Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7]1([S:13]([CH2:16][C:17]2[O:18][C:19]([C:22]([F:25])([F:24])[F:23])=[N:20][N:21]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:26]1(=[O:31])[CH2:30][CH2:29][CH:28]=[CH:27]1>C1COCC1.[NH4+].[Cl-]>[C:7]1([S:13]([CH:16]([C:17]2[O:18][C:19]([C:22]([F:24])([F:25])[F:23])=[N:20][N:21]=2)[CH:28]2[CH2:29][CH2:30][C:26](=[O:31])[CH2:27]2)(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cc1nnc(C(F)(F)F)o1)c1ccccc1
Reactant: O=C1C=CCC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: O=C1CCC(C(c2nnc(C(F)(F)F)o2)S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 0.1 %

Procedure:
At 0° C. 170 mg (0.5 mmol, 0.2 eq) of Cs2CO3 were added to a stirred solution of 760 mg (2.6 mmol) of 2-benzenesulfonylmethyl-5-trifluoromethyl-[1,3,4]oxadiazole in 30 mL of THF. After 45 min, 0.23 mL (2.9 mmol) of 2-cyclopenten-1-one were added. The reaction mixture was stirred at RT for 15 hours, diluted with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. Column chromatography on silica gel with heptane/EtOAc 1:1 yielded 0.88 mg (90%) of 3-[benzenesulfonyl-(5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-methyl]-cyclopentanone as colorless foam, 375 (MH+).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][N:21]1S(C1C=CC(C)=CC=1)(=O)=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[NH4+].[Cl-].C(Cl)Cl>CO>[Si:1]([O:18][CH2:19][CH:20]1[CH2:26][CH:25]2[CH:23]([CH2:24]2)[CH2:22][NH:21]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC3CC3CC2CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)[Si](OCC1CC2CC2CN1)(c1ccccc1)c1ccccc1
Temperature: 23 °C
Yield: 75.2 %

Procedure:
To a solution of 4-(((tert-butyldiphenylsilyl)oxy)methyl)-3-tosyl-3-azabicyclo[4.1.0]heptane (D12) (3.12 g, 6 mmol) in MeOH (430 ml), under a nitrogen atmosphere, magnesium turnings (previously flame dried) (8.46 g, 348 mmol) and NH4Cl (8.9 g, 168 mmol) were added sequentially and the mixture was stirred at 23° C. Two further additions of magnesium (4.3 g), each one after 2 hrs stirring, were done. DCM (210 ml) and NH4Cl sat. sol. (285 ml) were added to the reaction mixture. The formed emulsion was filtered through a celite pad. The organic layer was separated and washed with brine (2×55 ml). The combined organic layers were evaporated and the resulting residue was purified by SPE-SCX (20 g) cartridge. Collected ammonia fractions after solvent evaporation afforded the title compound (D13) (1.65 g).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11](=[O:19])[NH:10][CH:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]1=[O:28])(=O)C.[OH-].[Na+].Cl.N1C=CN=C1.[Si:37](Cl)([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]>O1CCCC1.C(OCC)(=O)C.CO>[Si:37]([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11](=[O:19])[NH:10][CH:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:8]1=[O:28])([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(=O)OCCN1C(=O)C(Cc2ccccc2Cl)NC(=O)c2cc(Cl)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN1C(=O)C(Cc2ccccc2Cl)NC(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2-(7-chloro-3-(2-chlorobenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)ethyl acetate (0.62 g, 1.47 mmol) suspended in tetrahydrofuran (10 mL) was added 2M aqueous sodium hydroxide (2.2 mL, 4.4 mmol). Methanol (2 mL) was added, which caused the solution to become homogeneous. The solution was stirred at ambient temperature for 2 hours, then acidified with 1M hydrochloric acid, partitioned between ethyl acetate and brine, separated, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting solid was dissolved in N,N-dimethylformamide (10 mL), and imidazole (0.14 g, 2 mmol) was added followed by tert-butyldimethylsilyl chloride (0.24 g, 1.6 mmol). This mixture was stirred at ambient temperature overnight, then diluted with ethyl acetate, washed with 10% citric acid, water, and brine, dried with sodium sulfate, filtered and concentrated in the presence of silica gel. The product was purified by column chromatography eluting with a gradient of 0-50% ethyl acetate in hexanes to yield 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:24](O)=[O:25])[C:14]3[C:15]([CH3:23])=[CH:16][N:17]([CH:20]([CH3:22])[CH3:21])[C:18]=3[CH:19]=2)[CH2:7][CH2:6]1)[CH3:3].[NH2:27][CH2:28][C:29]1[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=1[CH3:35].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:24]([C:13]1[C:14]2[C:15]([CH3:23])=[CH:16][N:17]([CH:20]([CH3:21])[CH3:22])[C:18]=2[CH:19]=[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7]2)[CH:12]=1)=[O:25]
Reactant: Cc1cn(C(C)C)c2cc(N3CCC(CN(C)C)CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCC(CN(C)C)CC3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 61.1 %

Procedure:
To a solution of 6-{-4-[(dimethylamino)methyl]-1-piperidinyl}-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylic acid (62 mg, 0.173 mmol) in dimethyl sulfoxide (1 mL) were added 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (42.5 mg, 0.225 mmol), N-methylmorpholine (0.095 mL, 0.867 mmol), 1-hydroxy-7-azabenzotriazole (47.2 mg, 0.347 mmol) and EDC (66.5 mg, 0.347 mmol), and the mixture was stirred overnight. The mixture was purified using reverse-phase HPLC (Gemini 5u C18(2) 100A, AXIA; 30×100 mm 5 micron; 30 mL/min, 8% ACN/H2O, 0.1% formic acid to 38% ACN/H2O, 0.1% formic acid) to give the title compound (52 mg, 55%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.26 (m, 2H), 1.35-1.41 (m, 6H), 1.57-1.71 (m, 1H), 1.80 (d, J=11.12 Hz, 2H), 2.10 (d, J=10.36 Hz, 6H), 2.22 (s, 3H), 2.26-2.33 (m, 8H), 2.57-2.72 (m, 2H), 3.61 (d, J=12.13 Hz, 2H), 4.31 (d, J=5.05 Hz, 2H), 4.58-4.72 (m, 1H), 5.86 (s, 1H), 6.69 (d, J=2.02 Hz, 1H), 6.92 (d, J=1.77 Hz, 1H), 7.05 (d, J=1.01 Hz, 1H), 7.92-7.99 (m, 1H). MS: (M+H)+=492.1.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:12]([O:14]C)=O)=[C:5]([N:9]=[C:10]=[S:11])[S:6][C:7]=1[CH3:8])[CH3:2].[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>>[CH2:1]([C:3]1[C:4]2[C:12](=[O:14])[N:24]([CH2:23][CH2:22][CH2:21][N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)[C:10](=[S:11])[NH:9][C:5]=2[S:6][C:7]=1[CH3:8])[CH3:2]
Reactant: NCCCn1ccnc1
Reactant: CCc1c(C)sc(N=C=S)c1C(=O)OC
Product: CCc1c(C)sc2[nH]c(=S)n(CCCn3ccnc3)c(=O)c12

Procedure:
The compound was synthesized starting from methyl 4-ethyl-2-isothiocyanato-5-methylthiophene-3-carboxylate (0.010 g. 0.04 mmol) and 3-(1H-imidazol-1-yl)propan-1-amine (0.005 g, 0.04 mmol) as described above.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29].[CH2:31]([N:33](C(C)C)C(C)C)C.Cl.CN>CN(C)C=O>[F:1][C:2]1([F:30])[CH2:8][N:7]([CH:9]([CH3:11])[CH3:10])[C:6]2[N:12]=[C:13]([NH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH:33][CH3:31])=[O:23])=[CH:19][C:18]=3[O:26][CH3:27])[N:14]=[CH:15][C:5]=2[N:4]([CH3:28])[C:3]1=[O:29]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C(C)C)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Nc2ncc3c(n2)N(C(C)C)CC(F)(F)C(=O)N3C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 0.08 g (0.19 mmole) of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-292), 0.13 mL (0.76 mmole) of ethyldiisopropyl amine and 0.014 g (0.21 mmole) of methylamine hydrochloride in 2.0 mL of dimethylformamide was added 0.082 g (0.21 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.082 g of 4-(7,7-difluoro-9-isopropyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-295) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:26][OH:27])=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1.[Si:35](OC[C@@H](NC(=O)OC1C=CC([N+]([O-])=O)=CC=1)CC1CCCCC1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].ClC1C=C([C@]([C@@H]2CCCNC2)(O)CCCCOC)C=CC=1>>[Si:35]([O:27][CH2:26][C@@H:25]([NH:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])[CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CC1CCCCC1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO)CC2CCCCC2)C1
Agent: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Product: COCCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC2CCCCC2)C1

Procedure:
(3R)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)-N-((S)-3-cyclohexyl-1-hydroxypropan-2-yl)piperidine-1-carboxamide (I-158A) was prepared by applying analogous procedures to those described in Example 32 Step 1 to (S)-4-nitrophenyl 1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-ylcarbamate and (S)-1-(3-chlorophenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol to afford (R)-N-((S)-1-(tert-butyldimethylsilyloxy)-3-cyclohexylpropan-2-yl)-3-((S)-1-(3-chlorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamide followed by removal of the t-butyldimethylsilyl group with aqueous acid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:20])[F:19])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccncc3)c1)=N2
Yield: 71.6 %

Procedure:
Prepared from {5-dimethylamino-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M2) (284 mg, 0.52 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (158 mg).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([OH:19])=O)=[N:12][C:11]([NH:20][C:21]1[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=1)=[CH:10]2>>[CH3:2][N:3]([CH3:4])[C:17]([C:13]1[C:14]2[C:9](=[CH:8][C:7]([O:6][CH3:5])=[CH:16][CH:15]=2)[CH:10]=[C:11]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:12]=1)=[O:19]
Reactant: COc1ccc2c(C(=O)O)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CNC
Agent: Cl
Product: COc1ccc2c(C(=O)N(C)C)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 317 was used, starting from dimethyl-amine hydrochloride and 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid to give 6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-1-carboxylic acid dimethylamide. LC-MS: m/e 326 (MH+).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][C@@H:3]12.C[CH2:32][N:33](C(C)C)C(C)C.Cl.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[CH3:32][NH:33][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:14][CH2:15]2)=[N:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51 %

Procedure:
(S)-6-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (100 mg, 0.245 mmol) was suspended in DMF (1.5 mL) and DIPEA (0.3 mL) was added followed by methylamine hydrochloride (27 mg, 0.400 mmol) and HATU (200 mg, 0.526 mmol). The reaction mixture was stirred at ambient temperature for 4 h and diluted with MeOH (2 mL). The solution was purified using HPCL (25-95% acetonitrile in water, NH4HCO3 buffered). The fractions were concentrated in vacuo and the resulting residue was crystallized with MeOH—water (1:5, 15 mL) to afford the title compound as an off-white solid (52.3 mg, 51%). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 1.80-2.03 (m, 3H) 2.09-2.25 (m, 1H) 2.41 (br. s., 4H) 2.74 (d, J=4.29 Hz, 3H) 3.34-3.44 (m, 3H) 3.46-3.64 (m, 5H) 3.92-4.05 (m, 1H) 6.82 (d, J=9.09 Hz, 1H) 6.99 (d, 1H) 6.93-7.04 (m, 1H) 7.61 (s, 1H) 7.91 (dd, J=8.97, 2.15 Hz, 1H) 8.17-8.23 (m, 1H) 8.56 (d, J=1.77 Hz, 1H) 10.44 (s, 1H); [M+H] calc'd for C22H27N7O2, 422; found, 422.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:15][C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10])#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[CH:13]=[C:14]([CH2:25][NH:26][CH3:27])[CH:15]=[C:16]1[C:17]1[C:18]([C:23]#[N:24])=[N:19][CH:20]=[CH:21][CH:22]=1)(=[O:11])=[O:10])#[N:2]
Reactant: CN(Cc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C#N)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2C#N)n(S(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
tert-Butyl {[1-[(2-cyanophenyl)sulfonyl]-5-(2-cyanopyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (239 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 185 mg, yield 89%).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10]Cl)[N:9]=1)(=[O:3])[CH3:2].[CH:13]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:12])=[C:8]([CH2:10][N:29]2[CH2:30][CH2:31][N:26]([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCl)c(Cl)s1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c(Cl)s1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 40.3 %

Procedure:
A mixture of 2-acetamido-5-chloro-4-chloromethylthiazole (450 mg), 1-benzhydrylpiperazine (504 mg) and potassium carbonate (276 mg) in N,N-dimethylformamide (3 ml) was stirred at 70° C. for 20 minutes. After the reaction mixture was poured into ice-water, the precipitated crystals were collected by filtration, washed with water and then dried, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain crystals (355 mg) of 2-acetamido-5-chloro-4-(4-benzhydrylpiperazin-1-ylmethyl)thiazole, mp 227°-230° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2O[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:17]1[CH2:21][CH2:20][CH2:19][CH:18]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C>ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:18]3[CH2:19][CH2:20][CH2:21][C:17]=3[CH:15]=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: C1=CCCC1
Reactant: Fc1cc(-c2cnco2)ccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1Cl
Product: Fc1cc(-c2cncc3c2CCC3)ccc1C(F)(F)F
Yield: 43.8 %

Procedure:
A solution of 5-(3-fluoro-4-(trifluoromethyl)phenyl)-oxazole (0.50 g, 2.16 mmol), cyclopentene (2.95 g, 43.3 mmol) and trifluoroacetic acid (0.49 g, 4.33 mmol) in o-dichlorobenzene (12 mL) was heated under microwave irradiation to 220° C. for 6 h. To the reaction mixture was added triethylamine (5 mL) and the solvent mixture removed under reduced pressure. Purification by flash chromatography (70 g SiO2, Telos-cartridge) eluting with a 0 to 50% EtOAc/n-heptane gradient provided the title compound (266 mg, 44%) as a slightly brown solid. MS: 282.5 (M+H)+.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[H-].[Na+].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[C:19]=1F.Cl>CN(C=O)C.O>[C:11]([O:10][C:8]([NH:1][C@@H:2]([CH2:3][O:4][C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])[C:5]([OH:7])=[O:6])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(F)cccc1[N+](=O)[O-])C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
A solution of BOC-Ser-OH (2.58 g, 12.6 mmol) in DMF (10.00 mL) was added to a suspension of NaH (60% in mineral oil, 1.06 g, 26.4 mmol) in DMF (10 mL) at 0° C. over 10 min. After 1 h at 0° C. a solution of 1,2-difluoro-3-nitrobenzene (2 g, 12.6 mmol) in DMF (10 mL) was added and the mixture stirred at 0° C. for 2 h. The mixture was diluted with H2O and acidified to pH 3 with 1 N HCl, then extracted with EtOAc. The combined extracts were dried over MgSO4 and the filtrate was concentrated to give a residue that was purified by silica gel chromatography to afford (S)-2-(tert-butoxycarbonylamino)-3-(2-fluoro-6-nitrophenoxy)propanoic acid (2.94 g, 68%) as a yellow foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([C:22]([OH:24])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:25](=O)([O-])[O-].[Cs+].[Cs+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([C:22]([O:24][CH3:25])=[O:23])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2c1COC
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)OC)cc3c2c1COC
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
202 mg of 3-ethoxycarbonyl-4-methoxymethyl-β-carboline-6-carboxylic acid is combined in 15 ml of ethanol and 5 ml of water with 206 mg of cesium carbonate in 1.5 ml of water and stirred until a clear solution is obtained. The solution is then evaporated to dryness, taken up in 10 ml of dimethylformamide, 0.14 ml of methyl iodide is added, and the mixture is agitated at room temperature for 3 hours. After evaporation, the mixture is distributed in methylene chloride/saturated sodium chloride solution. The organic phase is dried, filtered, concentrated, and chromatographed over silica gel with methylene chloride/ethanol=6:1 as the eluent. After recrystallization of the corresponding fractions from ethanol/hexane, 92 mg of 6-methoxycarbonyl-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4](=O)[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O.O.[NH2:18][NH2:19]>C(O)C>[CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4]1[NH:19][N:18]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=1
Reactant: NN
Reactant: COC(OC)C(=O)CC(=O)c1ccccn1
Solvent: CCO
Solvent: O
Product: COC(OC)c1cc(-c2ccccn2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
To a stirred slurry of 4,4-dimethoxy-1-(pyridin-2-yl)butane-1,3-dione (9a) (5.11 g, 22.9 mmol) in ethanol (200 mL) was dropwise added hydrazine monohydrate (1.28 mL, 26.3 mmol). The reaction mixture was stirred at room temperature overnight and concentrated in vacuo. A saturated solution of sodium hydrogenocarbonate (30 mL) was added to the residue. The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-[5-(dimethoxymethyl)-1H-pyrazol-3-yl]pyridine (9b) (3.51 g, 16.0 mmol, 70%) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:12][N:13]1[C:17](Cl)=[C:16]([Cl:19])[C:15]([Cl:20])=[N:14]1.O>CS(C)=O>[CH3:12][N:13]1[C:17]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:16]([Cl:19])[C:15]([Cl:20])=[N:14]1
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Reactant: SCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cn1nc(Cl)c(Cl)c1SCc1ccc(Cl)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A stirred mixture of 10.3 g (0.065 moles) 4-chlorobenzyl mercaptan and 3.0 g (0.054 moles) potassium hydroxide in 50 ml dimethylsulfoxide was heated (at about 120° C.) for about 20 minutes. Then 10 g (0.054 moles) 1-methyl-3,4,5-trichloropyrazole were added. Heating (at about 120° C.) of the stirred reaction mixture was continued for about 4 hours. The reaction mixture was allowed to cool. The reaction mixture was added to water (about 50 ml); the resulting mixture was extracted with ether. The etheral phase was separated and dried over magnesium sulfate. The solvent was stripped and the residue was hard-topped. The product was purified by high pressure liquid chromatography to give 6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[NH:13][C:12]1=[O:22].[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[N:11]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:23])[C:12]1=[O:22]
Reactant: O=C([O-])[O-]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-n1ncc2c(Cl)cccc21
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-n2ncc3c(Cl)cccc32)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 168B (100 mg, 0.3 mmol), dry acetonitril (3 mL), potassium carbonate (0.05 g, 0.33 mmol) and methyl iodide (0.1 g, 0.7 mmol) is stirred overnight at room temperature. The solids are removed by filtration. The motherliquor is concentrated under reduced pressure. The residue obtained is purified by flash chromatography (ethyl acetate/petrol ether 3/7) which yields the product as an orange semi-solid (41 mg).