Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]4[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 9, 0.5 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.35 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.5 g of desired product. MS (electrospray): 385 (M+1) for C17H18FN8O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.20 (d, 1H) 6.40 (m, 1H) 6.20 (d, 1H) 5.45 (m, 1H), 1.90 (m, 1H) 1.70 (d, 3H) 1.05 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CCCCCC>N1C=CC=CC=1.CCOC(C)=O>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[C:16]4[S:20][C:19](=[O:21])[NH:18][C:17]4=[O:22])[CH:10]=3)=[O:7])=[CH:23][CH:24]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)Nc2cccc(C=C3SC(=O)NC3=O)c2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1NC(=O)C(=Cc2cccc(NC(=O)c3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3)c2)S1

Procedure:
4-Amino-N-[3-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-phenyl]-benzamide was dissolved in pyridine and treated with 4-chloro-benzenesulfonyl chloride in pyridine at 60° C. for 12 h. The solution-was cooled and diluted with EtOAc then washed with 10% aq. NaHSO4 followed by saturated aq. NaCl. The organic phase was separated, dried over Na2SO4 and concentrated under reduced pressure to give an oil. Trituration with hexane gave pure product.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[O:15][C:14](=O)[C:13]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:12]=2[C:11]=1[C:24]1[C:25]([CH3:34])=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2)(C(C)(C)C)(C)C.[CH3:35][NH2:36]>CCO>[OH:8][CH2:9][C:10]1[N:36]([CH3:35])[C:14](=[O:15])[C:13]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:12]=2[C:11]=1[C:24]1[C:25]([CH3:34])=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][CH2:28][CH2:27]2
Reactant: CN
Reactant: Cc1c(-c2c(CO[Si](C)(C)C(C)(C)C)oc(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Solvent: CCO
Product: Cc1c(-c2c(CO)n(C)c(=O)c3sc4c(c23)CCCC4)ccc2c1CCCO2
Temperature: 65 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5-methylchroman-6-yl)-5,6,7,8-tetrahydro-1H-benzo[4,5]thieno[2,3-c]pyran-1-one (100 mg, 0.2 mmol) was dissolved in 4N MeNH2 (g)/EtOH (20 mL) and stirred at 65° C. for 3 hrs. After cooling to room temperature, the mixture was concentrated, and 4N HCl/ethyl acetate (20 ml) was added. The mixture was stirred at room temperature for 15 min and concentrated in vacuo. The residue was partitioned between ethyl acetate and sat. aq. NaHCO3 and the organic layer washed with water, dried over Na2SO4 and evaporated to afford the crude title product (60 mg, 75% yield) which was used for the next step directly. LCMS (m/z) ES+=396 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][OH:16])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]2.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)=O>C1COCC1.CCOC(C)=O>[C:7]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:16][C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[C:36](=[O:40])[CH2:35][CH2:34][CH2:33]3)[N:10]=[CH:9]1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCCc2cc(OCCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc21

Procedure:
According to the method of Example 32, Step 1, 3-[1-(triphenylmethyl)-1H-imidazole-4-yl]propanol (see for example, J. Med. Chem., 1996;39: 1220-1226) (2.58 g, 7 mmol) was coupled to 6-hydroxy tetralone (1.30 g, 7 mmol) with diethylazodicarboxylate (1.26 mL, 8 mmol) and triphenylphosphine (2.10 g, 8 mmol) in 10 mL of dry THF to afford, after chromatography (SiO2, 50% EtOAc in hexanes), 2.73 g of a 1:1 mixture of the title compound and Ph3PO as determined by HPLC analysis (C18, 0.1% TFA in H2O:0.1% TFA in AcCN gradient 80:20 to 20:80): title compound, retention time=15.87 minutes (48.2%); Ph3PO, retention time=13.12 minutes (50.1%). CI-MS m/e 279 (Ph3PO), 513 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[I:25]I.[N+]([O-])(O)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([I:25])=[C:18]([CH3:22])[N:17]([CH3:23])[C:16]2=[O:24])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: II
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.50 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 10 ml of acetic acid are treated with 0.70 g of iodine and the reaction mixture is stirred for 1 hour at room temperature. Subsequently the reaction mixture is treated with 0.67 g of 100% nitric acid and stirred at room temperature for 3 hours. The reaction mixture is poured into 150 ml of ice/water and extracted with 100 ml of ethyl acetate. The organic phase is washed with 150 ml of water, thereafter with 150 ml of aqueous sodium bicarbonate solution and finally with 150 ml of saturated aqueous sodium bisulphite solution. The upper phase is dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from methylene chloride/n-hexane. Isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-iodo-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 147°-150° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].Cl[CH:15]([O:17]C)Cl.Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:15]=[O:17])=[CH:10][CH:11]=1)([CH3:5])[CH3:12]
Reactant: COC(=O)C(C)(C)c1ccccc1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
6.80 g (38 mmol) of 2-methyl-2-phenyl-propionic acid methyl ester was dissolved at rt in 200 mL MeCl2 and 7.01 ml (90.4 g=76 mmol) of dichloromethylmethylether was added and the mixture cooled down to 0° C.; 21.47 mL (36.93 g=191 mmol) TiCl4 was added over 15 min and the reaction warmed up to ambient temperature; stirring was continued for 16 hours. The reaction mixture was then treated at 0° C. with 20 ml of HCl (37% in water) and extracted twice with MeCl2; the organic phases were washed with water, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography (silicagel, eluent:gradient of n-heptane/EtOAc) to yield 5.00 g of the title compound as yellow oil. MS: 206.1 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2[OH:20])[CH3:2].O.[C:22]([OH:26])(=[O:25])[CH:23]=O>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]1[C:13]([CH:14]=[CH:23][C:22]([OH:26])=[O:25])=[N:12][C:11]2[C:6]([CH:5]=1)=[C:7]([OH:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]=2)[CH3:2]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1cnc2nc(C=CC(=O)O)c(OCC)cc2c1O

Procedure:
A mixture of ethyl 6-ethoxy-4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxylate (2.8 g), glyoxylic acid monohydrate (1.5 g) acetic acid (20 ml) and trifluoroacetic acid (10 ml) was heated at 90°-95° C. for 2 hours, with stirring. The mixture was evaporated down under reduced pressure. The residue was triturated with hot ethanol and filtered to give 3-(3-ethoxy-6-ethoxycarbonyl-5-hydroxy-1,8-naphthyridin-2-yl)acrylic acid, m.p.>280° C.
Reaction SMILES: CN(C)C(N(C)C)=S.IC.[F:11][C:12]([F:52])([F:51])[C:13]1[CH:14]=[C:15]([C:23]([CH3:50])([CH3:49])[C:24]([N:26]([C:28]2[CH:29]=[N:30][C:31]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[CH2:47][OH:48])=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[CH3:41])[CH3:27])=[O:25])[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.[H-].[Na+].[CH3:55][N:56]([CH3:59])[CH:57]=[O:58]>CCCCCC.O>[F:52][C:12]([F:11])([F:51])[C:13]1[CH:14]=[C:15]([C:23]([CH3:49])([CH3:50])[C:24]([N:26]([CH3:27])[C:28]2[C:33]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=3[CH3:41])=[CH:32][C:31]([N:42]3[CH2:46][CH2:45][CH2:44][C@H:43]3[CH2:47][O:48][C:57](=[O:58])[N:56]([CH3:59])[CH3:55])=[N:30][CH:29]=2)=[O:25])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: CN(C)C(=S)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CCCCCC
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2COC(=O)N(C)C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.83 h
Yield: 40 %

Procedure:
To a solution of 44 mg (0.33 mmol) 1,1,3,3-tetramethyl-2-thiourea in 1.5 ml N,N-dimethylformamide were added 0.027 ml iodomethane at room temperature. After stirring for 50 min. 0.20 g (0.33 mmol) (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide and a suspension of 45 mg (0.90 mmol) sodium hydride (ca. 50% dispersion in mineral oil) in 0.5 ml n-hexane were added. After stirring at room temperature for 1 h the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 90 mg (40%) of the title compound as an off-white solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]2[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>ClCCl>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:10]([C:16]2[N:17]([CH3:21])[N:18]=[CH:19][CH:20]=2)[CH:11]=1)=[O:32]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCn1ccnc1
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClCCl
Product: Cn1nccc1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1OCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.08 g, 0.256 mmol) in 2.0 mL of dichloromethane was added 2,4-difluoro phenyl isocyanate (0.042 g, 0.280 mmol), and the mixture was stirred at ambient temperature overnight. The DCM was evaporated from the reaction mixture, the crude residue was dissolved in 5.0 mL of DMSO and purified by RP-HPLC. The proper fractions were collected and lyophilized to afford the 1-(2,4-difluoro-phenyl)-3-[4-(2-imidazol-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea as an off-white solid in 75% yield. LCMS m/z (%)=439 (M+H). 1H NMR (400 MHz, Acetone-d6) δ: 8.46 (bs, 1H), 7.96-8.02 (m, 1H), 7.48 (dd, J=8.9 and 2.72 Hz, 1H), 7.39-7.41 (m, 2H), 7.31 (d, J=1.81 Hz, 1H), 7.17 (t, J=1.42 Hz, 1H), 6.94 (d, J=8.94 Hz, 1H), 6.7-6.8 (m, 2H), 6.01 (d, J=1.78 Hz, 1H), 4.62 (t, J=4.74 Hz, 2H), 4.33 (t, J=5.07 Hz, 2H), 3.48 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:30][C:31]1[N:36]=[CH:35][N:34]=[C:33](Cl)[CH:32]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH3:29])[C:16]3[CH2:22][CH2:21][N:20]([C:33]4[CH:32]=[C:31]([CH3:30])[N:36]=[CH:35][N:34]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(Cl)ncn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(c2cc(C)ncn2)C3)cc1

Procedure:
Compound du was prepared according to the procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 6-methyl-4-chloropyrimidin. LC-MS: m/z=+489 (M+H)+.
Reaction SMILES: [Cl:1]CCN1N=CC2C(=CC(OC)=C(OC)C=2)C1=O.Cl[CH2:20][CH2:21][N:22]1[N:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[CH:27][CH:28]=2)[C:23]1=[O:35].C1(N2CCNCC2)C=CC=CC=1.[F:48][C:49]1[CH:62]=[CH:61][C:52]([C:53]([CH:55]2[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]2)=[O:54])=[CH:51][CH:50]=1>C(O)C>[ClH:1].[F:48][C:49]1[CH:50]=[CH:51][C:52]([C:53]([CH:55]2[CH2:60][CH2:59][N:58]([CH2:20][CH2:21][N:22]3[N:31]=[CH:30][C:29]4[C:24](=[CH:25][C:26]([N+:32]([O-:34])=[O:33])=[CH:27][CH:28]=4)[C:23]3=[O:35])[CH2:57][CH2:56]2)=[O:54])=[CH:61][CH:62]=1
Reactant: COc1cc2cnn(CCCl)c(=O)c2cc1OC
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=c1c2cc([N+](=O)[O-])ccc2cnn1CCCl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: Cl
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2ncc3ccc([N+](=O)[O-])cc3c2=O)CC1

Procedure:
Working as described in Example 3 but replacing 2-[2-chloroethyl]-6,7-dimethoxy-1(2H)-phthalazinone with an equivalent amount of 2-(2-chloroethyl)-7-nitro-1(2H)-phthalazinone and replacing N-phenyl piperazine with an equivalent amount of 4-(4-fluorobenzoyl)-piperidine, 2-{2-[4-(4-fluorobenzoyl)-piperidin-1-yl]-ethyl}-7-nitro-1-(2H)-phthalazinone hydrochloride is obtained (m.p. 280°-285° C., from ethyl alcohol).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[C:8]2[N:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:32]=[CH:31][C:19]4[N:20]=[C:21]([NH:23][C@@H:24]5[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]5[OH:30])[S:22][C:18]=4[CH:17]=3)[C:9]2=[N:10][CH:11]=1.[C:33]([O-])([O-])=O.[Cs+].[Cs+]>CI>[CH3:33][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([CH2:15][C:16]4[CH:32]=[CH:31][C:19]5[N:20]=[C:21]([NH:23][C@@H:24]6[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]6[OH:30])[S:22][C:18]=5[CH:17]=4)[C:9]3=[N:10][CH:11]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(-c5nn[nH]n5)cnc43)cc2s1
Agent: [Cs+]
Solvent: CI
Product: Cn1nnc(-c2cnc3c(c2)ncn3Cc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)n1
Temperature: 90 °C

Procedure:
To the remaining portion of the reaction mixture from Example 93 were added excess Cs2CO3 (300 mg) and excess MeI (200 μL). The resulting mixture was heated at 90° C. for 4 h. LCMS showed that the reaction was mostly completed. After cooling to rt, the mixture was purified by preparative HPLC using a mixture of water (5% CH3CN, 0.05% AcOH) and CH3CN (0.05% AcOH) as the mobile phase and Varian Pursuit XRs Diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(2-methyl-2H-tetrazol-5-yl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (8 mg) as a white powder. The regiochemistry assignment of the compound was consistent with the result from a NMR Nuclear Overhauser Effect (NOE) experiment. 1H NMR (300 MHz, MeOH-d4) δ 9.17 (s, 1H), 8.69 (s, 1H), 8.55 (s, 1H), 7.67 (s, 1H), 7.25-7.41 (m, 2H), 5.58 (s, 2H), 4.36-4.51 (m, 3H), 3.57 (d, J=9.6 Hz, 1H), 3.36-3.49 (m, 1H), 2.13 (d, J=11.3 Hz, 1H), 2.01 (br s, 1H), 1.71 (d, J=10.0 Hz, 2H), 1.12-1.48 (m, 4H). LCMS (ESI) m/z 462 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]>>[CH3:12][CH:13]([CH3:31])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[N:21][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:4](=[O:5])[C:3]3[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=3[Cl:1])[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)=[O:18]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccc(Cl)cc3Cl)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 2,4-dichlorobenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (90% yield). 1H NMR (500 MHz, CDCl3) δ 8.07, 7.85, 7.47, 7.35, 7.28, 7.01, 4.02-4.09, 3.75-3.93, 3.33-3.52, 1.65-1.75, 1.52, 0.94. MS (ES+) m/z 450 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][N:12]([CH3:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)S([Cl:41])(=O)=O>O1CCCC1>[Cl:41][C:11]1[N:12]([CH3:22])[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)n(C)c2-c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 92.1 %

Procedure:
A mixture of 4,5-bis(4-methoxyphenyl)-1-methyl-1H-imidazole (10.0 g, 0.034 mol) and N, N, N',N'-tetramethylethylenediamine (three equivalents) in 75 ml of dry tetrahydrofuran was cooled to -78° and treated with n-butyllithium (1.1 equivalents). The mixture was stirred at -78° under nitrogen for one hour and treated with dimethylsulfamoyl chloride (5.5 g, 0.038 mol). The mixture was stirred at -78° for 30 minutes and then overnight at room temperature. The reaction mixture was concentrated in vacuo, and the residue triturated with 10% citric acid. The resulting solid was collected by filtration, washed with water, and dried in vacuo to yield 10.3 g (92%) of the title compound, homogenous by tlc (toluene-ethyl acetate, 6:4; Rf=0.56), m.p. 132°-133°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:22]([O-:25])(O)=[O:23].[Na+].Cl[S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]=[CH:38]C(O)=O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].Cl>O1CCOCC1.O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37](=[CH2:38])[C:22]([OH:25])=[O:23])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(C(=O)O)c1ccc(S(=O)(=O)N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Yield: 71.8 %

Procedure:
To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL), the pH of the medium was brought to ˜4 with 2 N HCl, and extracted with ethyl acetate. The extract was washed successively with water, brine, and dried (Na2SO4). The solvent was removed and the crude product was crystallized from dioxane to give the title compound (0.58 g, 63%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 2.19-2.50 (4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6 and 5.6 Hz); 7.72 (1H, d, J=116.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][OH:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:5]1[NH:6][C:7]([CH:11]=[O:12])=[C:8]([I:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(I)c(CO)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCc1nc(I)c(C=O)[nH]1
Yield: 84.2 %

Procedure:
A stirred mixture of 174.1 g (0.62 mol) of 2-n-butyl-5-hydroxymethyl-4-iodoimidazole and 360 g (4.14 mol) of manganese dioxide in 3 L of dichloromethane was refluxed for 24 hr using a trap to remove water. The hot reaction mixture was filtered through a Celite® pad which was then washed with 4.5 L of boiling methylene chloride. The combined filtrates were concentrated to dryness. The residue was dissolved twice in 150 ml of methanol and each time the solution was concentrated to dryness. The residue was dissolved in 130 ml of methanol and chilled. After crystallization stopped, 700 ml of water was added slowly. The mixture was chilled, and the solid was collected by filtration, washed with water and dried to give 145.2 g (84%) of product; mp 104-105° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:12]2[CH2:13][CH2:14][CH:10]([OH:9])[CH2:11]2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: OC1CCNC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: OC1CCN(c2cccc(Br)n2)C1
Temperature: 70 °C
Reaction time: 11 h
Yield: 100.9 %

Procedure:
A mixture of 5.7 g of 2,6-dibromopyridine, 2.5 g of 3-hydroxypyrrolidine, 3.6 ml of 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) and 20 ml of tetrahydrofuran was heated under stirring under nitrogen atmosphere in an oil bath at 70° C. for 11 hours. The reaction mixture was separated with ethyl acetate-water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silicagel column chromatography with 10–30% ethyl acetate/hexane, to give 5.9 g of 2-bromo-6-(3-hydroxypyrrolidin-1-yl)pyridine.
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([CH:21]=1)[NH2:20]>CC(C)=O.ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:22])=[C:19]([NH:20][C:11]([NH2:12])=[S:10])[CH:21]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(Cl)cc1N
Agent: [NH4+]
Solvent: ClCCl
Solvent: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Product: Cc1ccc(Cl)cc1NC(N)=S

Procedure:
8.9 ml of benzoyl chloride are added to a solution of 5.9 g of ammonium thiocyanate in 130 ml of anhydrous acetone. The reaction mixture is heated under reflux for 15 minutes and then after cooling, 10 g of 5-chloro-2-methylaniline are added. The reaction mixture is heated under reflux for 2 hours and the acetone is removed by distillation under vacuum. The residue obtained is taken up in dichloromethane. The mixture is washed with water, dried over sodium sulphate and evaporated under vacuum. The expected product is obtained in the form of an oil with a quantitative yield.