Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)[CH3:17])[CH:11]=[CH:12]2)=[N:7]1.[NH2:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>C(O)(C)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[C:14]([CH3:15])=[C:13]2[C:8]([CH:9]=[C:10]([N:16]([CH3:17])[C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:28][C:29]4[CH:30]=[C:31]([S:35]([NH2:38])(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=4)[N:19]=3)[CH:11]=[CH:12]2)=[N:7]1
Reactant: Cc1c2ccc(N(C)c3ccnc(Cl)n3)cc2nn1Cc1cccc(Cl)c1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1c2ccc(N(C)c3ccnc(Nc4cccc(S(N)(=O)=O)c4)n3)cc2nn1Cc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine (40 mg, 0.1 mmol) and 3-aminobenzenesulfonamide (17.3 mg, 0.1 mmol) in isopropanol (2 ml) was added 2 drops of conc. HCl. The mixture was heated to reflux overnight The mixture was cooled to rt. Precipitate was collected via filtration and washed with EtOH. HCl salt of 3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]-pyrimidin-2-yl}amino)benzenesulfonamide was isolated as off-white solid. 1H NMR (400 MHz, d6DMSO+NaHCO3) 69.52 (br s, 1H), 8.54 (br s, 1H), 7.85 (d, J=5.9 Hz, 1H), 7.77–7.79 (m, 2H), 7.49 (s, 1H), 7.30–7.36 (m, 5H), 7.22 (br s, 2H), 7.14 (br s, 1H), 6.90 (d, J=8.7 Hz, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.64 (s, 2H), 3.48 (s, 3H), 2.62 (s, 3H). MS (ES+, m/z) 534 (M+H).
Reaction SMILES: [CH2:1]1[N:6]2[CH2:7][N:8]3[CH2:10][N:4]([CH2:5]2)[CH2:3][N:2]1[CH2:9]3.[Cl:11][C:12]1[S:13][C:14]([CH2:17]Cl)=[CH:15][CH:16]=1>C(Cl)(Cl)Cl>[Cl:11][C:12]1[S:13][C:14]([CH2:17][CH:1]2[N:6]3[CH2:5][N:4]4[CH2:10][N:8]([CH2:9][N:2]2[CH2:3]4)[CH2:7]3)=[CH:15][CH:16]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: C1N2CN3CN1CN(C2)C3
Solvent: ClC(Cl)Cl
Product: Clc1ccc(CC2N3CN4CN(C3)CN2C4)s1
Yield: 99.5 %

Procedure:
To a suspension of hexamethylenetetramine (HMTA) (3.12 g, 22.2 mmol) in CHCl3 (35 mL) was added 2-chloro-5-chloromethylthiophene (1.02 mL, 8.46 mmol). The reaction mixture was heated at reflux for 4 hr, cooled, and filtered to give white solid 5-chloro-2-[(1,3,5,7-tetraazatricyclo-[3.3.1.1 (3,7)]decyl) methyl]thiophene (2.28 g, 88%). ES-MS (M)+=271, 273 (Cl). 1H-NMR (DMSO-d6): δ 4.27 (s, 2H), 4.39–4.57 (ABq, 6H), 5.06 (s, 6H), 7.21–7.24 (ABq, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]2[N:14]([CH2:33][CH2:34][CH2:35][CH2:36][O:37]C(=O)C(C)(C)C)[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH:29]4[CH2:31][CH2:30]4)[C:19]3=[O:32])=[N:16][C:12]=2[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO.O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:45]=[CH:44][C:13]2[N:14]([CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[C:15]([CH2:17][N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:21](=[O:28])[N:20]([CH:29]4[CH2:31][CH2:30]4)[C:19]3=[O:32])=[N:16][C:12]=2[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCOC(=O)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc2c(c1)nc(Cn1c(=O)n(C3CC3)c(=O)c3ccccc31)n2CCCCO
Temperature: 75 °C
Yield: 63.2 %

Procedure:
To a solution of 2,2-dimethyl-propionic acid 4-[5-(tert-butoxycarbonylamino-methyl)-2-(3-cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-benzoimidazol-1-yl]-butyl ester (110 mg, 0.178 mmol) in methanol (5 mL) and water (1.5 mL) was added 1M NaOH (356 μL, 0.356 mmol). The resulting mixture was heated at 70-80° C. for 2 hrs. The solution was neutralized with 1M HCl, methanol was removed in vacuo and the aqueous residue extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine and dried (MgSO4). Purification by flash chromatography (eluent 2%, 5% methanol in DCM) afforded [2-(3-Cyclopropyl-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-ylmethyl)-1-(4-hydroxy-butyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (60 mg, 63%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9](I)[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:2].[C:18](=[O:21])([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.[C]=O>C1(OC)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:18](=[O:21])[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=2)[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14](=[O:16])[CH3:15])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)c1cc(I)c(F)cc1NC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [K+]
Solvent: COc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C(=O)c2cccc(F)c2)c(F)cc1NC(C)=O
Temperature: 25 °C
Yield: 29.1 %

Procedure:
A total of 812 mg of 2-acetylamino-4-fluoro-5-iodo-benzoic acid ethyl ester obtained in Production Example II-7-c was dissolved in 13.9 ml of anisole, and 956 mg of potassium carbonate, 356 mg of 3-fluorophenyl-boronic acid and 49 mg of bis(triphenylphosphine)palladium dichloride were added. After replacing the inside atmosphere of the reaction system with carbon monoxide gas, the mixture was stirred at 80° C. in an atmosphere of carbon monoxide (normal pressure) for 14 hours. After cooling to room temperature and replacing the inside atmosphere of the reaction system with nitrogen gas, water was added and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:5), to give 234 mg of the title compound as pale yellow crystals.
Reaction SMILES: CC([Si](C(C)C)([O:8][C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][CH2:13][CH2:14][C:15]1[N:20]=[C:19](CN)[CH:18]=[CH:17][CH:16]=1)C(C)C)C.[F-].[CH2:30]([N+:34](CCCC)(CCCC)CCCC)CCC.Br[CH2:48][C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53]>C1COCC1>[CH3:30][NH:34][C:19]1[N:20]=[C:15]([CH2:14][CH2:13][O:12][C:11]2[CH:10]=[C:9]([CH:25]=[CH:24][CH:23]=2)[O:8][CH2:48][C:49](=[O:57])[CH2:50][CH2:51][C:52]([O:54][CH2:55][CH3:56])=[O:53])[CH:16]=[CH:17][CH:18]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)[Si](Oc1cccc(OCCc2cccc(CN)n2)c1)(C(C)C)C(C)C
Reactant: CCOC(=O)CCC(=O)CBr
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)COc1cccc(OCCc2cccc(NC)n2)c1
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
To a solution of [6-(2-{3-[1,1-bis(Methylethyl)-2-methyl-1-silapropoxy]phenoxy}ethyl)(2-pyridyl)]methylamine (1.60 g, 4.0 mmol) in THF (30 ml) under argon at room temperature, was added tetrabutylammonium fluoride (4.4 ml, 4.4 mmol, 1M in THF). After stirring for 15 minutes, a solution of ethyl 5-bromo-4-oxopentanoate (0.98 g, 4.4 mmol) in THF (5 ml) was added. The mixture was stirred for an additional 3 hours. The solvent was removed under vacuum and the remaining residue was chromatographed over silica gel to yield 860 mg (56%) of Ethyl 5-(3-{2-[6-(methylamino)(2-pyridyl)]ethoxy}phenoxy)-4-oxopentanoate. NMR 1H Cl3CD δ: 7.38 (m, 1H), 7.16 (t, 1H, J=8.2 Hz), 7.08 (t, 1H, J=7.9 Hz), 6.64 (m, 1H), 6.45 (m, 3H), 6.26 (dd, 1H, J=8.2, 2.3 Hz), 4.57 (s, 2H), 4.30 (t, 2H, J=6.8Hz), 4.13 (c, 2H, J=7.2 Hz), 3.07 (m, 2H), 2.91 (m, 5H), 2.63 (t, 2H, J=6.6 Hz), 1.24 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][OH:28].Cl.[CH3:31][CH2:32][O:33][CH2:34][CH3:35].[C:36](=O)([O-])[O-].[K+].[K+]>O1C=CCCC1.O>[CH3:1][C:2]1([CH3:29])[CH:11]([N:12]([CH3:23])[S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:24][CH3:25])=[CH:7][CH:8]=2)[C:3]1=[CH:26][CH2:27][O:28][CH:32]1[CH2:31][CH2:36][CH2:35][CH2:34][O:33]1
Reactant: COc1ccc2c(c1)C(=CCO)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Reactant: O=C([O-])[O-]
Reactant: CCOCC
Agent: C1=COCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1ccc2c(c1)C(=CCOC1CCCCO1)C(C)(C)C(N(C)S(=O)(=O)c1ccc(C)cc1)C2
Reaction time: 1 h
Yield: 80 %

Procedure:
To a mechanically stirred suspension of 126 g of 2,2-dimethyl-1-(2-hydroxyethylidene)-7-methoxy-3-(N-methyl-p-toluenesulphonamido)-1,2,3,4-tetrahydronaphthalene in 550 ml of 2,3-dihydropyran there is added 5 ml of concentrated hydrochloric acid when under the development of heat a clear solution is being formed. After the mixture has been kept at 25° C. for one hour 400 ml of ether is added followed by an aqueous solution of potassium carbonate in water. The mixture is shaken and the organic layer is dried and evaporated, respectively. The residue is treated with petroleum ether (boiling range 40°-60° C.) which results in the formation of a clear solution covering a semi crystalline layer. From the supernatant a first crop of crystalline product can be secured. The rest can be gathered by dissolving the semi solid mass in boiling ether and cooling the ethereal solution whereupon crystallization of the product takes place. The product melts at 128°-130° C. Yield 80%.
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[CH:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](O)=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH:31]1([CH:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]([N:3]2[CH2:4][CH2:5][C:6]3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]=3[CH2:2]2)=[O:29])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)C(c1ccccc1)C1CCCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
Step a): To a stirred solution of Intermediate 1 (25 mg, 0.085 mmol), cyclohexyl-phenylacetic acid (27.7 mg, 0.127 mmol) and DIEA (73 μl, 0.424 mmol) in dichloromethane (1 ml) is added POCl3 (9 μl, 0.093 mmol). The resulting yellow reaction mixture is stirred at rt overnight, then saturated aqueous NaHCO3 solution (2 ml) is added. The organic layer is separated and washed with water (2 ml). Evaporation of the solvent gave a crude that is purified by silica gel column chromatography (hexane/EtOAc 3:1) affording ethyl [2-(2-cyclohexyl-2-phenyl-acetyl)-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl]-acetate as a white solid (29 mg) in 74% yield: tR (LC-2) 2.74 min; ESI-MS (positive ion): m/z 459.25 [M+H]+ (calcd 458.59 for C29H34N2O3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=O)=[C:4]2[N:3]=1.[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].N1CCCCC1.C(O)(C)C>CCO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:10][CH2:11]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[C:21]3[S:17][C:18](=[O:23])[NH:19][C:20]3=[O:22])=[C:4]2[N:3]=1
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Reactant: O=C1CSC(=O)N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(Cl)nc23)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (440 mg, 1.86 mmol) in EtOH was added thiazolidine-2,4-dione (458 mg, 3.91 mmol) and piperidine (208 μl, 2.05 mmol). The reaction was heated at 80° C. overnight. To the reaction mixture, isopropanol (3 mL) was added in the along with 218 mg thiazolidine-2,4-dione and 94 μL of piperidine. The temperature was increased to 90° C. and the reaction was stirred at that temperature overnight. The precipitate was filtered while hot and dissolved in MeOH. To the reaction mixture, 1M HCl (1 mL) was added and the mixture sonicated. The precipitate was filtered and washed with MeOH to yield 340 mg (54% yield) 5-((5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione as a yellow powder. LCMS (M+1=336)
Reaction SMILES: [N:1]1([CH:6]([C:10]([OH:12])=O)[C:7]([OH:9])=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH2:13](N(CC)CC)[CH3:14].C.[C:21]([O:24][CH2:25][C:26]1[CH2:33][S:32][CH:31]2[N:28]([C:29](=[O:35])[CH:30]2[NH2:34])[C:27]=1[C:36]([OH:38])=[O:37])(=[O:23])[CH3:22]>CN(C)C=O.C(Cl)(Cl)Cl>[C:21]([O:24][CH2:25][C:26]1[CH2:33][S:32][CH:31]2[N:28]([C:29](=[O:35])[CH:30]2[NH:34][C:10](=[O:12])[CH:6]([C:7]([O:9][CH2:13][CH3:14])=[O:8])[N:1]2[CH:2]=[CH:3][CH:4]=[CH:5]2)[C:27]=1[C:36]([OH:38])=[O:37])(=[O:23])[CH3:22]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(C(=O)O)n1cccc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
A solution of the monoethyl ester of 2(1-pyrryl) propanedioic acid (1 g., 5.07 mM) and 0.87 g. (5.2 mM) of N, N"-carbonyldiimidazole in 10 ml of dimethylformamide is stirred at room temperature for one hour. In a second flask, 3[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (1.37 g, 5.07 mM) is dissolved in 35 ml of chloroform upon the addition of 2.05 g (20.3 mM) of triethylamine and is stirred under nitrogen for 30 minutes in the presence of Linde 44 molecular sieves. The two solutions are combined and the mixture stirred for 4 hours after the addition of 0.5 g of charcoal. The reaction mixture is filtered, concentrated by flash evaporation and the residue is dissolved in 25 ml of water and washed several times with ether. The aqueous phase is covered with 50 ml of ethyl acetate and is then acidified to pH of 2.5 with 6 N hydrochloric acid. A small amount of solid is removed by filtration and the organic phase is separated, dried and concentrated to 5 ml. The title compound is obtained as a powder (425 mg., 19% yield) upon addition of the ethyl acetate solution to hexane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][CH2:11][C:12]#[CH:13])=[O:7])=[CH:4][CH:3]=1
Reactant: C#CCN
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To 4-bromobenzoyl chloride (4.39 g, 20 mmol) in 40 mL dichloromethane at 0° C., propargylamine (1.10 g, 20 mmol) was added, followed by triethylamine (4.05 g, 40 mmol). The mixture was stirred at room temperature for 40 minutes. 150 mL ethyl acetate was added and filtered. The filtrate was washed with 2×40 mL water and 40 mL brine, dried and concentrated to give 4-Bromo-N-(2-propynyl)benzamide. 4-Bromo-N-(2-propynyl)benzamide was added into ice cooled 47 mL concentrated sulfuric acid. The reaction was stirred at 5°-10° C. for 3 hours and at room temperature overnight. The mixture was poured into 500 mL ice water, neutralized with sodium carbonate to pH 8 and extracted with 3×250 mL ethyl acetate. The combined organic extracts were washed with 200 mL water and 100 mL brine, dried and concentrated to afford compound A (4.5 g, 95%) as a light yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:51]=[CH:50][CH:49]=[CH:48][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH:35]4[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]4)=[N:33][CH:34]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:38]1[CH2:37][CH2:36][CH:35]([C:32]2[N:33]=[CH:34][C:29]([NH:28][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:48]=[CH:49][CH:50]=[CH:51][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][N:21]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2C(F)(F)F)CC1
Yield: 63.3 %

Procedure:
A solution of TFA (0.386 mL, 5.04 mmol) and tert-butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A12) (0.077 g, 0.13 mmol) in DCM (10.0 mL) was stirred at room temperature for 3.5 h under N2. The volatiles were removed in vacuo and the residue was dissolved in DCM (˜1 mL). Cyclohexane (˜5 mL) was added until a white precipitate formed. The resulting suspension was sonicated for 10 minutes and the solid was isolated by filtration and dried to give the title compound 5 as an off-white solid (0.042 g, 65%); 1H NMR (400 MHz, d6-DMSO) δ 10.31 (s, 1H), 8.75 (d, J=2.4 Hz, 1H), 8.72 (s, 1H), 8.13 (d, J=7.3 Hz, 1H), 7.39-7.18 (m, 5H), 6.98 (s, 1H), 6.02 (s, 1H), 3.19-3.05 (m, 6H), 2.81-2.59 (m, 3H), 1.79 (d, J=11.0 Hz, 2H), 1.63 (qd, J=12.5, 3.8 Hz, 2H), 1.47-1.41 (m, 2H), 1.02-0.92 (m, 2H). LCMS-A: rt 4.445 min; m/z 511 [M+H]+.
Reaction SMILES: [CH2:1]=[O:2].Cl[Si](C)(C)C.[Sn](Cl)(Cl)(Cl)[Cl:9].[CH:13]([C:16]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]2[C:17]=1[C:18](=O)[NH:19][S:20]2(=[O:22])=[O:21])([CH3:15])[CH3:14]>ClCCCl.O>[Cl:9][CH2:18][N:19]1[C:1](=[O:2])[C:17]2[C:23](=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:16]=2[CH:13]([CH3:15])[CH3:14])[S:20]1(=[O:22])=[O:21]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: C=O
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCCl
Solvent: O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of 24 g of paraformaldehyde (0.8 mole) and 86.4 g of chlorotrimethylsilane (1.6 moles) in 200 mL of 1,2-dichloroethane was added 0.8 ml anhydrous tin(IV) chloride and the resulting solution stirred on a steam bath for one hour. 4-Isopropyl-6-methoxysaccharin (51.4 g, 0.2 mole) was added to the clear solution and the mixture was refluxed for 18 hours, cooled to room temperature and poured into water. The organic layer was separated, washed with 50 mL of 2N sodium hydroxide solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by crystallization from ethyl acetate/hexane to give 57 g (87%) of 2-chloromethyl-4-isopropyl-6-methoxysaccharin, m.p. 151° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH2:9].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>CCOCC>[C:24]1([CH3:34])[CH:25]=[CH:26][C:27]([S:30]([OH:33])(=[O:31])=[O:32])=[CH:28][CH:29]=1.[CH3:1][N:2]([CH3:10])[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[NH:9][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CN(C)[C@@H]1CCCC[C@H]1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CN(C)[C@@H]1CCCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Yield: 47 %

Procedure:
This titled amide was prepared by general procedure B from trans-2-(dimethylamino)cyclohexylamine and 3-trifluoromethylbenzoyl chloride. The crude oil was converted to the salt with 1 mole of p-toluenesulfonic acid in ether, and was crystallized from MeOH-ether, 47% yield, colorless plates, m.p. 208°-209°. uv λmax 222 nm (ε 22,150); sh 227 (17,900); sh 259 (1,550); sh 266 (1,100); sh 274 (566). ir NH/N+H 3280, 3040; C=O 1660; C=C/amide II 1615, 1595, 1550, 1495; CF3 /SO3- /CN 1335, 1320, 1275, 1200, 1180, 1160, 1120, 1075, 1035, 1010; aromatic/SO3- 705, 690, 680. NMR in CDCl3 (100 MHz) was in accord. Mass spectrum M+ 314.
Reaction SMILES: C([Li])CCC.[CH2:6]1[C:19]2[C:10](=[N:11][C:12]3[C:17]([C:18]=2[NH2:20])=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][CH2:7]1.Cl[C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:23].O>O1CCCC1>[CH2:16]1[C:17]2[C:12](=[N:11][C:10]3[C:19]([C:18]=2[NH:20][C:22](=[O:23])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:13][CH2:14][CH2:15]1
Reactant: CCCCCCCCOC(=O)Cl
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
n Butyllithium, 0.033 mol, is added to a suspension of 6.5g (0.033 mol) of 1,2,3,4-tetra -hydro-9-acridinamine (Petrow, V., Journal of the Chemical Society, pages 634 to 637 (1947)) in 200 ml of tetrahydrofuran at 0° C. The mixture is stirred at 0° C. for 20 minutes, the cooling bath removed and 6.36 g (0.033 mol) of octyl chloroformate added and the solution stirred over the weekend. Water, 200 ml, is added and the mixture extracted with ethyl acetate. The ethyl acetate layer is separated and evaporated to afford a yellow oil. Chromatography (elution with isopropanol-chloroform (5:95)) affords 6.59 g of octyl (1,2,3,4-tetrahydro-9-acridinyl)carbamate, as a yelIow solid; mp 96-99° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CS([O:11][CH:12]1[CH2:21][CH2:20][C:15]2([O:19][CH2:18][CH2:17][O:16]2)[CH2:14][CH2:13]1)(=O)=O.[CH2:22]([N:29]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][C:34]([O:41][CH3:42])=[C:35](O)[CH:36]=2)[N:31]=[CH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C)C=O>[CH2:22]([N:29]1[C:38](=[O:39])[C:37]2[C:32](=[CH:33][C:34]([O:41][CH3:42])=[C:35]([O:11][CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:36]=2)[N:31]=[CH:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1O
Reactant: CS(=O)(=O)OC1CCC2(CC1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncn(Cc3ccccc3)c(=O)c2cc1OC1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 18 h

Procedure:
16.0 g potassium carbonate and 20.0 g 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are added at 50° C. to 20.0 g 3-benzyl-3,4-dihydro-4-oxo-6-hydroxy-7-methoxy-quinazoline in 150 ml N,N-dimethylformamide and the mixture is vigorously stirred for 18 hours at 80° C. To complete the reaction potassium carbonate and 8-methanesulphonyloxy-1,4-dioxa-spiro[4.5]decan are each added three times and in each case the mixture is stirred for several hours at 80° C. The reaction mixture is cooled and slowly combined with a total of 500 ml of water. The precipitate is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH2:6][C:7]1[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=2)[CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)(=O)C.[Rh]>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH3:31])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(Cc2cccn2CCCCCCn2cccc2Cc2ccc(OC)c(OC)c2)cc1OC
Reactant: [H][H]
Agent: [Rh]
Solvent: CC(=O)O
Product: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Yield: 92 %

Procedure:
A solution of 1,6-bis[2-(3,4-dimethoxybenzyl)-pyrrol-1-yl]hexane (2.5 g) in glacial acetic acid (30 mL) containing suspended 5% rhodium on alumina catalyst (1.87 g) was reduced at room temperature and an initial hydrogen pressure of 45 p.s.i.g. (3 hour reaction, followed by TLC). The mixture was filtered through Celite. The filtrate was dried at reduced pressure, and the residue dissolved in dichloromethane, washed with ammonium hydroxide solution and dried over sodium sulfate. The solvent was removed in vacuo, and the residue subjected to column chromatographic purification on silica gel (100 g) using dichloromethane, to elute 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane, 2.5 g (92% yield) as an oil.