Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27]1[C:28](=O)[C:29](=[O:34])[C:30]=1[O:31]CC)[CH3:25]>>[C:1]1([CH2:7][O:8][C:9](=[O:23])[NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:28]2[C:29](=[O:34])[C:30](=[O:31])[C:27]=2[O:26][CH2:24][CH3:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)CNCCCNC(=O)OCc1ccccc1
Product: CCOc1c(N(CCCNC(=O)OCc2ccccc2)CC(=O)OC(C)(C)C)c(=O)c1=O
Yield: 90.6 %

Procedure:
An ethanolic solution (60 mL) of [3-[[(1,1-dimethylethyloxycarbonyl)methyl]amino]propyl]carbamic acid phenylmethyl ester (4.49 g, 13.9 mmol) under nitrogen was added to 3,4-diethoxy-3-cyclobutene-1,2-dione (2.0 mL, 13 mmol) in the same solvent (60 mL) over 1 hour. After 3.5 more hours, the reaction mixture was preadsorbed onto silica gel and purified by flash chromatography (7.5 cm diameter, gradient elution with 30 to 60% ethyl acetate in petroleum ether) to afford [3-[[(1,1-dimethylethyloxycarbonyl)methyl]-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]propyl]carbamic acid phenylmethyl ester as a viscous colorless oil (5.26 g, 91%); MS (+CI): 447 (MH+, 100), 391 (38); 1H NMR (CDCl3, 400 MHz): δ 7.35 (m, 5H), 5.55, 4.97 (br m, NH), 5.10 (s, 2H), 4.75, 4.73 (q, J=7 Hz, 2H), 4.29, 3.99 (s, 2H), 3.74, 3.49 (t, J=6.5 Hz, 2H), 3.29-3.22 (m, 2H), 1.84-1.75 (m, 2H), 1.48, 1.47 (s, 9H), 1.45-1.40 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[NH:15][N:14]=[N:13][N:12]=2)=[CH:3]1.[H-].[Na+].Br[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21]>C1COCC1>[C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:14]1[N:15]=[C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[N:12]=[N:13]1)(=[O:21])[CH3:19]
Reactant: Cn1cc(-c2nnn[nH]2)c2ccccc21
Reactant: O=C(CBr)N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCCCC1n1nnc(-c2cn(C)c3ccccc23)n1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
5-(1-Methyl-1H-indol-3-yl)tetrazole (0.080 g, 0.402 mmol) was dissolved in dry THF (5 ml) and treated with sodium hydride (80%) (0.014 g, 0.441 mmol). When effervescence had ceased, 1-(bromoacetyl)piperidine (Bull. Soc. Chim. France 1964 5, 1063) (0.093 g, 0.422 mmol) in dry THF (2 ml) was added. After 1 h, a further amound of 1-(bromoacetyl)piperidine (0.047 g, 0.211 mmol) in dry THF (1 ml) was added. After a further 2 h, the reaction mixture was evaporated under reduced pressure to give a brown solid which was partitioned between CHCl3 and water. The organic layer was washed with NaHCO3 solution, and the combined aqueous layers were extracted with CHCl3. The combined organic layers were then dried (Na2SO4) and evaporated to give an off white foam which was dried in vacuo and then purified by silica-gel chromatography (pentane: EtOAc 1:1 as eluant) to give the title compound (D3 ) as a white solid (0.080 g, 61%)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:16]=4[CH3:15])[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)c1C

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-(2,3-dimethylphenyl)piperazine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=379 (M+ of free base). α[D]589 =-9.84 (c=0.75, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[C:19]([O:29][CH3:30])[CH:18]=2)[C:13](=[O:31])[CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([OH:28])([CH3:26])[CH3:27])=[C:19]([O:29][CH3:30])[CH:18]=3)[C:13](=[O:31])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2ccc(O)cc2=O)ccc1OCC(C)(C)O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1OCC(C)(C)O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-chloro-4-(chloromethyl)benzene (26.4 mg, 0.16 mmol), 4-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one Part C (50 mg, 0.16 mmol) and K2CO3 (67.9 mg, 0.49 mmol) in DMF (1.0 mL) was stirred at 100° C. for 90 min The mixture was cooled to RT, filtered and the filtrate was concentrated. The crude product was purified by prep-HPLC (C18 column/Water:MeOH:TFA 90:10:0.1 to 10:90:0.1 gradient) yielding the title compound D-2-4-(4-chlorobenzyloxy)-1-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)pyridin-2(1H)-one D-2 (30 mg, 41.2% yield) as white solid. LC/MS 430 (M+H)+, tR 0.93 min (method 5); 1H NMR (400 MHz, Chloroform-D) δ ppm 7.32-7.44 (4H, m), 7.24-7.28 (1H, m), 6.96 (1H, d, J=8.53 Hz), 6.80-6.91 (2H, m), 6.06-6.18 (2H, m), 5.03 (2H, s), 3.85 (5H, d, J=1.76 Hz), 1.35 (6H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=Cc1ccc(N2CCOCC2)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
A 100 mL round-bottom flask was charged with 2-fluoro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.82 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.840 g, 4.20 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.40 g, 11.3 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (10 mL), extracted with dichloromethane (3×10 mL). The organic layers were combined and washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.40 g (93% yield) of tert-butyl (2S)-4-[[2-fluoro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 394 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:28])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[O:13][CH:14]=1)=[O:7].Br[CH:30]([CH3:32])[CH3:31]>>[F:28][CH:2]([F:1])[O:3][C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[C:6]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH:30]([CH3:32])[CH3:31])[CH:16]=2)[O:13][CH:14]=1)=[O:7]
Reactant: CC(C)Br
Reactant: COc1ccc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)cc1O
Product: COc1ccc(-c2nc(CNC(=O)c3ccccc3OC(F)F)co2)cc1OC(C)C

Procedure:
Using the compound obtained in Example 321 and 2-bromopropane, white powdery 2-difluoromethoxy-N-[2-(3-isopropoxy-4-methoxyphenyl)oxazol-4-ylmethyl]benzamide was obtained following the procedure of Example 3.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=1[CH:10]=[O:11].Cl[CH2:18][C:19]1[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.CCOC(C)=O>[OH:7][C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:18][C:19]2[CH2:20][CH2:21][N:22]([CH3:31])[CH2:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]=1[CH:10]=[O:11]
Reactant: O=Cc1c(O)cccc1O
Reactant: CN1CCC(CCl)=C(c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(COc2cccc(O)c2C=O)=C(c2ccccc2)C1
Temperature: 50 °C
Yield: 26.6 %

Procedure:
To a suspension of K2CO3 (350 mg, 2.56 mmol) and 2,6-dihydroxybenzaldehyde (180 mg, 1.28 mmol) in DMF (3 ml) was added a solution of 4-(chloromethyl)-1-methyl-5-phenyl-1,2,3,6-tetrahydropyridine (140 mg, 0.64 mmol) in DMF (4 mL), the mixture was heated at 50° C. for 3 h, cooled to room temperature, and was diluted with EtOAc, organic layer was separated and aqueous layer was extracted with EtOAc. EtOAc layers were combined, washed with Sat. NaHCO3, brine, dried over Na2SO4, and was concentrated to give crude oil, which was purified by column (Hexane/EtOAc=1:1 followed by DCM/MeOH=90:10) to give 2-hydroxy-6-((1-methyl-5-phenyl-1,2,3,6-tetrahydropyridin-4-yl)methoxy)benzaldehyde (55 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 10.35 (s, 1H), 7.34 (m, 5H), 7.19 (dd, J=8.4, 8.0 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 6.16 (d, J=8.0 Hz, 1H), 4.45 (s, 2H), 3.20 (s, 2H), 2.68 (t, J=5.6 Hz, 2H), 2.47 (m, 2H), 2.42 (s, 3H); MS (ESI) m/z 324.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])#[N:2].[C:33](N1C=CN=C1)(N1C=CN=C1)=O.CO>C1COCC1>[C:1]([C:3]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)([CH:20]([CH3:22])[CH3:21])[CH2:4][CH2:5][CH2:6][N:7]([CH3:19])[CH2:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH3:33])=[O:13])#[N:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(C#N)(CCCN(C)CCc2ccccc2C(=O)O)C(C)C)cc1OC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CCN(C)CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To 331 mg (0.839 mmol) of 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile in 8.3 mL of benzene was added 226 mg (1.01 mmol) of palladium(II)acetate and the mixture was stirred for 72 h at 22° C. under nitrogen. The solution was transferred into a pressure flask, 10 mL of methanol was added and the mixture was treated with carbon monoxide at 40 psi for 24 h. After addition of 175 μL (1.26 mmol) of triethylamine, the mixture was filtered through a pad of celite and evaporated to give a crude mixture of 3au and 2-(3,4-dimethoxyphenyl)-2-isopropyl-5-(methyl(phenethyl)amino)pentanenitrile. In order to afford purification, a solution of 57 mg of the crude product was dissolved in 1 mL of methanol and treated with 63 μL of 10 N NaOH. After stirring for 1 h at 22° C., an additional 1264 of 10 N NaOH and 2 mL of methanol was added. The solution was heated to 50° C. then cooled to 22° C., evaporated and partitioned between ether and 0.5 N NaOH. The aqueous layer was acidified to about pH 6 with 12 N HCl then extracted with ethyl acetate (3×). The combined organic layers were dried (Na2SO4) and evaporated to give 2-(2-((4-cyano-4-(3,4-dimethoxyphenyl)-5-methylhexyl)(methyl)amino)ethyl)benzoic acid. The carboxylic acid was esterified by treating with 44 mg (0.24 mmol) of carbonyldiimidazole in 1 mL of THF for 3 h at 22° C. followed by addition of 8 mL of methanol and continued stirring for about 16 hours at 22° C. The solvent was evaporated and the residue was purified by flash chromatography on silica gel, eluting first with dichloromethane and then gradually increasing to 3% methanol/dichloromethane to give 3au. MS found M+H=453. Substitution of the ester group in the indicated ortho-position of the phenyl ring was confirmed by 1H NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][N:3]=1.[OH-].[Na+].O>CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][C:12](=[O:14])[CH:13]=2)=[CH:4][N:3]=1
Reactant: CC(=O)CCCC(=O)c1ccc(C)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C2=CC(=O)CCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A 72.2 g. portion of 1-(2-methyl-5-pyridinyl)hexan-1,5-dione was dissolved in 200 ml. of methanol and added to a solution containing 50 g. of sodium hydroxide in 500 ml. of water plus 100 ml. of methanol. The reaction mixture was stirred for one hour at room temperature and the methanol was then distilled off in vacuo at a low temperature. The remaining aqueous mixture was extracted four times with ether; the ether extracts were combined, dried over anhydrous sodium sulfate and filtered; and, the dried ether solution was stripped in vacuo to remove the ether and to yield 54 g. (82% yield) of 3-(2-methyl-5-pyridinyl)-2-cyclohexen-1-one. This 54 g. portion of 2-(2-methyl-5-pyridinyl)-2-cyclohexen-1-one was converted, as in Example C-3, to 36.0 g. (62% yield) of the corresponding oxime derivative, m.p. 171°-173° C. The 10 g. portion of this oxime was converted, as in Example D-3, to 6.4 g. of 5-(3-aminophenyl)-2-methylpyridine, m.p. 115°-116° C., using 8.5 ml. of acetic anhydride and 70 ml. of acetic acid and gaseous hydrogen chloride for one hour while heating the reaction mixture at 80°-90° C.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9]>O.C1COCC1>[CH:1]([N:4]([CH3:5])[S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19])([CH3:3])[CH3:2]
Reactant: CNC(C)C
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
A 250 mL round bottom flask was equipped with a magnetic stirrer. The flask was charged with isopropylmethylamine (0.85 g, 11.6 mmol) followed by THF (50 mL). The mixture was cooled to 0° C. by placing the flask in an ice bath. Potassium hydroxide (23.2 mmol) was dissolved in water (20 mL) and added to the flask. An addition funnel was installed and charged with 3-nitrobenzenesulfonyl chloride (11.6 mmol) in THF (40 mL). The solution was added dropwise over 20 minutes, then the ice bath was removed. TLC (dichloromethane) indicated that the reaction was complete after addition of the 2-nitrobenzenesulfonyl chloride. The reaction was concentrated under diminished pressure, water (100 mL) was added, the mixture extracted with ethyl acetate (150 mL), dried (Na2SO4), and filtered. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and loaded onto a plug of silica gel (400 g in a 600 mL sintered glass funnel), and eluted with dichloromethane. Fractions were taken (100 mL) until the product eluted, as determined by TLC. Fractions containing the product were collected, and the solvent was removed in vacuo to yield N-(isopropyl)-N-(methyl)-3-nitrobenzenesulfonamide as a pale yellow, crystalline solid. 2.38 g, (79%). 1H-NMR (CDCl3): δ 1.03-1.05 (d, 6H, J=6.7 Hz); 2.78 (s, 3H); 4.23-4.32 (m, 1H, J=6.7 Hz); 7.70-7.76 (t, 1H, J=8.0 Hz); 8.13-8.15 (d, 1H, J=6.8 Hz); 8.40-8.43 (d, 1H, J=8.2 Hz); 8.64 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].[OH-].[K+:17]>CO>[K+:17].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:11](=[O:12])[C:10]([O-:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(=O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To a mixture of 4-bromobenzaldehyde (35.0 g, 189.0 mmol) and pyruvic acid (15.8 mL, 227.0 mmol) in methanol (100.0 mL), was slowly added a solution of potassium hydroxide (19.0 g, 340.0 mmol) in methanol (100.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The resulting solid was washed with diethyl ether to give 48.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[C:5]([CH3:15])[N:6]2[CH2:11][C:12]([OH:14])=[O:13].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:4]2[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[N:34]3[CH2:33][CH2:32][N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:36][CH2:35]3)[N:6]([CH2:11][C:12]([OH:14])=[O:13])[C:5]=2[CH3:15])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Sc2ccc(Cl)cc2)c2c(Br)cccc2n1CC(=O)O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(Sc2ccc(Cl)cc2)c2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1CC(=O)O
Temperature: 110 °C

Procedure:
To a dry flask was charged the product from example 22 part (ii) (1 g), N-tert-Butoxycarbonylpiperazine (0.48 g), Pd2(dba)3 (3 mg), 2,2′-bis(diphenylphosphino)-1,1′-binapthyl Binap (10 mg) and toluene (5 ml). The reaction was heated to 110° C. for 1 hour then allowed to cool. The mixture was diluted with EtOAc, washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified using Flash column chromatography (eluent 25% EtOAc/Hexane then 50% EtOAc/Hexane/1% Acetic acid). Further purification using reverse phase preparative HPLC (eluent MeCN/NH3 (aq)) gave titled compound (0.021 g).
Reaction SMILES: [CH2:1]([O:3][CH:4](OCC)[CH2:5][O:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[SH:18]CCO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:7]([O:6][CH2:5][CH:4]1[S:18][CH2:2][CH2:1][O:3]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCS
Reactant: CCOC(COC(=O)c1ccccc1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OCC1OCCS1)c1ccccc1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 5-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a Dean-Stark apparatus, and a glass stopper is added 2-(benzoyloxy)acetaldehyde diethyl acetal (0.469 mol, 111.85 g, 1.0 equiv.), 2-mercaptoethanol (0.516 mol, 40.34 g, 1.1 equiv.), para-toluenesulfonic acid monohydrate (0.047 mol, 8.92 g, 0.1 equiv.) and toluene (3.5 L). The reaction was heated to reflux and stirred while monitoring progress by TLC. When determined to be complete, the reaction was allowed to cool to ambient temperature before washing with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give (+/−)-2-(benzoyloxymethyl)-1,3-oxathiolane as an oil (95.75 g, 90.9% yield). The crude product was advanced to the next reaction step without further purification.
Reaction SMILES: COC1C=CC([O:9][C:10](=O)[NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:19]([CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:20]4[C:25]([C:26]=3[C:27]#[N:28])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][O:32][CH3:33])[CH:21]=4)=[CH:14][CH:13]=2)=CC=1.[CH3:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[C:27]([C:26]1[C:25]2[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][O:32][CH3:33])=[CH:23][CH:24]=2)[N:19]([CH:34]2[CH2:35][CH2:36][CH2:37]2)[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:10]([N:43]2[CH2:44][CH2:45][CH:40]([CH3:39])[CH2:41][CH2:42]2)=[O:9])=[CH:13][CH:14]=1)#[N:28]
Reactant: CC1CCNCC1
Reactant: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)Oc4ccc(OC)cc4)cc3)n(C3CCC3)c2c1
Solvent: ClCCl
Product: COCCOc1ccc2c(C#N)c(-c3ccc(NC(=O)N4CCC(C)CC4)cc3)n(C3CCC3)c2c1
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a solution of {4-[3-cyano-1-cyclobutyl-6-(2-methoxy-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 4-methoxy-phenyl ester (40 mg, 0.082 mmol) in DCM (4 mL) is added 4-methylpiperidine (0.16 mmole) and the reaction is stirred for 18 h at reflux temperature. The solvent is removed under reduced pressure. The residue is dissolved in EtOAc and then triturated with hexane. The precipitate is collected by filtration and washed with 50% EtOAc/hexane and dried in vacuo to afford 4-methyl-piperidine-1-carboxylic acid {4-[3-cyano-1-cyclobutyl-6-(2-methoxyethoxy)-1H-indol-2-yl]-phenyl}-amide, compound 1377, (26 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[NH:7][C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:20]Br>CN(C)C=O>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:20][N:7]1[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11]
Reactant: COc1ccc2c(c1)OCC(=O)N2
Reactant: Clc1cc(Br)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OCC(=O)N2Cc1cc(Cl)cc(Br)c1
Reaction time: 1 h
Yield: 84 %

Procedure:
0.5 grams of 7-methoxy-1,4-benzoxazin-3-one (2.8 mmole) was dissolved in 10 ml of dimethylformamide and cooled in an ice bath. 0.17 grams (3.5 mmole) of sodium hydride (60% wt. inn oil) was added, and after 5 minutes 0.8 grams (2.9 mmole) of 3-bromo-5-chloro-benzylbromide was added all at once. The mixture was stirred at ice bath temperature for 1 hour, and then quenched by addition of 1% hydrochloric acid. The product was extracted with ethyl acetate, that was evaporated under reduced pressure to give an oil which was chromatographed via medium pressure eluting with 10% ethyl acetate in hexanes to yield 0.9 grams of 4-(3-bromo-5-chloro-benzyl)-7-methoxy-4H-benzo[1,4]oxazin-3-one as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7](=[O:12])(=[O:11])[N:8]([CH3:10])[CH3:9])=[C:5]([S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])[C:4]([CH3:19])=[N:3]1.[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([CH3:29])[N:22]=1>>[CH3:28][O:27][C:25]1[CH:24]=[C:23]([CH3:29])[N:22]=[C:21]([NH:20][C:17]([NH:16][S:13]([C:5]2[C:4]([CH3:19])=[N:3][N:2]([CH3:1])[C:6]=2[S:7](=[O:11])(=[O:12])[N:8]([CH3:10])[CH3:9])(=[O:15])=[O:14])=[O:18])[N:26]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: Cc1nn(C)c(S(=O)(=O)N(C)C)c1S(=O)(=O)N=C=O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2c(C)nn(C)c2S(=O)(=O)N(C)C)n1

Procedure:
From the compound as prepared above, following the procedures of Examples 1 and 2, there was synthesized 1,3-dimethyl-5-dimethylsulfamoylpyrazole-4-sulfonyl isocyanate, which was in turn allowed to react with 2-amino-4-methoxy-6-methylpyrimidine to obtain the title compound. m.p. 215°-217° C.,
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10](Br)[CH2:9]1)=O)(C)(C)C.[C:16]([NH2:24])(=[S:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([C:16]2[S:23][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[N:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reactant: NC(=S)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3c(s2)CNCC3)cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of 1-tert-butoxycarbonyl-3-bromopiperidin-4-one (8 g) and thiobenzamide (3.4 g) in DMF was heated at 70 ° C. for 16 h, then cooled to room temperature. The solvent was evaporated in vacuo and the residue dissolved in water (100 ml) and washed with ether (100 ml), then basified with sodium hydroxide and extracted into ethyl acetate (3×100 ml). The solvent was dried (MgSO4) and evaporated to give the title compound as cream solid (2.81 g, 53% based on thiobenzamide used).