Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:15]([NH:21][C:22]([N:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:14])[NH:9][C:10]1=[O:13])=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: O=c1[nH]cc(-c2ccccc2)c(=O)[nH]1
Product: CCCCCCNC(=O)n1cc(-c2ccccc2)c(=O)[nH]c1=O
Yield: 44 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 1, starting from 5-phenyluracil (0.05 g, 0.26 mmol); 1.8 equivalents of hexyl isocyanate were used herein. The crude was purified by silica gel column chromatography (cyclohexane:EtOAc 70:30) to afford the title compound (0.04 g, 44%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (t, J=6.5 Hz, 3H), 1.16-1.37 (m, 6H), 1.43-1.61 (m, 2H), 3.23-3.32 (m, 2H), 7.30-7.46 (m, 3H), 7.48-7.57 (m, 2H), 8.28 (s, 1H), 9.19 (t, J=5.6, 1H), 11.94 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.14, 22.67, 26.66, 29.31, 31.53, 41.50, 116.87, 128.53, 128.76, 131.49, 136.05, 149.92, 151.03, 161.31. MS (ESI) m/z: 333 [M-NH4]+. MS (ESI) m/z: 314 [M-H]−.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]([CH:25]=O)=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.[CH3:29][NH2:30].[BH4-].[Na+].[ClH:33].C(=O)([O-])O.[Na+]>CO>[ClH:33].[CH3:29][NH:30][CH2:25][C:16]1[CH:17]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]([S:11]([C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: CN
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)c1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
1-{[4-(Methylsulfonyl)phenyl]sulfonyl}-5-phenyl-1H-pyrrole-3-carbaldehyde (60 mg) was dissolved in methanol (20 mL), 40% methylamine methanol solution (120 mg) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (30 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (20 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→7:3), and dissolved in methanol (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 42 mg, 62%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55]1([N:61]=[C:62]=[O:63])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][N:49]([C:62]([NH:61][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[O:63])[CH2:48]1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)Nc2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and phenyl isocyanate as the starting materials in 70% yield. LCMS for C31H32ClN8O2 (M+H)+: m/z=583.0.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])(=O)=O)=CC=1.[C-:30]#[N:31].[Na+].C(OCC)C.O>CS(C)=O>[C:30]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])#[N:31]
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCCCCCCCC(=O)O)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCCCCCCCCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 5 h
Yield: 93.5 %

Procedure:
The methyl ester of 16-paratoluenesulfonyloxy-hexadecanoic acid (600 mg) was dissolved in dimethylsulfoxide (DMSO). Sodium cyanide (250 mg) was added to the solution, and the mixture was stirred at 80° C. for 5 hours. After the reaction mixture was cooled, it was distributed into diethyl ether and water. The diethyl ether layer is dried over anhydrous sodium sulfate and concentrated to give the methyl ester of 16-cyanohexadecanoic acid (370 mg). The product was dissolved in a mixed solvent of ethanol-water (1:1), and lithium hydroxide (180 mg) was added to the solution. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was cooled and ethanol was removed by distillation and extracted with ethyl acetate which had been adjusted to a weak acidic range of pH by adding citric acid. The ethyl acetate layer was dried and concentrated to give 16-cyanohexadecanoic acid (316 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=[N:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[NH2:4].[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=O)=[CH:20][CH:19]=1.N1C=CC=CC=1>O1CCOCC1>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=3)[N:5]=[C:3]([C:2]([F:14])([F:15])[F:1])[N:4]=2)=[CH:20][CH:19]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(NN=C(N)C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(-c2nc(C(F)(F)F)nn2-c2ccc(C)cc2)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
A mixture of 2,2,2-trifluoro-N′-(4-methylphenyl)ethanehydrazonamide (0.62 g, 2.85 mmol), 4-methoxybenzoyl chloride (584 mg, 3.43 mmol), and pyridine (0.277 mL, 3.43 mmol) in dioxane (6 mL) was refluxed with stirring for 1 hour. After cooling, the solvent was removed under reduced pressure. ethyl acetate-tetrahydrofuran (9:1) and water was poured into the residue and the organic layer was separated, washed with 0.1 N hydrochloric acid, water, and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-ethyl acetate 8:1-1:1). The desired product was recrystallized from hexane and dried in vacuo to give 5-(4-methoxyphenyl)-1-(4-methylphenyl)-3-(trifluoromethyl)-1H-1,2,4-triazole (370 mg, 38.9% yield).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:3])[CH3:2].N1C(C)=CC=CC=1C>[Pd].O1CCCC1>[C:1]([O:4][CH:5]([CH3:11])[CH2:6][CH2:7][CH:8]=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)CCC(=O)Cl
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CC(=O)OC(C)CCC=O
Reaction time: 1 h

Procedure:
45.0 g (0.25 mol) of 4-acetoxypentanoic acid chloride are dissolved in 450 ml of abs. tetrahydrofuran. Then 31.9 ml (0.27 mol) of 2,6-lutidine and 9 g of 5% Pd/C are added and hydrogenation is carried out for 1 hour at 10°-15° C. Upon cessation of hydrogenation, the catalyst and the 2,6-lutidine are removed by filtration and the filtrate is concentrated by evaporation. Distillation of the residue gives 4-acetoxypentanal as a colourless liquid of b.p.34 98°-100° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>C(#N)C>[CH:15]1([NH:20][C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: CC#N
Product: O=C(NC1CCCC1)NS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 8 h

Procedure:
To 20 mL of the acetonitrile solution containing 2,3-dichlorobenzenesulfonyl isocyanate, prepared as described in the previous example, was added 2.5 mL of cyclopentylamine. This mixture was allowed to sit overnight. The solid precipitate was filtered off and triturated with 5 mL of acetonitrile. Filtration and drying afforded 5.0 g of the title compound as an off-white solid, m.p. 202°-207° C.; NMR (DMSO-d6): δ1.1-1.8 (m, 8H), 3.7 (m, 1H), 6.5 (br d, 1H), 7.6 (t, 1H), 7.9 (dd, 1H), 8.0 (dd, 1H), 10.8 (br s, 1H); IR (nujol): 3343, 1660, 1375, 1170 cm-1.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([CH:26]([CH3:28])[CH3:27])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:24][N:23]([CH3:25])[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:26]([CH3:28])[CH3:27])=[O:22]
Reactant: CC(C)C(N)C(=O)N(C)C
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)C(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 80 mg, 0.34 mmol) and 2-amino-3,N,N-trimethyl-butyramide hydrochloride (CAN 1257848-66-0, 40.1 mg, 0.27 mmol) as starting materials and isolated (35 mg, 28.4%) as white solid; LC-MS (UV peak area, ESI) 93.77%, 361.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+]>C(O)(C)C>[I:1][C:2]1[C:3]([O:13][CH:14]([CH3:16])[CH3:15])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(OC(C)C)c(I)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)Oc1ncc(C(=O)O)cc1I
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 210 mg (0.63 mmol) of ethyl 5-iodo-6-isopropoxynicotinate (from Step B) in 2.5 mL isopropanol was added 250 μL of 5.0 N NaOH. After stirring at rt for S h, the reaction mixture was partitioned between EtOAc (10 mL) and 1.0 N HCl (10 mL). The organic layer was separated, washed with brine (3×5 mL), dried over MgSO4, and concentrated to give 190 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.44 (d, J=6.4, 6H), 5.44 (m, 1H), 8.66 (d, J=2.1, 1H), 8.83 (d, J=2.1, 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:36][C:35]=1[Cl:46].O>CN(C1C=CN=CC=1)C.C(O)(=O)C>[Cl:46][C:35]1[CH:36]=[C:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH:38]=[CH:39][C:34]=1[N:33]1[C:27](=[O:28])[C:11]2[C:12]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]3=[C:9]([O:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]=2[C:30]1=[O:31]
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)c(Cl)c1

Procedure:
A mixture of 1 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (5.0 g, 11.68 mmol), ethyl (4-amino-3-chlorophenyl)acetate (4.74 g, 22.2 mmol) and DMAP (0.427 g, 3.59 mmol) were heated to 120° C. in acetic acid (20 ml) for 18 hours. Water was added and the mixture and resulting brown solid collected by filtration and washed with water. This was triturated with ether to give a cream solid which was collected by filtration and dried in the vacuum oven (5.34 g, 8.83 mmol). LC/MS: Rt=4.15, [MH]+ 606.
Reaction SMILES: [F-].[K+].[CH3:3][C:4]([O:19][Si](C)(C)C)([C:15]([F:18])([F:17])[F:16])[CH2:5][CH:6]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]1([CH3:14])[CH3:13].OP([O-])(O)=O.[K+]>CO>[CH3:3][C:4]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH2:5][CH:6]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]1([CH3:13])[CH3:14]
Reactant: COC(=O)C1C(CC(C)(O[Si](C)(C)C)C(F)(F)F)C1(C)C
Agent: O=P([O-])(O)O
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: COC(=O)C1C(CC(C)(O)C(F)(F)F)C1(C)C
Reaction time: 3 h

Procedure:
444 mg of potassium fluoride were added at ambient temperature to 500 mg of the product of Stage B in 5 ml of methanol. The reaction mixture was stirred for 3 hours, poured into 25 ml of an aqueous solution of potassium acid phosphate. Extraction was carried out with ethyl ether and the extracts were dried and the solvent was evaporated to obtain 360 mg of the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](N2CCNCC2)=[CH:4][CH:3]=1.N1[NH:15][C:16](CCC(O)=O)=[C:17]2C=1C[CH2:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Clc1ccc(C2CCNCC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(5-benzoyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3-yl)propionic acid obtained in Starting Material Synthesis Example 8 and 1-(4-chlorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Stating Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 5-benzyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([CH3:9])[CH2:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[NH:16][C:17]([C:19]2[C:28]([NH:29]C(=O)OCC3C=CC=CC=3)=[CH:27][C:26]3[C:21](=[CH:22][C:23]([N:40]4[CH2:45][CH2:44][CH2:43][CH2:42][C:41]4=[O:46])=[CH:24][CH:25]=3)[N:20]=2)=[O:18])[CH2:3]1.[H][H]>CO.[Pd]>[NH2:29][C:28]1[C:19]([C:17]([NH:16][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:10]=2[N:4]2[CH2:5][C@H:6]([CH3:9])[C@@H:7]([OH:8])[C@H:2]([NH2:1])[CH2:3]2)=[O:18])=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C:41]1=[O:46])[CH:22]=2
Reactant: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2NC(=O)OCc2ccccc2)C[C@@H](N)[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2NC(=O)c2nc3cc(N4CCCCC4=O)ccc3cc2N)C[C@@H](N)[C@@H]1O

Procedure:
A mixture of benzyl [2-[({4-[(3R,4R,5S)-3-amino-4-hydroxy-5-methylpiperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-(2-oxopiperidin-1-yl)quinolin-3-yl]carbamate (0.004 g, 0.007 mmol) in 3.0 mL of MeOH was hydrogenated in the presence of 5 mg of 10% Pd on carbon under a balloon of hydrogen at room temperature for 1 h. The mixture was filtered and the filtrate was purified by preparative HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at a flow rate of 30 mL/min.) to afford the title compound. LCMS calc. for C26H31N7O3 [M+H]+: m/z=490.3. found: 490.2.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:8][C:7]=2[CH:31]=1.C1(C(N2C3C=CC=CC=3CNCC2)=O)C2C(=CC=CC=2)C=CC=1.Cl.N1C=C(CN2C3C=CC=CC=3CN(C(C3C4C(=CC=CC=4)C=CC=3)=O)CC2)N=C1>C(Cl)Cl>[ClH:1].[ClH:1].[Br:2][C:3]1[CH:31]=[CH:7][C:8]2[N:9]([C:19]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:20])[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)[CH2:6][C:5]=2[CH:4]=1
Reactant: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccc(Br)cc2C1
Agent: Cl
Agent: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)c2ccccc2C1
Agent: O=C(c1cccc2ccccc12)N1CCNCc2ccccc21
Solvent: ClCCl
Product: O=C(c1cccc2ccccc12)N1CCN(Cc2c[nH]cn2)Cc2cc(Br)ccc21

Procedure:
Example 42 was prepared as an off white solid from 7-bromo-1,4-benzodiazepine (prepared as described in Compound B of Example 11) using the following procedure: Compound A of Example 4; Compound B of Example 4; Compound C of Example 4; Compound D of Example 1, using methylene chloride as solvent, purification by prep HPLC (YMC S5 ODS 30×250 mm; gradient elution with 0 to 100% buffer B over 45 min; buffer A=MeOH:H2O:TFA (10:90:0.1); buffer B=MeOH:H2O:TFA (90:10:0.1); 25 mL/min) and conversion to the HCl salt by lyophilization from 1M HCl.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:39]=[N:40][C:41]([NH2:44])=[CH:42][CH:43]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C1(C)C=CC=CC=1>C(OCC)C>[CH2:1]([O:3][C:4]([C:6]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:9]2[N:10]=[C:11]([NH:44][C:41]3[CH:42]=[CH:43][C:38]([N:35]4[CH2:36][CH2:37][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:33][CH2:34]4)=[CH:39][N:40]=3)[N:12]=[CH:13][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 100 °C
Yield: 27.8 %

Procedure:
8-Cyclopentyl-2-methanesulfinyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (0.936 g, 2.68 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.0 g, 10.8 mmol) were added to toluene (5 ml) and heated to 100° C. 1 hour. Diethyl ether (10 ml) was added causing a solid to precipitate. This solid was collected by filtration, washed with diethyl ether, and dried in vacuo yielding 2-[5-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-8-cyclopentyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester as a yellow solid (0.42 g, 28%). MS (APCI); M++1: Calc'd 564.29. Found 564.3
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([C:30]3([OH:34])[CH2:33][CH2:32][CH2:31]3)[CH2:16][N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:35]>>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([C:30]3([OH:34])[CH2:31][CH2:32][CH2:33]3)[CH2:16][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)C2(O)CCC2)CC1
Agent: Cl
Product: OC1(C(CN2CCNCC2)c2ccc(-c3ccc(Cl)c(Cl)c3)cc2)CCC1

Procedure:
In an analogous manner to Example 135, step 4, 1-[1-(3′,4′-dichloro-111′-biphenyl-4-yl)-2-piperazin-1-ylethyl]cyclobutanol dihydrochloride was prepared from tert-butyl 4-[2-(3′,4′-dichloro-1,1′-biphenyl-4-yl)-2-(1-hydroxycyclobutyl)ethyl]piperazine-1-carboxylate. MS (ES) m/z 405.3 ([M+H]+); HRMS: calcd for C22H26Cl2N2O.2.00 HCl, 476.0956; found (ESI), 405.1486.
Reaction SMILES: C(OC1C=CC([CH:11]([S:16][CH:17]([C:22]2C=CC(OC(=O)C)=CC=2)[CH:18]=[C:19](C)C)[CH:12]=[C:13]([CH3:15])[CH3:14])=CC=1)(=O)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[K+].[CH2:48]([OH:50])[CH3:49]>P(=O)(O)(O)O.O>[CH3:15][C:13]1([CH3:14])[C:18]2[C:17](=[CH:22][CH:49]=[C:48]([OH:50])[CH:19]=2)[S:16][CH2:11][CH2:12]1
Reactant: CCO
Reactant: CC(=O)Oc1ccc(C(C=C(C)C)SC(C=C(C)C)c2ccc(OC(C)=O)cc2)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Solvent: O
Product: CC1(C)CCSc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 6.8 g (0.029 mmol) of 4-acetoxyphenyl-3-methylbut-2-enylsulfide and 17 g of 1:10 (w/w) phosphorus pentoxide in phosphoric acid was stirred at room temperature under nitrogen for 15hours. The reaction mixture was then treated with water and stirred for 40 min. The mixture was then extracted with 2×50 ml ether. The ether extracts were combined and the solvent removed in-vacuo. The residue was then stirred under nitrogen with a solution of 1.93 g (0.034 mmol) of potassium hydroxide in 6 ml of water and 12 ml of ethanol for 1 hour. The ethanol was then removed from the mixture on the rotary evaporator and the aqueous solution then acidified to PH-2 with sulfuric acid. The acidified solution was extracted with 2×50 ml ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The ether solution was then filtered and the solvent removed in-vacuo. The resultant crude product was purified by flash chromatography (silica; 20% ethyl acetate in hexanes) to give the title compound as a colorless, low-melting solid. PMR (CDCl3): 6 1.25 (6H, s), 1.90 (2H, m), 2.97 (2H, m), 6.57 (1H, dd, J~8.6, 2.7 Hz), 6.88 (1H, d, J~2.7 Hz), 6.90 (1H, d, J~8.6 Hz).
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3[CH:17]=[CH:18][C:19]([O:21][CH2:30][C:29]4[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:20][C:15]=3[O:14][C:13]2([CH3:23])[CH3:22])=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)c1ccc(C2c3ccc(O)cc3OC2(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc3c(c2)OC(C)(C)C3c2ccc(C(C)C)cc2)cc1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 179.0 mg, 4.48 mmol) was added to a solution of 3-(4-isopropylphenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-6-ol (1.12 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (636.8 mg, 4.07 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the title compound (1.19 g, yield 74%).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]1[NH:16][N:17]=[CH:18][C:13]=1[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[OH-].[Na+].[NH2:21]OS(O)(=O)=O>C(O)C>[NH2:21][N:17]1[CH:18]=[C:13]2[CH2:12][CH2:11][C:10]3[C:15]([C:14]2=[N:16]1)=[C:2]([NH2:1])[C:3]1[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=1)[N:9]=3
Reactant: NOS(=O)(=O)O
Reactant: Nc1c2c(nc3ccccc13)CCc1cn[nH]c1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1c2c(nc3ccccc13)CCc1cn(N)nc1-2
Temperature: 55 °C
Yield: 13.6 %

Procedure:
To a suspension of 11-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine (40.0 g) in an aqueous sodium hydroxide solution (37.1 g in 561 ml of water) at 50° C. was added ethanol (1550 ml). The resulting solution was heated to 55° C. and solid hydroxylamine-o-sulfonic acid (51.6 g) was added in portions over 15 minutes. The reaction was stirred for a half hour without heat, the resulting solid was filtered, washed with water, boiled in methanol (1500 ml), filtered hot to remove inorganics, concentrated, and triturated with diethyl ether to yield 5.79 g of a product containing approximately 20% of the starting material which was inseparable by chromatography.