Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.[CH3:26][O:27][CH2:28][C:29](O)=[O:30].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH:20]1([CH2:19][CH2:18][CH2:17][C@@H:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH:1][C:29](=[O:30])[CH2:28][O:27][CH3:26])[N:7]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COCC(=O)O
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCC(=O)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of tert-butyl(3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (206 mg, 0.57 mmol) and methoxyacetic acid (48 μl, 0.63 mmol) in DCM (5 ml) was treated with a solution of WSCDI (120 mg, 0.63 mmol), HOBt (85 mg, 0.63 mmol) and NMM (69 μl, 0.63 mmol) in DCM (10 ml) and stirred at room temperature for 18 hours. The reaction mixture was washed with sat. NaHCO3 solution followed by brine, dried over MgSO4 and filtered. The solvent was removed under reduced pressure. The residue was purified on a silica column eluting with Et2O to afford the title compound as a colourless oil (230 mg, 93%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[N:20]=[C:2]([NH:21][C:22]3[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:27])=[CH:24][C:23]=3[O:38][CH3:39])[N:3]=[CH:4][C:5]1=2
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Reactant: CC(C)CCN1CC(C)C(=O)N(C)c2cnc(Cl)nc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CCC(C)C)CC(C)C(=O)N2C
Yield: 55 %

Procedure:
A solution of 0.05 g, (0.00017 mole) of (rac)-2-chloro-5,7-dimethyl-9-(3-methyl-butyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-27), 0.044 g, (0.00017 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.049 g, (0.00026 mole) of p-toluenesulfonic acid monohydrate and 4 mL of 2-propanol was heated at 180 degree for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75:25) to give 0.049 g of (rac)-4-[5,7-dimethyl-9-(3-methyl-butyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-27). HRMS (ES+) m/z Calcd for C28H41N7O2+H [(M+H)+]: 524.3344. Found: 524.3342.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](OC(=O)C)(=[O:30])[CH3:29].CC1C=CC=CC=1>CO>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(=O)N1CC(=O)N(C)C(=O)N1c1cc(Cl)c(C(C#N)c2ccc(Cl)cc2)c(Cl)c1
Reaction time: 90 h
Yield: 42.9 %

Procedure:
A mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4 methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)benzeneacetonitrile, 12 parts of acetic acid anhydride and 36 parts of methylbenzene was stirred for 90 hours at reflux temperature. After cooling, 16 parts of methanol were added. The solvent was evaporated in vacuo. The residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol. The precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.0 parts (42.9%) of 1-acetyl-2-[3,5-dichloro-4[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 178.1° C. (compound 78).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[C:1]1([CH2:7][CH2:8][S:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=2[O-:16])=[O:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1ccccc1SCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(CCc1ccccc1)c1cccc[n+]1[O-]

Procedure:
The procedure employed is identical to that of Example 68 using 2.8 gm (0.012 mol) 2-(2-phenylethylthio)pyridine N-oxide in 25 ml of chloroform with 2.4 gm (0.012 mol) MCPBA in 50 ml chloroform.
Reaction SMILES: [C:1]([O-:10])(=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Na+].Cl[CH2:13][CH2:14][CH2:15][Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([S:9][CH2:13][CH2:14][CH2:15][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC([O-])=S
Reactant: CCO[Si](CCCCl)(OCC)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: CCCCCCCC(=O)SCCC[Si](OCC)(OCC)OCC
Temperature: 25 °C

Procedure:
The aqueous solution of sodium thiooctanoate was heated to 80° C. and stirred with a mechanical stirrer throughout this procedure. To this solution was added, all at once, 4 grams of a concentrated aqueous solution of tetrabutylammonium bromide. Immediately thereafter was added a solution of 3-chloro-1-propyltriethoxysilane (120 grams, 0.5 moles). This mixture was kept at 80° C. with continued stirring for 6 hours, and then allowed to cool to ambient temperature. After cooling to ambient temperature, the organic phase was separated from the aqueous phase. Gas chromatography and mass spectrometry (GC and GCMS) revealed a product containing 93% 3-octanoylthio-1-propyltriethoxysilane. Product identity using this process confirmed by nuclear magnetic resonance spectroscopy (NMR).
Reaction SMILES: [CH3:1][C:2]1([C:18]([OH:20])=O)[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[C:16]([CH3:17])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:55][O:56][C:57]1[CH:58]=[C:59]([CH:61]=[CH:62][CH:63]=1)[NH2:60]>CN(C=O)C>[CH3:55][O:56][C:57]1[CH:58]=[C:59]([NH:60][C:18]([C:2]2([CH3:1])[CH2:7][CH2:6][N:5]([C:8]3[C:9]4[C:16]([CH3:17])=[CH:15][NH:14][C:10]=4[N:11]=[CH:12][N:13]=3)[CH2:4][CH2:3]2)=[O:20])[CH:61]=[CH:62][CH:63]=1
Reactant: COc1cccc(N)c1
Reactant: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(NC(=O)C2(C)CCN(c3ncnc4[nH]cc(C)c34)CC2)c1
Reaction time: 8 h
Yield: 328.5 %

Procedure:
To a solution of 4-methyl-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4yl)-piperidine-4-carboxylic acid from step B (0.020 g, 0.073 mmol) in DMF (1 mL) were added BOP reagent (0.065 g, 0.15 mmol), triethylamine (0.019 mL, 0.15 mmol), and 3-methoxyaniline (0.012 mL, 0.11 mmol). The reaction was stirred overnight, and then concentrated under vacuum. The residue was purified by prep HPLC to give the title compound (0.091 g, 33%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[CH2:6].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>Cl.C(OCC)C>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1)[CH:5]=[CH2:6]
Reactant: C=Cc1ccc(O)c(O)c1
Reactant: C1=COCCC1
Agent: Cl
Solvent: CCOCC
Product: C=Cc1ccc(OC2CCCCO2)c(OC2CCCCO2)c1
Temperature: 40 °C
Reaction time: 12 h

Procedure:
To 100 g (0.73 mol) of the 3,4-dihydroxystyrene prepared in a) are added 320 g (3.8 mol) of dihydropyran and a few drops of concentated hydrochloric acid. The reaction mixture is stirred for 12 h at 40° C. The solution is then diluted with diethyl ether and poured on to ice. The organic phase is washed twice at 0° C. with 1N NaOH, dried, and treated with activated carbon. After filtration and concentration of the filtrate there is obtained a colourless viscous liquid which is chromatographed over a column of silica gel with a 4:1 mixture of hexane/ethyl acetate.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:38][CH3:39])[C:26]([NH:35][C:36]#[N:37])=[N:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)C.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOC(C)=O.O>[CH2:28]([N:27]=[C:26]([NH:35][C:36]#[N:37])[N:25]([CH2:24][C:15]1[CH:16]=[C:17]([C:20]([F:22])([F:23])[F:21])[CH:18]=[CH:19][C:14]=1[C:8]1[C:9]([O:12][CH3:13])=[CH:10][CH:11]=[C:6]([CH2:5][C:4]([OH:40])=[O:3])[CH:7]=1)[CH2:38][CH3:39])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccccc2)NC#N)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1OC)C(=NCc1ccccc1)NC#N

Procedure:
[2′-(N′-Benzyl-N″-cyano-N-ethyl-guanidinomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.055 g, 0.1 mmol) in TIFF (2 mL) and H2O (0.5 mL) was treated with lithium hydroxide (0.02 g, 0.5 mmol), and the reaction was monitored by analytical LCMS. Once no starting material was seen, the mixture was diluted with EtOAc and H2O. Citric acid was added to neutralize the solution to pH 3, and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated twice from CH2Cl2 to give the title compound. M+H is 525.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[S:16][C:17]([C:20]([CH3:41])([CH3:40])[CH2:21][O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18][N:19]=1)(C)(C)C>C(Cl)Cl>[C:36]([Si:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:22][CH2:21][C:20]([C:17]1[S:16][C:15]([NH2:14])=[N:19][N:18]=1)([CH3:41])[CH3:40])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)Nc1nnc(C(C)(C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1nnc(N)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.4 %

Procedure:
A 10% solution of TFA in DCM (720 mL) is added at 0° C. to a solution of {5-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-1,3,4-thiadiazol-2-yl}-carbamic acid tert-butyl ester (12.0 g, 23.4 mmol) in DCM (800 mL). The reaction mixture is stirred at room temperature for 14 h. The solvent is removed under reduced pressure and the crude purified by column chromatography to afford 8.8 g of 5-[2-(tert-butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-1,3,4-thiadiazol-2-ylamine as a viscous liquid. Yield: 91%; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.05 (9H, s), 1.30 (6H, s), 3.60 (2H, s), 7.30-7.50 (6H, m), 7.50-7.70 (4H, m), 9.00 (2H, s); m/z 412 [M+H].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][CH2:14][CH2:15][NH2:16])[CH3:12].ClCCl>C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: CCOCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOCCNc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
According to the method of R. Iemura et al., J. Med. Chem., 29 1178-1183 (1986), combine 1-chloro-2-nitrobenzene (69.0 g, 440 mmol) and 2-aminoethyl ethyl ether (102.5 g, 1.15 mol) and heat to reflux. After 18 hours, cool and dilute the reaction mixture with ethyl acetate (400 mL). Extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give N-(2-ethoxyethyl)-2-nitroaniline.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20]OS(C)(=O)=O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:28][NH:29][CH2:30][CH2:31][OH:32]>>[CH3:28][N:29]([CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:27])([F:1])[F:26])=[CH:8][CH:7]=3)=[N:10][S:11][C:12]=2[CH:17]=1)[CH2:30][CH2:31][OH:32]
Reactant: CNCCO
Reactant: CS(=O)(=O)OCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: CN(CC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1)CCO

Procedure:
In analogy to example 17.1, Methanesulfonic acid 3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl ester and 2-Methylaminoethanol were converted to yield 2-(Methyl-{3-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-prop-2-ynyl}-amino)-ethanol as light brown oil, MS: 391 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([OH:8])=[C:6]([F:9])[CH:5]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.10 mmol) and NCS (155 mg, 1.16 mmol) in THF (30 mL) according to method C to yield 264 mg (78%) of grey solid: mp 209-210° C.; 1H NMR (DMSO-d6): δ 7.32 (1H, d, J=8.89 Hz), 7.50-7.61 (2H, m), 7.83 (1H, d, J=8.96 Hz), 7.92 (1H, dd. J=8.94 Hz, J=1.59 Hz), 8.05 (1H, d, J=8.88 Hz), 8.22 (1H, d, J=1.19 Hz), 10.36 (1H, s), 10.54 (1H, s); MS (ESI) m/z305/307 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOCCOCCBr
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: [CH2:1]([C@@H:4]([C@H:12]([CH2:17][N:18]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:13]([O:15][CH3:16])=[O:14])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:2]=C.[O:36]=[O+][O-].CSC>ClCCl>[CH2:29]([N:18]([CH2:17][C@@H:12]([C@H:4]([CH2:1][CH:2]=[O:36])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])[C:13]([O:15][CH3:16])=[O:14])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C=CC[C@H](C(=O)OC(C)(C)C)[C@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)C(=O)OC
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)[C@@H](CN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@H](CC=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a stirred solution of 4-methyl 1-tert-butyl(2S,3R)-2-allyl-3-({benzyl[(benzyloxy)cabonyl]amino}methyl)butanedioate (2.336 g, 4.851 mmol) in dichloromethane (97 mL) at −78° C. was bubbled ozone. After the solution turned blue, ozone bubbling continued for additional 15 min. Nitrogen was then bubbled into the mixture until the blue color disappeared. The reaction was quenched with dimethyl sulfide (1.78 mL, 24.26 mmol) and the solution was stirred at rt for 2 h. The solvent was removed under reduced pressure and the residue was purified by Combiflash (15-25% EtOAc/hexane) to provide 1.853 g (79%) of 1-methyl 4-tert-butyl(2R,3S)-2-({benzyl[(benzyloxy)cabonyl]amino}methyl)-3-(2-oxoethyl)butanedioate as a colorless viscous oil (1.853 g, 79% in yield). MS (ESI): 506.1 (M+Na+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9]\[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Reaction time: 0.03 h
Yield: 60.1 %

Procedure:
A 500 mL par shaker charged with ethyl (2Z)-3-(4-hydroxyphenyl)-3-phenylprop-2-enoate (1 g, 3.7 mmol) in Ethanol/Ethyl acetate was degasified with nitrogen for 2 min. Added 10% of Pd/C (0.4 g, 10%) and applied 50 psi of H2 pressure for 3 h. Reaction mixture was filtered through celite pad and washed the pad with excess Ethanol. Organic phase was dried over anhydrous Na2SO4 and concentrated to afford oil as product. (0.6 g, Yield: 60.1%); 1H NMR (300 MHz, DMSO-d6): δ 9.21 (s, 1H), 7.07-7.29 (m, 7H), 6.63-6.66 (d, 2H), 4.29-4.34 (t, 1H), 3.89-3.96 (q, 2H), 3.02-3.03 (d, 2H), 0.99-1.04 (t, 3H)
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:10])[C:4]1=[C:24]=[O:25])[CH3:2].[NH3:26]>>[CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:26])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:10])[C:4]1=[C:24]=[O:25])[CH3:2]
Reactant: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(=O)(=O)Cl)cc2)CC1C
Reactant: N
Product: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)CC1C
Reaction time: 0.5 h

Procedure:
To a cooled (0–5° C.) solution of chlorosulfonic acid (22.4 ml), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene (15 gm) was added in small portions over a period of 1 to 2 hrs. Further it was stirred for 30 minutes at this temperature and then temperature was gradually raised to 30 to 35° C. and stirred for 5 hrs. The reaction mixture was quenched into ice-water, and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (18.8 g). To a cooled (0–5° C.) solution of concentrated ammonia (100 ml), 4[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (10 gm) was added in small portions over 30 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then the reaction mixture was allowed to come to room temperature and then stirred for 5 hrs and filtered and dried to obtain 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonamide (7.9 gm) having HPLC purity of about 83 to 85%.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]3=2)[N:3]=1.[F-:18].[K+].C1OCCOCCOCCOCCOCCOC1>CN1C(=O)CCC1>[F:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:17])[N:6]=[C:7]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:8]3=2)[N:3]=1
Reactant: [F-]
Reactant: Cc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)nc(N)c1nc(F)ccc12
Temperature: 210 °C

Procedure:
A mixture of 3-chloro-8-methylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) (1.0 eq.) potassium fluoride (4.0 eq.), and 18-crown-6 (0.4 eq.) in NMP (0.1M) was heated in microwave reactor at 210° C. for 2 hours. After cooling to ambient temperature, the reaction residue was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-30% EtOAc/Hexanes to give 3-fluoro-8-methylbenzo[f][1,7]naphthyridin-5-amine as a white solid. 1H NMR (acetone-d6): δ 9.20 (dd, 1H), 8.32 (d, 1H), 7.58 (dd, 1H), 7.46 (d, 1H), 7.21 (dd, 1H), 6.51 (br s, 2H), 2.47 (s, 3H). LRMS [M+H]=228.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH:37]4[CH2:39][CH2:38]4)[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: O=CC1CC1
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CC4CC4)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(1-cyclopropylmethyl-piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using cyclopropanecarboxaldehyde instead of acetone and was obtained as a light brown oil. MS m/e: 578.2 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]([C:12](Cl)=[O:13])=[CH:5]2.N1C=CC=CC=1.[CH:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([S:28]([NH:31][C:32]2[S:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])[CH:22]=1>C(Cl)Cl>[S:36]1[CH:35]=[CH:34][N:33]=[C:32]1[NH:31][S:28]([C:23]1[CH:22]=[CH:21][C:26]([NH:27][C:12]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=3[Cl:11])=[O:13])=[CH:25][CH:24]=1)(=[O:30])=[O:29]
Reactant: Nc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=C(Cl)c1cc2cc(Cl)cc(Cl)c2[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1)c1cc2cc(Cl)cc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 5,7-dichloro-indole-2-carbonylchloride (186 mg, 0.75 mmol) in pyridine (0.8 mL, 1 mmol) and DCM (5.2 mL) was added N′-(2-thiazolyl)sulfanilamide (128 mg, 0.5 mmol) and the reaction mixture stirred at rt for 16 h. The resulting solid was filtered, washed with DCM (3×5 mL), and dried under vacuum overnight to provide the product (0.21 g; yield=90%) as a white-green solid. 1H-NMR (DMSO-d6) 12.78 (s, 1H), 12.33 (s, 1H), 10.67 (s, 1H), 7.97 (d, J=7.0 Hz, 2H), 7.82 (d, J=7.0 Hz, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.47 (s, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.27 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H). LC/MS (10-99%) M/Z: M+1 obs=467.0; tR=3.12 min.