution was continuously extracted with chloroform for 35 hr. (The condenser became plugged overnight and the pressure caused a joint to open and an unknown amount of material was lost). The chloroform was concentrated and distilled. Yield 18.5 g, b.p. 70°-80° C./20-30 mm. Two grams of the distillate was dissolved in ethanol and treated with ethereal hydrogen chloride. The resulting crystals were recrystallized from ethanol, yield of title compound from the 2 g sample was 1.35 g, m.p. 167°-170° C.
Reaction SMILES: Br[CH:2]([C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=O)[C:3]([NH2:5])=[O:4].[NH2:15][C:16]([NH2:18])=[S:17]>C(O)C>[NH2:18][C:16]1[S:17][C:2]([C:3]([NH2:5])=[O:4])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:15]=1
Reactant: NC(N)=S
Reactant: NC(=O)C(Br)C(=O)c1ccccc1Cl
Solvent: CCO
Product: NC(=O)c1sc(N)nc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
A mixture of 2.33 g (8.43 mmole) of 2-bromo-3-(2-chloro-phenyl)-3-oxo-propionamide, 0.77 g (10.11 mmole) of thiourea and 20 mL of ethanol was stirred at room temperature for 18 hours. The mixture was then concentrated under reduced pressure. The residue was purified by chromatography on C18 reverse phase silica gel, eluting with acetonitrile-water (gradient 0:100-50:50) to give 0.72 g of 2-amino-4-(2-chloro-phenyl)-thiazole-5-carboxylic acid amide (V.20).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:15]3[C:11](=[N:12][N:13]=[C:14]3[C@H:16]3[CH2:21][CH2:20][C@H:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:18][CH2:17]3)[CH2:10][NH:9][CH2:8][C:7]=2[CH:29]=1.C(N(CC)CC)C.[CH3:37][N:38]([CH3:43])[S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH3:37][N:38]([CH3:43])[S:39]([N:9]1[CH2:8][C:7]2[CH:29]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=2[N:15]2[C:11](=[N:12][N:13]=[C:14]2[C@H:16]2[CH2:17][CH2:18][C@H:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:10]1)(=[O:41])=[O:40]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc([C@H]3CC[C@H](Oc4ccccc4)CC3)n1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](Oc3ccccc3)CC2)C1
Reaction time: 72 h

Procedure:
To a solution of trans-8-chloro-1-(4-phenoxy-cyclohexyl)-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzoazulene hydrochloride (0.062 g, 0.14 mmol) and triethylamine (0.030 ml, 0.22 mmol) in dichloromethane (2.5 ml) was added N,N-dimethylsulfamoyl chloride (0.023 ml, 0.22 mmol) at room temperature. After stirring for 72 h the reaction mixture was transferred directly onto a silica gel chromatography column. Elution with n-heptane/ethyl acetate gave the title compound (0.042 g, 58%) as white solid. MS m/e: 502 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:28]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2ccc(F)cc2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [N:1]([C:3]1C=CC=CC=1)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C]=[O:14].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Rh]>[C:15]1([N:1]=[C:3]=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [C]=O
Reactant: c1ccccc1
Reactant: O=Nc1ccccc1
Agent: [Rh]
Agent: [Al+3]
Agent: [Cl-]
Product: O=C=Nc1ccccc1
Temperature: 190 °C

Procedure:
The procedure of Example 14 is repeated using 12.3 parts of nitrosobenzene, 80 parts of benzene, 5 parts of rhodium on carbon and 0.75 part of aluminum chloride. After carbon monoxide is introduced to a pressure of 3,000 p.s.i., the pressure vessel is heated at 190°C. for 5 hours. Phenyl isocyanate is obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[C:13]([CH:15]=[C:16]([O-])[CH3:17])#[N:14].[Na+].[NH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[NH:24][C:23](=[O:28])[CH:22]=1.C(O)(=O)C>CC(O)C>[C:7]([C:6]1[CH:9]=[CH:10][C:3]([CH:1]2[C:22]3[C:23](=[O:28])[NH:24][C:25]([CH3:27])=[CH:26][C:21]=3[NH:20][C:16]([CH3:17])=[C:15]2[C:13]#[N:14])=[C:4]([O:11][CH3:12])[CH:5]=1)#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: Cc1cc(N)cc(=O)[nH]1
Reactant: CC([O-])=CC#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)Nc2cc(C)[nH]c(=O)c21

Procedure:
908 mg (5.64 mmol) of 4-formyl-3-methoxybenzonitrile are dissolved with 592 mg (5.64 mmol) of sodium 1-cyanoprop-1-en-2-olate, 700 mg (5.64 mmol) of 4-amino-6-methylpyridin-2(1H)-one [Bisagni, E., Hung, N. C., Synthesis, 765-766 (1984)] and 484 μl (8.46 mmol) of acetic acid in 30 ml of 2-propanol and heated at the reflux temperature under argon for 12 h. After cooling, the reaction mixture is filtered and the remaining solid is washed with diethyl ether (20 ml). 1798 mg (96% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>CCCCCCC.O>[C:1]([C:5]1[CH:10]=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccccc1O
Solvent: O
Solvent: CCCCCCC
Product: CC(C)(C)c1cc([N+](=O)[O-])ccc1O
Reaction time: 2 h

Procedure:
To a vigorously stirred solution of 2-tert-butylphenol (10 g, 66.6 mmol) in heptane (67 ml) was added at a fast drip a solution of 70% nitric acid (4.25 ml, 66.6 mmol) diluted with water (4.25 ml). The resulting dark red/brown mixture was stirred vigorously for 2 h. The suspended solid was collected by filtration washed with hexane (300 mL), water (200 mL) and once again with hexane (200 mL) to give a cocoa colored powder that was dried to constant mass (4.65 g, 35.6%).
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](Cl)=[N:10][N:9]=1>CO>[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[N:10][N:9]=1
Reactant: COc1nnc(Cl)c2ccccc12
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.95 g(0.01 mol) of 1-methoxy-4-chlorophthalazine obtained from Preparation 7. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:20][C:21]([O:23]C)=O.[OH-].[Na+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:21](=[O:23])[CH2:20][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11](=[O:12])[N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: COC(=O)CBr
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)N1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C(=O)CC(C(=O)N2CCCCC2)c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
1-[(4-Nitrophenyl)acetyl]piperidine was alkylated with methyl bromoacetate in the same manner as in Reference Example 47, hydrolyzed with 1 M sodium hydroxide aqueous solution in methanol, and then condensed with 1-methylpiperazine in the same manner as in Reference Example 5 to obtain 1-methyl-4-[3-(4-nitrophenyl)-4-oxo-4-piperidin-1-ylbutanoyl]piperazine (ESI: 389). This piperazine compound was subjected to the reduction of nitro group in the same manner as the catalytic hydrogenation shown in Reference Example 3 and then treated with lithium aluminum hydride to obtain 4-[3-(4-methylpiperazin-1-yl)-1-(piperidin-1-ylmethyl)propyl]aniline. ESI: 331.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.O1CCC[CH2:34]1.C[Zn]C.C(OCC)(=O)C>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>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH3:34])=[C:12]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc(C2=C(OS(=O)(=O)C(F)(F)F)c3ccc(OC)cc3C3CCCCC23)cc1
Reactant: C1CCOC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Zn]C
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C2=C(C)c3ccc(OC)cc3C3CCCCC23)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Combine trifluoro-methanesulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,10a-hexahydro-phenanthren-9-yl ester (0.523 g, 1.12 mmol), Pd-tetrakis (45.0 mg, 0.04 mmol), and tetrahydrofuran (10.0 mL), and stir under nitrogen atmosphere at 0° C. After 15 minutes, add dimethylzinc (3.5 mL, 3.44 mmol) dropwise. Allow the reaction to warm to room temperature and stir for 18 hours, then heat reaction at 40° C. for 3 hours. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous sodium sulfate, concentrate, and chromatograph eluting with 0% to 20% ethyl acetate/hexanes to yield the titled compound (0.224 g, 60%) as a white solid. TLC Rf=0.30 in 5:1 hexanes:ethyl acetate. 1H NMR (CDCl3): 7.32 (s, 1H), 7.20 (d, 2H, J=8.8 Hz), 6.95 (m, 3H), 6.79 (m, 1H), 3.88 (m, 6H), 3.21 (m, 1H), 2.46 (m, 2H), 1.97 (s, 3H), 1.74 (m, 1H), 1.55 (m, 3H), 1.38 (m, 1H), 1.15 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1.[C:23]([O-])([O-])(OCC)[CH3:24].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH3:24])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:6]=2[CH:22]=1
Reactant: CCOC(C)([O-])[O-]
Reactant: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2=NCc3nnc(C)n3-c3ccc(Cl)cc32)cc1
Reaction time: 0.25 h

Procedure:
To a mixture of 2.1 parts of 7-chloro-2-hydrazino-5-(p-methoxyphenyl)-3H-1,4-benzodiazepine, prepared in Example 2, 4.33 parts of ethyl orthoacetate and 60 parts by volume of ethanol is added dropwise 0.75 part by volume of concentrated sulfuric acid. The mixture is stirred for about 15 minutes. After completion of the reaction, the reaaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate, whereby 8-chloro-1-methyl-6-(p-methoxyphenyl)-4H-s-triazolo [4,3-a] [1,4] benzodiazepine is yielded as crystals. Recrystallization from a mixture of methanol and chloroform yields colorless needles melting at 268° C to 269° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH2:13].[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27](OC)[CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1>>[CH:14]1([N:18]2[CH2:23][CH2:22][CH:21]([O:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]4[N:13]([CH3:12])[C:4](=[O:6])[C:3]5[C:2](=[C:10]([F:11])[CH:9]=[CH:8][CH:7]=5)[N:1]=4)=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH2:17][CH2:16][CH2:15]1
Reactant: COc1cc(OC2CCN(C3CCC3)CC2)ccc1C=O
Reactant: CN
Reactant: Nc1c(F)cccc1C(=O)O
Product: Cn1c(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)nc2c(F)cccc2c1=O

Procedure:
The entitled compound was obtained according to the method of Example 15 but starting from 2-amino-3-fluorobenzoic acid, methylamine and 4-[(1-cyclobutylpiperidin-4-yl)oxy]-2-methoxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]([NH2:27])=[N:25][OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[C:34](OC(=O)C)(=O)[CH3:35].C(O)(=O)C.O>O1CCCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[N:27]=[C:34]([CH3:35])[O:26][N:25]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(C(N)=NO)cc12
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3noc(C)n3)cc12
Yield: 45.4 %

Procedure:
A solution of tert-butyl[6-[amino(hydroxyimino)methyl]-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.46 g, 1 mmol), acetic anhydride (0.14 ml, 1.5 mmol) and a catalytic amount of acetic acid in tetrahydrofuran (10 ml) was refluxed under heating for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give tert-butyl[4-butoxy-2-isobutyl-6-(5-methyl-1,2,4-oxadiazol-3-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 45.8%) as crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH:13]1[CH:18]2[CH:14]1[CH2:15][N:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17]2)[CH2:8][CH2:9][CH2:10][CH2:11]Br)(C)(C)[CH3:2].BrCCCCl.[CH2:32]([O:39][C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][C:41]=1[CH:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH2:48][C:49]([OH:51])=[O:50])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH2:19]([N:16]1[CH2:15][CH:14]2[CH:18]([CH:13]2[N:7]([C:6]([O:5][CH2:1][CH3:2])=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][O:50][C:49](=[O:51])[CH2:48][CH:47]([C:41]2[CH:42]=[C:43]([CH3:46])[CH:44]=[CH:45][C:40]=2[O:39][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:17]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(OCc2ccccc2)c(C(CC(=O)O)c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N(CCCCBr)C1C2CN(Cc3ccccc3)CC21
Agent: ClCCCBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1C
Product: CCOC(=O)N(CCCCOC(=O)CC(c1ccccc1)c1cc(C)ccc1OCc1ccccc1)C1C2CN(Cc3ccccc3)CC21

Procedure:
The compound, 3-benzyl-3-azabicyclo[3.1.0]hex-6-yl-(4-bromobutyl)-carbamic acid t-butyl ester, 211.5 mg, 0.5 mmole, 1 eq (prepared by reacting boc-protected 3-benzyl-3-azabicylo[3.1.0]hex-6-yl amine, which in turn, was prepared following the procedure of T. F. Braish et al., Synlett, 1996, 1100, with 1-bromo-3-chloropropane) was dissolved in xylene (15 ml). To this reaction mixture, 3-(2-benzyloxy-5-methylphenyl) 3-phenyl propionic acid (260 mg, 0.75 mmole, 1.5 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.75 mmole, 1.5 eq) were added. The resulting reaction mixture was refluxed for 2 hrs. Xylene was removed under reduced pressure and the residue was purified by column chromatography by using ethyl acetate in hexane solvent system to yield the organic compound, 3-(2-benzyloxy-5-methylphenyl)-3-phenyl propionic acid 4-[(3-benzyl-3-azabicylo[3.1.0]hex-6-yl)-ethoxy carbonylamino]butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:16].O>CN(C)C=O>[CH3:16][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c([N+](=O)[O-])cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17.7 %

Procedure:
To a solution of 4-nitro indazole [WO-A-0135947] (5.0 g, 31 mmol) in dimethylformamide at 0° C. was added sodium hydride (1.34 g of a 60% dispersion in oil, 34 mmol). The mixture was stirred at room temperature for 10 minutes. Iodomethane (2.28 ml, 37 mmol) was added and the reaction stirred at room temperature for 90 minutes. Water (500 ml) was added and the reaction extracted into ethyl acetate (3×200 ml). The combined organic layers were washed with water (2×200 ml) then dried (Mg2SO4) and evaporated. Trituration overnight in dichloromethane/hexane gives 0.97 g of pure 1-methyl-4-nitro-1H-indazole. The remaining solution was condensed and purified by column chromatography on silica eluting with 40-20% hexane in dichloromethane to give additional 1-methyl-4-nitro-1H-indazole (1.30 g, total 2.27 g, 42%) as the less polar product 1H NMR (360 MHz, CDCl3) 4.18 (3H, s), 7.52 (1H, t, J 8.0), 7.77 (1H, d, J 8.4), 8.15 (1H, d, J 7.7), 8.61 (1H, s); and as the more polar, 2-methyl-4-nitro-2H-indazole (1.50 g, 28%). 1H NMR (400 MHz, CDCl3) 4.32 (3H, s), 7.40 (1H, t, J 8.0), 8.07 (1H, d, J 8.6), 8.18 (1H, d, J 7.6), 8.55 (1H, s).