Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[OH-].[Na+].[C:21](Cl)(=[O:28])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25]>C(OCC)(=O)C>[C:15]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:28])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[N:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(C#N)cc2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.9 %

Procedure:
4-(5-Amino-3-tert-butyl-1H-pyrazol-1-yl)benzonitrile (11.8 g, 49.1 mmol) was added to 70 mL of 3 N NaOH and 100 mL of ethyl acetate and the reaction mixture was cooled in an ice-bath. 2,2,2-Trichloroethyl carbonochloridate (9.34 mL, 68.7 mmol) was slowly added and the reaction was warmed to ambient temperature with stirring overnight. The ethyl acetate layer was washed with 3 N HCl and brine, and the organic layer was dried over MgSO4, filtered and concentrated to an oil. Hexane was added to this oil and the mixture was stirred rapidly until a solid formed. The solids were triturated in hexanes, filtered, and dissolved in minimal warm ethyl acetate. Hexanes were added to the ethyl acetate solution until a slight cloudiness was observed. Material was allowed to crystallize and the solids were collected by filtration to yield 6.3 g of the desired product as a white solid, MS M+1 (416).
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH:11]([CH3:20])[CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:13][C:7]=12)=[O:5])C.[OH-].[K+].[CH2:23]([C:25]([NH2:38])([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:26][CH3:27])[CH3:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCO.CCOC(C)=O.O>[CH2:23]([C:25]([NH:38][C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH:11]([CH3:20])[CH:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:13][C:7]=12)=[O:5])([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=1)[CH2:26][CH3:27])[CH3:24]
Reactant: CCOC(=O)c1cnn2c1NC(c1ccccc1)C2C
Reactant: CCC(N)(CC)c1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(CC)(NC(=O)c1cnn2c1NC(c1ccccc1)C2C)c1ccc(C(F)(F)F)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.4 %

Procedure:
Compound 3 (0.085 g, 0.3 mmol) was dissolved in EtOH (3 mL). KOH (6M in water, 0.9 mL, 1.78 mmol) was added. The reaction stirred at 60° C. for 3 h. The solution was cooled, diluted with AcOEt (10 mL) and water (10 mL) and shaken vigorously. The Aqueous layer was separated and acidified to pH=3. This acidic layer was then extracted with AcOEt (3 times). The combined AcOEt layers were washed with brine, dried (Na2SO4) and concentrated. The residue was then dissolved in NMP (1 mL) and 1-ethyl-1-(4-trifluoromethyl-phenyl)-propylamine (0.087 g, 0.37 mmol), HATU (0.14 g, 0.37 mmol), and DIEA (0.14 mL, 0.78 mmol) were added. The reaction was heated to 80° C. for 2 days. The solution was then cooled, washed with water, dried (MgSO4), and concentrated. Flash chromatography (20% AcOEt/hexanes) gave 0.017 g (12% yield) of amide 5.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[N:5][N:6]=1.[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1)[CH:11]=[O:12].[NH4+].[Cl-].CC(OC)(C)C>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:11]([C:4]2[O:3][C:2]([CH3:1])=[N:6][N:5]=2)[OH:12])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1nnco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: Cc1nnc(C(O)c2cc(Br)cc(C(F)(F)F)c2)o1
Reaction time: 0.5 h

Procedure:
2.79 g (33.2 mmol) of 2-methyl-1,3,4-oxadiazole are dissolved in 45 ml THF at −5° C., 33.2 mmol (25.54 ml) of isopropyl magnesium chloride-lithium chloride complex are added during 20 minutes while the temperature is kept <0° C. The mixture is kept at 0° C. for 30 minutes, then 0.8 Eq (6.7 g) of 3-Bromo-5-trifluoromethyl-benzaldehyde are added and the resulting mixture is allowed to reach RT and stirred for additional 60 minutes. The reaction is then stopped by the addition of 10 ml saturated NH4Cl solution. 50 ml MTBE are added, the organic phase is separated, washed with brine and dried over MgSO4. The solvent is removed in vacuo and the crude material (9 g) is used without further purification in the next step:
Reaction SMILES: Cl[CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1.[NH3:11]>CO>[NH2:11][CH2:2][CH:3]([OH:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: OC(CCl)Cn1ccnn1
Reactant: N
Solvent: CO
Product: NCC(O)Cn1ccnn1
Temperature: 25 °C
Yield: 100 %

Procedure:
1-Chloro-3(1,2,3)triazol-1-ylpropan-2-ol (2.3 g, 13 mmol) was treated with the solution of NH3 in methanol (25% by weight, 20 mL) at 60° C. overnight in a sealed pressure vessel. After cooling to room temperature, nitrogen was bulbbed into the reaction mixture to remove the ammonia. Evaporation of solvent gave the hydrogen chloride salt of 1-amino-3-(1,2,3)triazol-1-ylpropan-2-ol (2.57 g, 100%). 1H NMR (DMSO-d6) δ2.68 (dd, J=8.8, 12.8 Hz, 1H), 2.97 (dd, J=3.6, 12.8 Hz, 1H), 4.15 (m, 1H), 4.44 (dd, J=6.4, 14 Hz, 1H), 4.57 (dd, J=4.6, 14 Hz, 1H), 5.95 (d, J=5.2 Hz, 1H, OH), 7.77 (s, 1H), 8.01 (brs., 3H, NH3+), 8.12 (s, 1H). MS (m/z) 143.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=1)[CH3:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (4-chloro-3-hydroxy-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: CN(C)CC(N1C2C(=CC(OC)=C(NC3N4C(=NC5C(C4=O)=C(F)C=CC=5)C4C=CN(S(C5C=CC(C)=CC=5)(=O)=O)C=4N=3)C=2)CC1)=O.C(N)CC.[CH3:52][N:53]([CH3:102])[CH2:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][C:62]([O:100][CH3:101])=[C:63]([NH:66][C:67]3[N:68]=[C:69]([NH:86][C:87]4[CH:98]=[CH:97][CH:96]=[C:95]([F:99])[C:88]=4[C:89]([NH:91][CH2:92][CH2:93][CH3:94])=[O:90])[C:70]4[CH:75]=[CH:74][N:73](S(C5C=CC(C)=CC=5)(=O)=O)[C:71]=4[N:72]=3)[CH:64]=2)[CH2:59][CH2:58]1)=[O:56].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C.O1CCOCC1>[CH3:102][N:53]([CH3:52])[CH2:54][C:55]([N:57]1[C:65]2[C:60](=[CH:61][C:62]([O:100][CH3:101])=[C:63]([NH:66][C:67]3[NH:72][C:71]4=[N:73][CH:74]=[CH:75][C:70]4=[C:69]([NH:86][C:87]4[CH:98]=[CH:97][CH:96]=[C:95]([F:99])[C:88]=4[C:89]([NH:91][CH2:92][CH2:93][CH3:94])=[O:90])[N:68]=3)[CH:64]=2)[CH2:59][CH2:58]1)=[O:56]
Reactant: CCCNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCCN
Product: CCCNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (200 mg, 0.305 mmol) in THF (5 mL) was added propylamine (0.125 mL, 1.52 mmol). The resulting mixture was let stir at rt for 3 h at which time it was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was attempted to be purified via chromatography on SiO2 and afforded a solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-propylbenzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a solution of 2M NaOH, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-propylbenzamide (68 mg, 0.121 mmol) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.38 Hz, 3 H), 1.44-1.57 (m, 2H), 2.26 (s, 6 H), 3.06-3.28 (m, 6 H), 3.18 (s, 2 H), 3.77 (s, 3 H), 4.18 (t, J=8.34 Hz, 2 H), 6.25 (dd, J=3.25, 1.79 Hz, 1 H), 6.84-7.00 (m, 3 H), 7.25-7.38 (m, 1 H), 7.57 (s, 1 H), 8.32 (d, J=8.25 Hz, 1 H), 8.55-8.67 (m, 2 H), 9.86 (s, 1 H), 11.26 (s, 1 H). (ESIMS (M+H)+=561)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>CN(C=O)C.O>[CH2:18]([O:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)c1cnc(-n2cccn2)nc1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 60 °C
Yield: 42 %

Procedure:
To a solution of ethyl 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylate, 3-a, (0.62 g, 2.7 mmol) in DMF (7 ml) were added benzyl chloride (0.5 g, 3.99 mmol) and Et3N (0.8 g, 7.97 mmol). The resulting mixture was then heated at 60° C. for 12 hours. Then the mixture was cooled to room temperature and diluted with water followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of ethyl acetate/petroleum ether=1/1 (Rf=0.7) to afford the compound, 3-b, (0.36 g, 42%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Cl.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=C(OC)C(OC)=C(OC)C=3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: COc1cc(Cn2nc3c(c2-c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC3)cc(OC)c1OC
Product: COc1cc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCNCC3)cc(OC)c1OC
Yield: 7 %

Procedure:
The title compound (0.006 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4,5-trimethoxybenzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(3,4,5-trimethoxy-benzyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C23H26ClN3O3, 427.17; found, m/z 428.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.51-7.49 (m, 2H), 7.46-7.44 (m, 2H), 6.44 (s, 2H), 5.32 (s, 2H), 3.78 (s, 6H), 3.74 (s, 3H), 2.95-2.89 (m, 6H), 2.81-2.79 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2cccc(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 30.44 g of 5-aminopyridine-2-carboxylic acid methyl ester, 30.9 g of m-chlorobenzaldehyde and 400 ml of benzene is refluxed on a water-trap for 3 days. It is evaporated and the residue recrystallized from benzene/ethylacetate/diethyl ether, to yield the 5-(m-chlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 139°-142°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].C([Li])(CC)C.[CH3:16][S:17]SC>C1COCC1>[F:1][C:2]1[C:7]([S:17][CH3:16])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(C)ccc1F
Reactant: CSSC
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(C)cc(SC)c1F
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 1-fluoro-2-methoxy-4-methylbenzene (1.0 g) and THF (dry) (60 mL) was added sec-butyllithium (1.04 mol/L cyclohexane solution, 13.72 mL) dropwise over a period of 20 min at −78° C. After stirring at −78° C. for 20 min, to the mixture was added dimethyl disulfide (1.41 mL) at the same temperature. The mixture was stirred at −78° C. under argon atmosphere for 1 h. The mixture was quenched with saturated aqueous NH4Cl at −78° C. and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (1.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:15]([O-])=O.O.Cl>C(O)C.CO>[NH2:15][C:3]1[CH:4]=[C:5]([NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CN(C)CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: O
Product: CN(C)CC(=O)Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.6 %

Procedure:
A solution of N1-(4-chloro-3-nitrophenyl)-N2,N2-dimethylglycinamide (1.0 g, 3.89 mmol), SnCL2×2 H2O (5.26 g, 23.3 mmol, Aldrich), and 1M HCl (2 mL, Aldrich) in absolute ethanol (100 mL) was allowed to stir at RT overnight. The reaction was diluted with methanol (100 mL) and quenched with saturated NaHCO3 (200 mL). After stirring 2 hrs at rt, the emulsion was filtered through a celite pad and filtrate evaporated. The residue was then resuspended in dichloromethane (200 mL), washed with water (200 mL), organic layer concentrated by rotary evaporation, and placed under high vacuum to provide N1-(3-amino-4-chlorophenyl)-N2,N2-dimethylglycinamide (0.9 g, 55%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.22 (s, 6 H) 2.99 (s, 2 H) 5.29 (s, 2 H) 6.68-6.74 (m, 1 H) 7.03 (d, J=8.61 Hz, 1 H) 7.22 (d, J=2.38 Hz, 1 H) 9.49 (s, 1 H). ESIMS (M+H)+=228.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([OH:16])=[O:15])=[N:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[C:17](=O)([O-])O.[Na+].CI.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C(=O)O)n[nH]c(=O)c2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1n[nH]c(=O)c2cc(OC)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
A mixture of 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid (10.0 g.), sodium hydrogen carbonate (15.0 g.) and methyl iodide (15.0 ml.) in dry dimethylformamide (200 ml.) was stirred at room temperature for 16 hours. The mixture was then poured into water (600 ml.). The precipitated solid was separated, washed first with water then cold methanol, and then recrystallised from methanol to give methyl 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylate (8.6 g.), m.p. 222°-225° C.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:27]=[CH:26][C:13]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20][CH3:21])=[O:19])=[CH:12][CH:11]=2)=[CH:28][CH:29]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 97.1 %

Procedure:
Methyl 2-({4-[3-(4-hydroxyphenoxy)propyl]phenoxy}methyl)benzoate (0.32 g, 0.81 mmol) was dissolved in dichloromethane (10 ml) and cooled to −20° C. Triethylamine (0.123 g, 1.22 mmol) was added drop wise and methanesulfonyl chloride (0.10 g, 0.89 mmol) was added drop wise. The ice bath was removed and the mixture was wormed to room temperature. Diethyl ether (5 ml) was added and the precipitate was filtered off. The organic phase was washed with two portions of brine (5 ml) and dried (MgSO4). Removing the solvent by evaporation gave 0.37 gram of methyl 2-{[4-(3-{4-[(methylsulfonyl)oxy]-phenoxy}propyl)phenoxy]methyl}benzoate (yield 97.3%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:19][O-:20].[Na+].CO.Cl>O.CCOC(C)=O.[Cu]I.CN1C(=O)CCC1>[CH3:14][C:6]1[C:5]2[C:4]([C:15]([OH:17])=[O:16])=[CH:3][C:2]([O:20][CH3:19])=[CH:10][C:9]=2[N:8]([CH:11]([CH3:12])[CH3:13])[CH:7]=1
Reactant: C[O-]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)O)c2c(C)cn(C(C)C)c2c1
Temperature: 120 °C
Yield: 80 %

Procedure:
To methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (1.3 g, 4.19 mmol) and copper(I) iodide (1.0 g, 5.25 mmol) was added NMP (8 mL). To the mixture was added dropwise a solution of sodium methoxide 25 wt % in methanol (4.0 mL, 17.49 mmol) with stirring. The reaction was heated to 120° C. and stirred for 1.5 hr. The reaction was allowed to cool and when the temperature reached 80° C., water (200 uL) was added. The reaction was allowed to continue to cool to RT and stirred overnight. The reaction was acidified with 1 N HCl (17 mL) and diluted with water and EtOAc. The mixture was filtered through Celite and washed with EtOAc. The filtrate was poured into a separatory funnel and the organic phase was separated, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60 g, 20 to 50% EtOAc in hexanes) gave after concentration, trituration with hexanes, filtration and drying under vacuum 3-methyl-1-(1-methylethyl)-6-(methyloxy)-1H-indole-4-carboxylic acid (825 mg, 3.34 mmol, 80% yield) as an light yellow solid. MS(ES)+ m/e 248.3 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Mg]Br)C.[Cl:21][C:22]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25].O>C1COCC1>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:14][C:24](=[NH:25])[C:23]2[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:22]=2[Cl:21])=[CH:15][CH:16]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(Cl)cc1Cl
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: CC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.8 %

Procedure:
4-Benzyloxyaniline hydrochloride (5.0 g, 21.2 mmol) was dropwise added to a solution of ethylmagnesium bromide (44.5 ml, 1M in THF, 44.5 mmol) in 25 ml dry TIHF under nitrogen atmosphere. After stirring for 20 minutes a solution of 2,4-dichlorobenzonitrile (3.65 g, 21.2 mmol) in 25 ml THF was added. The reaction mixture was stirred for 20 hours at room temperature. Water (50 ml) was carefully added. Extraction with EtOAc (2×100 ml), drying (Na2SO4), filtration and evaporation to dryness afforded 7.7 g (98%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10](OCC)[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1.CO.O.[NH2:27][NH2:28]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:27][NH2:28])[CH2:9][N:8]=[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:6]=2[CH:23]=1
Reactant: CCOC1=Nc2ccc(Cl)cc2C(c2ccc(OC)cc2)=NC1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc(C2=NCC(NN)=Nc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 0.11 part of 7-chloro-2-ethoxy-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine in 5 parts by volume of methanol is added 0.2 part by volume of hydrazine hydrate (100%). The mixture is stirred at room temperature for 1.5 hours, and poured into 20 parts by volume of water. The mixture is extracted with chloroform. Chloroform layer is washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off. Treatment of the residue with benzene gives 7-chloro-2-hydrazino-5-(4-methoxyphenyl)-3H-1,4-benzodiazepine as crystals melting at 213°-215° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:45][CH:46]1[C@H:50]2[C@H:51](OC3CCCCO3)[N:52](C(OC(C)(C)C)=O)[C:53]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:54]=3[C:55](=[O:56])[N:49]2[CH2:48][CH2:47]1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[C@H:18]2[C@H:19](OC3CCCCO3)[N:20](C(OC(C)(C)C)=O)[C:21]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:22]=3[C:23](=[O:24])[N:17]2[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:45][CH:46]1[C@@H:50]2[CH:51]=[N:52][C:53]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:54]=3[C:55](=[O:56])[N:49]2[CH2:48][CH2:47]1)[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH:14]1[C@@H:18]2[CH:19]=[N:20][C:21]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:22]=3[C:23](=[O:24])[N:17]2[CH2:16][CH2:15]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 63.2 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15c (180 mg, 0.19 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16c (70 mg, 0.12 mmol, 65%) as a solid: [α]20D=+626° (c=0.17, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.62-1.71 (m, 2H, 14-H), 1.89-1.99 (m, 4H, 13-H, 13′-H), 2.0-2.11 (m, 4H, 2-H, 2′-H), 2.25-2.36 (m, 4H, 1-H, 1′-H), 3.53-3.62 (m, 2H, 3-H, 3′-H), 3.66-3.76 (m, 2H, 11a-H, 11a′-H), 3.77-3.85 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.01-4.16 (m, 4H, 12-H, 12′-H), 6.78 (s, 2H, 9-H, 9′-H), 7.50 (s, 2H, 6-H, 6′-H), 7.64 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 22.5, 29.6, 46.6, 53.7, 56.1, 68.7, 110.5, 111.6, 120.1, 140.6, 147.8, 150.8, 162.3, 164.6; IR (neat): 3350, 2946, 1600, 1505, 1455, 1433, 1383, 1262, 1217, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 625 ([M+2×MeOH]+., 4), 593 ([M+MeOH]+., 12), 547 (M+., 100).