Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([NH2:9])[CH:6]=[N:5]1)([CH3:3])[CH3:2].[Br:10][C:11]1[N:12]=[C:13](Br)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Br:10][C:11]1[N:12]=[C:13]([NH:9][C:7]2[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=2)[C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CC(C)n1cc(N)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cc(Nc2nc(Br)cn3ccnc23)cn1
Temperature: 25 °C
Yield: 144.8 %

Procedure:
A mixture of impure 1-isopropyl-1H-pyrazole-4-amine (2) (1.00 g), from above, 6,8-dibromoimidazo[1,2-a]pyrazine (3) (750 mg, 2.71 mmol), and N,N-diisopropylethylamine (526 mg, 4.16 mmol) in DMF (20 mL) was stirred at 100° C. for 3 h. After this time, the reaction was cooled to room temperature and poured into ice water (200 mL). The resulting suspension was filtered and the filter cake dried to a constant weight under vacuum to afford impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (1.26 g) as an off-white solid, which was used without further purification: 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 4.49 (m, 1H), 1.40 (d, 6H); ESI MS m/z 323.3 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1.O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:29]#[N:30])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CCl)ccc3o2)n1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Yield: 85.7 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-chloromethylphenylmethoxy)benzofuran-2-yl]thiazole (0.8 g), potassium cyanide (0.25 g) and Adogen 464 ((Aldrich phase transfer) one drop) in a mixture of toluene (8 ml) and water (8 ml) was stirred under reflux for 4 hours. After being cooled, the organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with toluene. The fractions containing object compound were combined and concentrated under reduced pressure to give an oil of 4-tert-butyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.67 g).
Reaction SMILES: [BH4-].[Na+].[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([C:6]3=[O:13])[CH2:4]1)[CH2:10]2>CO.[Cl-].[Na+].O>[N:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH:6]3[OH:13])[CH2:4]1)[CH2:10]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1C2CC3CC1CN(C3)C2
Temperature: 0 °C

Procedure:
Sodium borohydride (0.7 g) is added to 20 ml of ice-chilled MeOH. Then 1.88 g (0.012 mole) of 1-azatricyclo[3.3.1.13,7 ]decane-4-one, in 20 ml MeOH, is added dropwise over 5 minutes. A further 0.8 g NaBH4 (total 1.5 g, 0.04 mole) is added portionwise over 5 minutes. The reaction is stirred in ice one-half hour more, and then 1 hour at room temperature. The reaction is diluted with 20 ml brine, and extracted into ether. The ether is dried over MgSO4 and stripped to dryness, to give 1-azatricyclo-[3.3.1.13,7 ]decane-4-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[CH:17]([N-]C(C)C)(C)[CH3:18].[Li+].C(Br)C.Cl>O1CCCC1>[CH2:17]([C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:10]1=[O:16])[CH3:18]
Reactant: COc1cccc(C2CCCCNC2=O)c1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC1(c2cccc(OC)c2)CCCCNC1=O
Temperature: 25 °C

Procedure:
Hexahydro-3-(3-methoxyphenyl)-2H-azepin-2-one (2.19 g) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (from butyllithium 1.4 molar 15.7 ml, and diisopropylamine 3.15 ml) under nitrogen at 0° C. Ethyl bromide (1 ml) was added in one portion and the reaction allowed to warm up to room temperature. After two hours the reaction was poured into 2 M HCl, the organic layer separated and the aqueous layer extracted with chloroform. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to an oil which was crystallised from ethyl acetate giving 1.68 g of the title compound m.p. 85°-7° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CO[C:19](OC)([N:21]([CH3:23])[CH3:22])[CH3:20]>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](/[C:8](=[C:19](/[N:21]([CH3:23])[CH3:22])\[CH3:20])/[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: COC(C)(OC)N(C)C
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C

Procedure:
To a solution of 14.5 g. (0.10 m) of (p-fluorobenzoyl)acetonitrile in 100 ml. of chloroform, cooled in an ice-salt bath, was added 13.3 g. (0.1 m) of N,N-dimethylacetamide dimethylacetal in 20 ml. chloroform. The reaction mixture was stirred in the ice-salt bath for 2 hours, then evaporated in vacuo to an orange oil. The oil was dissolved in 150 ml. benzene and passed through Magnesol®. The filtrate was evaporated and the oil thus obtained was dissolved in 50 ml. benzene to which petroleum ether was added until the solution became cloudy. The precipitate which formed upon cooling was collected. The solid was recrystallized twice from benzene-petroleum ether, with charcoal treatment to yield 5.8 g. (27%) of light yellow crystals, m.p. 90°-92° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:23])([F:22])[O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:12])([F:22])[F:23])=[CH:16][CH:17]=1
Reactant: BrCCCBr
Reactant: Oc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCCCBr)cc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
To a mixture of 20.4 g of 1,3-dibromopropane, 7.1 g of potassium carbonate and 100 ml of N,N-dimethylformamide was added dropwise a solution of 9 g of 4-trifluoromethoxyphenol dissolved in 30 ml of N,N-dimethylformamide, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was filtered, and the solvent was removed from the filtrate by distillation under reduced pressure. The residue was subjected to silica gel chromatography, which afforded 9.1 g of 1-(3-bromopropyloxy)4-trifluoromethoxybenzene (60% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[SH:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].C(N(C(C)C)C(C)C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([S:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[N:6][C:5]=1[O:8][CH3:9]
Reactant: COC(=O)CCS
Reactant: COc1cc(Br)cnc1OC
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(OC)c(OC)c1
Yield: 105.1 %

Procedure:
To a solution of 5-bromo-2,3-dimethoxypyridine (2 g, 9.17 mmol) in dioxane (30 ml) was added methyl 3-sulfanylpropanoate (1.21 g, 10.1 mmol), N-ethyl-N-isopropylpropan-2-amine (3.03 ml, 18.3 mmol), Pd2(dba)3 (0.34 g, 0.37 mmol) and Xantphos (0.43 g, 0.73 mmol) at room temperature under an atmosphere of nitrogen. The reaction was degassed by evacuating and flushing with nitrogen and heated at reflux for 18 hours and then allowed to cool and filtered, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give an orange oil. Purification by column chromatography (SiO2; 0-20% ethyl acetate in petrol), gave methyl 3-[(5,6-dimethoxypyridin-3-yl)sulfanyl]propanoate as a yellow oil (2.48 g, quantitative yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:8]1[CH:9]=[C:4]([CH2:3][O:2][CH3:1])[C:5](=[O:11])[NH:6][C:7]1=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCc1c[nH]c(=O)[nH]c1=O
Reactant: BrCc1ccccc1
Product: COCc1cn(Cc2ccccc2)c(=O)[nH]c1=O

Procedure:
substituting 5-methoxymethyl-2,4(1H,3H)-pyrimidinedione and benzyl bromide gave 1-benzyl-5-methoxymethyl-2,4(1H,3H)-pyrimidinedione, m.p. 134°-136° C.;
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:60]1(=[O:66])[O:65][C:63](=[O:64])[CH2:62][CH2:61]1.C1(NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@H:17]([C@@H:18]([O:47][C:60](=[O:66])[CH2:61][CH2:62][C:63]([OH:65])=[O:64])[CH2:19][C@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)[NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43](=[O:46])[O:44][CH3:45])[CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OC(=O)CCC(=O)O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Yield: 98.5 %

Procedure:
A solution of Example 111 (60 mg, 0.074 mmol) in tetrahydrofuran (0.25 mL) and diethyl ether (0.5 mL) was treated with succinic anhydride (8.2 mg, 0.082 mmol) and dicyclohexylamine (16.3 μL, 0.082 mmol) at 25° C. for 6 h. Over the next 2 days more succinic anhydride (16.4 mg, 0.16 mmol) was added in portions. The mixture was partitioned between dichloromethane and 10% citric acid. The organic layer was separated, washed with brine, dried over MgSO4, and the solvents were evaporated to give the title compound (66 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86(s, 9H), 0.89(s, 9H), 1.25(m, 1H), 1.66(m, 1H), 2.34-2.24(m, 1H), 2.83-2.55(m, 9H), 2.98-2.89(m, 1H), 3.22-2.12(m, 1H), 3.46(s, 3H), 3.86-3.83(d, J=9.93 Hz, 1H), 4.48-1.09(m, 6H), 5.15-5.10(m, 1H), 6.61-6.58(d, J=9.56 Hz, 1H), 7.05-7.00(m, 3H), 7.13-7.11(m, 2H), 7.31-7.25(m, 4H), 7.44-7.36(m, 3H), 7.92-7.87(m, 3H), 7.96(m, 2H), 8.06-8.02(d, J=9.56 Hz, 1H), 8.68-8.66(m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].C(N(CC)C(C)C)(C)C.[Br:23][C:24]1[CH:25]=[N:26][C:27](Cl)=[N:28][CH:29]=1>O1CCOCC1>[Br:23][C:24]1[CH:25]=[N:26][C:27]([NH:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:2]=2[F:1])=[N:28][CH:29]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCc1cc(C(F)(F)F)ccc1F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)F)cc1CNc1ncc(Br)cn1
Temperature: 25 °C
Yield: 46.6 %

Procedure:
2-Fluoro-5-trifluoromethyl-benzylamine (2.0 g) is dissolved in 1,4-dioxane (10 ml) and thereto are added N,N-diisopropylethylamine (2.7 ml) and 5-bromo-2-chloropyrimidine (3.02 g) and the mixture is heated under reflux overnight. The reaction solution is cooled to room temperature and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 7:3) to give (5-bromo-pyrimidin-2-yl)-(2-fluoro-5-trifluoromethyl-benzyl)-amine (1.69 g). MS (m/z): 350/352 [M+H]+
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[C:27]([Cu])#[N:28].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:27]#[N:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: N#C[Cu]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.6 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid butyl ester (624 mg, 1.5 mmol; prepared as shown in Scheme 2, and according to US 2004/0254215 A1, 1H NMR (CDCl3): δ=11.89 (s, 1H), 8.35 (d, 1H), 7.63 (d, 1H), 7.08 to 7.52 (m, 6H), 4.47 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.99 (t, 3H)), CuCN (271 mg, 3 mmol) and dimethylformamide (6 mL) was refluxed with stirring under nitrogen for 15 min. After cooling to ambient temperature the mixture was diluted with ethyl acetate (100 mL). The resulting suspension was filtered through a pad of celite. The filtrate was washed with water (2×250 mL), and dried over MgSO4 before silica gel was added. Subsequently, the mixture was concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with dichloromethane gave the title compound as a white solid (313 mg); MS-(−)-ion: M−1=361.2.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O1CCCC1>[CH3:24][S:25]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12][CH2:13]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: c1cc2[nH]ncc2cc1NC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2ccc3[nH]ncc3c2)CC1
Yield: 21.5 %

Procedure:
Triethylamine (0.39 ml, 2.80 mmol) was added to a solution of the N-(4-piperidinyl)-1H-indazol-5-amine (0.300 g, 1.39 mmol) obtained in Example 15, (a) in tetrahydrofuran (5 ml) at room temperature, followed by adding thereto a solution of methanesulfonyl chloride (0.175 g, 1.53 mmol) in tetrahydrofuran (2 ml) at 0° C., and the resulting mixture was stirred at room temperature for 1 hour. Then, the reaction solution was poured into a 1N-aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=30/1) to obtain N-[1-(methylsulfonyl)-4-piperidinyl]-1H-indazol-5-amine (0.088 g, 22%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.NC(N)=[S:27].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:16]1([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]3[S:27][CH2:23][CH2:22][C:3]=3[C:4]([CH3:21])=[N:5][C:6]=12
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCS4)c(C)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (500 mg, 1.38 mmol), thiourea (105 mg, 1.38 mmol) and sodium carbonate (180 mg, 1.73 mmol) in ethanol (10 mL) was heated under reflux for one hour. After overnight, water was added and the resulting crystals were collected by filtration. The crystals were washed with water, to give the title compound (436 mg) as white crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]([OH:21])=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1>>[CH:5]1[C:18]2[C:9](=[N:10][C:11]3[C:16]([C:17]=2[C:19]([Cl:3])=[O:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Product: O=C(Cl)c1c2ccccc2nc2ccccc12

Procedure:
Thionyl chloride (20 me) was added to 2.2 g of 9-acridinecarboxylic acid, followed by heating under reflux for 5 hours. After the thionyl chloride was distilled off under reduced pressure, 20 ml of methylene chloride were added further. Distillation was repeated twice under reduced pressure, whereby 2.4 g of the compound (2) were obtained (yield: stoichiometric).
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C(C)=C(S(O)(=O)=O)C(C)=C(N)C=2C)=[CH:4][C:3]=1S(O)(=O)=O.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(N)c(C)c(S(=O)(=O)O)c(C)c1Sc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-4-(3'-amino-2',4',6'-trimethyl-5'-sulfophenylthio)anthraquinone-2-sulfonic acid (23.7 cyanuric chloride (9.3 parts) and 1-aminobenzene-3-β-sulfatoethylsulfone (14.1 parts) were subjected to condensation reactions one after another in an aqueous medium in a usual manner, followed by further condensation reaction with 3-aminobenzenesulfonic acid (8.7 parts) at 50° to 60° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of the following formula (free acid form). ##STR519##
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([C:2]2[CH:3]=[C:4]([CH:27]=[CH:28][N:29]=2)[C:5]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:10][CH:9]=2)=[O:6])[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccnc(Cl)c1
Product: CC(=O)N1CCN(c2cc(C(=O)Nc3ccc(OCCN4CCOCC4)c4ccccc34)ccn2)CC1

Procedure:
Compound is formed by reacting 2-chloro-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide and 4-acetylpiperazine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.32 (d, 1H, J=5.4), 8.20 (m, 1H), 7.84 (m, 1H), 7.58 (m, 2H), 7.46 (d, 2H), 7.23 (d, 1H, J=5.4), 7.05 (d, 1H, J=8.1), 4.31 (t, 2H), 3.58 (m, 12H), 2.88 (t, 2H), 2.57 (t, 4H), 2.06 (s, 3H). MS: 504.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:13]([O-])=O)[N:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[N:4]2
Reactant: [H][H]
Reactant: COc1ccc2c([N+](=O)[O-])cccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc2c(N)cccc2n1

Procedure:
550 mg (2.7 mmol) of 2-methoxy-5-nitroquinoline is stirred in 15 ml of ethyl acetate in the presence of 138 mg of 10% Pd—C for 5 hours in a hydrogen atmosphere. The batch is filtered, and the filtrate is concentrated by evaporation: 520 mg of a light yellow oil.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([Cl:18])[C:16]=1[N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 82.2 %

Procedure:
General procedure C (See Example 1) was followed using isonipecotamide (380 mg, 3.0 mmol), 3,4,5-trichloropyridine (600 mg, 3.3 mmol), triethylamine (0.84 mL, 6.0 mmol) and NMP (18 mL). The crude product was purified by flash column chromatography on silica gel (CH2Cl2/EtOH, 95:5-91:9) to furnish the title compound as a white solid (0.676 g, 83%); LC-MS (ESI, 4 min) Rt 1.46 min, m/z 274 (100%, [M+H]+); m/z (ESI) C11H13N3OCl2 requires 273.0436, found [M+H]+ 273.0446.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Cl[CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22].O>CN(C)C=O>[Cl:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(CCl)C(=O)O
Reactant: Sc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CSc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
Sodium hydride powder (0.86 g, 35.8 mmol) was added to a mixture of 4-(4-chlorophenoxy)thiophenol (3.55 g, 15 mmol) in N,N-dimethylformamide (12 mL) at 0° C. The mixture was warmed to room temperature over 5 minutes, stirred for an additional 20 minutes, and solid chloropivalic acid (1.64 g, 12.0 mmol) was added in one portion. This mixture was heated to 80° C. for 18 hours, cooled to room temperature, and water (1 mL) added. The residue was partitioned between methylene chloride (50 mL) and 2N hydrochloric acid (25 mL). The aqueous layer was separated and washed with additional methylene chloride (2×25 mL). The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo. Chromatography over silica gel, and eluting with 5% methanol/methylene chloride, gave slightly impure 3-[4-(4-chlorophenoxy)phenylthio]-2,2-dimethyl propionic acid (4 g, 99%). This material was recrystallized from the minimum amount of diethyl ether/hexanes to afford analytically pure acid as a white solid (3.20 g, 80%). mp 84.4-84.9° C.; IR (KBr) 3433 (br), 1732 cm-1 ; 1HNMR (DMSO-d6) δ 1.19 (s, 6H), 3.14 (s, 2H), 6.97 (d, J=8.7 Hz, 2H), 7.01 (d, J=8.9, 2H), 7.40 (d, J=8.8 Hz, 2H), 12.36 (br s, 1H). EIMS(M+): 378. Anal. Calcd. for C17H17SO3Cl: C, 60.62; H, 5.09. Found: C, 60.31; H, 4.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][NH:13][C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([CH:31]=[CH:32][CH2:33]Cl)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=3)=[N:14][N:13]([CH2:33][CH:32]=[CH:31][C:30]3[CH:35]=[CH:36][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:12](=[O:25])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: ClCC=Cc1ccc(Cl)cc1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1F
Product: COc1ccc(-c2cc(=O)n(CC=Cc3ccc(Cl)cc3)nc2-c2ccc(OC)c(F)c2)cc1F
Yield: 42.9 %

Procedure:
Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 42.9%.