Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:34]([CH:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35]>O1CCCC1>[C:37]1([CH:36]([NH:43][C:16]([C:12]2[S:11][C:10]([NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:14][C:13]=2[CH3:15])=[O:18])[CH2:34][CH3:35])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Reactant: CCC(N)c1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCC(NC(=O)c1sc(NC(=O)c2ccccc2)nc1C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 19 %

Procedure:
To a solution of 2-benzoylamino-4-methylthiazole-5-carboxylic acid (0.13 g, 0.50 mmol) and 4-methylmorpholine (0.08 mL, 0.70 mmol) in tetrahydrofuran (20 mL) at 0° C. was added iso-butylchloroformate (0.08 mL, 0.60 mmol). The reaction mixture was stirred for 15 minutes, then warmed to ambient temperature and stirred for another hour before α-ethylbenzylamine (0.1 mL, 0.70 mmol) was added. The reaction mixture was kept stirring at ambient temperature overnight and then concentrated. Purification of the residue by column chromatography afforded the title compound in 19% yield (0.037 g); m. p. 87-89° C.; 1H NMR (CDCl3, 300 MHz) δ 7.89-7.86 (m, 2H), 7.61-7.22 (m, 8H), 5.91 (d, J=7.5 Hz, 1H), 5.02-4.94 (m, 1H), 2.33 (s, 3H), 2.27-1.78 (m, 2H), 0.92 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 165.1, 161.4, 157.0, 152.1, 141.8, 133.3, 131.4, 129.1, 128.7, 127.6, 127.5, 126.6, 118.8, 55.6, 29.3, 16.7, 10.8. MS (ES+) m/z 380.5 (M+1).
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:36])[C:12]1[CH:17]=[C:16]([CH2:18][C:19]2[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=2[CH3:25])[CH:15]=[CH:14][C:13]=1[O:32]C(=O)C)[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][N:2]([C:11](=[O:36])[C:12]1[CH:17]=[C:16]([CH2:18][C:19]2[C:20](=[O:31])[C:21]([O:29][CH3:30])=[C:22]([O:27][CH3:28])[C:23](=[O:26])[C:24]=2[CH3:25])[CH:15]=[CH:14][C:13]=1[OH:32])[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)N(C)c3ccc(OC)cc3)c2)=C(C)C1=O
Yield: 78.2 %

Procedure:
N-Methyl-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-methoxyaniline (0.070 g, 0.142 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.050 g, 0.111 mmol, 78%).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][CH3:19])=[O:5].[CH3:21][Mg]Br.C1(C)C=CC=CC=1.C1COCC1>C1COCC1>[CH3:19][O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:10][C:6]=1[C:4](=[O:5])[CH3:21]
Reactant: C[Mg]Br
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COCc1nc(-c2ccccc2)sc1C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methoxy-methyl amide (6.706 g, 22.9 mmole, 1.0 eq) in dry THF (25 ml) at 0° C. was added dropwise a solution of 1.4M methylmagnesium bromide in (3:1)toluene-THF (32.7 ml, 45.8 mmole, 2.0 eq). The resulting tan suspension was stirred under nitrogen at room temperature for 30 minutes, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a brown oil. Silica gel chromatography using a gradient elution of (9:1) to (4:1) hexanes-ethyl acetate provided the title compound (6.033 g, 81%) as a yellow crystalline solid. 1H NMR (CDCl3): δ 2.7 (s, 3H), 3.5 (s, 3H), 4.9 (s, 2H) 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:4][CH:3]=1.[F:18][CH:19]([F:28])[C:20](=O)[CH2:21][C:22](=O)[CH:23]([F:25])[F:24].ClC1C=CC(OCCCC2N=C(N)NN=2)=CC=1.FC1C=CC(O)=CC=1>>[F:18][CH:19]([F:28])[C:20]1[CH:21]=[C:22]([CH:23]([F:25])[F:24])[N:12]2[N:11]=[C:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=[C:13]2[N:15]=1.[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)=[CH:16][CH:17]=1
Reactant: O=C(CC(=O)C(F)F)C(F)F
Agent: Nc1nc(CCCOc2ccc(Cl)cc2)n[nH]1
Agent: Nc1nc(CCCOc2ccc(F)cc2)n[nH]1
Agent: Oc1ccc(F)cc1
Product: Fc1ccc(OCCCc2nc3nc(C(F)F)cc(C(F)F)n3n2)cc1
Yield: 72 %

Procedure:
The title compound was prepared according to the experimentals described for Example 22 above from 3-[3-(4-fluorophenoxy)propyl]-1H-1,2,4-triazol-5-amine and 1,1,5,5-tetrafluoropentane-2,4-dione in 72% yield. The reagent 3-[3-(4-fluorophenoxy)propyl]-1H-1,2,4-triazol-5-amine was prepared by a similar procedure for the synthesis of 3-[3-(4-chlorophenoxy)propyl]-1H-1,2,4-triazol-5-amine in Example 22 above, beginning from 4-fluorophenol instead of 4-chlorophenol. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.83 (s, 1H), 7.63 (t, 1H), 7.18 (t, 1H), 7.09 (m, 2H), 6.95 (m, 2H), 4.08 (t, 2H), 3.11 (t, 2H), 2.24 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N2CCNCC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
To tert-butyl 4-(2-methyl-4-quinolyl)piperazine-1-carboxylate (4.382 g, 13.38 mmol) was added 40 ml of a 1:1 mixture of dichloromethane and trifluoroacetic acid. The mixture was stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue dissolved in dichloromethane. The solution was washed with 5% sodium bicarbonate solution and 3M NaOH was added until the aqueous phase remained basic. The phases were separated, the aqueous phase was extracted twice with dichloromethane, the combined organic phases were washed with saturated sodium carbonate solution, water, dried over magnesium sulfate and evaporated to dryness. 2.1 g of a solid were obtained (9.25 mmol, 69%). MS (APCI): m/z=227.8 [M+1]+.
Reaction SMILES: F[C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([F:21])[CH:14]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O-:28].[K+].O1CCOCCOCCOCCOCCOCC1>CN(C)C=O>[CH3:22][N:23]([CH3:29])[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:2]1[C:3]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ncccc3F)no2)c1
Reactant: CN(C)CCCC[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)CCCCOc1cccnc1-c1noc(-c2cc(F)cc(C#N)c2)n1

Procedure:
Alternatively, treatment of 3-(3-fluoropyrid-2-yl)-5-(3-fluoro-5-cyanophenyl)-1,2,4-oxadiazole with potassium 4-dimethylaminobutoxide in N.N-dimethylformamide with a catalytic amount of 1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) and heating at 110° C. affords crude product. Standard work up and purification by one or more methods, including silica gel chromatography, recystallization, trituration, and reversed-phase high-performance liquid chromatography (RP-HPLC) affords purified 3-(3-(4-dimethylaminobutoxy)-pyrid-2-yl)-5-(3-cyano-5-fluorophenyl)-1,2,4-oxadiazole.
Reaction SMILES: Cl.[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22][CH2:21]1.O>CN(C)C=O.C(OCC)(=O)C>[C:2]1([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:22][CH2:21]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCC(CBr)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Yield: 12.2 %

Procedure:
To a solution of trans-2-phenylcyclopropanamine hydrochloride (1.087 g, 6.41 mmol) in N,N-dimethylformamide (DMF) (30 mL) was added potassium carbonate (1.771 g, 12.81 mmol) followed by benzyl 4-(bromomethyl)piperidine-1-carboxylate (1 g, 3.20 mmol). The reaction mixture was refluxed overnight. Water (80 mL) was added followed by 80 mL of ethyl acetate. The organic layer was separated, washed with brine, dried over MgSO4, filtered and evaporated. The oil was purified via silica gel column (DCM to 100% EtOAc). The fractions were collected and evaporated. The oil was further purified on preparative HPLC (5 to 70% AcCN: H2O gradient with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with aq. NH4OH, concentrated and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated. Benzyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (150 mg, 0.391 mmol, 12.21% yield) was isolated as yellow liquid. 1H NMR (400 MHz, METHANOL-d4) 67.28-7.41 (m, 5H), 7.18-7.27 (m, 2H), 7.09-7.16 (m, 1H), 7.03-7.09 (m, 2H), 5.12 (s, 2H), 4.00-4.29 (m, 2H), 2.67-2.97 (m, 2H), 2.61 (d, J=6.82 Hz, 2H), 2.26-2.36 (m, 1H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.64-1.84 (m, 3H), 0.91-1.24 (m, 4H); LC-MS Rt=0.83 min; MS (ESI): 365.5 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[C:12]1([CH:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.C(OCC)(=O)C>ClCCl>[I:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:19](=[O:20])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][CH3:23])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: NC(=O)c1cc(N)ccc1I
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Temperature: 25 °C

Procedure:
0.823 g (3.14 mmol) of the compound from Example 4A are dissolved in 10 ml of dichloromethane at RT, and 0.688 mg (3.77 mmol) of 2-phenylbutyryl chloride and 0.298 mg (3.77 mmol) of pyridine are added. The mixture is stirred at RT over after. Ethyl acetate is added, and the mixture is extracted with water. The organic phases are dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by chromatography on a silica gel column (mobile phase ethyl acetate:cyclohexane 2:1). 0.943 g (72% of theory) of product are obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1.[CH2:37]([N:44]=[C:45]=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:37]([NH:44][C:45]([NH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][CH:5]=1)=[S:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: S=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=S)NCc4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 63.9 %

Procedure:
A mixture of 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg), benzyl isothiocyanate (248 mg), triethylamine (153 mg) and anhydrous N,N-dimethylformamide (8 ml) was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=2:1→3:1→4:1 as the eluant to afford the title compound (291 mg, mp 174.8-177.2° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[CH:4][N:3]=1.[CH2:14]([Mg]Br)[CH:15]([CH3:17])[CH3:16]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:12][CH:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of 6-chloro-N-methoxy-N-methylnicotinamide (2 g, 10 mmol) in THF (30 mL) was added the iso-butymagnesium bromide (15 mL of a 1.33M solution in THF, 20 mmol). The reaction mixture was stirred at 25° C. for 2 h. The reaction was quenched by addition of aqueous NH4Cl (30 mL) and extracted with ethyl acetate (30 mL*2). The organic layer was washed with brine (50 mL) and water (50 mL), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give 1-(6-chloropyridin-3-yl)-3-methylbutan-1-one (1.8 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.85 (d, J=2.0 Hz, 1H), 8.12 (dd, J=2.4, 8.4 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 2.75 (d, J=6.8 Hz, 2H), 2.26-2.19 (m, 1H), 0.94 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([SH:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>CN(C=O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([S:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: Sc1cccc2cnccc12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2cccc3cnccc23)nc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
According to the method in Example 10, a mixture of 5-isoquinolinethiol 1.12 g (6.9 mmol), DMF 20 ml, potassium carbonate 1.92 g (13.9 mmol) and 2-chloro-5-nitropyridine 1.00 g (6.3 mmol) was stirred at 100° C. for 2 hours, and 5-[(5-nitro-2-pyridyl)-sulfanyl)isoquinoline 1.40 g (78.4%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([C:16](O)=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.Cl>C1COCC1>[OH:17][CH2:16][CH:13]1[CH2:14][CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12]1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)C1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCC(CO)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[(benzyloxy)carbonyl]pyrrolidine-3-carboxylic acid (1.0 g, 4.0 mmol) in THF (37 mL) at 0° C. was added dropwise a solution of 1.0 M borane in THF (16.4 mL). The reaction was allowed to warm to room temperature and stir for 16 hours. The mixture was cooled to 0° C. and 10% HCl (50 mL) was added. After the addition, the mixture was extracted with DCM, and the extract was washed sequentially with saturated NaHCO3 solution and brine, then dried over sodium sulfate, filtered and the solvent was removed in vacuo. The product was used without further purification in the subsequent oxidation step.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].C(=O)([O-])[O-].[K+].[K+].CC(C)=O.O>C(OCC)(=O)C>[CH3:1][N:2]([CH2:11][CH:12]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]([C:23]2[N:24]([CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[O:22])[CH2:17][CH2:16]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCBr
Reactant: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3ccccc3)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 38 h

Procedure:
Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzamide (1.35 mmol), ethyl 4-bromobutyrate (5.4 mmol), and potassium carbonate (2.24 g, 16.2 mmol) in 13/1 acetone/water (25 mL). Heat to reflux. After 38 hours, cool to ambient temperature and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution. Dry the organic layer over MgSO4, filter, and concentrate invacuo to give the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:10][O:9][CH:8]2[CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH2:12][O:13][CH:7]12)(=O)=O.[N:25]([Na])=[N+:26]=[N-:27]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:6]1[CH:7]2[O:13][CH2:12][CH:11]([N:14]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]3=[O:24])[CH:8]2[O:9][CH2:10]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Reactant: [N-]=[N+]=N[Na]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1COC2C1OCC2N1C(=O)c2ccccc2C1=O
Temperature: 140 °C

Procedure:
To a solution of 6-(1,3-dioxoisoindolin-2-yl)hexahydrofuro[3,2-b]furan-3-yl methanesulfonate (2.80 g, 7.9 mmol) in DMF (60 mL) was added azido sodium (2.16 g, 33.2 mmol). The reaction was allowed to warm to 140° C. for 23 h. The solution was diluted with CH2Cl2 (100 mL), washed with water (100 mL×3) and dried over anhydrous Na2SO4, and then concentrated in vacuo to give the crude product. The product was used for next step without further purification.
Reaction SMILES: [CH2:1]([C:5]1[S:6][CH:7]=[CH:8][N:9]=1)[CH:2]([CH3:4])[CH3:3].[Br:10]N1C(=O)CCC1=O.C(OCC)(=O)C.CCCCCC>CN(C=O)C>[Br:10][C:7]1[S:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)Cc1nccs1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Cc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2-isobutylthiazole (600 mg, 4.25 mmol) in DMF (2 mL) was added N-bromosuccinimide (1.134 g, 6.37 mmol). The mixture was stirred at room temperature for 3 hours then subjected to flash column chromatography using 10% ethyl acetate/hexane to give a yellow oil (815.2 mg, 87% yield). LCMS (Conditions C): Tr 3.51 min; (M+H)+: 219.90 (100%), 221.90 (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:22]3[CH2:25][CH2:24][CH2:23]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][CH2:20][CH3:21])[CH:11]=3)=[CH:4][CH:3]=1.Cl[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28].N1C=CC=CC=1.[CH2:45]([CH2:47][NH2:48])[OH:46]>C(Cl)Cl>[C:17]([C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:19][CH2:20][CH3:21])=[CH:13][CH:14]=2)[N:9]([CH:22]2[CH2:23][CH2:24][CH2:25]2)[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:48][CH2:47][CH2:45][OH:46])=[O:28])=[CH:7][CH:6]=1)#[N:18]
Reactant: NCCO
Reactant: CCOc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ccc2c(C#N)c(-c3ccc(NC(=O)NCCO)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
2-(4-Aminophenyl)-1-cyclobutyl-6-ethoxy-1H-indole-3-carbonitrile (40 mg, 0.12 mmol), prepared as in example 1CM, step B, is combined with 4-nitrophenyl chloroformate (60 mg, 0.30 mmol), CH2Cl2 (400 μL), and pyridine (25 μL, 0.31 mmol). This suspension is stirred at room temperature for 1 hour. Ethanolamine (42 μL, 0.70 mmol) is added. After stirring at room temperature for an additional 30 min, the reaction mixture is diluted in CH2Cl2 and is washed with dilute aqueous NaOH to remove the yellow nitrophenol by-product. The organic layer is dried and concentrated. Purification by silica gel chromatography (CH2Cl2/Acetone, 7/3) yields 1-[4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-3-(2-hydroxy-ethyl)-urea (40 mg, 80%) as a white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][CH2:13][C:14]1[C:15]([NH:22][CH3:23])=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:13][C:14]2[C:15](=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=2)[N:22]([CH3:23])[C:1]1=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1ccccc1C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccccc1C)C2
Reaction time: 1 h
Yield: 101.3 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution containing 189 mg (0.69 mmol) of 5-(2-methylphenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution. The phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 210 mg (100%) of 3-(2-methylphenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a cream-colored solid. [Mass spectrum (ESI) MH+ =301].
Reaction SMILES: C([CH:3]([CH2:7][C:8](Cl)=[O:9])[C:4](Cl)=[O:5])C.N1C(C)=CC=C[C:12]=1[CH3:18].[O:19]1CCCC1>[Pd]>[O:9]=[CH:8][CH2:7][CH2:3][C:4]([O:5][CH2:12][CH3:18])=[O:19]
Reactant: Cc1cccc(C)n1
Reactant: C1CCOC1
Reactant: CCC(CC(=O)Cl)C(=O)Cl
Agent: [Pd]
Product: CCOC(=O)CCC=O
Reaction time: 24 h

Procedure:
Ethyl succinyl cloride (4.1 g) was added to a suspension of 10% palladium on carbon (0.3 g) and 2,6-lutidine (2.9 ml) in dry tetrahydrofuran (100 ml). The mixture was hydrogenated at 3 atmospheres pressure for 24 hours. The reaction mixture was filtered and the filtrate evaporated under reduced pressure. Yield 3.15 g. 1H NMR: δ (CDCl3) 9.82 (s,1H), 4.16 (q,2H), 2.80 (t,2H), 2.63 (t,2H), 1.26 (t,3H).