Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.CSC.CO.[H][H]>C1COCC1>[OH:13][C@H:10]1[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:9]1[CH2:14][OH:15]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: [H][H]
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1CO
Temperature: 15 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
The product from Example 51A (7.73 g, 33.5 mmol) in dry THF (100 mL) was treated with borane-methyl sulfide complex (10 M in THF, 7.4 mL, 74 mmol) dropwise over 10 minutes. The solution was refluxed for 1 hour, cooled to 10-20° C., and methanol was added cautiously until there was no obvious evolution of hydrogen. The mixture was concentrated under reduced pressure and the white residue was stirred with water (50 mL) for 10 minutes and then extracted with ethyl acetate (3×100 mL). The extracts were combined, washed with brine (2×10 mL), dried (Na2SO4), and concentrated to provide the title compound as a white solid (7.24 g, 99%). MS (DCI/NH3) m/z 218 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH3:29][C:30]1[S:31][CH:32]=[C:33]([CH2:35][C:36](O)=[O:37])[N:34]=1>>[OH:1][C@H:2]([CH2:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:36](=[O:37])[CH2:35][C:33]2[N:34]=[C:30]([CH3:29])[S:31][CH:32]=2)=[CH:18][CH:19]=1)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: Cc1nc(CC(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)COc1ccccc1
Product: Cc1nc(CC(=O)Nc2ccc(CCN(C[C@H](O)COc3ccccc3)C(=O)OC(C)(C)C)cc2)cs1
Yield: 90.6 %

Procedure:
621 mg of t-butyl (S)-N- (2-hydroxy-3-phenoxypropyl)-N-[2-(4-aminophenyl)ethyl]carbamate and 403 mg of 2-(2-methylthiazol-4-yl)acetic acid were subjected to an amidation reaction to obtain 765 mg of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-[4-[[2-(2-methylthiazol-4-yl)acetyl]-amino]phenyl]ethyl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][CH:8]([O:26]C(=O)C)[CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:26])[CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:14][CH2:15]2)=[CH:30][CH:31]=1
Reactant: CC(=O)OC(COc1ccc(F)cc1)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(CC(O)COc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2.2 g of 1-{1-[3-(p-fluorophenoxy)-2-acetyloxypropyl]-4-piperidyl}-2-oxobenzimidazoline, 1.1 g of potassium hydroxide, 5 ml of water and 20 ml of ethanol is stirred at room temperature for one hour. The reaction mixture is poured into 200 ml of water. After cooling, the precipitate formed is collected by filtration and dried to give 1-{1-[3-(p-fluorophenoxy)-2-hydroxypropyl]-4-piperidyl}-2-oxobenzimidazoline, m.p. 175° - 176° C. Recrystallization from benzene gives white crystals, m.p. 177° - 178° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[O:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1.F[S:24]([C:27]1[N:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=1)(=[O:26])=[O:25]>C1COCC1>[CH3:34][O:33][C:30]1[N:29]=[N:28][C:27]([S:24]([C:14]2[O:13][C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]=2[OH:22])(=[O:26])=[O:25])=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)F)nn1
Reactant: O=C1COc2ccccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(S(=O)(=O)c2oc3ccccc3c2O)nn1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 17 %

Procedure:
n-Butyl lithium (12 mmol, 4.7 mL) was added dropwise to a solution of diisopropyl amine (12 mmol, 1.7 mL) in THF (5 mL) at −78° C. After 10 minutes, a solution of 3-coumaranone (10 mmol, 1.92 g) in THF (10 mL) was added. The temperature was maintained at −78° C. and stirred for 10 minutes. To this was added a solution of 3-fluorosulfonyl-6-methoxy-pyridazine. The reaction mixture was brought to room temperature over one hour and quenched with ammonium chloride (1 g) and extracted with EtOAc (2×25 mL). The EtOAc extract was washed with H2O, the organic layer was collected, dried, filtered and the filtrate was evaporated to a residue. This residue was purified by silica gel chromatography (eluent: hexanes:EtOAc:9:1) to yield 3-methoxy-6-(3-hydroxy-benzofuran-2-sulfonyl)-pyridazine (17%, 622 mg).
Reaction SMILES: BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:18][C:19]1[CH:20]=[C:21]([NH:34][C:35]2[CH:40]=[C:39]([O:41]C)[CH:38]=[CH:37][C:36]=2[C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:18][C:19]1[CH:20]=[C:21]([NH:34][C:35]2[CH:40]=[C:39]([OH:41])[CH:38]=[CH:37][C:36]=2[C:43]2[CH:52]=[CH:51][C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH:44]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccc3ccccc3c2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: Oc1ccc(-c2ccc3ccccc3c2)c(Nc2ccc(OCCN3CCCCC3)c(F)c2)c1
Yield: 86.3 %

Procedure:
Synthesized from 5-methoxy-2-naphthalen-2-ylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl](5-methoxy-2-naphthalen-2-ylphenyl)amine (350 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (293 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=S)[NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10]C)=O)[CH3:2].IC.O.[NH2:22][NH2:23].O>CO>[NH2:22][N:23]1[C:8](=[O:10])[C:7]2[C:6](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]1[N:3]([CH2:1][CH3:2])[CH2:17][CH3:18]
Reactant: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Reactant: NN
Solvent: CI
Solvent: O
Solvent: CO
Product: CCN(CC)c1nc2ccccc2c(=O)n1N
Temperature: 80 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
Methyl 2-(3,3-diethyl-thioureido)benzoate (2.29 g, 8.59 mmol) was dissolved in methanol (15 mL), followed by addition of iodomethane (1.07 mL, 17.2 mmol). The reaction mixture was heated at 80° C. for 10 minutes under microwave conditions making sure the temperature did not exceed 80° C. The reaction mixture was evaporated to dryness and then redissolved in methanol (50 mL). Hydrazine monohydrate (1.25 mL, 25.8 mmol) was added followed by stirring at RT overnight. The reaction mixture was poured into water (200 mL), followed by extraction with diethyl ether (2×100 mL), drying (MgSO4) and evaporation in vacuo. The crude product was subjected to column chromatography (EtOAc/Heptane) giving the title compound (1.37 g, 69%).
Reaction SMILES: [CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:5]([CH2:19][C:20]1[CH:32]=[CH:31][C:23]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:22]([CH3:33])[CH:21]=1)[C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1nccc(-c2ccc(Cl)cc2)n1
Yield: 96.3 %

Procedure:
To a solution of ethyl [4-({butyl[4-(4-chlorophenyl)pyrimidin-2-yl]amino}methyl)-2-methylphenoxy]acetate (178 mg, 0.38 mmol) in THF (3 mL) and MeOH (3 mL) was added NaOH (2M; 2 mL) and the resultant mixture agitated for 1.5 h. The mixture was evaporated and acidified with 2M HCl, extracted with CH2Cl2 (10 mL), EtOAc (10 mL). The aqueous was filtered, the filtered solids and solvent extracts combined and the solvent removed in vacuo to afford the title compound as a white solid (161 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9](F)=[N:10]2)=[O:4].C(NC1C([Cl:39])=NC2C(N=1)=C(C(=O)C)C=CC=2)(C)(C)C>>[Br:1][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([Cl:39])=[N:10]2)=[O:4]
Reactant: CC(=O)c1cccc2nc(Cl)c(NC(C)(C)C)nc12
Reactant: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1F
Product: CC(C)(C)Nc1nc2c(C(=O)CBr)cccc2nc1Cl
Yield: 59 %

Procedure:
This compound (215 mg, 59% yield) as a yellow oil was prepared according to the procedures described for intermediate 343c, using 1-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)ethanone (345a) (285 mg, 1.02 mmol) as the starting material. 1H NMR (400 MHz, CDCl3) δ ppm 1.57 (s, 9H) 4.93 (s, 2H) 5.82 (br. s., 1H) 7.43 (t, J=7.82 Hz, 1H) 7.94 (d, J=7.63 Hz, 2H). MS (ESI, pos. ion) m/z: 356.0/358.0 (M+1).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C@@H:18]([NH:24][C:25](=[O:40])[C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:33])=[C:28]([CH3:39])[CH:27]=1)[CH2:19][CH2:20][C:21]([OH:23])=O)=O)(C)(C)C.CN(C(O[N:49]1N=NC2C=[CH:53][CH:54]=[CH:55][C:50]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CCCC1.FC(F)(F)C(O)=O.ClCl>O1CCCC1.C(OCC)(=O)C.C(O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[NH:8][C:9]([C@@H:18]([NH:24][C:25](=[O:40])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:33])=[C:28]([CH3:39])[CH:27]=3)[CH2:19][CH2:20][C:21]([N:49]3[CH2:50][CH2:55][CH2:54][CH2:53]3)=[O:23])=[N:10][C:11]=2[CH:16]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCC(=O)O)c2nc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)ccc1C(=O)N1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: Cc1cc(C(=O)N[C@@H](CCC(=O)N2CCCC2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 56 %

Procedure:
Prepared analogously to Example 1g from (1S)—N-[1-(1-tert-butoxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonylpropyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide, TBTU, diisopropylethylamine, and pyrrolidine in tetrahydrofuran followed by treatment with trifluoroacetic acid analogously to Example 17. Yield: 56%; Rf value: 0.22 (silica gel; ethyl acetate/ethanol=9:1); C28H32ClN5O3 (522.05); mass spectrum: (M+H)+=522/524 (chlorine isotope).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([NH:22][NH2:23])=[O:21])=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24](OC(OCC)OCC)C>>[CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[O:21][CH:24]=[N:23][N:22]=4)=[CH:16][CH:15]=3)[C:10]([CH3:13])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)NN)cc1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnco2)cc1

Procedure:
N-Cyclopropyl-4′-(hydrazinocarbonyl)-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 40) (50 mg) in triethylorthoformate (5 ml) was heated at 150° C. for 5 hours. The excess triethylorthoformate was evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. The solvent was evaporated from the product fractions under vacuum to give N-cyclopropyl-4′-(1,3,4-oxadiazol-2-yl)-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.[CH2:14]([O:16][C:17]([CH:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][CH:22]=O)=[O:18])[CH3:15]>>[CH2:14]([O:16][C:17]([CH:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21][CH:22]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[CH3:1])=[O:18])[CH3:15]
Reactant: CNCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)C(CCC=O)C(=O)OCC
Product: CCOC(=O)C(CCC1c2[nH]c3ccccc3c2CCN1C)C(=O)OCC
Yield: 55.2 %

Procedure:
1.78 g of N-methyl-tryptamine (i.e., 3-(2-methylaminoethyl)-indole) and 3.1 g of 4,4-bis(ethoxycarbonyl)-butanal were treated in the same manner as described in Example 21-(1). 2.1 g of 1,2,3,4-tetrahydro-1-[3,3-bis-(ethoxycarbonyl)propyl]-2-methyl-β-carboline were thereby obtained. Yield: 55.0%
Reaction SMILES: [CH3:1][CH:2]([S:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10](O)=[O:11])[CH3:3].C1N=C[N:19](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[CH3:1][CH:2]([S:4][C:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[S:8][C:9]=1[C:10]([NH2:19])=[O:11])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)Sc1c(C(=O)O)sc2ccccc12
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Sc1c(C(N)=O)sc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To 3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxylic acid (133 mg, 0.53 mmol) [Connor D. T., et al., U.S. Pat. No. 4,703,053 (1987)] in 6 mL of THF is added N,N-carbonyldiimidazole (99 mg, 0.61 mmol). The mixture is heated at reflux for 1.5 hours then cooled slightly. Aqueous NH4OH (1 mL) is added and the reaction mixture is stirred at room temperature for 30 minutes, then partitioned between ethyl acetate and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography eluting with 1:1 hexane:ethyl acetate to provide 3-[(1-methylethyl)thio]benzo[b]thiophene-2-carboxamide in 83% yield; mp=183-185° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12][CH2:13]O>>[NH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4]1
Reactant: NC1CCCC(C(=O)O)C1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1CCCC(N)C1

Procedure:
Conc. HCl (1 mL) was added to a solution of 3-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in EtOH (20 mL) and stirring was continued at reflux temperature for 3 h. The reaction mixture was concentrated under reduced pressure to afford the crude, which was washed with 10% aqueous NaHCO3 solution, extracted with DCM, dried over anhydrous sodium sulphate to afford 300 mg of the title compound.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[CH:22]=[C:23]([C:31]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32])[CH:24]=[C:25]3[C:30]=2[N:29]=[CH:28][CH:27]=[CH:26]3)[CH:16]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.[NH2:38][C:39]1[S:40][CH:41]=[CH:42][N:43]=1>CN(C=O)C.O.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:37][C:31]([C:23]1[CH:24]=[C:25]2[C:30](=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([C:2]4[N:43]5[C:39]([S:40][CH:41]=[CH:42]5)=[N:38][C:3]=4[C:5]4[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][CH:6]=4)[CH:16]=3)[CH:22]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)([S:33]([CH3:36])(=[O:35])=[O:34])[CH3:32]
Reactant: CC(C)(c1cc(-c2cccc(C(Br)C(=O)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1)S(C)(=O)=O
Reactant: Nc1nccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(c1cc(-c2cccc(-c3c(-c4ccc(S(C)(=O)=O)cc4)nc4sccn34)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 120 °C

Procedure:
To a solution of the alphabromoketone from EXAMPLE 1, step 4 (1.0 eq) in DMF (0.1M) was added 2-aminothiazole (1.6 eq). The mixture was heated at 120° C. for 1 h, cooled, diluted with water, saturated NaHCO3 solution and EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Toluene:EtOAc, 1:3) to afforded the title compound.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].Cl.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](OCC)=[O:24])[C:19](=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>CC(O)(C)C>[NH2:7][C:6]1[N:8]=[C:23]([OH:24])[C:20]2[CH2:21][CH2:22][N:17]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][C:19]=2[N:5]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)(C)O
Product: Nc1nc(O)c2c(n1)CN(Cc1ccccc1)CC2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
Guanidine carbonate (343 mg, 1.87 mmol) was added to a solution of 1-benzyl-4-ethoxycarbonyl-3-piperidone hydrochloride (488 mg, 1.87 mmol) in tBuOH (18 mL). The reaction was heated to reflux for 2 hours and then was acidified with 1N HCl to pH 5 and stirred for 30 minutes. The mixture was filtered and the solids were dried to obtain 2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ol as a yellow solid (320 mg, 67%). MS (ESI): mass calcd. for C14H16N4O 256.3 m/z found, 257.2[M+H]+. 1H NMR (500 MHz, MeOD) δ 7.40-7.26 (m, 5H), 3.71 (s, 2H), 3.25 (s, 2H), 2.73 (t, J=5.9 Hz, 2H), 2.46 (t, J=5.9 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>C(O)C>[N:20]1([C:2]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccccc1Nc1nc(Cl)nc2ccccc12
Reactant: C1CCNC1
Solvent: CCO
Product: Cc1ccccc1Nc1nc(N2CCCC2)nc2ccccc12
Yield: 65.2 %

Procedure:
2-chloro-4-(2-methylphenylamino)quinazoline (5 g, 0.0185 mol) and pyrrolidine (6.59 g, 0.093 mol) were dissolved in ethanol (65 ml) placed in a sealed vessel and heated to 135° for 5 hours. After cooling, the reaction mixture was dissolved in ethanol and then evaporated in vacuo. The oily residue afforded crystals of 2-pyrrolidino-4-(2-methylphenylamino)quinazoline (3.67 g, 65%) from ethanol/water, m.p. 152°-154°.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([CH:15]1[CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][N:17](C(OC(C)(C)C)=O)[C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[CH2:8]([CH:15]1[CH:19]([CH2:20][CH2:21][CH3:22])[CH2:18][NH:17][C:16]1=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCCC1CN(C(=O)OC(C)(C)C)C(=O)C1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCC1CNC(=O)C1Cc1ccccc1
Reaction time: 14 h
Yield: 99.5 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl 3-benzyl-2-oxo-4-propyl-1-pyrrolidinecarboxylate (1.22 g, 3.84 mmol) in methylene chloride (10 ml) while cooling on ice and the mixture was stirred for 14 hours. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. After washing the organic layer with brine and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield a crude product of the title compound (0.83 g) as white crystals. 1H-NMR (CDCl3) δ(ppm) 0.79 (3H, t, J=7.2 Hz), 1.08-1.36 (4H, m), 2.04-2.21 (1H, m), 2.28-2.40 (1H, m), 2.81-2.96 (2H, m), 3.09 (1H, dd, J=14.0 Hz, 4.8 Hz), 3.29 (1H, dd, J=8.4 Hz, 8.4 Hz), 5.73 (1H, brs), 7.15-7.36 (5H, m)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(#N)C>[C:14]([NH:18][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.203 mmol, Example 8D) in acetonitrile (3 mL) at room temperature under nitrogen was added tert-butylamine (0.043 ml, 0.406 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 234 (M+H)+.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH2:4]1.Cl.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](SCC)=[NH:21]>C(O)C>[ClH:1].[ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:13][C:20]([C:16]3[S:15][CH:19]=[CH:18][CH:17]=3)=[NH:21])=[CH:8][CH:9]=2)[CH2:4]1
Reactant: CCSC(=N)c1cccs1
Reactant: CN1CCc2ccc(N)cc2C1
Agent: Cl
Solvent: CCO
Product: CN1CCc2ccc(NC(=N)c3cccs3)cc2C1
Temperature: 0 °C

Procedure:
2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-ylamine hydrochloride (34.66 g) in 95% ethanol (600 ml) was warmed to 65° C. to dissolve most of the solids, and the mixture was then allowed to cool with stirring. The next day, the fine suspension of solids was treated with 2-thiophenecarboximidothioic acid, ethyl ester, hydrochloride (41 g) and stirred at 23° C. All solids had dissolved by 2 h, and by 4 h new solids had precipitated. The mixture was treated with concentrated hydrochloric acid (2 ml). The mixture was cooled to 0° C. and stirred for 30 minutes. The solids were filtered off, washed with ethanol (2×50 ml), and air dried to provide N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-thiophenecarboximidamide dihydrochloride, m.p. 142-146° C.; MS m /z 272 [M+H]+.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]1([CH3:14])[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1.C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:8]1[CH2:7][C:6]2([CH2:12][CH2:13][N+:3]([CH3:2])([CH3:14])[CH2:4][CH2:5]2)[O:10][C:9]1=[O:11]
Reactant: C[N+]1(C)CCC2(CC1)CNC(=O)O2
Reactant: CC(C)(C)OCl
Agent: [Cl-]
Solvent: CO
Product: C[N+]1(C)CCC2(CC1)CN(Cl)C(=O)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8,8-Dimethyl-2-oxo-1-oxa-3-aza-8-azoniaspiro[4.5]decane chloride (1.60 g, 7.25 mmol) was dissolved in methanol (80 ml). t-Butylhypochlorite (1.18 g, 10.87 mmol) was added to the solution, and the combined mixture was stirred for 1 hour at room temperature. The reaction mixture was monitored by HPLC-MS. The reaction mixture was concentrated in vacuo. The crude material was purified by Prep-HPLC to give 243 mg (13%). 1H NMR (CDCl3) δ 3.84 (s, 2H), 3.52-3.69 (m, 4H), 3.25 (s, 3H), 3.18 (s, 3H), 2.32-2.46 (m, 4H); MS(ESI+) calculated for C9H16ClN2O2: 219.09, Found: 219 (M+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1[CH:31]=[CH:30][C:14]([O:15][CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[OH:22])[CH3:18])=[CH:13][CH:12]=1)=O.O.[OH-].[Na+]>O1CCCC1>[OH:8][CH2:9][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH:17]([NH:19][CH2:20][CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[OH:22])[CH3:18])=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(COc1ccc(CO)cc1)NCC(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
0.83 mg of lithium aluminum hydride was slowly added, with stirring, to a solution of 1.95 g of 2-[2-(4-methoxycarbonylphenoxy)-1-methylethyl]amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 1) dissolved in 70 ml of tetrahydrofuran, and the resulting mixture was allowed to react at room temperature for 2 hours. At the end of this time, 0.9 ml of water, 0.9 ml of a 15% w/v aqueous solution of sodium hydroxide and 3 ml of water were added, in that order, to the reaction mixture, and the resulting mixture was stirred at room temperature. The reaction mixture was then filtered using a Celite (trade mark) filter aid, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 1.5 g of the title compound as a glass-like material, having an Rf=0.55 (thin layer chromatography over silica gel, using a 4:1 by volume mixture of ethyl acetate and ethanol as the developing solvent).