Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([NH2:6])(=[NH:5])[CH2:3][CH3:4].[CH3:7][N:8]([C:12](Cl)=[O:13])[C:9](Cl)=[O:10].[OH-].[Na+]>O.C1C=CC=CC=1>[CH3:7][N:8]1[C:12](=[O:13])[NH:6][CH:2]([CH2:3][CH3:4])[NH:5][C:9]1=[O:10]
Reactant: CN(C(=O)Cl)C(=O)Cl
Reactant: CCC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CCC1NC(=O)N(C)C(=O)N1
Yield: 49.6 %

Procedure:
10.9 g (0.1 mole) of propionamidine hydrochloride were suspended in 125 ml of water and 200 ml of benzene. 15.6 g (0.1 mole) of N-methyl-bis-(chlorocarbonyl)-amine in 100 ml of dry benzene and 18 g (0.45 mole) of sodium hydroxide dissolved in 100 ml of water were simultaneously slowly added dropwise from two dropping funnels, with vigorous stirring. The reaction took place exothermically. The mixture was stirred for a further hour, the aqueous phase was separated off and acidified with glacial acetic acid and the mixture was evaporated in vacuo. The residue was repeatedly extracted by boiling with ethyl acetate. The solution was concentrated in vacuo and cooled. The precipitate was filtered off. 7.8 g (50%) of 1-methyl-4-ethyl-tetrahydro-1,3,5-triazine-2,6-dione were obtained as colorless needles of melting point 202°-203° C.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])OCC.[H-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1.C(O)(=O)C>C1COCC1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:1]([O:5][CH2:6][CH3:7])=[O:8])=[CH:14][CH:13]=1
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 80.2 %

Procedure:
To a suspension of diethyl carbonate (47.4 mL, 391 mmol) and sodium hydride (55 wt % paraffin oil, 23.7 g, 543 mmol) in THF was added 4′-fluoroacetophenone (26.4 mL, 271 mmol) at 60° C. The reaction mixture was heated under reflux for 1 hr, cooled to room temperature, and poured into acetic acid (33.6 ml, 586 mmol) and ice water (1 L). The reaction mixture was extracted with diethyl ether (2×500 mL), the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure to give ethyl 3-(4-fluorophenyl)-3-oxopropanoate (45.7 g, 100%, keto form: enol for m=5:1) as a yellow oil.
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][O:33]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH:21]C(=O)C2C=CC=CC=2)=[N:19][C:17]1=[O:18])C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH2:21])=[N:19][C:17]1=[O:18]
Reactant: O=C(Nc1ccn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)n1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: Nc1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)n1

Procedure:
To a solution of nucleoside 57 (0.3 g, 0.55 mmol) in anhydrous methanol (22 cm3) were added 1,4-cyclohexadiene (5.0 cm3) and 10% palladium on carbon (0.314 g). The mixture was stirred under reflux for 18 h. Additional 10% palladium on carbon (0.380 g) and 1,4-cyclohexadiene (5.5 cm3) were added and the mixture was refluxed for 54 h. The reaction mixture was filtered through a pad of silica gel which was subsequently washed with methanol (1500 cm3). The combined filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92.5:7.5, v/v) as eluent to give compound 57A as a white solid material (0.051 g, 36%). δH ((CD3)2SO) 7.73 (1H, d, J 7.7, 6-H), 7.12-7.20 (2H, br s, NH2), 5.74 (1H, d, J 7.7, 5-H), 5.61 (1H, br s, 3′-OH), 5.39 (1H, s, 1′-H), 5.12 (1H, m, 5′-OH), 4.08 (1H, s, 2′-H), 3.80 (1H, d, J 7.7, 1″-Ha), 3.81 (1H, s, 3′-H), 3.74 (2H, m, 5′-Ha, 5′-Hb), 3.63 (1H, d, J 7.7, 1″-Hb). δC ((CD3)2SO) 165.66 (C-4), 154.58 (C-2), 139.68 (C-6), 93.19 (C-5), 88.42, 86.73 (C-1′, C-4′), 78.87, 70.85, 68.32, 56.04 (C-2′, C-1″, C-3′, C-5′). FAB-MS m/z 256 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10](CCl)[C:9]1=[O:20])C1C=CC=CC=1.[Na].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.CO.ClCCl>CN(C=O)C>[N:22]1([CH2:1][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:20])[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: c1nc[nH]n1
Reactant: O=c1c(CCl)cc2ccccc2n1Cc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=c1ccc2ccccc2n1Cn1cncn1

Procedure:
React 1-benzyl-3-chloromethyl-2(1H)-quinolone with the sodium salt of 1,2,4-triazole in DMF at 25° C. for 18 hours, following the procedure of example 22. Chromatograph the crude product using 5% methanol-dichloromethane to obtain the major product, 1-Benzyl-3-(1H-1,2,4-triazol-1-ylmethyl-2(1H)-Quinolone.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:32])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH3:23])[C:7]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOCCOc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOCCOc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (289 mg, 0.83 mmol) in chloroform (5 mL) was added 2-benzenesulfonyl-3-phenyl-oxaziridine (281 mg, 1.07 mmol). The reaction mixture was stirred at RT overnight, under nitrogen. The solvents were removed and the crude product was chromatographed on silica gel, eluting with a 5% methanol-ethyl acetate/hexane gradient to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a clear oil (210 mg, 0.56 mmol). 1H NMR δ (400 MHz, CDCl3) 8.84 (s, 1H), 6.89 (s, 1H), 6.06–5.98 (m, 1H), 4.23 (t, J=4.0 Hz, 2H), 3.89 (t, J=4.0 Hz, 2H), 3.60 (q, J=6.9 Hz, 2H), 2.95 (s, 3H), 2.28–2.19 (m, 2H), 2.15–2.10 (m, 2H), 1.97–1.88 (m, 2H), 1.71–1.64 (m, 2H), 1.21 (t, J=6.9 Hz, 3H); MS (APCI+) 350 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][OH:25])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C1COCC1>[CH3:37][S:38]([O:25][CH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:12]2[CH2:13][C:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)([C:26]([F:28])([F:29])[F:27])[CH2:10][N:11]=2)=[CH:15][CH:16]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Reaction time: 1 h

Procedure:
{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methanol (0.6 g) and triethylamine (0.35 g) were dissolved in THF (5 ml), and methanesulfonyl chloride (0.15 ml) was added gradually. The mixture was stirred for 1 hour, and then added water. The mixture was extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, to obtain the desired compound as crude product (0.7 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[O:11][N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:18]([O:25][C:26](=[O:36])[NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:14]([C:13]2[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=3)=[N:10][O:11][C:12]=2[CH3:17])=[O:16])[CH2:30]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)O
Reactant: NC1CCCC(CNC(=O)OCc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ncc(Cl)cc2Cl)c1C(=O)NC1CCCC(CNC(=O)OCc2ccccc2)C1
Yield: 89.6 %

Procedure:
Combine 3-(3,5-dichloro-pyridin-2-yl)-5-methyl-isoxazole-4-carboxylic acid (0.35 g, 0.0013 mol) with (3-amino-cyclohexylmethyl)-carbamic acid benzyl ester (0.38 g, 0.0013 mol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25, 0.0013 mol), 1-hydroxy-7-azabenzo-triazole (0.18 g, 0.0013 mol), and N,N-diisopropylethyl amine (0.67 mL, 0.0039 mol) in N,N-dimethylformamide (8 mL) and stir overnight at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Concentrate and elute over silica gel using ethyl acetate/dichloromethane to give 0.603 g (90%) of the desired amide. MS(ES): (M+1)+ 517.2, 519.2 m/z.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+:10].C([Li])CCC.[C:16]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][C:16]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:23][C:1](=[O:6])[CH:2]=1.[Na+:10].[C:16]([CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)CCCC1(c2ccccc2)CC(O)=CC(=O)O1
Product: O=C([O-])CCCC(=O)c1ccccc1

Procedure:
The title compound was prepared as described in General Method 1 using 25 mmol of methyl acetoacetate, 27.5 mmol of NaH 60% dispersion in oil, 26.25 mmol of 1.6M n-butyl lithium in hexane in 50 mL of tetrahydrofuran and 25 mmol of 4-benzoylbutyric acid acid sodium salt in 100 mL of tetrahydrofuran. 4-Benzoylbutyric acid sodium salt was prepared by reacting the acid (25 mmol) with hexane washed NaH (17.5 mmol) in tetrahydrofuran at 0° C. for 25 minutes. The crude product was flash chromatographed using CH2Cl2 /MeOH/CH3CO2H (99/1/0.1-97.5/2.5/0.1) to give a solid which was recrystallized from ethyl acetate (m.p. 134°-137° C.). 1H NMR (DMSO-d6) δ 1.1-1.2 (m, 1 H), 1.4-1.6 (m, 1 H), 1.8-2.0 (m, 2 H), 2.0-2.2 (m, 2 H), 2.9 (ABq, 2 H), 4.85 (s, 1 H), 7.2-7.4 (m, 5 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2c(c1)C(O)CC2

Procedure:
33.5 g (0.2065 mol) of 6-methoxy-2,3-dihydro-1H-indenone is added in portions to a solution of 3.8 g (0.1 mol) of lithium aluminium hydride in 700 ml of dry ether and 50 ml of dry tetrahydrofuran, under an inert atmosphere with cooling. (H.0. House et al. J. Org. Chem. 35 647-51, 1970 and J. Org. Chem. 42, 2155-60, 1977).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:18]([I:19])=[C:11]2[NH:12][C:13]([CH3:17])=[N:14][C:15](=O)[N:10]2[N:9]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:31]>C1(C)C=CC=CC=1>[Cl:31][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:18]([I:19])=[C:11]2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1nc(=O)n2nc(-c3ccccc3Cl)c(I)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(I)c2n1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a solution of 7-(2-chlorophenyl)-8-iodo-2-methyl-1H-pyrazolo[1,5-a][1,3,5]triazin-4-one (I-1A-1d; 1.00 g, 2.6 mmol) and diisopropylethylamine (0.68 ml, 3.8 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.28 ml, 14 mmol), dropwise. The mixture was heated at reflux for 5 hours, cooled to room temperature, and then concentrated, in vacuo, to a viscous oil. The residue was then purified by passing through a plug of silica gel on a sintered glass funnel using 20% ethyl acetate in hexanes as eluant to provide I-1A-1e as a yellow solid (0.93 g, 89%): +APcI MS (M+1) 316.3; 1H NMR (400 MHz, CD2Cl2) δ 7.57 (d, J=7.9 Hz, 1H), 7.53-7.43 (m, 3H), 2.74 (s, 3H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C1CCN2C(=NCCC2)CC1.[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[C:30]2[C:29](=[O:52])[NH:28][C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]>CN(C)C=O>[CH2:22]([N:26]1[C:31]2=[N:32][N:33]([CH2:41][C:42]3[C:51]4[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:45]=[CH:44][CH:43]=3)[C:34]([C:35]3[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=3)=[C:30]2[C:29](=[O:52])[N:28]([CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:27]1=[O:53])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n(CCN2CCOCC2)c(=O)c2c(-c3ccncc3)n(Cc3cccc4ccccc34)nc21
Temperature: 80 °C
Yield: 91.1 %

Procedure:
4-(2-chloroethyl)morpholine hydrochloride (0.0435 g) followed by DBU (0.094 g) were added to a solution of 7-isobutyl-2-(1-naphthylmethyl)-3-pyridin-4-yl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (0.0668 g) in dimethylformamide (1 ml). The mixture was heated at 80° C. for 18 hours then cooled to room temperature. The crude reaction was purified on preparative HPLC to give the title compound (0.077 g). Mass: 538.90 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([CH2:10][NH2:11])[OH:9]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[NH:11][CH2:10][CH2:8][OH:9]
Reactant: NCCO
Reactant: Clc1ncccn1
Solvent: O
Product: OCCNc1ncccn1

Procedure:
2-Chloropyrimidine (5 g) and ethanolamine (15 ml) were stirred for 2 hours at 140° C. After cooling, the mixture was added to water (200 ml) and continuously extracted with ethyl acetate (500 ml) for 16 hours. The organic extract was dried (MgSO4), filtered and evaporated to dryness. The title compound was obtained as a solid (m.p. 66° C.), following chromatography on silica-gel in 3% methanol in dichloromethane. 1H NMR δ (CDCl3)
Reaction SMILES: [I:1][C:2]1[N:3]=[N:4][C:5](I)=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[I:1][C:2]1[N:3]=[N:4][C:5]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:6][CH:7]=1
Reactant: Ic1ccc(I)nn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1cccc(N2CCN(c3ccc(I)nn3)CC2)c1
Temperature: 70 °C
Yield: 48 %

Procedure:
A mixture of 5.2 parts of 3,6-diiodopyridazine, 3.5 parts of 1-[3-(trifluoromethyl)phenyl]piperazine. 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylacetamide was stirred and heated overnight at 70° C. The reaction mixture was poured onto water. The precipitated product was filtered off and crystallized from 2-propanol, yielding 3.2 parts (48%) of 3-iodo-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp. 144.6° C. (compound 202).
Reaction SMILES: C(#N)C.[C:4](Cl)(=[O:8])[C:5](Cl)=O.C(N(CC)CC)C.[C:17]([NH2:25])(=[O:24])[CH2:18][CH2:19][CH2:20][C:21](N)=O.C([O-])(=[O:28])C.[Na+]>ClCCl>[OH:8][C:4]1[CH:5]=[CH:21][CH:20]=[CH:19][C:18]=1[C:17]([NH:25][OH:28])=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)[O-]
Reactant: NC(=O)CCCC(N)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NO)c1ccccc1O

Procedure:
Ten milliliters of unmodified M280 or M450 magnetic beads (Dynal) were gradually dehydrated into acetonitrile, and converted to aldehyde modified beads using oxalyl chloride activated N,N-dimethylsulfoxide and triethylamine in dichloromethane at −78° C. The resulting aldehyde bearing beads were gradually rehydrated and suspended in 5 mL of 0.1 M sodium acetate pH 5.5. The aldehyde groups were coupled N′-[(4-(N-hydroxycarbamoyl)-3-hydroxy-phenyl)methyl]-N-(2-{N-[2-(4-{N-[(N-hydroxycarbamoyl)-3-hydroxyphenyl)methyl]carbamoyl}-butanoylamino)ethyl]-4-(N-aminocarbamoyl)butanoylamino}ethyl)pentane-1,5-diamide (21Y-SHA-hydrazide) by adding 25 milligrams dissolved in 200 uL N,N-dimethylsulfoxide, and rotating coupling reaction over night at room temperature. The beads were then washed extensively with water and stored in 5 mL of 10% ethanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C(Cl)Cl.CCN(CC)CC>[Cl:26][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCCO[C@@H](c1cc(F)cc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (1.1 g, 2.85 mmol) in dry CH2Cl2 (20 mL), Et3N (2 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of ethyl chloroformate (615 mg, 5.7 mmol) in dry CH2Cl2 (2 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 hr at rt. Water (20 mL) was added to quench the reaction. The aqueous layer was extracted with CH2Cl2 (3×20 mL), the combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(2-(ethoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (1.3 mg, 100%). 1H NMR (CD3OD, 400 MHz) δ 7.01 (d, 2H), 6.87 (d, 1H), 4.32 (m, 2H), 4.09 (m, 2H), 3.92 (m, 2H), 3.33 (m, 5H), 1.75 (s, 1H), 1.55 (m, 1H), 1.43 (s, 9H), 1.34 (m, 2H), 1.23 (t, 3H), 1.09 (t, 1H).
Reaction SMILES: [OH-:1].[K+].[OH2:3].Cl[C:5](Cl)(Cl)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.S(=O)(=O)(O)O>C(O)CCC>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([CH2:6][C:5]([O:3][CH2:5][CH2:6][CH2:7][CH3:8])=[O:1])[CH:12]=[CH:11][CH:10]=1
Reactant: O
Reactant: FC(F)(F)c1cccc(CC(Cl)(Cl)Cl)c1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCO
Product: CCCCOC(=O)Cc1cccc(C(F)(F)F)c1

Procedure:
To a suspension of 5.6 g. of potassium hydroxide, containing 14% of water, in 35 ml. of dried butanol was added 4.0 g. of 1,1,1-trichloro-2-(3-trifluoromethylphenyl)ethane over about 2 minutes. The mixture was stirred under reflux for 5 hours, was cooled, and was made acid with 6 ml. of concentrated sulfuric acid. The mixture was heated to reflux with a distillation head on the flask, and about 11 ml. of butanol-water azeotrope was removed. Ten ml. of butanol was added back to the flask, and the mixture was cooled overnight to ambient temperature. It was then poured into 150 ml. of water, and the aqueous layer was extracted with two 40 ml. portions of dichloromethane. The organics were combined, and washed twice with 30 ml. portions of water. The organics were then dried over sodium sulfate, and concentrated under vacuum to obtain 4.0 g. of oily product, which was redissolved in 30 ml. of dichloromethane and washed twice with 10 ml. portions of water. The organic solution was dried over sodium sulfate and evaporated under vacuum to obtain 3.4 g. of product, found to be 94.5% pure by vapor phase chromatography.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[C:36]1(=O)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH:36]4[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCN(C3CCCCC3)CC2)c2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on mono(trifluoroacetate) obtained in Example 140 and 12 ml (0.12 mmol) of cyclohexanone were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes. 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[N:13]=[CH:14][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:32])([CH3:31])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[N:16][CH:17]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[N:16][C:15]([C:18]2[CH:19]=[C:20]([C:25]3[C:29](=[O:30])[C:28]([CH3:31])([CH3:32])[O:27][N:26]=3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[CH:14][N:13]=1)=[O:5]
Reactant: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(N)cn1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C2=NOC(C)(C)C2=O)cc1-c1cnc(NC(=O)c2ccccc2Cl)cn1
Temperature: 0 °C
Yield: 33.8 %

Procedure:
To a 0° C. cooled and stirred, solution of 2-chlorobenzoyl chloride (43 μL, 0.34 mmol, 1.0 eq) in DCM (2 mL) was added drop wise a solution of Intermediate 1b, (100 mg, 0.34 mmol, 1.0 eq) in DCM (5 mL) followed by pyridine (47 μL, 0.44 mmol, 1.3 eq). The resulting mixture was stirred at room temperature for 15 h. The reaction was diluted with DCM (10 mL), and washed with 10% hydrochloric acid (5 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, ethyl acetate in hexane as eluent) to afford 50 mg of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.80 (s, 1H, D2O exchangeable), 8.39 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 8.09 (dd, J=8.0, 2.0 Hz, 1H), 7.84 (dd, J=7.0, 1.5 Hz, 1H), 7.52-7.40 (m, 4H), 2.47 (s, 3H), 1.48 (s, 6H); ESI-MS (m/z) 435, 437 [(MH)+, Cl35,37].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10].[H-].[Na+]>O>[CH2:8]([O:11][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[CH:9]=[CH2:10]
Reactant: C=CCO
Reactant: Brc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C=CCOc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
5-Bromo-pyrimidine (0.063 mol) was slowly added to 2-propen-1-ol (4.03 mol) at 0° C. and this mixture was stirred at room temperature for 1 hour. Then NaH 60% (0.126 mol) was added and the reaction mixture was stirred and refluxed for 48 hours. Water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: hexane/ethyl acetate 50/50). The desired fractions were collected and the solvent was evaporated, yielding 2.3 g of 5-(2-propenyloxy)-pyrimidine (intermediate 48).