Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[CH2:11]([CH:13]1O[CH2:14]1)[Cl:12].[Br-].[Li+].C(P(=[O:31])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Cl:12][CH2:11][CH:13]1[O:10][C:9](=[O:31])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:14]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CCCCP(=O)(CCCC)CCCC
Reactant: ClCC1CO1
Agent: [Br-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: O=C1OC(CCl)CN1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 93 %

Procedure:
A toluene (10 ml) solution of 5.9 g of 4-chlorophenyl isocyanate and 3.3 ml of epichlorohydrin was added dropwise to a toluene (1 ml) solution of 0.2 g of lithium bromide and 0.42 g of tri-n-butylphosphine oxide at 100° C. The mixture was stirred at the same temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. Ethanol was added to the obtained residue to collect the crystals by filtration. Thus, 8.9 g of the title compound was obtained (yield 93%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:34])[CH2:7][CH:8]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:25]=3)=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)[CH2:9][CH2:10][CH3:11])C.Cl>CO.O>[N:25]1[C:26]2[NH:27][CH2:28][CH2:29][CH2:30][C:31]=2[CH:32]=[CH:33][C:24]=1[CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([CH:8]([CH2:9][CH2:10][CH3:11])[CH2:7][C:6]([OH:34])=[O:5])[CH:13]=[CH:14]2
Reactant: CCCC(CC(=O)OCC)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(CC(=O)O)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Reaction time: 8 h
Yield: 28 %

Procedure:
Sodium hydroxide (0.01 g, 0.23 mmol) was added to a solution of 3-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-indol-1-yl}-hexanoic acid ethyl ester (0.02 g, 0.04 mmol) in methanol/water (9/1, 1 mL) and stirred overnight. The reaction was acidified to pH 6 with 1N HCl and the crude product was extracted with ethyl acetate (3×10 mL) and concentrated. The residue was purified by flash chromatography on silica gel (10% methanol in ethyl acetate) to give the title compound (28% yield). 1H NMR (CDCl3) δ 10.4 (bs, 1H), 7.38 (d, 1H, J=8.0 Hz), 7.21 (d, 1H, J=3.2 Hz), 7.14 (d, 1H, J=8.0 Hz), 7.00 (d, 1H, J=2.3 Hz), 6.73 (m, 1H), 6.48 (d, 1H, J=7.3 Hz), 6.32 (d, 2H, J=3.0 Hz), 4.80 (s, 1H), 4.22 (t, 2H, J=7.0 Hz), 3.47 (m, 2H), 2.95 (t, 2H, J=6.8 Hz), 2.68 (m, 4H), 1.88 (m, 4H), 1.15 (m, 2H), 0.81 (t, 3H, J=7.4 Hz). Mass Spectrum (LCMS, ESI) calculated for C24H30N3O3 408.2 (M+H); found 408.3.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].Cl.[CH:8]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)([CH3:10])[CH3:9].[OH2:23]>>[C:1]([OH:2])(=[O:4])[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:23].[CH:8]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)([CH3:10])[CH3:9]
Reactant: O
Reactant: O=C([O-])[O-]
Agent: COc1ccc2c(c1)CCNC2C(C)C
Agent: Cl
Agent: [K+]
Product: O=C(O)C(O)c1ccccc1
Temperature: 95 °C

Procedure:
Potassium carbonate (92 g) and water (500 mL) were added to 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (86 g). The reaction mixture was extracted with EtOAc and dried over magnesium sulfate, and then the solvent was evaporated. To the resulting residue were added iPrOH (1100 mL) and (+)-mandelic acid (50 g), followed by stirring under heating at 95° C. for dissolution. The mixture was left to cool and stirred at room temperature overnight. The resulting solid was collected and repeatedly recrystallized three times using iPrOH to obtain 1-isopropyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (+)-mandelate (43 g) as a single enantiomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH2:20])=[CH:7]2.[NH2:21][C:22]1[N:30]=[C:29]2[C:25]([NH:26][CH:27]=[N:28]2)=[C:24](Cl)[N:23]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[C:8]([CH2:19][NH:20][C:24]1[N:23]=[C:22]([NH2:21])[N:30]=[C:29]3[C:25]=1[N:26]=[CH:27][NH:28]3)=[CH:7]2
Reactant: NCc1cc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCc2cc3cccc(Cl)c3nc2-c2ccccc2Cl)c2nc[nH]c2n1
Reaction time: 8 h

Procedure:
A mixture of (8-chloro-2-(2-chlorophenyl)quinolin-3-yl)methanamine (144.8 mg, 0.478 mmol), 2-amino-6-chloropurine (89.1 mg, 0.525 mmol) and N,N-diiso-propylethylamine, redestilled, 99.5% (0.166 mL, 0.955 mmol) in 1-butanol, anhydrous, 99.8% (5.24 mL) was heated to reflux and stirred overnight. The reaction was cooled solvents removed and subjected to chromatography, 89:9:1(DCM/MeOH, NH4OH)gradient,
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[N:12]=[C:11]([S:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:25])=[CH:19][CH:18]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.CCOC(C)=O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:13]2[CH:14]=[C:9]([Cl:8])[N:10]=[C:11]([S:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)=[O:25])=[CH:19][CH:18]=3)[N:12]=2)[NH:4][N:3]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)C1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2cc(Cl)nc(Sc3ccc(NC(=O)C4CCCC4)cc3)n2)[nH]n1
Temperature: 80 °C

Procedure:
To a solution of 3-methyl-1H-pyrazol-5-amine (160 mg, 1.63 mmol) and N-(4-(4,6-dichloropyrimidin-2-ylthio)phenyl)cyclopentane carboxamide (600 mg, 1.63 mmol) in dimethyl formamide (10 ml) was added diisopropylethylamine (248 mg, 1.96 mmol, 0.34 ml). The mixture was then heated to 80° C. for 18 hrs and allowed to cool to rt. EtOAc (40 ml) was added and washed with brine, dried (MgSO4), and concentrated in vacuo. Crude product was then purified by flash chromatography 7:3 EtOAc:hexane EtOAc 5% MeOH:EtOAc to give title compound as an off white solid (431 mg, 62%). 1H NMR (DMSO-d6) 1.50-1.55 (2H, m), 1.61-1.78 (4H, m), 1.79-1.85 (2H, m), 1.90 (3H, brs), 2.72-1.81 (1H, m), 5.21 (1H, brs), 6.46 (1H, brs), 7.52 (2H, d), 7.78 (2H, d), 10.11 (1H, s), 10.18 (1H, brs), 11.95 (1H, brs). ES+ 429.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH3:6])[CH3:5].[OH-].[Li+].Cl.C(OCC)(=O)C>O1CCOCC1>[CH2:17]([O:16][C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[C:4]([CH3:6])([CH3:5])[C:3]([OH:24])=[O:2])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(C)(C)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C(=O)O)c1cc([N+](=O)[O-])ccc1OCc1ccccc1
Temperature: 100 °C
Yield: 91.9 %

Procedure:
To the compound (1.54 g) obtained in Example 562 in 1, 4-dioxane (20 ml) was added an aqueous lithium hydroxide solution (1.0M, 47 ml). The reaction mixture was heated under reflux at 100° C. for 12 h and then 2 N HCl and ethyl acetate were added. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethyl acetate to give 1.355 g of the titled compound (yield, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[NH:13][C:12](=O)[N:11]2[CH:21]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:12]1[N:11]2[CH:21]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]2[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3

Procedure:
To 50 mL of POCl3 was added 2-(2-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (600 mg) and the resultant mixture was refluxed for 48 h. The mixture was then cooled and the POCl3 was removed in vacuo. To the residue was added 20 mL of water and the pH adjusted to 7 with ammonium hydroxide. After cooling, the precipitated solid was collected to yield 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 30), m.p. 175-176° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:3]=1[C:4](O)=[O:5].CC[N:21]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.N>C1COCC1.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([O:15][CH:16]([CH3:18])[CH3:17])[C:3]=1[C:4]([NH2:21])=[O:5]
Reactant: CC(C)Oc1cc(OC(C)C)c(C(=O)O)c(N)n1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)Oc1cc(OC(C)C)c(C(N)=O)c(N)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-amino-4,6-diisopropoxy-nicotinic acid (1.48 g, 5.83 mmol) in THF (30 mL) were added EDCl (1.34 g, 6.99 mmol), HOBt (0.94 g, 6.99 mmol), NMM (0.70 g, 6.99 mmol) and liquid NH3 (10 mL). Then, the reaction mixture was stirred at room temperature for 24 hours. Then, water (100 mL) was added and the products were extracted with ethyl acetate (2×200 mL). The combined organic phase was washed with water, then brine, and dried over anhydrous Na2SO4. Removal of solvent gave crude 2-amino-4,6-diisopropoxy-nicotinamide as a yellow oil. Yield: 450 mg (26%, crude).
Reaction SMILES: C(Cl)Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[C:13]([C:16]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:17]=1[C:18]([OH:20])=O)([CH3:15])[CH3:14].FC(F)(F)C(OC(=O)C(F)(F)F)=O>O>[CH3:26][O:25][C:22]1[CH:21]=[C:17]2[C:16]([C:13]([CH3:15])([CH3:14])[C:5]3[O:4][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:6]=3[C:18]2=[O:20])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(C)(C)c2cc3ccccc3o2)c(C(=O)O)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(=O)c1c(oc3ccccc13)C2(C)C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To the DCM solution (1 ml) of 2-(1-benzofuran-2-yl-1-methylethyl)-5-methoxy benzoic acid (63 mg), trifluoroacetic anhydride (0.03 ml) was added at room temperature under nitrogen atmosphere. The mixture was stirred for 30 min. The reaction mixture was then added with water and extracted with DCM. The organic layer was dried over sodium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column (DCM) to obtain the title compound (50 mg, 84%).
Reaction SMILES: CO[C:3](OC)([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[CH2:4][NH:5][C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][N:10]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:15][C:14]1[C:9]([NH:8][C:6]2[S:7][C:3]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[CH:4][N:5]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(CNC(=S)Nc1ncccc1C)(OC)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1cccnc1Nc1ncc(-c2ccncc2)s1
Temperature: 140 °C

Procedure:
1-(2,2-Dimethoxy-2-pyridin-4-yl-ethyl)-3-(3-methyl-pyridin-2-yl)-thiourea (19-2, 0.050 g, 0.16 mmol) and p-toluenesulfonic acid monohydrate (0.003 g, 0.02 mmol) were combined and heated to 140° C. The reaction was terminated at partial conversion and was purified by reverse phase HPLC to provide the titled compound. 1H NMR (CD3OD) δ 8.61 (d, 2H, J=7.1 Hz), 8.48 (s, 1H), 8.30 (dd, 1H, J=1.0, 4.8 Hz), 8.15 (d, 2H, J=7.3 Hz), 7.74 (dd, 1H, J=0.7, 7.3 Hz), 7.10 (dd, 1H, J=5.1, 7.3 Hz), 2.43 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])OC(C)(C)OC2=O)=[CH:4][CH:3]=1.[CH2:19]([N:21]1[C:25]([NH2:26])=[CH:24][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:22]1)[CH3:20].[CH3:33]N(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]2[CH2:7][C:12](=[O:13])[NH:26][C:25]3[N:21]([CH2:19][CH3:20])[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[C:24]2=3)=[C:17]([CH3:33])[CH:18]=1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(Br)cc2)C(=O)O1
Reactant: CN(C)C=O
Reactant: CCn1nc(-c2ccccn2)cc1N
Solvent: O
Product: CCn1nc(-c2ccccn2)c2c1NC(=O)CC2c1ccc(Br)cc1C
Temperature: 60 °C
Yield: 80 %

Procedure:
A mixture of 5-(4-bromobenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.1 g, 3.54 mmol, Preparation W.1) and 1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (0.67 g, 3.54 mmol, prepared using B from Example #2, step A with ethyl hydrazine oxalate) in DMF (5 mL) was heated under nitrogen at about 60° C. for about 30 min. The reaction was cooled to rt, diluted with water (20 mL) and then the product was filtered off and rinsed with water (˜20 mL). The product was dried under vacuum at about 50° C. for about 16 h to yield 4-(4-bromo-2-methylphenyl)-1-ethyl-3-(pyridin-2-yl)-4,5-dihydro-1H-pyrazolo[3,4-b]pyridin-6(7H)-one as a tan solid (1.41 g, 3.54 mmol, 80%). LC-MS (Table 1, Method g) Rt=2.11 min, m/z 397/399 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 8.44-8.41 (m, 1H), 7.84 (dt, J=8.0, 1.1 Hz, 1H), 7.77-7.69 (m, 1H), 7.43-7.36 (m, 2H), 7.21-7.17 (m, 1H), 7.10-7.04 (m, 2H), 6.63 (d, J=6.6 Hz, 1H), 4.22-4.03 (m, 2H), 3.14 (dd, J=16.0, 7.8 Hz, 1H), 2.53 (d, J=26.1 Hz, 1H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][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[C:15]([CH3:18])([O-])[CH3:16].[K+].CN(C)C=O.[CH2:25](Cl)[CH:26]=[CH2:27]>O.CCCCCC>[CH2:16]([C:12]1([CH2:27][CH:26]=[CH2:25])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH:15]=[CH2:18]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: C=CCCl
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC1(CC=C)c2ccccc2-c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
There were charged 10 g of fluorene manufactured by Wako Pure Chemical Industries, Ltd. and 10.1 g of potassium tert-butoxide manufactured by Sigma Aldrich Japan Co., Ltd. into a 200 mL round bottom flask, and then 120 mL of dehydrated N,N-dimethylformamide manufactured by Wako Pure Chemical Industries, Ltd. was added to the round bottom flask. While stirring the round bottom flask at 50° C. in an atmosphere of nitrogen, 5.86 mL of allyl chloride manufactured by Kanto Chemical Co., Inc. was added dropwise to the round bottom flask over 2 hours. The round bottom flask was stirred further for 8 hours at 50° C., and then 10.1 g of potassium tert-butoxide manufactured by Sigma Aldrich Japan Co., Ltd. was additionally added to the round bottom flask, and 5.86 mL of allyl chloride manufactured by Kanto Chemical Co., Inc. was additionally added dropwise to the round bottom flask over 2 hours. The round bottom flask was stirred at 50° C. overnight, thereby obtaining a reaction product. The reaction product was added to 900 mL of water to obtain a mixture, and then 300 mL of hexane was added to the mixture, thereby obtaining a mixture containing an organic phase a water phase. The organic phase was extracted with ether three times. The extract was washed with water four times. The washed extract was further washed with dilute hydrochloric acid and with water in this order. The washed extract (ether solution) was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried ether solution was subjected to solvent elimination by evaporation, and the remainder was distilled under a reduced pressure, thereby obtaining 12.8 g (yield: 86.4%) of 9,9-diallylfluorene as yellow oil at 90° C./4 mmHg.
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][C@H:4]([OH:7])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1.O>CS(C)=O.C(OCC)C>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([C:20]([F:21])([F:23])[F:22])[CH:13]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: O[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#Cc1ccc(OC2CCC(O)CC2)cc1C(F)(F)F
Temperature: 25 °C
Yield: 60 %

Procedure:
Trans-cyclohexane-1,4-diol (4.30 mmol) and sodium hydride (60% suspension in oil, 2.15 mmol) are suspended in dry dimethylsulfoxide (4 mL) and a solution of 4-fluoro-2-trifluoromethyl-benzonitrile (2.15 mmol) in dry dimethylsulfoxide (4 mL) is added dropwise. The resulting mixture is stirred at room temperature. After 1 hour reaction time, the reaction is treated with water (10 mL), the precipitate formed is separated by filtration and the filtrate is extracted with dichloromethane (25 mL). The organic phase is washed with aqueous saturated ammonium chloride (5 mL), dried over magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The precipitate is triturated with diethylether (15 mL), filtered and the filtrate concentrated under reduced pressure. Both fractions of crude product are combined, dissolved in dichloromethane and purified by chromatography through a short pad of silica gel (dichloromethane and then diethylether as eluents) to afford the desired product (60% yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=2)=[N:5][N:6]=1.[CH3:19][O:20][C:21]([C:23]#[C:24][C:25]([O:27]C)=O)=[O:22].[CH2:29](O)C>>[CH2:19]([O:20][C:21]([C:23]1[N:6]2[N:5]=[C:4]([C:7]3[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=3)[S:3][C:2]2=[N:1][C:25](=[O:27])[CH:24]=1)=[O:22])[CH3:29]
Reactant: COc1cc(-c2nnc(N)s2)cc(OC)c1OC
Reactant: CCO
Reactant: COC(=O)C#CC(=O)OC
Product: CCOC(=O)c1cc(=O)nc2sc(-c3cc(OC)c(OC)c(OC)c3)nn12

Procedure:
The reaction of 9.7 g of 2-amino-5-(3', 4', 5'-trimethoxyphenyl)-1,3,4-thiadiazole with 6.2 g of acetylene dicarboxylic acid dimethyl ester in 200 ml of ethanol in accordance with Example 12 gives 2-(3',4',5'-trimethoxyphenyl)-7H-1,3,4-thiadiazolo-[3,2-a]-pyrimidin-7-one-5-carboxylic acid ethyl ester which, as a crude product, melts at 205°-207° C. with decomposition and which is converted as described in Example 12 into the corresponding free acid melting at 220°-223° C. with decomposition.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.C(N=C=NC(C)(C)CC)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)=[O:34])=[CH:30][CH:31]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NC(C)(C)CC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(OCc2ccccc2)cc1)Nc1ccc2cnn(CCN3CCCC3)c2c1
Reaction time: 6 h

Procedure:
A mixture of 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine (48 mg, 0.21 mmol), (4-benzyloxy-phenyl)-acetic acid (50 mg, 0.21 mmol), ethyldimethylpropylcarbodiimide hydrochloride (47 mg g, 0.25 mmol), N-hydroxybenzotriazole (33 mg, 0.25 mmol), N-methyl morpholine (50 mg, 0.50 mmol) in 2 mL of DMF was shaken for 6 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in 1.5 mL of a 1:1 mixture of dimethyl sulfoxide/methanol and purified by preparative reverse-phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.82 (t, 2H, J=6.78), 3.60 (s, 2H), 4.38 (t, 2H, J=6.78), 5.09 (s, 2H), 6.97 (m, 2H), 7.11–7.45 (m, 8H), 7.65 (m, 1H), 7.93 (m, 1H), 8.12 (s, 1H), 10.27 (s, 1H); MS (DCI/NH3) m/z 455 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]1([CH3:30])[CH:26]=[CH:25][CH:24]=[C:23]([C:27](Cl)=[O:28])[CH:22]=1.CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:27](=[O:28])[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:30])[CH:22]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1cccc(C(=O)Cl)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(=O)Nc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g; 2 mmol) in THF (30 ml) was added m-toluoyl chloride (0.53 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid that was slurried in diethyl ether (20 ml), filtered, reslurried in ethyl acetate (20 ml), and filtered to give 0.69 g (88%) of product as an off-white solid: mp 234-236° C.; 1H NMR (DMSO-d6) d 10.97 (s, 1H), 10.31 (s, 1H), 8.64 (d, J=8.4 Hz, 1H), 7.92-7.47 (m, 6H), 5.16 (dd, J=5.5 and 12.7 Hz, 1H), 2.97-2.84 (m, 1H), 2.68-2.43 (m, 5H), 2.14-2.09 (m, 1H); 13C NMR (DMSO-d6) d 172.13, 169.15, 168.03, 166.30, 164.80, 138.18, 136.54, 135.95, 133.14, 132.87, 131.09, 128.57, 127.45, 126.64, 123.95, 118.23, 117.33, 48.88, 30.67, 21.76, 20.62; Anal. Calcd. For C21H17N3O5: C, 64.45; H, 4.38; N, 10.74. Found: C, 64.23; H, 4.18; N, 10.56.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8](=[O:16])[C:7]2=[CH:17][S:18][CH:19]=[C:6]12)=[O:4].[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8](=[O:16])[C:7]3=[CH:17][S:18][CH:19]=[C:6]23)=[O:4])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCC(CN2CCCC2)NC1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2cscc21
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)CN2CCCCC2CN2CCCC2)c2cscc21

Procedure:
The title compound is prepared analogously to Example 2 from 4-(chloroacetyl)-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2-[(1-pyrrolidinyl)methyl]piperidine to give colorless crystals, Mp. 205°-207° C. (acetonitrile/activated charcoal).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7](=[CH:9][CH:10]=1)[OH:8].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[OH2:22]>CN(C=O)C>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][O:11][C:6]2[CH:5]=[C:4]([Br:3])[CH:10]=[CH:9][C:7]=2[O:8][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:22][CH2:18][CH2:17]2)[CH2:17][CH2:18]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccc(Br)cc1O
Reactant: O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(OCCN2CCOCC2)c(OCCN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
64 mg (36.0 mmol) of sodium hydride was added to a suspension of 900 mg (5.0 mmol) of 4-bromocatechol and 3.72 g (20.0 mmol) of 2-chloroethylmorpholine hydrochloride in 50 ml of anhydrous DMF at 0° C. over 25 minutes. The mixture was stirred for 3 days at room temperature. 5 ml water was added to quench the reaction. After removal of the solvent, the black oily residue was adsorbed onto celite and the resulting solid washed with ethyl acetate. The filtrate was then concentrated to give 0.75 g (1.81 mmol; 36% yield) of 3,4-bis(2-morpholinoethoxy)bromobenzene as a hygroscopic yellow solid. 1H-NMR (CD3OD) δ: 8.42 [1H] d (2.0 Hz), 8.18 [1H] d (1.5 Hz), 7.64 [1H] s, 7.56 [1H] dd (1.5 Hz, 7.5 Hz), 7.30 [1H] dt (1.5 Hz, 7.5 Hz), 7.25 [1H] d (2.5 Hz), 7.19 [1H] dd (2.5 Hz, 8.5 Hz), 7.12 [1H] d (8.5 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [1H] dt (1 Hz, 7.5 Hz) 4.25 [2H] t (5.75 Hz), 4.20 [2H] t (5.5 Hz), 3.72 [8H] m, 2.84 [4H] m, 2.66 [8H] m. MS: 559.2 [MH+].