Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:30])=[CH:20]\[C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1.[Hg]>[C:1]12([C:11]3[CH:12]=[C:13](/[C:19](/[CH3:30])=[CH:20]/[C:21]4[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:26])=[CH:23][CH:22]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: BrCc1ccccc1
Reactant: COc1ccc(/C(C)=C\c2ccc(C(=O)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [H-]
Agent: [Hg]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(/C(C)=C/c2ccc(C(=O)OCc3ccccc3)cc2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 21.9 %

Procedure:
2 g (5 mmol) of 4-[(Z)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoic acid obtained in Example 23(c) in 900 ml of THF are irradiated under UV by means of a HANOVIA mercury lamp (550 W) for 10 h at room temperature, to give a 1/1 mixture of E and Z isomers. After evaporation of the THF, this mixture is treated with 190 mg (6 mmol) of 80% NaH in oil and 0.83 ml (7 mmol) of benzyl bromide. After the same treatment as in Example 1(a), followed by a recrystallization from hexane, 0.54 g of benzyl 4-[(E)-2-(3-(1-adamantyl)-4-methoxyphenyl)propenyl]benzoate is isolated which melts at 230°-240° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:21][CH2:22][CH3:23])[CH2:5][CH2:6][NH:7][C:8]1[NH:13][C:12]2[CH:14]=[CH:15][S:16][C:11]=2[C:10](=[O:17])[C:9]=1C(O)=O)[CH3:2].C[O-].[Na+:26]>>[CH2:22]([O:21][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]2[CH:14]=[CH:15][S:16][C:11]2=[C:10]([O-:17])[CH:9]=1)[CH3:23].[Na+:26]
Reactant: CCOC(CCNc1[nH]c2ccsc2c(=O)c1C(=O)O)OCC
Agent: C[O-]
Agent: [Na+]
Product: CCOC(CCNc1cc([O-])c2sccc2n1)OCC
Temperature: 25 °C

Procedure:
5-(3,3-Diethoxypropylamino)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylic acid (432 g, 1.27 mol) was mixed with sodium methoxide (95% pure, 75.8 g, 1.33 mol) and suspended in xylenes (2 L). The resultant mixture was heated at reflux for 2 h. The reaction mixture was gradually cooled to room temperature with stirring to afford light brown solids. The solids were collected by filtration and washed with toluene and dried under vacuum at 50-60° C. for 48 h to give the desired intermediate sodium 5-(3,3-diethoxypropylamino)thieno[3,2-b]pyridin-7-olate (a solid). This crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO d6) δ 1.08 (m, 6H), 1.72 (q, 2H, J=6.8 Hz), 3.15 (m, 2H), 4.55 (t, 1H, J=6 Hz), 6.22 (s, 1H), 6.98 (d, 1H, J=5.2 Hz), 7.53 (d, 1H, J=5.2 Hz).
Reaction SMILES: [C:1](=[S:3])=S.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH:24]([NH2:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][CH:21]=1>CCOCC>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([N:31]=[C:1]=[S:3])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:32][CH:33]=1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: S=C=NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: -35 °C
Reaction time: 3 h

Procedure:
A mixture of 80 ml of carbon disulfide and 39.82 g (0.193 mole) of dicyclohexylcarbodimide in 100 ml of anhydrous ether, under dry N2, is cooled with stirring to -35° C. Then 42.23 g (0.194 mole) of p-chlorobenzhydrylamine in 500 ml of dry ether is added over about 5 min such that the temperature within the reaction vessel does not rise above -20° C. The temperature is allowed to rise slowly over 3 hrs. to ca.25° C and stirring is continued overnight. Dicyclohexylthiourea was removed by filtration and the filtrate is taken to dryness in vacuo. The cloudy oil is treated with 500 ml of pentane which dissolves the product and precipitates more insoluble impurities. Filtration through filter aid (diatomaceous earth) and solvent removal in vacuo gives p-chlorobenzhydryl isothiocyanate as an oil; IR (neat) 2140 cm-1.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][N:6]([C:8](=[S:23])[CH2:9][CH2:10][C:11]1[S:12][C:13]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[C:16]([F:22])[C:14]=2[N:15]=1)[CH3:7])C.[OH-].[Na+]>O.O1CCOCC1>[F:22][C:16]1[C:14]2[N:15]=[C:11]([CH2:10][CH2:9][C:8]([N:6]([CH3:7])[CH2:5][C:4]([OH:24])=[O:3])=[S:23])[S:12][C:13]=2[C:19]([F:20])=[CH:18][C:17]=1[F:21]
Reactant: CCOC(=O)CN(C)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN(CC(=O)O)C(=S)CCc1nc2c(F)c(F)cc(F)c2s1
Yield: 89 %

Procedure:
To a solution of N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]-N-methylglycine ethyl ester (190 mg, 0.5 mmol) in a mixture of water (3 ml) and dioxane (6 ml) was added dropwise 2N sodium hydroxide (0.6 mmol) with stirring under ice-cooling and the mixture was stirred for 1 hour at room temperature, then diluted with water and washed with ether. The aqueous phase was acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried and then evaporated to yield a residue, which was crystallized from isopropyl ether to give N-[3-(4,5,7-trifluorobenzothiazol-2-yl)-1-thioxopropyl]-N-methylglycine (155 mg, 88%) as a pale brown powder.
Reaction SMILES: Cl[CH:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1>C(O)C.[Pd]>[CH2:3]([C:4]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc(CCc2cccnc2CC(Cl)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(CCc2cccnc2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.8 %

Procedure:
Methyl 4-[2-(2-(2-chloro-2-(phenyl)ethyl)-3-pyridyl)ethyl]benzoate (0.537 g, 1.29 mmol) was dissolved in ethanol (10 ml). The solution was treated with palladium on carbon (10% Pd, 0.1 g) and placed under a hydrogen atmosphere. The reaction was stirred at ambient temperature for 18 hours, then filtered and the solvent evaporated to give methyl 4-[2-(2-(phenethyl)-3-pyridyl)ethyl]benzoate (0.467 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCc1ncco1
Product: COc1cc(F)ccc1-c1ccncc1N(Cc1ncco1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-oxazol-2-ylmethyl-amine and 3-methanesulfonyl-5-trifluoromethyl-benzoic acid (example 144, intermediate a) after a reaction time of 72 hours. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product-containing fractions were pooled and evaporated. The remaining red solid was purified by preparative HPLC (Gemini NX) with a gradient of methanol:water containing 0.05% formic acid (80:20 to 98:2). Colorless foam (41%). MS (ESI): m/z=550.105 [M+H]+.
Reaction SMILES: [N+:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([O-:3])=[O:2].O.[NH2:14][NH2:15].C(O)(=O)C>C(O)C>[N+:1]([CH2:4][C:5](=[N:14][NH2:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: NN
Reactant: O=C(C[N+](=O)[O-])c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NN=C(C[N+](=O)[O-])c1ccccc1
Yield: 81.1 %

Procedure:
A solution of 2-nitroacetophenone (12.28 g, 0.074 mol) in ethanol (100 mL) was treated with hydrazine hydrate (10.24 g, 0.163 mol) and glacial acetic acid (4.2 mL, 0.074 mol) and the mixture was heated at reflux for 3 hours. The solvent was then evaporated in vacuo. The residue was dissolved in trichloromethane and extracted three times with water to remove the excess of hydrazine hydrate. Evaporation of the organic layer yielded the product (11 g, 0.06 mol, 81%), which was used in the next step without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]CC)=[O:19])=[CH:13][C:12]=1[Cl:23].[OH-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[Cl:23]
Reactant: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)c1
Yield: 79.7 %

Procedure:
Ethyl (4-(2-benzoxazolyl)amino-3-chlorophenyl)acetate (1.70 g, 5.14 mmol) was dissolved in THF (30 ml). To the resulting solution was added 0.5N NaOH (30 ml, 15.0 mmol) under stirring. The resulting mixture was stirred at room temperature for 20 hours. The mixture was concentrated and the residue was acidified with ice-1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(2-benzoxazolyl)amino-3-chlorophenyl)acetic acid (1.24 g, 80%) as a pale yellow crystalline powder.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14]>ClCCl>[C:5]1([CH:6]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)[CH:8]=[CH:9][C:2]([CH:1]2[S:15][CH2:11][CH2:12][CH2:13][S:14]2)=[CH:3][CH:4]=1
Reactant: SCCCS
Reactant: O=Cc1ccc(C=O)cc1
Solvent: ClCCl
Product: c1cc(C2SCCCS2)ccc1C1SCCCS1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 69.9 %

Procedure:
In a three-neck flask, 100 ml in inner volume, made of glass and provided with a stirrer, 4.0 g (30 mmols) of terephthal aldehyde and 30 g of dichloromethane were placed. The reactants, after having added 8.1 g (75 mmols) of 1,3-propane dithiol, were stirred continuously at 25° C. for 20 minutes and, after having subsequently added 6.3 ml (50 mmols) of a boron trifluoride diethyl ether complex, further stirred continuously at 25° C. for two hours, to form a white precipitate. The resultant white precipitate was filtered, to obtain 6.6 g (70% in yield) of 2,2′-(1,4-phenylene) bis-1,3-dithian (hereinafter referred to as “Intermediate (3)”).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=1)[C:7]([OH:9])=O)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH:36]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH2:37][C:38]([O:40][CH3:41])=[O:39]>>[CH3:46][O:45][C:43](=[O:44])[CH2:42][N:36]([CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: COC(=O)CNCC(=O)OC
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)N(CC(=O)OC)CC(=O)OC)cc([N+](=O)[O-])c1
Yield: 79 %

Procedure:
Conversion of 3-nitro-5-(octadecyloxy)benzoic acid to the acid chloride with thionyl chloride followed by treatment with dimethyl iminodiacetate gave a 79% yield of N-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy)benzoyl]glycine methyl ester as an oil after chromatography on silica gel using 25% ethyl acetate-hexane. The nmr spectrum was consistent with the structure.
Reaction SMILES: O1CCCC1.Cl.[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[N:9]=1.[CH3:28][C:29](=[CH:33][CH3:34])[C:30](Cl)=[O:31]>C(N(CC)CC)C>[NH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[C:10]([N:22]2[CH2:27][CH2:26][N:25]([C:30](=[O:31])[C:29]([CH3:28])=[CH:33][CH3:34])[CH2:24][CH2:23]2)[N:9]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: CC=C(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC=C(C)C(=O)N1CCN(c2nc(N)c3cc(OC)c(OC)cc3n2)CC1
Reaction time: 0.33 h
Yield: 47.4 %

Procedure:
To 20 ml of tetrahydrofuran were added 2.4 g of 4-amino-6,7-dimethoxy-2-(1-piperazinyl)quinazoline hydrochloride and 2.6 g of triethylamine, after which the mixture was stirred for 20 minutes. There was then added 0.7 g of 2,3-dimethylacryloyl chloride, after which the mixture was stirred at room temperature for 12 hours. The crystals which were produced were collected by filtration, washed with water and recrystallized from ethanol, to give 1.04 g of the desired Compound No. 3 in the form of pale yellow prisms melting at 219.5°-221.5° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([C:15]1([CH3:39])[C:19](=[O:20])[NH:18][C:17]([C:21]2[N:30]=[CH:29][C:28]([CH2:31][S:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[N:16]1)([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>C(Cl)Cl.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[CH:12]([C:15]1([CH3:39])[C:19](=[O:20])[NH:18][C:17]([C:21]2[N:30]=[CH:29][C:28]([CH2:31][S:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:6])=[CH:27][C:22]=2[C:23]([O:25][CH3:26])=[O:24])=[N:16]1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(CSc2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(CS(=O)c2ccccc2)cnc1C1=NC(C)(C(C)C)C(=O)N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
3-Chloroperoxybenzoic acid (20 mL, 0.00252 mol) is added dropwise to a -78° C. solution of 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-[(phenylthio)methyl]nicotinic acid, methyl ester (1.0 g, 0.00252 mol) and sodium bicarbonate (0.2 g, 0.00238 mol) in methylene chloride. The reaction mixture is stirred at -78° C. for 30 minutes and then at room temperature for 24 hours. The reaction mixture is diluted with 5% sodium metabisulfite solution. The methylene chloride layer is separated, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. The oil is chromatographed using silica gel and hexanes/ethyl acetate (1:1) to (1:2) to (1:9) and finally 100% ethyl acetate as eluant to give the title compound as a yellow solid (0.97 g, 90%), mp 132°-136° C., identified by IR and NMR spectral analyses.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C@@H:2]1[CH2:3][OH:4].S(O[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:4][CH2:3][C@H:2]1[CH2:5][CH2:6][CH2:7][N:1]1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: OC[C@H]1CCCN1CCc1ccc(N2CCCC2)cc1
Temperature: 90 °C

Procedure:
D-Prolinol (2.72 g, 25.0 mmol), 4-pyrrolidinophenethyl mesylate (6.06 g, 22.5 mmol) and sodium carbonate (3.45 g, 25.0 mmol) were added to acetonitrile (150 ml), and they were heated at 90° C. under reflux for 3.5 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was concentrated to dryness under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. 1 M hydrochloric acid was added to the organic layer and pH of the aqueous layer was kept at 1 to extract the intended product in the aqueous layer. 4 M sodium hydroxide was added to the aqueous layer to adjust pH of the aqueous layer to 14, and the intended product was extracted from the precipitates thus formed with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-2-hydroxymethyl-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (4.96 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=2.P(Cl)(Cl)([Cl:19])=O>C(OCC)(=O)C>[Cl:19][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:11]([CH2:12][C:13]([OH:15])=[O:14])=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1[nH]c(=O)c2ccccc2c1CC(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2ccccc2c1CC(=O)O

Procedure:
1,2-Dihydro-3-methyl-1-oxo-4-isoquinoline acetic acid (770 mg., 3.30 mmol) and phosphorous oxychloride (1.0 ml. 10.7 mmol) were refluxed in 8 ml. ethyl acetate for 16 hr then vacuum evaporated to dryness. The residue was partitioned between water and ethyl acetate. The aqueous phase was washed with ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and vacuum evaporated to yield a viscous, homogeneous oil, 1-chloro-3-methyl-4-isoquinoline acetic acid; 772 mg. (99%). This oil (623 mg., 2.65 mmol) in 6 ml. dimethylformamide was added to a solution of 3,4-dichlorobenzyl alcohol (2.75 g., 15.5 mmol) and potassium tert-butoxide (600 mg., 534 mmol) in 2 ml. dimethylformamide and the mixture was heated at 115° for 3 hr. After cooling the mixture was poured onto crushed ice and washed with 3×60 ml. ether. The basic aqueous layer was acidified to pH 3 with 1 N hydrochloric acid and extracted 3×100 ml. ether. The organic extract was dried over magnesium sulfate, filtered, and vacuum evaporated to an oily solid; 568 mg. (57%). Trituration of this residue with methanol then hexane and fractional crystallization from chloroform afforded pure title compound: 44 mg. (4%), mp 180°-183°.
Reaction SMILES: C([O:8][C:9]1[C:10]2[C:11]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[OH:8][C:9]1[C:10]2[C:11]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[C:18]([C:28]([O:30][CH3:31])=[O:29])[C:12]=3[NH:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(OCc3ccccc3)c12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cccc(O)c12
Yield: 110.4 %

Procedure:
A mixture of methyl 9-(benzyloxy)-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.28 g, 3.13 mmol), 10% Pd on carbon (0.567 g, 0.533 mmol) and ammonium formate (0.988 g, 15.7 mmol) in EtOH (8 mL) was heated at reflux for 1 hr. This was filtered and the solvent was removed from the filtrate to leave methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.10 g) which was carried on. A suspension of methyl 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxylate (1.1 g, 3.11 mmol) in 7 N NH3 in MeOH (40 mL) in a sealed microwave vial was heated at 80° C. for 48 h. Filtration afford 9-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide (675 mg, 1.78 mmol, 58% yield) as a solid. MS (ESI) m/z 304.12 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.36 (1H, s), 8.07-8.11 (2H, m), 7.52-7.66 (4H, m), 7.24 (1H, d, J=7.93 Hz), 6.79 (1H, d, J=7.93 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([N:26]([CH3:35])[CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(Cc5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), ethanol (4 ml), and 4-dimethylaminobenzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with 1% to 5% methanol in ethyl acetate. The title compound was obtained as a yellow solid after trituration with diethyl ether (0.006 g, 11%); 1H-NMR (500 MHz, DMSO-d6) 1H-NMR (500 MHz, DMSO-d6) 2.66 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 6.82 (d, J=9.00 Hz, 2H) and 8.01 (d, J=8.76 Hz, 2H) (3,5-C6H4NMe2 and 2,6-C6H4—NMe2), 7.28 (dd, J=4.00, 5.86 Hz, 1H), 7.53 (d, J=9.00 Hz, 1H), 7.80 (td, J=1.70, 9.09 Hz, 1H), and 8.52 (d, J=4.96 Hz, 1H) (pyrid-2-yl protons), 8.14 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.13 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: C([N:5](C1C=CC=CC=1)[C:6](=[O:27])[CH2:7][N:8]1[C:14](=[O:15])[CH2:13][C:12](=[O:16])[N:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]2[CH:23]=[CH:24][CH:25]=[CH:26][C:9]1=2)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:45][C:46]1[C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[N:47]=1>C1COCC1>[C:58]([O:57][C:55]([N:48]1[C:49]2[C:54](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:46]([CH2:45][CH:13]2[C:14](=[O:15])[N:8]([C:7]([C:58]([CH3:61])([CH3:60])[CH3:59])([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:6](=[O:27])[NH2:5])[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[N:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:16])=[N:47]1)=[O:56])([CH3:61])([CH3:60])[CH3:59]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Reactant: CC(C)(C)N(C(=O)CN1C(=O)CC(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(c3ccccc3)c3ccccc3N(C(C(N)=O)(c3ccccc3)C(C)(C)C)C2=O)c2ccccc21
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
To a stirred slurry of 514 mg (1.17 mmol) N-tert-Butyl-2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-phenyl-acetamide, prepared as in Part B, in 15 mL THF cooled to 0° C. is added 1.28 mL (1.28 mmol, 1.1 equiv) of 1M Sodium bis(trimethylsilyl)amide in THF at ambient temperature and stirred 0.5 h. To this solution is added 381 mg (1.22 mmol, 1.05 equiv) 3-bromomethyl-1-tert-butoxycarbonyl-1H-indazole and the resultant reaction mixture stirred 1 h at 0° C. followed by 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into EtOAc (50 mL), washed with H2O (30 mL) and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product is purified by flash chromatography on 20 g silica gel eluted with EtOAc/Hexanes (1:3, 350 mL). Appropriate fractions were combined and concentrated in vacuo to give 263 mg (0.392 mmol) of the title compound as a white foam: 1H NMR (CDCl3, 300 MHz) δ8.04 (d, 1H, J=8.4), 7.89 (d, 1H, J=7.9), 7.51-7.20 (m, 14H), 7.10 (m, 1H), 6.94 (m, 1H), 4.28 (m, 1H), 4.20-4.06 (m, 2H), 3.84 (m, 1H), 3.56 (m,1H), 1.66 (s, 9H), 1.39 (s, 9H); TLC Rf =0.16 (EtOAc/Hexanes, 1:3).