Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][O:7][CH:8]([CH3:10])[CH3:9].C(=O)([O-])[O-:12].[Na+].[Na+]>O>[CH:8]([O:7][CH2:6][CH2:5][CH:4]=[CH:3][CH2:2][OH:12])([CH3:10])[CH3:9]
Reactant: CC(C)OCCC=CCCl
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)OCCC=CCO

Procedure:
8.13 g (0.05 mol) of 1-chloro-5-isopropoxy-2-pentene are added to a solution of 6.5 g of sodium carbonate in 60 cc of water and the mixture is heated to 95°-98° during 18 hours. After cooling the organic parts are extracted with benzene, the benzene extract is washed with saturated salt solution and dried with sodium sulphate. The solvent is distilled off and then it is distilled at reduced pressure. According to gas-chromatography pure 5-isopropoxy-2-penten-1-ol distils at 102°-104°/15 mm. nD20 = 1.4363.
Reaction SMILES: C(O[CH2:4][NH:5][C:6]1[N:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9])C.[BH4-].[Na+].O>CS(C)=O>[CH3:4][NH:5][C:6]1[N:27]=[CH:26][CH:25]=[CH:24][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[S:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9]
Reactant: CCOCNc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 2-(ethoxymethyl-amino)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide described in Preparation Example A+-6 (148 mg, 0.385 mmol) in dimethylsulfoxide (3 mL) was added sodium borohydride (44 mg, 1.15 mmol), and the solution was stirred for 30 minutes at 100° C., followed by stirring for 20 minutes at 110° C. Furthermore, sodium borohydride (35 mg, 0.925 mmol) was added thereto, followed by stirring for 20 minutes at 110° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (86 mg, 0.26 mmol, 67%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]4[CH2:29][O:28]C(C)(C)[O:26]4)=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH:25]([OH:26])[CH2:29][OH:28])=[CH:19][CH:18]=3)[O:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC4COC(C)(C)O4)cc3)n2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(OCC(O)CO)cc3)n2)cc1Cl
Temperature: 70 °C
Yield: 88 %

Procedure:
3-(3-chloro-4-isopropoxyphenyl)-5-(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)phenyl)-1,2,4-oxadiazole (0.1 g, 0.225 mmol) and p-toluenesulfonic acid monohydrate (8.55 mg, 0.045 mmol) were added in methanol (2.4 mL). The reaction mixture was heated at 70° C. for 16 hr. The solution was cooled, methanol (1.5 mL) was added to the mixture and recrystallized, the resulted suspension was filtered, the solid was washed by abundant water to afford 3-(4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenoxy)propane-1,2-diol (0.08 g, 0.198 mmol, 88% yield) as white solid. LC/MS (Purity QC) Rt=2.97 min.; MS m/z: 405.18 (M+H)+. 1H NMR (400 MHz, Solvent d-DMSO) ppm 8.16-8.09 (m, 2H), 8.05 (d, J=2.13 Hz, 1H), 7.99 (dd, J=8.64, 2.15 Hz, 1H), 7.38 (d, J=9.05 Hz, 1H), 7.25-7.16 (m, 2H), 5.03 (d, J=5.19 Hz, 1H), 4.87-4.78 (m, 1H), 4.72 (t, J=5.68 Hz, 1H), 4.15 (dd, J=3.97, 10.01 Hz, 1H), 4.01 (dd, J=6.20, 10.03 Hz, 1H), 3.84 (dt, J=4.04, 5.69, 5.91 Hz, 1H), 3.47 (t, J=5.84 Hz, 2H), 1.35 (d, J=6.03 Hz, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1N)=[O:5])[CH3:2].[I:17]CI.C(#N)C.N(OCCC(C)C)=O>CCCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]([CH2:14][CH3:15])=[C:9]([C:12]#[N:13])[C:10]=1[I:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)c(C#N)c(CC)n1C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCCCCCC
Product: CCOC(=O)c1c(I)c(C#N)c(CC)n1C
Temperature: 78 °C
Yield: 57.6 %

Procedure:
Alternatively the title compound may be prepared by the following procedure. Charge the 3-amino-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester prepared in preparation 37, diiodomethane, and acetonitrile to a 22 L round-bottom flask equipped with an addition funnel, thermocouple, overhead stirrer, and condenser. Dilute isoamyl nitrite with heptane and charge the resulting solution to the addition funnel. Warm the reaction mixture to 78° C. Add 0.65 L of the isoamyl nitrite solution over 1.75 hours, at which point vigorous evolution of nitrogen is observed. Suspend the addition of the isoamyl nitrite solution for about 20 minutes to allow the off-gassing to subside. Add the remainder of the isoamyl nitrite solution over 15 minutes. Stir the reaction mixture at reflux for an additional 2 hours, then cool to room temperature. Remove the solvent under reduced pressure and dilute the resulting concentrate with a mixture of 0.2 L pentane and 0.2 L methylene chloride. Pour the resulting mixture onto a 4 kg column of silica gel that is pre-wetted with cyclohexane. Elute the column with 5′ gallons of cyclohexane, and discard the eluent. Next, elute the column with 6 gallons of a 1:1 mixture of cyclohexane:methylene chloride, followed by 5 gallons of 3:2 cyclohexane:methylene chloride. Combine these fractions and remove the solvent under reduced pressure. Suspend the resulting solid in 0.5 L of heptane and stir for 45 minutes. Collect the product by filtration, rinse with heptane, and vacuum-dry at 40° C. to afford the title compound (432.8 g) in 57.6% yield. Mass spectrum (m/e): 333.0 (M+1).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.[O:30]=[C:31]1[NH:35][CH:34]([C:36](O)=[O:37])[CH2:33][S:32]1>>[CH3:1][N:2]([C:36]([C@@H:34]1[CH2:33][S:32][C:31](=[O:30])[NH:35]1)=[O:37])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: O=C1NC(C(=O)O)CS1
Reactant: CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1
Product: CN(C(=O)[C@@H]1CSC(=O)N1)C1CCN(c2ccc(NC(=O)N3CCC(c4ccc(Cl)cc4)CC3)cc2)C1

Procedure:
(R)-4-(4-Chlorophenyl)piperidin-1-carboxylic acid [4-(3-methylamino-pyrrolidin-1-yl)phenyl]amide was reacted with 2-oxothiazolidine-4-carboxylic acid by method E. This resulted in the product with the molecular weight of 542.10 (C27H32CIN5O3S); MS (ESI): 542 (M+H+).
Reaction SMILES: CS(O[CH:6]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(=O)=O.[K].[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>O>[O:31]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26](=[O:36])[N:30]1[CH:6]([CH2:16][NH:17][C:18](=[O:19])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:7][NH:8][C:9](=[O:10])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Agent: [K]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
To a solution of 2-[(tert-butoxycarbonyl)amino]-1-{[(tert-butoxycarbonyl)amino]methyl}ethyl methanesulfonate (200 g) was added phthalimide potassium salt (101 g), and the mixture was stirred overnight at 75° C. To the reaction mixture was added water (6 L), and the mixture was extracted with ethyl acetate (6 L). The organic layer was washed with water (1.5 L×3) and brine, and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave a residue, which was triturated with hexane (500 ml). The collected crystals was washed with hexane (100 ml×3), and the mother liquor was recrystallized from hexane (300 ml) and combined with the former crystals to give di-tert-butyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1,3-propanediyl]biscarbamate (168 g).
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:24])(=[NH:23])[CH2:20][CH2:21][CH3:22]>>[CH2:20]([C:19]1[N:23]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:24]=1)[CH2:21][CH3:22]
Reactant: CCCC(=N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Agent: Cl
Product: CCCc1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 84 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and butyramidine hydrochloride. Yield: 84%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.C(#N)C.[Cl:22]N1C(=O)CCC1=O>>[Cl:22][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)=[CH:8]2
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: C[C@@]1(c2ccc3c(Cl)c(O)ccc3c2)COC(=O)N1
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
(R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (0.5895 g, 0.002423 mol) was suspended in acetonitrile (3.37 mL, 0.0646 mol) in a 40 mL vial equipped with a magnetic stir bar. N-Chlorosuccinimide (0.356 g, 0.00266 mol) was added and the mixture was heated at 80° C. After 2 hours, HPLC analysis showed that the reaction was complete. The mixture was cooled to room temperature and filtered. The residue was washed with acetonitrile, azeotroped with toluene then dried under vacuum and collected to give 590 mg of the title compound (62% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:10]([NH:14][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: ClCc1ccc(Cl)nc1
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)NCc1ccc(Cl)nc1
Temperature: 80 °C
Yield: 58.8 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (537 mg, 3.31 mmole) in 7 mL of dry acetonitrile is 0.7 mL (6.62 mmol) of tert-butylamine followed by 457 mg (3.31 mmol) of potassium carbonate. The reaction is heated at 80° C. for 12 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 387 mg (59% yield) of tert-Butyl-(6-chloro-pyridin-3-ylmethyl)-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.16 (s, 9H), 1.60–1.80 (brs, 1H0, 3.72 (s, 2H), 7.26 (d, 1H, J=8.3 Hz), 7.71 (dd, 1H, J=8.3 and 2.5 Hz), 8.33 (d, 1H, J=2.0 Hz); MS 199.2 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:17]SC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([O:5][C:6]1[C:7]([C:11]2[CH2:12][N:13]([CH3:17])[CH2:14][CH2:15][CH:16]=2)=[N:8][NH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCCCOc1c[nH]nc1-c1cccnc1
Product: CCCCOc1c[nH]nc1C1=CCCN(C)C1

Procedure:
Compound 32C was converted to the title compound (33C), using the methodology described for the conversion of 21A to 22A (see Scheme 3).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[CH3:28][S:29]([CH2:32][CH2:33][NH2:34])(=[O:31])=[O:30]>>[CH3:28][S:29]([CH2:32][CH2:33][NH:34][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[O:15][CH2:14][CH2:13][N:12]3[CH:25]=[C:9]([C:8]4[N:4]([CH2:3][C:2]([F:27])([F:26])[F:1])[N:5]=[CH:6][N:7]=4)[N:10]=[C:11]3[C:17]=2[CH:18]=1)=[O:23])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)CCN
Reactant: O=C(O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Product: CS(=O)(=O)CCNC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2

Procedure:
Following the procedure for 109, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylic acid and 2-(methylsulfonyl)ethanamine gave 119. MS: (ESI+)=485.1. 1H NMR (400 MHz, DMSO) δ 8.93 (d, J=2.1 Hz, 1H), 8.72 (t, J=5.4 Hz, 1H), 8.10 (s, 2H), 7.78 (dd, J=8.6, 2.2 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 5.94 (q, J=8.9 Hz, 2H), 4.58 (s, 4H), 3.69 (dd, J=12.7, 6.5 Hz, 2H), 3.38 (t, J=6.8 Hz, 2H), 3.04 (s, 3H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](I)[CH2:20][CH3:21]>CN(C=O)C>[Cl:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:19][CH2:20][CH3:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(C(=O)OC)cc1Cl
Temperature: 70 °C
Yield: 100.9 %

Procedure:
Methyl 4-hydroxy-3-chlorobenzoate (10 g, 53.6 mmol) was dissolved in DMF (110 ml) and then potassium carbonate (14.8 g, 107.2 mmol) was added followed by n-propyliodide (10.4 ml, 107.2 mmol). The reaction was heated to 70° C. overnight, filtered and then the fitrate was partitioned between EtOAc and water. The organic layer was separated, dried and evaporated to give the title compound as a yellow oil (12.37 g). MS (ES) C11H1335ClO3 requires 228; found 229 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:9][CH:10]([CH2:29][OH:30])[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(Cl)(Cl)Cl>[OH:9][CH:10]([CH2:29][OH:30])[CH2:11][N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)CCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
Hexanoyl chloride (2.65g, 19.7 mmoles) was added dropwise to a reactor containing N-(2,3-dihydroxypropyl)-hexadecylamine (2.65g, 19.7 mmoles)in 8 mL of chloroform. The reaction was stirred for 16 hours at room temperature. When the reaction was completed, the mixture was concentrated, ethanol and water was added, and the pH of the reaction was adjusted to 14. This mixture was extracted with chloroform, and organic layer was collected and concentrated. The crude sample was purified on silica column chromatography to give 1.56 g of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41].[CH3:42][NH:43][CH3:44]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:43]([CH3:44])[CH3:42])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([F:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH2:12][NH:11][C:10]1=[O:41]
Reactant: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reactant: CNC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(C)c(-c3nc(N(C)C)nc4c3CNC(=O)N4c3c(F)cccc3F)c2)cc1F
Reaction time: 72 h

Procedure:
To the compound N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylphenyl}-3-fluoro-4-methylbenzamide (0.075 g, 0.129 mmol) in THF (4 mL) was added a 1.0 M solution of dimethylamine in THF (0.322 mL, 0.322 mmol). The mixture was stirred under argon for 3 days. The completed reaction mixture was diluted with EtOAc and the organic phase washed with water, brine (2×), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography on silica gel, eluting with 1% MeOH/CH2Cl2 to afford the title compound as a white solid. mp 257.8-264.3° C.; LC-MS m/z 547 (M+H)+, 2.24 min (ret. time).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>C(OCC)(=O)C>[CH2:25]([NH:32][C:14]1[N:13]=[C:12]2[N:11]([CH3:23])[C:10](=[O:24])[N:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Reactant: NCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(NCc3ccccc3)nc21
Temperature: 180 °C
Yield: 77.4 %

Procedure:
A mixture of 110 mg (0.29 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one and 0.31 ml (2.9 mmol) of benzylamine was heated at 180° C. for 10 minutes and then cooled. 30 ml of ethyl acetate and 30 ml of 2M aqueous hydrochloric acid were added to the residue. The phases were separated and the organic phase was washed in sequence with 20 ml of 5% aqueous sodium bicarbonate solution and 20 ml of brine, dried over magnesium sulfate, filtered and evaporated to give 93 mg (79%) of 7-benzylamino-3-(2,6-dichlorophenyl)-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 195-198° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][C:9]([OH:12])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]Cl>C(N(CC)CC)C>[C:1]1([N:7]2[C:11]([Cl:13])=[N:10][C:9]([OH:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ncn(-c2ccccc2)n1
Reactant: ClCl
Solvent: CCN(CC)CC
Product: Oc1nc(Cl)n(-c2ccccc2)n1

Procedure:
32.2 g of 1-phenyl-3-hydroxy-1,2,4-triazole and 40.5 g of triethylamine are dissolved in 300 ml of absolute alcohol. While cooling, 21.3 g of chlorine are passed in (20° to 30°C). Triethylamino hydrochloride is filtered off and the filtrate is concentrated in a rotary evaporator. The residue is treated with 300 ml of water and extracted 4 times with 200 ml of ether each time. The combined ethereal extracts are dried over sodium sulphate. The drying agent is filtered off and the filtrate concentrated. The solid residue is recrystallised from 70 ml of acetonitrile. Yield: 11.4 g (29.2 % of theory); m.p. 147°-149°C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C@H:32]([CH3:33])[CH2:31][N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1
Reactant: C[C@@H](O)CN1CC[C@@H](N)C1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)CN1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 24.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (60 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl)-propan-2-ol (100 mg), HBTU (180 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 484.7. 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (m, 1H), 8.08 (s, 1H), 7.93-7.92 (d, 1H), 7.75 (br. m, 1H), 7.47-7.45 (br. d, 1H), 7.40-7.37 (m, 1H), 4.52-4.42 (m, 2H), 3.77-3.73 (m, 1H), 3.66 (s, 3H), 2.92-2.78 (m, 2H), 2.63-2.60 (m, 2H), 2.46-2.43 (m, 2H), 2.19-2.14 (m, 1H), 1.86-1.78 (m, 1H) 1.07-1.06 (d, 3H) —NH and OH proton signal was not observed.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=[O:13])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[C:7]1[NH:14][C:12](=[O:13])[C:11]2[C:10](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1ccccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2ccccc2c(=O)[nH]1

Procedure:
2-(2-Propoxybenzamido)benzamide (2.73 g) was added to a refluxing mixture of 2 Normal aqueous sodium hydroxide (55 ml) and pyridine (2 ml). The resulting solution was stirred under reflux for 15 minutes and was then poured onto ice (150 ml) and acidified with concentrated hydrochloric acid to yield a sample of the title compound, 2.28 g, m.p. 88-89° C. This together with another sample (0.77 g) similarly prepared was recrystallized from ethanol/water to yield the pure title compound as a white solid, 2.57 g, m.p. 89-90° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CN(C=O)C.O>[O:18]1[CH2:19][CH2:20][N:15]([C:2]2[S:6][C:5]([NH2:7])=[N:4][N:3]=2)[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: Nc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc(N2CCOCC2)s1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine, K2HPO4 (5.7 g), and 5.3 ml of morpholine in 20 ml of DMF is heated at 80° C. under nitrogen for 18 hours, then diluted with 50 ml of water. The clear solution is placed in a continuous extractor and extracted with a brisk flow of dichloromethane for 18 hours. The solution is dried over MgSO4 and concentrated under reduced pressure, with toluene azeotropes to remove DMF. Recrystallization of the residual solid from 50 ml of acetonitrile and 100 ml of toluene affords 3.92 g of the title compound.