Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.[CH2:19]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C1COCC1.CN(C=O)C.ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:30]3[CH2:31][CH2:32][N:27]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: c1ccc(CCN2CCNCC2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(c1ccc2[nH]ccc2c1)N1CCN(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Indole-5-carboxylic acid (57 mg, 0.35 mmol) was dissolved in THF(2 ml) and DMF (1 drop), then oxalyl chloride (37 μl, 54 mg, 0.42 mmol) was added. The mixture was stirred at room temperature for 3 hours, the solvent was evaporated under reduced pressure and the residue was dissolved in DMF (2 ml) and added to a stirred solution of 1-phenethylpiperazine (66 mg, 0.35 mmol) and diisopropylethylamine (91 μl, 68 mg, 0.52 mmol) in dichloromethane (1 ml). The mixture was stirred at room temperature for 24 hours, then the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /CH3OH/NH3 ; 95:5:0.5 and crystallized from EtOAc/hexane to give the piperazine as microcrystals (32 mg, 27%), mp 105°-108° C. δH (CDCl3) 8.47(1H, br s), 7.73(1H, s), 7.38(1H, d J 8.4 Hz), 7.32-7.19(7H, m), 6.56(1H, br s), 3.7(4H, br s), 2.81(2H, m), 2.65(2H, m), and 2.6(4H, br s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].C1C(=O)N([Br:24])C(=O)C1.N#N>CC#N.CC(N=NC(C#N)(C)C)(C#N)C>[Br:24][CH2:16][C:4]1[C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: N#N
Solvent: CC#N
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1CBr
Temperature: 80 °C
Yield: 83.1 %

Procedure:
To a solution of methyl 3-methoxy-2-methyl-4-nitrobenzoate (800 mg, 3.6 mmol) in CH3CN (10 mL) was added NBS (770 mg, 4.3 mmol) and AIBN (12 mg, 0.072 mmol) under the protection of N2. The mixture was refluxed at 80° C. for overnight. After the solvent was evaporated in vacuo, the resulting residue was purified by silica gel-column (eluting with PE/EA=15:1) to afford methyl 2-(bromomethyl)-3-methoxy-4-nitrobenzoate as yellow oil (910 mg, yield 84%). m/z (ES+APCI)+: [M−Br]+224.1.
Reaction SMILES: COC1C=C[C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:5]C=1.[O:31]1[CH:35]=CC(C=O)=[CH:32]1>>[O:31]1[CH:35]=[CH:5][C:6]([CH2:7][NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][C:18]=2[NH:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]3[NH:26][CH:27]=[CH:28][C:21]=23)=[O:13])=[CH:32]1
Reactant: O=Cc1ccoc1
Reactant: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Product: O=C(NCCNCc1ccoc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]amide using 3-furaldehyde instead of 4-methoxy benzaldehyde. LCMS (ESI) 382 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.49 (1H, br. s.) 10.25 (1H, s) 7.93-8.05 (2H, m) 7.75 (1H, d, J=5.37 Hz) 7.52 (1H, t, J=1.61 Hz) 7.46 (1H, d, J=0.68 Hz) 7.44 (1H, d, J=5.42 Hz) 7.28 (1H, dd, J=3.20, 2.66 Hz) 6.77 (1H, d, J=5.42 Hz) 6.38-6.43 (2H, m) 3.49 (2H, s) 3.30-3.35 (2H, m) 2.60 (2H, t, J=6.49 Hz)
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=1)[CH3:2].[Br:14]Br>C(Cl)Cl>[Br:14][C:4]1[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][NH:7][C:3]=1[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCc1cc(-c2ccccc2)n[nH]1
Solvent: ClCCl
Product: CCc1[nH]nc(-c2ccccc2)c1Br
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of 5-ethyl-3-phenyl-1H-pyrazole (10.0 g, 58.1 mmol) in DCM (150 mL) was added dropwise bromine (9.28 g, 58.1 mmol) at 0° C. The reaction was stirred at that temperature for 30 min and continued for 2 h at room temperature before quenched with aqueous Na2SO3 solution (10% wt, 10 mL). DCM was removed and the residue was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow liquid (9.5 g). LCMS m/z=250.9 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.58 Hz, 3H), 2.66 (q, J=7.58 Hz, 2H), 7.40-7.56 (m, 3H), 7.82 (d, J=7.58 Hz, 2H), 13.15 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1>>[NH2:33][C:32]1[CH:34]=[CH:35][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Yield: 14.1 %

Procedure:
Methyl 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (150 mg, 0.51 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (135 mg, 0.62 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (25 mg, 14%).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[N:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][N:15]=3)[C:8]=2[F:13])[C:3]=1[OH:27].[CH2:28]([CH:31]1[O:33][CH:32]1[CH2:34]O)[CH2:29][CH3:30]>>[CH2:21]([O:20][C:17]1[CH:18]=[N:19][C:14]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:27][CH2:34][CH:32]3[CH:31]([CH2:28][CH2:29][CH3:30])[O:33]3)[C:8]=2[F:13])=[N:15][CH:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCC1OC1CO
Reactant: CCCCCCOc1cnc(-c2ccc3c(O)c(F)c(F)cc3c2F)nc1
Product: CCCCCCOc1cnc(-c2ccc3c(OCC4OC4CCC)c(F)c(F)cc3c2F)nc1

Procedure:
From 2,3,5-trifluoro-6-(5-hexyloxypyrimidin-2-yl)naphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH:18]1[CH2:20][CH2:19]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: NCC1CC1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNCC1CC1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and (aminomethyl)cyclopropane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH:18]([F:20])[F:19])[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:52]=[CH:51][C:34]([C:35](Cl)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)=[CH:33][CH:32]=1>ClCCl>[CH3:43][O:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([NH:17][C:10]2[CH2:11][S:12](=[O:16])(=[O:15])[CH2:13][CH2:14][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:21])([CH:18]([F:19])[F:20])[N:9]=2)([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH3:29])=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:41][CH:40]=1
Reactant: NC1=N[C@@](c2cc(Br)ccc2F)(C(F)F)CCS(=O)(=O)C1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@@](c3cc(Br)ccc3F)(C(F)F)CCS(=O)(=O)C2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.3 %

Procedure:
A solution of (S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-ylamine (318 mg, 826 μmol) and triethylamine (167 mg, 1.65 mmol) in dichloromethane (15 ml) was treated at 0° C. with 4,4′-dimethoxytritylchloride (336 mg, 991 μmol). The green reaction mixture was stirred at room temperature for 6 hours. Thereafter, the reaction mixture was evaporated, and the crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate 100:0 to 50:50 as the eluent. The [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(S)-5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-1,1-dioxo-2,5,6,7-tetrahydro-1H-1λ6-[1,4]thiazepin-3-yl]-amine (365 mg, 63% yield) was obtained as a grey foam. MS (ISP): m/z=687.0 [M+H]+and 689.3 [M+2+H]+.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:3]=1[CH3:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C:3]1[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5][N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[CH:11]=2)(=[O:9])=[O:8])[C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cn(S(=O)(=O)c2cccc(C)c2)c(Br)c1C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cn(S(=O)(=O)c2cccc(C)c2)c(-c2ccccc2)c1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 96.1 %

Procedure:
Under an argon atmosphere, a suspension of ethyl 5-bromo-4-methyl-1-[(3-methylphenyl)sulfonyl]-1H-pyrrole-3-carboxylate (2.80 g), phenylboronic acid (1.84 g), tetrakis(triphenylphosphine)palladium (0.84 g), sodium carbonate (2.31 g) in 1,2-dimethoxyethane (12 mL)-water (12 mL) was stirred at 70° C. for 12 hr. After cooling, the reaction mixture was filtered through celite, and celite was washed with ethyl acetate. The organic layer was separated from the filtrate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:3) to give the title compound as a colorless oil (yield 2.67 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:22][CH2:23][CH2:24][C@H:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:26](OC(N1CCCCC1C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:25])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3[CH2:26][CH2:22][CH2:23][CH2:24][CH:18]3[CH2:17]2)=[O:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Product: COc1ccc(C(=O)CCC(=O)N2CCN3CCCCC3C2)cc1OC

Procedure:
360 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6].C([O-])(=O)C.[K+].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:55]1[N:60]=[C:59]([NH2:61])[CH:58]=[CH:57][CH:56]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[NH2:61][C:59]1[N:60]=[C:55]([C:2]2[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[O:6])[CH:56]=[CH:57][CH:58]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Reactant: Nc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1cccc(N)n1
Temperature: 85 °C

Procedure:
To a degassed mixture of 3-iodo-4-methyl-N-[3-(trifluoromethyl)phenyl]benzamide (0.500 g, 1.23 mmol), potassium acetate (424 mg, 4.32 mmol), DMF (15 mL), and 4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (0.329 g, 1.30 mmol) was added [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with DCM (1:1) (101 mg, 0.123 mmol). The reaction was heated to 80° C. for 3 hours, at which time conversion to the boronic ester was complete. The mixture was cooled and potassium carbonate (512 mg, 3.70 mmol), water (2.24 mL), and 6-bromopyridin-2-amine (214 mg, 1.23 mmol) were added. After degassing the mixture, it was heated to 85° C. for 1 hour. The solvent was then removed in vacuo. Water was added and the product was extracted with three portions of ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated. Purification was carried out by flash column chromatography (eluting with a gradient from 0-50% ethyl acetate in hexanes) afforded the product. (254 mg, 50%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:32])[C:29](=[O:31])[CH3:30])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cc1ccccc1C
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Reaction time: 30 h
Yield: 65.6 %

Procedure:
To a solution of 2 (181.2 g, 0.557 mol) in THF (1 L) was added TEA (84.6 g, 0.836 mol) in portions at 15-20° C. The mixture was stirred for 30 h. After the reaction was complete, the solution was concentrated to give crude 7. To a solution of 35 (82.5 g, 0.557 mol) and Cs2CO3 (91 g, 0.279 mol) in DMSO (1 L) was added slowly crude 7 in DMSO (500 mL) over 30 min at 15-20° C. The mixture was stirred for 1 h. After the reaction was complete, the mixture was partitioned with water and MTBE (5 L), and extracted with MTBE twice. The combined organic layer was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 36 (138 g, 65% yield).
Reaction SMILES: ClCCl.[CH2:4]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(=O)([O-])[O-].[Na+].[Na+]>[CH2:4]([N:11]1[CH2:16][CH2:15][N:14]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:13][CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Yield: 66.4 %

Procedure:
To dichloromethane (50 ml) was added 1-benzylpiperazine (10.0 g, 56.73 mmol), methanesulfonyl chloride (4.4 ml, 56.85 mmol) was added under ice-cooling with stirring, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with 10% aqueous sodium carbonate solution, and extracted with dichloromethane. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (9.58 g, yield 66%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:9]#[N:10])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.B.C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: N#CC(c1ccc(Br)cc1)C1CCCCC1
Agent: B
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: NCC(c1ccc(Br)cc1)C1CCCCC1
Reaction time: 2 h

Procedure:
A solution of Example 1A (1.5 g, 5.4 mmol) in toluene (15 mL) at room temperature was treated dropwise with 1M DIBAL-H in toluene (5.4 mL, 5.4 mmol). After TLC showed complete consumption of the starting material, the concentrate was dissolved in THF (20 mL), treated with 1M BH3.THF (11.0 mL, 11.0 mmol), stirred for 2 hours, treated dropwise with saturated NH4Cl, stirred for 2 hours, and partitioned between dichloromethane and saturated NaHCO3. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH2:7])[CH:4]=[N:3]1.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29](O)=[O:30])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:7][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:30]
Reactant: Cn1cc(N)cn1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cn1cc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)cn1
Yield: 70 %

Procedure:
Following the procedures as described in Example 113, 1-methyl-1H-pyrazol-4-amine, 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid and HATU were reacted to give 102 as a white solid (45 mg, 70%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.78 (s, 1H), 8.00 (d, J=37.3, 1H), 7.70-7.47 (m, 4H), 7.28 (t, J=8.4, 2H), 3.81 (d, J=12.5, 3H). ESIMS m/z=336.1 (M+1)
Reaction SMILES: [CH2:1](I)[CH3:2].C(=O)(O)[O-].[Na+].[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)(=[O:11])[NH2:10]>CN(C)C=O>[C:9]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH2:1][CH3:2])(=[O:11])[NH2:10]
Reactant: CCI
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(N)=O
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
0.362 ml of ethyl iodide and 315 mg of sodium bicarbonate to a solution of 1000 mg of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 10 ml of dry dimethylformamide were added, whilst ice-cooling, and the mixture was stirred at room temperature for 5.5 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was subjected to column chromatography through silica gel (Katayama Chemicals Co., Silica Gel 60K070) and 560 mg of the title compound were obtained as crystals, melting at 124°-125° C., from the fractions eluted with ethyl acetate.
Reaction SMILES: [CH3:1][S:2]([N:5]=[C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7]1)(=[O:4])=[O:3].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][S:21][CH2:22][CH2:23][NH2:24].C1C=CC=CC=1>C(Cl)Cl>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][S:21][CH2:22][CH2:23][NH:24][C:6](=[N:5][S:2]([CH3:1])(=[O:3])=[O:4])[O:10][C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[OH:7]
Reactant: CS(=O)(=O)N=c1oc2ccccc2o1
Reactant: NCCSCc1ccco1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)N=C(NCCSCc1ccco1)Oc1ccccc1O
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
42.6 g of 2-methanesulfonylimino-1,3benzodioxole was suspended in 126 ml of methylene chloride. Thereto was dropwise added 31.4 g of 2-[(2furyl)methylthio]ethylamine at 10° to 15° C. Stirring was effected at the same temperature for 30 minutes. The reaction mixture was mixed with 250 ml of benzene and the resulting mixture was stirred at the same temperature for 30 minutes. The crystals deposited were collected by filtration to obtain 65.5 g (yield: 88%) of N-[2-[(2-furyl)methylthio]ethyl]-O-(2-hydroxyphenyl)-N'-methanesulfonylisourea.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[NH3:29]>C(Cl)Cl>[CH2:2]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH2:29])=[O:27])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: N
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CC(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(CC(N)=O)cc1

Procedure:
A sample of (4-hexadecylaminophenyl)acetyl chloride hydrochloride is slurried in methylene chloride at 0° as anhydrous ammonia gas is bubbled in for one half hour. At the end of this time, the reaction mixture is washed with water and then aqueous sodium bicarbonate. The organic phase is then dried, filtered and evaporated, providing 2-(4-hexadecylaminophenyl)acetamide.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([C:41]([F:44])([F:43])[F:42])[CH:35]=1)[CH2:18][N:19]([CH2:32][CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH2:32][CH3:33])=[CH:35][C:36]=1[C:41]([F:42])([F:43])[F:44]
Reactant: CCN(C[C@@H](N)c1ccc(Cl)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CCNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Compound 33 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-chloro-3-trifluoromethyl-phenyl)-ethyl]-N-ethyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a beige solid. LC/MS [439 (M+H)]; 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.27 (s, 1H), 9.00 (d, J=4.5 Hz, 1H), 8.54 (s, 1H), 8.38 (d, J=4.5 Hz, 1H), 8.16 (s, 1H), 8.00 (d, J=1.8 Hz, 1H), 7.76 (dd, J=8.3, 1.9 Hz, 1H), 7.66 (d, J=8.3 Hz, 1H), 5.51 (s, 1H), 3.17 (dd, J=12.4, 8.0 Hz, 1H), 3.00 (dd, J=12.4, 5.6 Hz, 1H), 2.60-2.55 (m, 2H), 2.54 (s, 1H), 0.97 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=O)C1C=CC=CC=1>C(O)C.[Pd].C(OCC)(=O)C>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][O:14][CH2:13][CH2:12][NH2:11]
Reactant: COCCOCOCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCOCCN
Reaction time: 8 h

Procedure:
N-Benzyloxycarbonyl-O-(2-methoxyethoxymethyl)ethanolamine (6.25 g, 22.0 mmol) was dissolved in ethanol (10 ml) and placed under a blanket of argon. A slurry of 10% palladium on charcoal (1 g) in ethyl acetate was added and hydrogen gas was bubbled through the suspension for 3 hours and then the mixture was placed under hydrogen atmosphere overnight. TLC indicated that some starting material still remained so a further batch ofcatalyst (1 g) was added and hydrogenation was allowed to continue for a further 6 hours, after which all the starting material had been consumed. The catalyst was removed by filtration and the filtrate was used directly in Example 1 h (product volatile).