Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.F[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.CC(N(C)C)=O>C(OCC)(=O)C>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=C1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC3=O)cc1
Reaction time: 4 h
Yield: 51.3 %

Procedure:
Combine 5-Hydroxyindanone (2.0 g, 13.50 mmol), 4-Fluorobenzonitrile (1.55 g, 12.80 mmol), K2CO3 (2.65 g, 19.20 mmol) and toluene/DMA (20 ml/40 ml), reflux under Nitrogen using a Dean-Stark Trap. After 4.0 hours, cool the reaction to room temperature and add Ethyl Acetate. Wash several times with 10% LiCl and Brine solution, then dry the organic layer over Na2SO4 follow by concentration. Flash chromatograph using 411 then 1/1 hexanes/ethyl acetate eluant to afford 1.64 g, 6.57 mmol (49% yield) of the title compound: 1H NMR (500 MHz CDCl3); 2.7-2.8 (2H, m), 3.1-3.2 (2H, m), 7.0-7.1 (2H, m), 7.1-7.2 (2H, m), 7.6-7.7 (2H, m), 7.7-7.8 (1H, m); MS m/z 250 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][S:3]1.O=P(Cl)(Cl)[Cl:14]>>[Cl:14][C:9]1[C:10]2[CH:2]([CH3:1])[S:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: CC1SCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CC1SCc2ncnc(Cl)c21
Reaction time: 1 h
Yield: 54 %

Procedure:
5-Methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (10 g, 59.54 mmol) in POCl3 (100 mL) was heated to reflux for 15 minutes. After cooling, excess POCl3 was removed under vacuum. The residue was dissolved in CH2Cl2 (100 mL) and saturated NaHCO3 (400 mL) was added at 0° C. The reaction mixture was stirred for 1 hour. The aqueous phase was extracted with DCM (3×250 mL). The organic phase was combined, dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (4:1) to give 4-chloro-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidine (6 g, 54%). 1H NMR (CDCl3, 400 MHz) δ 8.80 (s, 1H), 4.68 (m, 1H), 4.44 (m, 1H), 4.13 (d, J=16.8 Hz, 2H), 1.68 (d, J=7.2 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11](=[O:21])[NH:12][N:13]=[C:14]([C:16]2[CH:17]=[N:18][NH:19][CH:20]=2)[CH:15]=1.[Br:22]N1C(=O)CCC1=O>C(COC)OC>[Br:22][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]=1[C:10]1[C:11](=[O:21])[NH:12][N:13]=[C:14]([C:16]2[CH:20]=[N:19][NH:18][CH:17]=2)[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]nc(-c2cn[nH]c2)cc1-c1cc2ccccc2[nH]1
Solvent: COCCOC
Product: O=c1[nH]nc(-c2cn[nH]c2)cc1-c1[nH]c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
39 mg of 4-(1H-indol-2-yl)-6-(1H-pyrazol-4-yl)-2H-pyridazin-3-one is dissolved in dimethoxyethane and 28 mg of N-bromosuccinimide is added. The solution is stirred for 3 h at RT. The product is purified by preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Yield 11 mg. LC-MS (ES+) 355/357 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1.Cl.P(OCC)(OCC)OCC>C(OCC)(=O)C.CN(C)C=O>[CH3:19][Si:18]([CH3:20])([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8]2)[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CCOC(=O)/C=C/c1c(O)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(O[Si](C)(C)C(C)(C)C)cccc2[nH]1
Temperature: 170 °C
Yield: 63.7 %

Procedure:
To a round-bottomed flask at rt was charged with ethyl (2E)-3-(2-hydroxy-6-nitrophenyl)prop-2-enoate (Example 206, 260 mg, 1.10 mmol), N,N-dimethylformamide (2 mL), t-butyldimethylsilyl chloride (198 mg, 1.32 mmol), and imidazole (150 mg, 2.20 mmol). The resulting mixture was left stirring at rt for 2 hours before hydrochloric acid was added and the mixture was extracted with diethyl ether (2×20 mL). The combined organic layer was washed with water, brine, and dried over anhydrous sodium sulfate. The concentrated residue was used without further purification. It was mixed with triethyl phosphite (920 mg, 5.50 mmol) and heated to 170° C. for 3 hours before it was cooled to rt and diluted with ethyl acetate. The mixture was washed with water, brine and dried over anhydrous sodium sulfate. The concentrated residue was purified with silica gel flash chromatography by using hexane/ethyl acetate (3/1) as the eluant to give ethyl 4-(1,1,2,2-tetramethyl-1-silapropoxy)indole-2-carboxylate as a white solid (224 mg, 64%): Rf0.57 (3/1 hexane/ethyl acetate); %): MS (MH+) calcd for C17H26NO3Si 320.2, found 320.2; 1H NMR (DMSO-d6) δ 11.87 (br s, 1H), 6.99-7.15 (m, 3H), 6.47 (dd, J=7.3, 0.6 Hz, 1H), 4.33 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.0 Hz, 3H), 1.01 (s, 9H), 0.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34]([O:36]CC)=[O:35])[N:29]=5)[C:25]=4[S:39][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[OH-].[K+]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:23]3[C:24]4[CH2:32][CH2:31][C:30]5[C:26](=[CH:27][N:28]([CH2:33][C:34]([OH:36])=[O:35])[N:29]=5)[C:25]=4[S:39][C:22]=3[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CCOC(=O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 158.9 %

Procedure:
To THF/MeOH/H2O (150 mL, 10/1/1) cooled to 0° C. was added ethyl [6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]acetate (1673 mg, 2.7 mmol), followed by a solution of potassium hydroxide (1.2 g, 21.6 mmol) in THF/MeOH/H2O (20 mL, 10/1/1). The contents were stirred with warming to rt over 1 h, after which time the solvent was removed under reduced pressure. The crude residue was diluted with water (200 mL) which was vigorously stirred for 0.5 h, neutralized with aq. 1N HCl (12.0 mL) to pH=2-3. The contents were filtered to a light yellow solid, which was washed with water, and then hexanes. The collected product was dried in vacuo, to afford the final product (2.3 g, 99%) as a light yellow solid. 1H-NMR (DMSO-d6) δ 13.1 (br s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.52 (dd, 1H), 7.45 (dd, 1H), 7.14-7.33 (m, 4H), 5.24 (s, 2H), 4.92 (s, 2H), 3.39 (t, 2H), 2.95 (t, 2H); LCMS RT=3.32 min; [M+H]+=536.1.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:20]>C(Cl)(Cl)Cl>[CH2:1]([N:8]([CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCNCc1ccccc1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: CN(CCNC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
To a cooled (˜5° C.) solution of compound A (6.2 g, 25.0 mmol) and TEA (3.0 g, 29.7 mmol, 4.13 mL) in chloroform (50 mL) was added iodomethane (4.2 g, 29.7 mmol, 1.85 mL). The pressure tube was sealed, and the mixture stirred at ambient temperature for 20 h. The mixture was then precipitated with ether (300 mL); the white solid was filtered off and washed with ether (50 mL). The filtrate was concentrated and the residual yellow oil (5.2 g) was purified by silica gel column chromatography (2-10% MeOH gradient in DCM) to give compound B (3.3 g, 12.5 mmol, 50%) as a colorless oil. TLC Rf (DCM/MeOH 9:1): 0.55. LC-MS [M+H] 264.3 (C15H24N2O2+H, calc: 264.4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([Br:12])=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[Br:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]2[N:11]([CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:1]=2)[CH:10]=1
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: O=C(CBr)c1ccccc1
Solvent: CCO
Product: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Reaction time: 8 h
Yield: 55.9 %

Procedure:
A 40 mL pressure rated scintillation vial was charged with methyl 2-amino-5-bromoisonicotinate (500 mg, 2.16 mmol) and 2-bromo-1-phenylethanone (474 mg, 2.38 mmol). The mixture was partially dissolved in ethanol (10.8 mL) and the reaction vessel was placed in a reaction block preheated to 100° C. The reaction mixture was let stir overnight. After heating for 18 hours, LCMS showed complete conversion of the starting material to a major peak with the desired mass (m/z=332 [M+H]+). The mixture was allowed to come to ambient temperature. After several hours a red precipitate had formed and was filtered. The solid was dried in open air overnight. Methyl 6-bromo-2-phenylimidazo[1,2-a]pyridine-7-carboxylate (400 mg, 1.208 mmol, 55.8% yield) was collected as a red solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1H, s), 8.58 (1H, s), 8.18 (1H, s), 8.01 (2H, dd, J=8.28, 1.25 Hz), 7.53 (2H, t, J=7.53 Hz), 7.41-7.47 (1H, m), 3.93 (3H, s). Mass found 332 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[OH:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:37])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:42]3[CH2:43][CH2:44][CH:39]([OH:38])[CH2:40][CH2:41]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:6][CH:7]=1
Reactant: OC1CCNCC1
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(F)(F)F)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-hydroxy-piperidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C32H33N3O3F3Cl2 [(M+H)+] 634.1846, observed 634.1846.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:31]1[C:36]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([NH2:44])[N:38]=2)=[CH:35][CH:34]=[CH:33][N:32]=1>C1COCC1>[NH2:44][C:39]1[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:36]2[C:31]([NH:1][C:2]3[CH:3]=[C:4]([NH:9][S:10]([C:13]4[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=4)(=[O:11])=[O:12])[C:5]([Cl:8])=[N:6][CH:7]=3)=[N:32][CH:33]=[CH:34][CH:35]=2)[N:38]=1
Reactant: Nc1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.1 %

Procedure:
A solution of N-(5-amino-2-chloropyridin-3-yl)-4-fluorobenzenesulfonamide (0.124 g, 0.409 mmol) in THF (5 mL) was cooled to 0° C. under N2. Lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (Aldrich) (1.706 mL, 1.706 mmol) was added dropwise and the mixture was stirred at 0° C. for 30 min. 4-(2-Fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.070 g, 0.341 mmol) was added and the mixture was stirred at 0° C. for 10 min. The reaction mixture was then stirred at rt for 20 h. The reaction was quenched with sat. NH4Cl and the resulting mixture was partitioned between sat. NaHCO3 and CHCl3. The aqueous layer was extracted with CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by prep HPLC. Fractions containing the product were combined and concentrated. The residue was basified using sat. NaHCO3 (10 mL). The aqueous layer was extracted with CHCl3 (3×15 mL). The combined organic layers were dried over MgSO4 and concentrated to give the product as a yellow solid (0.050 g). m/z (ESI, +ve ion) 486.8 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 12.38 (s, 1H); 8.74-9.01 (m, 2H); 8.44 (d, J=3.22 Hz, 1H); 8.39 (d, J=2.34 Hz, 1H); 7.95 (dd, J=8.62, 5.12 Hz, 2H); 7.15 (t, J=8.48 Hz, 2H); 6.86-7.03 (m, 2H); 5.43 (br. s., 2H); 2.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH2:12][Cl:13])(=[O:11])=[O:10])=[CH:6][C:5]([NH:14][C:15]([N:17]2[CH2:21][C@@H:20]([F:22])[CH2:19][C@@H:18]2[C:23](O)=[O:24])=[O:16])=[C:4]([F:26])[CH:3]=1.S(Cl)(Cl)=O>ClCCl.CN(C)C=O>[Cl:13][CH2:12][S:9]([NH:8][C:7]1[CH:6]=[C:5]([N:14]2[C:23](=[O:24])[C@H:18]3[CH2:19][C@H:20]([F:22])[CH2:21][N:17]3[C:15]2=[O:16])[C:4]([F:26])=[CH:3][C:2]=1[Cl:1])(=[O:10])=[O:11]
Reactant: O=C(O)[C@H]1C[C@H](F)CN1C(=O)Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1[C@H]2C[C@H](F)CN2C(=O)N1c1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 84.7 %

Procedure:
Crude (2R-trans)-1-[[[4-chloro-5-[[(chloromethyl)sulfonyl]amino]-2-fluorophenyl]amino]carbonyl]-4-fluoro-2-pyrrolidinecarboxylic acid (173.43 g) was suspended in 550 mL of dichloromethane and 0.65 mL (0.61 g, 8.4 mmol) of N,N-dimethylformamide was added, followed by the dropwise addition of 58 mL (95 g, 0.80 mol) of thionyl chloride at room temperature, and stirring was continued at room temperature. After 2.5 hours, the mixture became homogeneous. After 22 hours, the mixture was poured into 500 mL of ice-water, the layers were separated and the aqueous layer was extracted with dichloromethane (twice with 75 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (twice with 400 mL), dried over magnesium sulfate and evaporated under reduced pressure to afford 140.69 g of the crude title compound (84.7% yield from the isocyanate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36](=[O:39])[CH2:37]Cl)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH2:32][N:33]([C:36](=[O:39])[CH2:37][O:22][C:19]2[CH:20]=[C:21]3[C:16]([CH2:15][CH2:14][N:13]=[C:12]3[C:8]3([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:11][CH2:10][CH2:9]3)=[CH:17][CH:18]=2)[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Oc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc3c(c2)C(C2(c4ccc(Cl)cc4)CCC2)=NCC3)CC1
Reaction time: 2 h

Procedure:
1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (example 82) (400 mg, 1.18 mmol) and 4-(2-chloro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (404 mg, 1.54 mmol) were dissolved in N,N-dimethyl-formamide (10 ml). After addition of potassium carbonate (355 mg, 2.57 mmol) the mixture was stirred for 2 h under reflux. The solvent was removed and the residue (690 mg) was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CO>[CH2:26]([N:25]([CH2:23][CH:2]([OH:1])[CH2:3][CH:4]([CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2ccccc12)CC1CO1
Reactant: CNCc1ccccc1
Solvent: CO
Product: CN(Cc1ccccc1)CC(O)CC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Yield: 94.4 %

Procedure:
2.39 g (7.65 mmole) of t-butyl 4,5-epoxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 11) were reacted with 1.39 g (11.5 mmole) of N-methylbenzylamine in 20 ml of methanol for 2 days. At the end of this time, the reaction mixture was concentrated by evaporation underreduced pressure, and the residue was purified by column chromatography through silica gel (eluent: a 5: 95 by volume mixture of methanol and methylene chloride), to afford 3.13 g of the title compound as a pale brown oil.
Reaction SMILES: C([N:8]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:68])[C:64]([CH3:67])([CH3:66])[CH3:65])[C@@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[C@H:43]([O:44][C:45](=[O:50])[C:46]([CH3:49])([CH3:48])[CH3:47])[C@H:35]3[O:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[N:27][NH:28][C:29]=2[CH:30]([CH3:32])[CH3:31])=[C:20]([CH3:69])[CH:19]=1)[CH2:9][CH2:10][C:11](=[O:13])[NH2:12])C1C=CC=CC=1>O1CCCC1.[C].[Pd]>[C:11]([CH2:10][CH2:9][NH:8][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]2[C:26]([O:33][C@@H:34]3[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:68])[C:64]([CH3:67])([CH3:66])[CH3:65])[C@@H:51]([O:52][C:53](=[O:58])[C:54]([CH3:56])([CH3:55])[CH3:57])[C@H:43]([O:44][C:45](=[O:50])[C:46]([CH3:47])([CH3:48])[CH3:49])[C@H:35]3[O:36][C:37](=[O:42])[C:38]([CH3:39])([CH3:40])[CH3:41])=[N:27][NH:28][C:29]=2[CH:30]([CH3:31])[CH3:32])=[C:20]([CH3:69])[CH:19]=1)(=[O:13])[NH2:12]
Reactant: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(OCCCNCCC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.96 g) in tetrahydrofuran (5 mL) was added 10% palladium-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.87 g).
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1

Procedure:
Pigmentary 2,9-dimethylquinacridone was prepared exactly as described in comparison Example 1 except that 10% by weight, relative to the 2,5-di(4-methylanilino)terephthalic acid, of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid (6.8 g) was included in the ring-closure reaction. 2,9-Dimethylquinacridone (59 g) was obtained as a magenta pigment.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1.O>CC(C)=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][O:13][C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:21]=[C:22]([CH:37]=[CH:38][CH:39]=2)[CH2:23][N:24]2[C:29](=[O:30])[CH:28]=[CH:27][C:26]([C:31]3[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=3)=[N:25]2)=[N:18][CH:19]=1
Reactant: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(O)cn4)c3)n2)cn1
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: Cn1cc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC(O)CO)cn4)c3)n2)cn1
Temperature: 80 °C
Reaction time: 120 h

Procedure:
75 mg (0.68 mmol) of 3-chloro-1,2-propanediol and 322 mg (0.99 mmol) of caesium carbonate are added to 150 mg (0.41 mmol) of 2-[3-(5-hydroxy-pyrimidin-2-yl)benzyl]-6-(1-methyl-1H-pyrazol-4-yl)-2H-pyridazin-3-one, and the mixture is suspended in acetone. The reaction mixture is stirred at 80° C. for 5 days. Water is added to the reaction mixture, which is then extracted a number of times with ethyl acetate, dried over sodium sulfate and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36](O)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]>C(Cl)Cl>[CH3:19][O:20][C:21]1[C:22](=[O:50])[C:23]([CH3:49])=[C:24]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)=[C:35]([CH:39]=2)[C:36]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:37])[C:25](=[O:29])[C:26]=1[O:27][CH3:28]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccc(OC)c3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Piperidine (0.096 g, 1.128 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.324 g, 1.692 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenoxy)benzoic acid (0.247 g, 0.564 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.165 g, 0.327 mmol, 58%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:12][CH:11]([NH:27]C(OC(C)(C)C)=O)[C:10]2=[O:35])=[O:7])=[CH:2]1>Cl.O1CCOCC1>[S:1]1[CH:5]=[CH:4][C:3]([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=3[N:13]([C:21](=[O:26])[C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:12][CH:11]([NH2:27])[C:10]2=[O:35])=[O:7])=[CH:2]1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccsc1)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccsc1)C(=O)C(N)CN2C(=O)C(C)(C)C
Temperature: 57.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
1-(Thiophen-3-yl)carbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (0.94 g) was dissolved in 4N HCl-dioxane (10 ml), the solution was stirred for one hour at 55-60° C. The react ion mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 0.69 g of the titled compound as a brown solid(Yield: 100%).