Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[NH:26][NH2:27]>C(O)C>[C:30]([O:29][C:25]([NH:26][N:27]=[C:21]1[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])[CH2:23][CH2:22]1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
A solution of 1-[(9H-fluoren-9-yl)methyloxycarbonyl]-4-piperidone (16.0 g, 50.0 mmol) and tert-butyl carbazate 7.25 g, 55.5 mmol) in ethanol (250 mL) was refluxed for 1 h. The solution was cooled and concentrated. Addition of ether (100 mL) produced the title compound as a white precipitate (21.0 g). 1H NMR (500 MHz, CDCl3) □ 7.77 (d, J=7 Hz, 2H), 7.57 (d, J=7 Hz, 2H), 7.40 (t, J=7 Hz, 2H), 7.32 (t, J=7 Hz, 2H), 4.50 (br s, 2H), 4.24 (t, J=6 Hz, 1H), 3.4-3.7 (br m, 4H), 2.47 (br s, 2H), 2.1-2.2 (br m, 2H), 1.56 (s, 9H).
Reaction SMILES: [CH2:1]1[O:8]C(=O)C[O:4][C:2]1=[O:3].[CH3:9][C@@H:10]1[O:17]C(=O)[C@H](C)[O:13][C:11]1=[O:12]>O>[C:2]([OH:4])(=[O:3])[CH2:1][OH:8].[C:11]([OH:13])(=[O:12])[C@H:10]([CH3:9])[OH:17]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: O=C1COC(=O)CO1
Solvent: O
Product: C[C@H](O)C(=O)O
Product: O=C(O)CO
Temperature: 170 °C

Procedure:
An operation was conducted in the same manner as in Example 10 except that 22,050 g (glycolic acid: 50 ppm, glycolic acid dimer: 380 ppm, water: 20 ppm; overall proton concentration of impurities: 0.053 mol %) of glycolide prepared by the same process as in Synthesis Example 1 and 450 g (lactic acid: 0 ppm, lactic acid dimer: 270 ppm, water: 8 ppm; overall proton concentration of impurities: 0.030 mol %) of L-lactide were used as monomers, 1.45 g [in view of the amount (0.27 g) of water (moisture) contained in an atmosphere within the container] of water were added to control the overall proton concentration (set proton concentration) to 0.105 mol %, a heat transfer oil heated to 170° C. was circulated in the jacket part of the polymerization equipment, and the temperature of the upper and lower plates was also kept to 170° C. to hold the contents for 24 hours. After completion of the polymerization, the yield of bulk matter of a poly(glycolic acid/L-lactic acid) copolymer formed was almost 100%. The bulk matter was ground by a grinder, and the physical properties of the ground product were measured. The results are shown in Table 5.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:52]=[CH:53][CH:54]=2)[O:44][CH2:45][CH2:46][O:47]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C[O:56]C[CH2:58][NH:59][CH3:60].C1[CH2:65][O:64][CH2:63][CH2:62]1>>[CH:46]([OH:47])=[O:56].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:54]=[CH:53][CH:52]=[C:43]([O:44][CH2:45][CH2:58][N:59]([CH2:62][CH2:63][O:64][CH3:65])[CH3:60])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C1CCOC1
Reactant: CNCCOC
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Product: COCCN(C)CCOc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Product: O=CO
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of Intermediate 154a (50.5 mg, 0.067 mmol) and N-(2-methoxyethyl)methylamine (35 μL, 0.33 mmol) in THF (1 mL) was stirred at 60° C. for 20 h in a sealed tube. Additional N-(2-methoxyethyl)methylamine (35 μL, 0.33 mmol) was added and the mixture subsequently stirred at 60° C. in a sealed tube for 24 h. The mixture was concentrated in vacuo and the residue purified by MDAP (Method 7). The title product was isolated as an off-white solid (24 mg, 48%). LCMS (Method 5): Rt 3.72 min, m/z 750.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=8.0 Hz), 1.27 (9H, s), 1.44-1.56 (2H, m), 1.61-1.73 (2H, m), 1.73-1.98 (4H, m), 1.98-2.22 (2H, m), 2.24 (3H, s), 2.55 (2H, t, J=8.0 Hz), 2.74 (2H, t, J=8.0 Hz), 2.86-2.95 (1H, m), 3.12-3.18 (1H, m, obscured by water), 3.19 (3H, s, obscured by water), ˜3.30 (1H, m, obscured by water), 3.38 (2H, t, J=8.0 Hz, obscured by water), 4.07 (2H, t, J=8.0 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.94-6.99 (1H, m), 7.05-7.14 (3H, m), 7.19 (1H, dd, J=8.0 Hz, 4.0 Hz), 7.24-7.42 (5H, m), 7.64 (1H, d, J=8.0 Hz), 7.69 (1H, d, J=4.0 Hz), 8.13 (1H, s), 8.19 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:9]1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]([NH:39][NH2:40])=[O:38])[CH:34]=[CH:33][C:31]=2[N:32]=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[NH:29][C:30]2[CH:36]=[C:35]([C:37]3[O:38][C:9]([NH:1][C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)=[N:40][N:39]=3)[CH:34]=[CH:33][C:31]=2[N:32]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(Nc4ccncc4)o3)cc2[nH]1
Temperature: 25 °C

Procedure:
Combine 4-amino pyridine (30 mg, 0.312 mmol) and di-imidazol-1-yl -methanethione (56 mg, 0.312 mmol) in DMF (0.3 mL) and stir for 2 days. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (77 mg, 0.240 mmol) and dilute with DMF (1.5 mL). Heat the reaction to 80° C. for 1 hr. Add EDCI (92 mg, 0.480 mmol) and heat for 1 hr at 80° C. Allow reaction to cool to room temp and dilute the reaction with water. Collect the resulting precipitate by filtration. Purify the solid by reverse-phase HPLC (20-50% ACN/H2O+5 mM NH4OH) to afford the title compound: 1H NMR (400 MHz, DMSO-d6) ppm 7.63-7.68 (m, 1 H) 7.71 (s, 1 H) 7.73 (d, J=2.02 Hz, 1 H) 7.76-7.97 (m, 4 H) 8.05-8.27 (m, 1 H) 8.58 (d, J=6.44 Hz, 2 H) 1 H); MS (m/z) 423.0 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([N:12]([CH2:20][CH2:21][OH:22])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)[CH3:11]>CC(C)=O.N1C=CC=CC=1>[CH3:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[N:12]([CH2:10][CH3:11])[CH2:20][CH2:21][O:22][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CCO)c1cccc(C)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CCN(CCOC(=O)c1ccccc1)c1cccc(C)c1

Procedure:
Benzoylchloride (3.3 g) was added to a mixture of N-ethyl-N-hydroxyethyl-3-methylaniline (2.1 g) in acetone (25 cm3) and pyridine (1 cm3) and stirred at reflux for 1 hour. The reaction mixture was cooled and used directly in iv) below.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH2:20])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([O:17][C:18](=[O:22])[CH:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)COC(=O)C(C)N
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Product: Cc1ccc(CC(=O)NC(C)C(=O)OCC(C)C)cc1

Procedure:
Following General Procedure BB and using 4-methylphenylacetic acid (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 102°-104° C. The reaction was monitored by tlc on silica gel (Rf=0.6 in 33% ethyl acetate/hexanes) and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [NH3:1].CS(O[C@H:7]1[CH2:10][N:9]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]1[CH2:24][CH3:25])(=O)=O>C(O)(C)C>[C:12]1([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:9]2[CH2:10][C@H:7]([NH2:1])[C@@H:8]2[CH2:24][CH3:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H]1[C@@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Reactant: N
Solvent: CC(C)O
Product: CC[C@H]1[C@@H](N)CN1C(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
28% aqueous ammonia (1.2 ml) was added to a solution of cis(±)-1-(diphenylmethyl)-2-ethylazetidin-3-yl methanesulfonate obtained in Example (235c) (315 mg, 0.91 mmol) in isopropanol (2 mL), and the mixture was stirred at 70° C. for four hours. The reaction solution was concentrated under reduced pressure. Then, saturated aqueous sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and filtered. Thereafter, the filtrate was concentrated under reduced pressure to obtain 206 mg of the title compound as a pale yellow oily substance (85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:26])[C:17](Br)=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:27])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C-:28]#[N:29].[K+]>CN1CCCC1=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[C:20]3[C:15]([C:16](=[O:26])[C:17]([C:28]#[N:29])=[CH:18][N:19]3[CH:22]3[CH2:24][CH2:23]3)=[CH:14][C:13]=2[F:27])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(Br)cn3C2CC2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(c2cc3c(cc2F)c(=O)c(C#N)cn3C2CC2)CC1
Temperature: 202.5 °C
Yield: 94.3 %

Procedure:
A mixture of 4-(3-bromo-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-piperazine-1-carboxylic acid ethyl ester (11.0 g, 25.1 mmol), Cul (5.3 g, 27.6 mmol) and KCN (1.8 g, 27.6 mmol) in 110 mL of 1-methyl-2-pyrrolidinone (NMP) was heated at 200-205° C. for 16 hours. On cooling to room temperature, the reaction mixture was diluted with chloroform (250 ml) upon which a thick precipitate formed. The mixture was filtered over celite (2×) and the clear brown organic filtrate was washed with water/brine (2×), dried (Na2SO4), filtered and concentrated in vacuo to a black oil. An off-white solid precipitated out by addition of hexane (150 ml) and ethyl acetate (300 ml). The solid was dissolved in chloroform, and activated charcoal and celite were added. The mixture was then filtered over celite. Evaporation of the solvent gave a white solid which was suspended in hot ethyl acetate and filtration afforded 9.1 g (94%) of 4-(3-cyano-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinolin-7-yl)-piperazine-1-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[C:14]([O:19]C)(=O)[C:15]([CH3:17])=[CH2:16].S(Cl)([Cl:23])=O>>[C:14]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([Cl:23])=[O:11])=[CH:12][CH:13]=1)(=[O:19])[C:15]([CH3:17])=[CH2:16]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCO)cc1
Reactant: C=C(C)C(=O)OC
Product: C=C(C)C(=O)OCCOc1ccc(C(=O)Cl)cc1

Procedure:
This compound was synthesized by the reaction of 4-(2-hydroxyethoxy)benzoic acid, methyl methacrylate and thionyl chloride in the same manner as in Example 6-(1).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH3:29])[N:12]2[C:13](=[O:28])[C:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[CH:15][N:16]=[C:11]2[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>O>[CH2:21]([O:20][C:18]([NH:17][C:14]1[C:13](=[O:28])[N:12]2[C:8]([CH3:29])([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][C:11]2=[N:16][CH:15]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C1(C)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 105.5 %

Procedure:
A solution of intermediate 19a (55 mg, 0.138 mmol) in 4 mL 1:1 TFA/CH2Cl2 with 2 drops water was stirred at rt for 12 h. The mixture was concentrated in vacuo, then coevaporated with CCl4 to afford 50 mg of intermediate 19b (quantitative), which was used without further purification in the following step.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>CCCCCC.C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: CN1CCc2[nH]c3ccc(Br)cc3c2C1
Reactant: O=C(CCl)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN1CCc2c(c3cc(Br)ccc3n2CC(=O)N2CCCCC2)C1
Reaction time: 0.5 h
Yield: 51.2 %

Procedure:
Sodium hydride (0.6 g, 15 mmol) washed with hexane for removal of oil and dried under vacuum. Then sodium hydride was taken in THF. To this solution 8-bromo-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 7.5 mmol) in THF was added drop wise at 0° C. Then reaction mixture stirred for 0.5 h. The solution of 2-chloro-1-(piperidin-1-yl)ethanone (1.8 g, 11.3 mmol) in THF was added drop wise in reaction mixture. Then reaction mixture stirred at rt for 2 h. Reaction was monitored by TLC. After completion of the reaction, reaction mixture quench with ice-water. THF was evaporated and aqueous layer was extracted with ethyl acetate. Organic layer was dried over anhydrous sodium sulphate. The crude compound was washed with hexane and diethyl ether for removal of color impurities then recrystallized by using methanol to gives 1.5 g of desired compound then out of that 0.8 g compound was stirred in ethanolic HCl to give HCl salt of 2-(8-bromo-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][C:18](SC)=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1.Cl[C:25]1C=CC=C(C(OO)=O)C=1.[S:35]([O-:39])([O-])(=[O:37])=S.[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([C:15]4[CH:20]=[CH:19][C:18]([S:35]([CH3:25])(=[O:39])=[O:37])=[CH:17][CH:16]=4)[C:11]=3[CH:23]=2)=[N:4][N:3]=1
Reactant: O=S([O-])([O-])=S
Reactant: CSc1ccc(-n2cnc3ccc(-c4nnc(C)o4)cc32)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc3ncn(-c4ccc(S(C)(=O)=O)cc4)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-[4-(methylthio)phenyl]-1H-benzimidazole (322 mg, 1.00 mmol) in dichloromethane (10 mL) was added m-chloroperbenzoic acid (479 mg, 2.00 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was stirred for 1 hr. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1-0/1), and recrystallized from hexane/chloroform to give the title compound (302 mg, yield 85%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[N:10]=[C:11]([CH3:12])[C:3]=12.[CH2:22]([NH:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:22]([NH:26][CH2:27][CH2:28][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[N:10]=[C:11]([CH3:12])[C:3]=12)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCNCC
Reactant: Cc1cc(C)c(-n2nc(C)c3c(Cl)cc(C)nc32)c(C)c1
Solvent: CS(C)=O
Product: CCCCNCCc1cc(C)nc2c1c(C)nn2-c1c(C)cc(C)cc1C
Temperature: 177.5 °C

Procedure:
A mixture of 4-chloro-3,6-dimethyl-1-(2,4,6-trimethylphenyl)-1H-pyrazolo[3,4-b]pyridine (98 mg, 0.33 mmol), N-butylethylamine (1 ml) in DMSO (2 ml) was heated in an oil bath at 175-180° C. for 20 hours. The reaction mixture was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried, and concentrated to give a brown oil. The oil residue was purified through silica gel column chromatography using EtOAc/Hexane in a ratio of 1/9 as eluent to give a colorless oil. 1H NMR (CDCl3) 6.92 (s, 2H), 6.29 (s, 1H), 3.42 (q, 2H), 3.27 (t, 2H), 2.65 (s, 3H), 2.44 (s, 3H), 2.30 (s, 3H), 1.91 (s, 6H), 1.57 (m, 2H), 1.33 (m, 2H), 1.13 (t, 3H), 0.90 (t, 3H) ppm. IR (neat) 2960, 2920, 1570 cm−1. High MS, calc. 364.2627, found 364.26306.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:22][CH:19]1[CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (300 mg, 1.13 mmol) was treated with cyclopropylamine following general procedure B to afford 4-cyclopropylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (200 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (170 mg) following general procedure E. The above ethylamide (0.6 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 1-cyclopropyl-3-ethyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (15 mg). LCMS: m/z 312 [M+1]+.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:25]2[CH2:26][CH2:27][NH:28][CH2:29][C:24]2=[N:23][N:22]=1.[Cl:30][C:31]1[C:32]([C:40]#[N:41])=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](O)=[O:35]>ClCCl.CN(C)C=O>[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:33]([C:34]([N:28]2[CH2:27][CH2:26][N:25]3[C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=4)=[N:22][N:23]=[C:24]3[CH2:29]2)=[O:35])[C:32]=1[C:40]#[N:41]
Reactant: N#Cc1c(Cl)cccc1C(=O)O
Reactant: c1ccc(-c2nnc3n2CCNC3)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cccc1C(=O)N1CCn2c(nnc2-c2ccccn2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
EDC (174 mg, 0.909 mmol) followed by HOBT (127 mg, 0.826 mmol) was added to a suspension of 3-(2-pyridinyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (I101) (166 mg, 0.826 mmol) and 3-chloro-2-cyanobenzoic acid (I125) (150 mg, 0.826 mmol) in Dichloromethane (DCM) (4 mL) and N,N-dimethylformamide (DMF) (1 mL) and the reaction was stirred at room temperature for 18 h. LCMS indicated that the major peak was the desired product. The solvent was evaporated and the residue partitioned between EtOAc and sat. NaHCO3 and the organic layer was collected. This was dried (Na2SO4) and the solvent evaporated to afford an orange oil. This was purified by MDAP to afford a pale yellow oil which solidified on standing to afford 174 mg of desired product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+]([O-])=O)[CH:34]=1)([O-:32])=[O:31]>CN(C)C=O>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([N+:30]([O-:32])=[O:31])[CH:34]=3)=[CH:3][CH:4]=2)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(c2ccc(O)cc2)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(c2ccc(Oc3cccc([N+](=O)[O-])c3)cc2)(C(F)(F)F)C(F)(F)F)cc1

Procedure:
334 g (1 mol) of 2-(4-hydroxyphenyl)-2-(4-methylphenyl)hexafluoropropane were dissolved in 1.5 dm3 of dimethylformamide, 276 g of potassium carbonate and 170 g (1.01 mol) of m-dinitrobenzene were added, and the mixture was refluxed for 24 hours. The dimethylformamide was subsequently removed by distillation, and the residue was recrystallized from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH2:28])[CH:27]=1)=[CH:15]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][C:20]=1[F:21])[NH:17][C:16]([C:22]1[CH:23]=[CH:24][C:25]([O:29][CH3:30])=[C:26]([NH:28][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:27]=1)=[CH:15]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cc(-c3cc4cc(F)c(F)cc4[nH]3)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.3 %

Procedure:
4-Methoxybenzaldehyde (0.204 g, 1.5 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.405 g, 1.48 mmol) in methylene chloride (125 mL), followed by acetic acid (0.3 g, 1.5 mmol). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give a yellow oil. Recrystallization from methanol/water gave the product as off-white crystals (270 mg); mp 173-175° C.
Reaction SMILES: [CH2:1]1[C@H:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[C:3](=[S:14])[S:2]1.[CH3:15][I:16]>>[I-:16].[CH3:15][S:14][C:3]1[S:2][CH2:1][C@@H:13]2[CH2:12][C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:5][N+:4]=12
Reactant: CI
Reactant: S=C1SC[C@@H]2Cc3ccccc3CN12
Product: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Product: [I-]
Reaction time: 15 h

Procedure:
(S)-1,5,10,10a-Tetrahydrothiazolo[3,4-b]isoquinoline-3-thione (38 g) is dissolved in methyl iodide (500 cc). After 15 hours at a temperature of about 20° C., the resulting crystals are filtered off, washed with diethyl ether (2×50 cc) and then dried at 20° C. under reduced pressure (1 mm Hg). (S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo[3,4-b]isoquinolinium iodide (61.5 g), which melts at 140°-150° C. with decomposition, is thus obtained.