Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(O)/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1cccc(Cl)c1)c1cccc(Cl)c1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 109 %

Procedure:
As in Example 115, (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid (4.79 g) and 4-nitrophenol (2.5 g) in dichloromethane (50 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.1 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 1 hour. The usual work up furnished 7.2 g of (E)-5,5-bis(3-chlorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH2:15])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3].[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C@@:26]21[CH2:44][C:36]1=[N:37][CH:38]=[C:39]([C:41](O)=[O:42])[CH:40]=[C:35]1[CH2:34]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:1]([C@@H:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([NH:15][C:41]([C:39]2[CH:40]=[C:35]3[CH2:34][C@@:26]4([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]4=[O:24])[CH2:44][C:36]3=[N:37][CH:38]=2)=[O:42])[CH2:7][CH2:6][C@H:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=1[F:23])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Reactant: O=C(O)c1cnc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
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: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](NC(=O)c2cnc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-amine (the mixture of diastereomers described in Intermediate 11) (90 mg, 0.28 mmol), (6S)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxylic acid (described in Intermediate 4) (85 mg, 0.30 mmol) and HATU (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (160 mg, 0.43 mmol) in DMF (3.0 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.86 mmol), and the resulting mixture was stirred at ambient temperature for 16 h. The reaction mixture was partially purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H2O:CH3CN:TFA-100:0:0.1 to 0:100:0.1. Product-containing fractions were combined and neutralized with saturated aqueous sodium carbonate and the acetonitrile was removed by evaporation under reduced pressure. The resulting mixture was extracted with ethyl acetate (50 mL) and dichloromethane (2×50 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of four diastereomers. Separation of the diastereomers was achieved by SFC on a ChiralCel OJ-H column, eluting with CO2:MeOH-80:20, to give four diastereomers in approximately a 2:1:2:5 ratio:
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[N:18]=[CH:19]3)=[CH:6][C:5]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[C:4]([CH3:15])[CH:3]=1
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)CCc1cc(Br)c(N)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCc1cc(-c2ccc3c(cnn3C)c2)c(N)cc1C
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
A solution of Intermediate 9 (460 mg) in 1,4-dioxane (5 ml, KANTO) was added with 1-methyl-1H-indazol-5-ylboronic acid (rgt1, 350 mg), cesium carbonate (410 mg, KANTO), and PdCl2dppf·CH2Cl2 (115 mg, Ald), and stirred at 90° C. for 18 hours. The reaction mixture was cooled to room temperature, and then added with water (30 ml) and ethyl acetate (30 ml×2) to perform extraction. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride, and saturated brine, the organic layer was dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Yamazen, n-hexane:ethyl acetate=3:1), and the solvent was evaporated under reduced pressure by using a rotary evaporator to obtain the title compound (400 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([OH:15])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[C:13]1(=[O:15])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1COc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A mixture of 2-(2-naphthoxy)acetic acid (3.06 g, 15.1 mmol) and oxalyl chloride (7 mL, 80.3 mmol) was heated at reflux for 45 min, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in toluene, and to this was added aluminium chloride (2.40 g, 18.1 mmol). The resulting mixture was stirred at room temperature for 1 h, then poured into ice. The organic phase was separated and washed with saturated aqueous NaCl. Removal of the solvent in vacuo provided the title compound (2.71 g, 97%).
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][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][CH:24]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[CH:24][CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: O=CCCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Product: ClCC=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be reacted with α-chloroacetaldehyde to give 7-chloro-2-[(2-chloroethylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1](N(CC)CC)C.[F:8][C:9]([F:27])([F:26])[C:10]1[S:14][C:13]([NH:15][C:16](=[S:25])[S:17][CH2:18][CH2:19][C:20]([F:24])=[C:21]([F:23])[F:22])=[N:12][N:11]=1.CI>CN(C)C=O.O>[CH3:1][N:15]([C:13]1[S:14][C:10]([C:9]([F:8])([F:26])[F:27])=[N:11][N:12]=1)[C:16](=[S:25])[S:17][CH2:18][CH2:19][C:20]([F:24])=[C:21]([F:23])[F:22]
Reactant: CCN(CC)CC
Reactant: FC(F)=C(F)CCSC(=S)Nc1nnc(C(F)(F)F)s1
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=S)SCCC(F)=C(F)F)c1nnc(C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.5 %

Procedure:
Triethylamine (0.69 gram, 0.0068 mole) was added to a stirred solution of (3,4,4-trifluoro-3-butenyl) N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)-dithiocarbamate (2.0 grams, 0.0057 mole) in dimethylformamide (5.7 ml) at ambient temperature. After addition was complete, the reaction mixture stirred for one hour and was then cooled to 0° C. Methyl iodide (1.0 gram, 0.0063 mole) was added to the cooled mixture. After warming to ambient temperature, the reaction mixture was stirred overnight. The reaction mixture was diluted with water (200 ml) and extracted three times with diethyl ether. The combined extracts were washed with 10% aqueous hydrochloric acid. The dried (magnesium sulfate) extracts were concentrated under reduced pressure, leaving a residue. This residue was passed through a column of silica gel, eluting with hexane to yield the first product (3,4,4-trifluoro-3-butenyl) N-(methyl)-N-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)dithiocarbamate (0.45 gram) as a yellow oil. Eluting solvent was then changed to hexane:ethyl acetate (1:1) to yield the second product methyl(3,4,4-trifluoro-3-butenyl) N-(5-trifluoromethyl- 1,3,4-thiadiazol-2-yl)imidodithiocarbonate (0.96 gram) as an orange oil. The NMR spectra were consistent with the proposed structures.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:37]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1>C(O)=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:37])[CH2:14][C@H:15]([OH:36])[C@@H:16]([NH:24][C:25](=[O:35])[C@H:26]([CH:32]([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=CO
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C

Procedure:
0.94 g (1.5 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane and 18 ml of formic acid are stirred at room temperature for 6 hours and worked up analogously to Example 2d to form the title compound: FAB MS (M+H)+ =526.
Reaction SMILES: CN(/[CH:4]=[N:5]/[C:6]([C:8]1[CH:9]=[C:10]2[C:19](=[CH:20][CH:21]=1)[C:18]1[N:14]([CH:15]=[C:16]([C:22]3[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=3)[N:17]=1)[CH2:13][CH2:12][O:11]2)=O)C.Cl.[C:32]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][NH2:43])[CH2:38][CH2:37]1)([CH3:35])([CH3:34])[CH3:33]>CC(O)=O>[C:32]([N:36]1[CH2:37][CH2:38][CH:39]([N:42]2[C:6]([C:8]3[CH:21]=[CH:20][C:19]4[C:18]5[N:14]([CH:15]=[C:16]([C:22]6[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[C:24]([CH3:30])[N:23]=6)[N:17]=5)[CH2:13][CH2:12][O:11][C:10]=4[CH:9]=3)=[N:5][CH:4]=[N:43]2)[CH2:40][CH2:41]1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)N1CCC(NN)CC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/N=C/N(C)C)cc2OCC3)n(C(C)C)n1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4ncnn4C4CCN(C(C)(C)C)CC4)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 48.5 %

Procedure:
A mixture of N-[(1E)-(dimethylamino)methylidene]-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene-12-carboxamide (50 mg, 0.12 mmol) and 1-tert-butyl-4-hydrazinylpiperidine hydrochloride (51 mg, 0.25 mmol) in AcOH (10 mL) was heated at 100° C. for 1 h. The solvent was removed under reduce pressure, and the residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 258 (30 mg, 48% yield) as a white solid. LCMS (ESI): RT=4.77 min, m/z: 516.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.43-7.41 (dd, J=8.5, 2.0 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 5.86 (m, 1H), 4.58 (s, 4H), 4.29 (m, 1H), 3.08-3.06 (m, 2H), 2.26 (s, 3H), 2.13-2.02 (m, 6H), 1.48-1.47 (d, J=6.5 Hz, 6H), 1.02 (s, 9H)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>>[C:1]([NH:4][C:5]1[S:6][C:7]([Br:18])=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1sccc1C(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)Nc1sc(Br)cc1C(N)=O
Reaction time: 8 h
Yield: 13.9 %

Procedure:
2-Acetylamino-thiophene-3-carboxylic acid amide (3.89 g, 27.4 mmol) was suspended in the aqueous solution of sodium acetate (2.47 g, 30.1 mmol)(136 mL). Bromine (1.4 mL, 27.4 mmol) was added dropwise to the solution. The resulting solution was stirred under nitrogen overnight. Once the LC-MS showed no remaining starting materials, the reaction mixture was then filtered and washed with water (50 mL). The filtrate was then purified utilizing a Gilson preparative. HPLC to give the above titled compound as a brown solid (1 g, 13.8%). LC-MS [M+H]+ m/z 263.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14]CCCC.C=CCCCC>C1COCC1>[CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Solvent: C1CCOC1
Solvent: C=CCCCC
Product: CCCC/C=C\CCCCCCCCO
Reaction time: 5 h
Yield: 77 %

Procedure:
In a glovebox, a 20 mL vial was charged with oleyl alcohol (1.0 g, 3.7 mmol), 1-hexene (4 mL), and THF (4 mL). A solution of 1 (0.023 g, 1 mol %) in THF (0.5 mL) was added, and the mixture was stirred in an open vial for 5 hours. The vial was removed from the glovebox, the reaction was quenched with excess ethyl vinyl ether, and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of hexanes to 20% EtOAc in hexanes) provided 3 (0.73 g, 77% yield, 86% Z as determined by 1H-NMR) as a colorless oil; 1H NMR (CDCl3): δ 5.35 (2H, m), 3.64 (2H, td, J=6.6, 5.3 Hz), 2.02 (4H, m), 1.57 (2H, m), 1.22-1.39 (15H, m), 0.90 (3H, t, J=7.1 Hz); 13C NMR (CDCl3): δ 129.9, 129.8, 63.1, 32.8, 32.0, 29.8, 29.5, 29.4, 29.2, 27.2, 26.9, 25.7, 22.4, 14.0; HRMS (FAB): 213.2215, [C14H28O+H]+ requires 213.2218.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]([OH:16])=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(OCC)C>ClCCl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=[CH:11][C:4]=2[CH:3]=1
Reactant: OC1=Cc2ccccc2C=Cc2cc(Cl)ccc21
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1Cc2ccccc2C=Cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
To a solution of 2-chloro-5-hydroxy-dibenzo[a,e]cyclooctene (1.5 g) in dry dichloromethane (60 ml) was added pyridinium dichromate (5 g) and crushed 4 A molecular sieves (2.5 g). After stirring at room temperature for 14 h, diethyl ether (150 ml) was added and the reaction mixture was filtered through a plug of celite. The solvent was removed in vacuo and the residue purified by chromatography on flash silica with 5% ethyl acetate in hexane as eluent to give. as a colourless oil, the title compound (1.4 g). δ (360 MHz, CDCl3) 4.04 (2H. s, CH2), 6.93 (1H, d, J =12.9 Hz, CHA =CHB), 7.10 (1H. d, J=12.9 Hz, CHA =CHB), 7.22-7.42 (6H, m, ArH), 8.17 (1H. d, J =8.4 Hz, ClC=CH--CH=C--C=O). m/e 256 and 254 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[N:5][C:4](=[N:20]O)[C:3]1=[O:22]>CO.[Ru]>[NH2:20][CH:4]1[N:5]=[C:6]([N:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]1=[O:22]
Reactant: CC1CCN(c2nc(=NO)c(=O)n(C)c3ccccc23)CC1
Agent: [Ru]
Solvent: CO
Product: CC1CCN(C2=NC(N)C(=O)N(C)c3ccccc32)CC1
Reaction time: 24 h

Procedure:
A suspension of 1,2-dihydro-1-methyl-3-oximino-5-(4-methylpiperidin-1-yl)-3H-1,4-benzodiazepin-2-one (0.27 g) and 5% ruthenium on carbon (0.16 g) in methanol (50 ml) was hydrogenated at 55 psi H2 at 70° for 24 h. The catalyst was then removed by filtration and the solvent evaporated. The residue was purified by filtration and the solvent evaporated. The residue was purified by column chromatography on silica with CH2Cl2:MeOH 98:2∆9:1 as eluant to afford product.
Reaction SMILES: [CH2:1]([N:3]1CCOCC1)[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C@H:25]([C:38]([OH:40])=O)[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][CH:28]=1.Cl.C(N)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[NH:24]([C:41]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:42])[C@H:25]([C:38]([NH:3][CH2:1][CH3:2])=[O:40])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[CH:29][CH:28]=1
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reactant: CCN1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
3.2 ml (25 mmoles) of N-ethylmorpholine and 5.56 g (27 mmoles) of dicyclohexylcarbodiimide are added at 0° C. to a solution in 50 ml of dimethylformamide of 9.27 g (25 mmoles) of Z-Tyr(But)-OH, 2.03 g (25 mmoles) of ethylamine hydrochloride and 3.38 g of 1-hydroxybenzotriazole. The mixture is stirred for two hours at 0° C. and for 5 hours at room temperature and is left to stand overnight at room temperature. The precipitate is filtered off and the filtrate is concentrated. The resulting oil is partitioned between ethyl acetate and water. The ethyl acetate phase is extracted by shaking with KHSO4 solution, NaHCO3 solution and water, is dried over Na2SO4 and is concentrated. The residue cyrstallizes from petroleum ether. Yield 9.63 g (96% ), melting point 107°-110°, [α]D22 =-0.5° (c=1, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1)[CH2:8][CH:7]2[C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:22]=1[C:9]1([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]1)[CH2:8][CH:7]2[C:23]([CH3:29])([CH3:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C(C)(C)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)c2c(Br)cccc21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)C1CC2(CCNCC2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-Tert-butyl 7-bromo-3-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (152 mg, 0.317 mol) was dissolved in 20% TFA at 0° C. The mixture was stirred for 1 h at rt. The solvent was removed under reduced pressure to give (±)-ethyl 2-(7-bromo-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)-2-methylpropanoate which was used without purification (120 mg, 100%).
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[N:10]2[CH:16]=[N:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]2[CH2:8][N:7]=1>C(O)(=O)C>[S:13]1[C:12]2[C:6]3[N:7]([CH:3]=[CH:4][N:5]=3)[CH2:8][C:9]3[N:10]([CH:16]=[N:17][C:18]=3[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]=2[CH:15]=[CH:14]1
Reactant: CCOC(=O)c1ncn2c1CN=C(NCC(OC)OC)c1sccc1-2
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1Cn1ccnc1-c1sccc1-2

Procedure:
6. By heating ethyl 6-[(2,2-dimethoxyethyl)amino]-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepine-3-carboxylate in acetic acid for 1.5 h. in an analogous manner to that described in Example 5, there is obtained ethyl 8H-diimidazo[1,5-a:1',2'-d]thieno[2,3-f][1,4]diazepine-7-carboxylate of m.p. 203°-204°.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11].CI>O1CCCC1>[Cl:6][C:7]1[C:8]([CH3:1])=[C:9]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:10]([OH:12])=[O:11]
Reactant: [Li]CCCC
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
n-Butyl lithium (2.5M in hexanes, 180 ml) was added during 1 hour to a stirred solution of 3,4-dichlorobenzoic acid (40.0 g) at -78° C. and stirring maintained at that temperature overnight. A solution of methyl iodide (72 ml) in tetrahydrofuran was then added during 1.5 hours and the mixture kept at -78° C. for 3 hours and allowed to warm to room temperature overnight. The solvent was evaporated and the mixture added to water, acidified (concentrated hydrochloric acid) and extracted (ethyl acetate). The extract was dried (magnesium sulphate), evaporated and triturated (ether) to give 3,4-dichloro-2-methylbenzoic acid (33.3 g) as a white solid, m.p. 177°-178° C.
Reaction SMILES: C[SiH2]C1C=CC=CC=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10].[N+:20]([CH3:23])([O-:22])=[O:21]>C(O)C>[N+:20]([CH2:23][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:19][CH:18]=1)[OH:17])([O-:22])=[O:21]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C[N+](=O)[O-]
Agent: C[SiH2]c1ccccc1
Solvent: CCO
Product: O=[N+]([O-])CC(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Poly (methylphenylsilane)-supported copper (204 mg, 5 mmol) was added to an ethanol (2.0 ml) solution of p-nitrobenzaldehyde (0.4 mmol) and nitromethane (1.2 mmol), and was stirred at room temperature for 3 hr. The reaction mixture was filtrated, and the filtrate was concentrated, and analyzed by 1H-NMR. Resultantly, 2-nitro-1-(4-nitrophenyl)ethanol was produced at the conversion rate of 95%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH3:40][N:41]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1)[CH3:42]>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:12]([C:13](=[O:15])[NH:50][C:47]2[CH:46]=[CH:45][C:44]([CH2:43][N:41]([CH3:42])[CH3:40])=[CH:49][CH:48]=2)[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)Cc1ccc(NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)cc1
Reaction time: 1 h

Procedure:
3-(tert-Butoxycarbonylamino-methyl)-benzoic acid, (754 mg, 3.0 mmol), EDC (958.5 mg, 5.0 mmol), and HOBt (540.5 mg, 5.0 mmol) were combined in a reaction vial and DMF (5 mL) then N-methylmorpholine (0.549 mL, 5.0 mmol) were added. The reaction mixture was agitated for 1 h, then 4-dimethylaminomethyl-phenylamine (451 mg, 3 mmol) was added as a solution in 1 mL DMF. Shaking was continued 48 h. The reaction mixture was diluted to 50 mL with dichloromethane, washed with NaHCO3 (satd. aq., 1×25 mL, and brine (1×25 mL), dried and evaporated to a residue weighing approximately 2 g, which was taken up in 10 mL dichloromethane and treated with Si-isocyanate (silica-bound alkyl isocyanate; 1.2 g, 14.4 mmol). The resulting mixture was agitated overnight and the silica reagent was filtered. The filtrate was evaporated to provide the intermediate ([3-(4-dimethylaminomethyl-phenylcarbamoyl)-benzyl]-carbamic acid tert-butyl ester), which was treated directly with a solution of TFA (2 mL) in dichloromethane (5 mL). The reaction mixture was stirred for 2 h, then the solvents were evaporated and the residue was re-dissolved in dichloromethane (25 mL). This solution was washed with NaHCO3 (satd. aq., 1×25 mL). To this wash was added 1 g Na2CO3 and the wash was extracted with dichloromethane (2×25 mL). The organic extracts were combined and washed with brine (1×25 mL), dried and evaporated to 160 mg of a solid (3-aminomethyl-N-(4-dimethylaminomethyl-phenyl)-benzamide-20%-2 steps) which was used directly. This intermediate (28.3 mg, 0.1 mmol) was dissolved in DMF (1 mL), and 4-isocyanato-1,2-dimethoxy-benzene (23.3 mg, 0.13 mmol) was added. The resulting mixture was agitated for 48 hours, then was purified directly by preparative HPLC using an acetonitrile/water/formic acid gradient. The title compound was collected as a formate salt (31 mg, 67% yield), MS analysis electrospray, 426 (M+H).