Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][Si:2]([OH:4])=[O:3].[NH2:5][C:6]([NH2:8])=[O:7]>>[Si:2]([OH:7])([OH:4])([OH:1])[OH:3].[NH2:5][C:6]([NH2:8])=[O:7]
Reactant: O=[Si](O)O
Agent: NC(N)=O
Product: O[Si](O)(O)O

Procedure:
One mol by weight of metasilicic acid and one mol by weight of urea are mixed, heated to 95° to 150° C. for 20 to 60 minutes, until the reaction is substantially complete, thereby producing white granules of urea silicate. The said urea silicate is mixed into about one mol of acetoaldehyde in an aqueous solution and the urea silicate goes into solution. The unreacted metasilicic acid is filtered out. About 15% to 25% of said metasilicic acid is filtered out. The urea silicate formaldehyde solution is heated to 70° to 110° C. for 20 to 60 minutes, until the desired viscosity is obtained, thereby producing poly (formaldehyde urea silicate) resin. The resin may be produced as a thick clear resin or a solid, depending on the length of time the resin is heated.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])O)[CH2:10][CH2:9]1.[CH3:24][S:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][CH:33]=[CH:32]2>ClCCl>[CH:8]1([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[C:32]2[C:31]3[C:35](=[C:27]([CH2:26][S:25][CH3:24])[CH:28]=[CH:29][CH:30]=3)[NH:34][CH:33]=2)[CH2:10][CH2:9]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(C(F)(F)F)cc1F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(C(F)(F)F)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.66 ml (8.61 mmol) of trifluoroacetic acid was added to 1.68 g (7.18 mmol) of the compound from Example 148A and 1.27 g (7.18 mmol) of the compound from Example 8A in 80 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by flash chromatography on silica gel (mobile phase: toluene/ethyl acetate 98/2) and preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 80.0 mg (3% of theory) of the title compound.
Reaction SMILES: [CH:1]12[O:12][CH:4]([CH:5]3[C:10](=[O:11])[O:9][C:7](=[O:8])[CH:6]31)[CH:3]=[CH:2]2.[C:13]([O:17][CH2:18][CH2:19][OH:20])(=[O:16])[CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[C:10]([CH:5]1[CH:6]([C:7]([O:20][CH2:19][CH2:18][O:17][C:13](=[O:16])[CH:14]=[CH2:15])=[O:8])[CH:1]2[O:12][CH:4]1[CH:3]=[CH:2]2)([OH:9])=[O:11]
Reactant: C=CC(=O)OCCO
Reactant: O=C1OC(=O)C2C3C=CC(O3)C12
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCOC(=O)C1C2C=CC(O2)C1C(=O)O

Procedure:
Maleic anhydride (50 g) and furan (150 ml) were heated under reflux for 1 hour, and then the excess of furan was distilled off. The residue was recrystallised from chloroform, yielding 72 g of 7-oxabicyclo [2.2.1]hept-2-ene-5,6-dicarboxylic acid anhydride (m.pt. 110° C., decomp.). This anhydride (40 g) and 30.75 g of 2-hydroxyethyl acrylate were heated in 250 ml of toluene at 100° C. for 3 hours, and then the toluene was distilled off under reduced pressure, leaving the desired compound as a viscous liquid.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15].[Si:31]([CH2:38][O:39][CH2:40]/[CH:41]=[C:42](/[C:44]1[CH:49]=[CH:48][C:47]([C:50]2[CH:55]=[CH:54][C:53](/[C:56](/[CH3:60])=[CH:57]/[CH2:58]O)=[CH:52][CH:51]=2)=[CH:46][CH:45]=1)\[CH3:43])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>C1COCC1.O.C(OCC)(=O)C>[CH2:21]([O:20][C:18](=[O:19])[C@@H:17]([O:16][CH2:14][CH3:15])[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([O:30][CH2:58]/[CH:57]=[C:56](/[C:53]2[CH:54]=[CH:55][C:50]([C:47]3[CH:48]=[CH:49][C:44](/[C:42](/[CH3:43])=[CH:41]/[CH2:40][O:39][CH2:38][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])=[CH:45][CH:46]=3)=[CH:51][CH:52]=2)\[CH3:60])=[CH:28][CH:29]=1)[CH3:22]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(=C\CO)c1ccc(-c2ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(/C(C)=C/COC[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
Under a atmosphere of nitrogen, azodicarboxylic dipiperidide (0.91 g, 3.62 mmol) was added at 0–5° C. to a stirred solution of tributylphosphine (0.89 mL, 3.62 mmol), (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.60 g, 2.53 mmol) and (E)(E) 3-(4′-{3-[(tert-butyidimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-en-1-ol (1.02 g, 2.41 mmol) in dry THF (15 ml). The mixture was warmed to room temperature, and stirred for 18 h. The resulting mixture was diluted with water and ethyl acetate, the aqueous layer collected and further extracted with ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4) and evaporated. The crude product was then purified by column chromatography on silica using heptane/ethyl acetate (4:1) as eluent to give 1.18 g (76%) of (E)(E)(S) 3-{4-[3-(4′-{3-[(tert-butyldimethylsilanyl)-methoxy]-1-methylpropenyl}-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[C:36]([CH2:38][C:39](O)=[O:40])#[N:37].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([C:4]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[C:7]2[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:9]([C:39](=[O:40])[CH2:38][C:36]#[N:37])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)NCC2
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OCC)N(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a mixture of ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (1.00 g), cyanoacetic acid (0.36 g) and methylene chloride (20 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.82 g) at room temperature. The reaction mixture is stirred overnight at room temperature, and then washed with 2% aqueous hydrochloric acid and brine. The organic layer is dried and evaporated to remove the solvent. The crude residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl-5-cyanoacetyl-4,5,6,7-tetrahydroimidazo[4,5-c}pyridine-4-carboxylate (0.76 g) as white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8](Br)=[CH:9][CH:10]=1.[CH2:21]([Sn](CCCC)(CCCC)C(C)=C)[CH2:22][CH2:23]C>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>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[S:7][C:8]([C:22]([CH3:23])=[CH2:21])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@@H](Cc1ccc(Br)s1)NC(=O)OC(C)(C)C
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(C)c1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)s1
Yield: 63.4 %

Procedure:
15.0 g (41.17 mmol) of 3-(5-bromo-thiophen-2-yl)-2(R)-tert-butoxycarbonylamino-propionic acid methyl ester was treated with tributyl-isopropenyl-stannane (17.88 g, 54.07 mmol) and Pd(PPh3)4 (4.8 g, 4.15 mmol) as described in the general procedure M to afford 8.50 g of 2(R)-tert-butoxycarbonylamino-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:49][C:50]([CH3:52])=[CH2:51])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[C:13]2[C:18]([CH:19]=1)=[CH:17][C:16]([CH2:51][C:50](=[O:49])[CH3:52])=[CH:15][CH:14]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reactant: C=C(C)OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(=O)Cc1ccc2c(c1)cc(C(=O)OCc1ccccc1)n2Cc1ccc([N+](=O)[O-])cc1
Yield: 33.2 %

Procedure:
A solution of 5-bromo-1-(4-nitro-benzyl)-1H-indole-2-carboxylic acid benzyl ester (1.733 g, 3.72 mmol), tributyltin methoxide (1.79 g, 1.6 ml, 5.58 mmol), isopropenyl acetate (0.56 g, 0.61 ml, 5.58 mmol), palladium (II) acetate (41.5 mg, 0.19 mmol) and tri-o-tolylphosphine (113 mg, 0.37 mmol) in toluene (5 ml) was heated at about 95° C. under nitrogen for about 6 hours. The reaction solution was cooled, concentrated in vacuo, and subjected to flash chromatography on silica (105 g, 30% ethyl acetate/hexanes). The partially pure product was re-chromatographed on silica (12 g, 50% methylene chloride/hexanes) to give the title compound (547 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[H-].[Na+].[F:11][C:12]1[CH:24]=[CH:23][C:15]([CH:16]=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1.C(O)C>CN(C)C=O.O.C(O)(=O)C>[C:1]([CH:3]([CH:16]([C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:24][CH:23]=1)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)C=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccc(F)cc1)C(C#N)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
12.9 g of ethyl cyanoacetate dissolved in 18 mL of N,N-dimethylformamide was added dropwise to a mixture of 4.5 g of sodium hydride and 40 mL of N,N-dimethylformamide under cooling with ice, and after 1.5 hours of stirring at room temperature, a solution of 20 g of ethyl p-fluorocinnamate in 18 mL of N,N-dimethylformamide was added. The mixture was heated at 50 to 60° C. for 21 hours. 30 mL of absolute ethanol was added under cooling with ice, and then an ethanol solution of acetic acid was added. After addition of water, the reaction mixture was extracted with ethyl acetate, and the extract was dried, concentrated and separated by silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 23.9 g of diethyl 2-cyano-3-(p-fluorophenyl)glutarate as a diastereomer mixture.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][OH:22]>N1C=CC=CC=1>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1

Procedure:
Compound 22 was prepared using the method described for the synthesis of compound 18. The reagents used were as follows, p-toluene sulphonyl chloride (170.4 g, 0.894 mol.), pyridine (400 ml) and 2-(2'-(2"-methoxy ethoxy)ethoxy)ethanol (148.7 g, 0.907 mol.) (Aldrich). The final product was a pale yellow liquid (122 g, 42%): 1H-NMR (CDCl3), d (ppm) 7.3-7.7 (m, 4H aromatic), 3.3-4.2 (m, 12H) 3.35 (s, 3H), 2.4 (s, 3H). Mass spectroscopy, m/e: 318 M+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][N:30]([CH3:40])[C:31]1[NH:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[N:32]=1>>[CH3:29][N:30]([CH3:40])[C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:14][CH2:15][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:17][CH2:18]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1
Reactant: Cn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CN(C)c1nc2ccccc2[nH]1
Product: CN(C)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol and N,N-dimethyl-1H-benzo[d]imidazol-2-amine were reacted to give 188. LCMS m/z: 534.3 (MH+)
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[CH:16])[C:5]([O:7][CH3:8])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(N(CC)CC)C.[Cu](Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]#[C:16][C:36](=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: C#Cc1ccccc1C(=NOC)C(=O)OC
Reactant: O=C(Cl)c1ccccc1
Agent: Cl[Cu]Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CON=C(C(=O)OC)c1ccccc1C#CC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Under a nitrogen blanket and at 90° C., 2 g (9.2 mmol) of the acetylene derivative from Example 1 is added to a mixture of 50 mg of copper(II) chloride, 110 mg of palladium(II) acetate, 380 mg of triphenylphosphine and 2.6 g (18.4 mmol) of benzoyl chloride in 100 ml of triethylamine. After 30 minutes, the mixture is allowed to cool and the solid is filtered off. The filtrate is evaporaed down, and the residue is taken up in methyl tert-butyl ether, washed with water, dried and evaporated down. The residue is stirred with diethyl ether and the precipitated pale brown solid is filtered off. 2.0 g (68%) of compound 26, Table 6, remain. Mp. 89°-94° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([CH3:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:26]3[CH:27]=[C:28]([CH3:30])[CH:29]=[C:24]([CH3:23])[CH:25]=3)[CH2:32][CH2:33]2)=[S:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2ccccc2nc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 65 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 63 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.[O:27]=[C:28]=[N:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C(N(CC)CC)C>C1COCC1>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:28]([NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:27])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)CN=C=O
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)N1CC(NC(=O)c2ccccc2)CC(c2ccc(OC(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.19 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide were initially charged in 2.5 ml of THF, and 22 mg (0.19 mmol) of methyl N-(oxomethylidene)glycinate and 29 μl (0.21 mmol) of triethylamine were added. The mixture was stirred at RT overnight. The reaction mixture was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 76 mg (82% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[C:9](Br)[CH:10]=[CH:11][C:12]=3[F:16])[NH:7][C:6]=2[CH2:5][CH2:4]1.CO.[OH-].[K+]>[Pd].O>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[F:16])[NH:7][C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C)C1CCc2[nH]c3c(Br)ccc(F)c3c2C1
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C1CCc2[nH]c3cccc(F)c3c2C1

Procedure:
Following a procedure similar to that described in Example 234 but using 2 g. of 3-(dimethylamino)-8-bromo-5-fluoro-1,2,3,4-tetrahydrocarbazole (Example 219), in 100 ml. of methyl alcohol, 1 g. of 10% palladium on charcoal and 1 g. of potassium hydroxide in 2 ml. of water there was obtained, after recrystallization from benzene, 1.3 g. of 3-(dimethylamino)-5-fluoro-1,2,3,4-tetrahydrocarbazole, m.p. 166°-168°C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][C:14]([C:22](OCC)=[O:23])([C:17](OCC)=[O:18])[CH2:13][CH2:12]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH3:7][O:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][C:14]([CH2:22][OH:23])([CH2:17][OH:18])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(OCOC)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: COCOC1CCC(CO)(CO)CC1
Reaction time: 0.67 h
Yield: 87 %

Procedure:
1.76 g of lithium aluminum hydride was suspended in 90 ml of tetrahydrofuran and ice-cooled. Then 11.1 g of diethyl 4-(methoxymethoxy)cyclohexane-1,1-dicarboxylate dissolved in 30 ml of tetrahydrofuran was dropped thereinto. After stirring for 40 minutes, 1.8 ml of water, 1.8 ml of 15% sodium hydroxide and 5.4 ml of water were successively added thereto so as to decompose the excessive reagent. After further adding anhydrous sodium sulfate and celite, the reaction mixture was stirred at room temperature, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with dichlorometheane/methanol) to thereby give 6.84 g of the title compound as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH2:25][C:26]#[N:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[C:26]([CH2:25][O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:28])#[N:27]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2OCC#N)Cc2ccccc2C1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)c1OCC#N
Reaction time: 18 h
Yield: 99.5 %

Procedure:
A 100 mL flask containing 2-(2-cyanomethoxy-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (330, 0.25 g, 0.66 mmol) is charged with 1,4-dioxane (2 mL) and MeOH (2 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1 mL) is added followed by the LiOH monohydrate (71 mg, 1.67 mmol). After 18 h, tlc analysis (silica, 5% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜8 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (25 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated by pumping to constant weight to give white solid (0.23 g, 99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[C:22]([C:19](=[O:21])[CH3:20])[CH:23]=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-acetyl-phenylboronic acid to give 1-{3-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-ethanone. LC-MS m/e 343(MH+).
Reaction SMILES: [CH:1]1([C:5](O)=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:15][NH:16][C:17]([NH2:19])=[O:18].C(N(CC)CC)C.[OH-].[Na+].S(=O)(=O)(O)O>C(Cl)Cl.O.CN(C=O)C>[CH:1]1([C:5]2[NH:19][C:17](=[O:18])[NH:16][N:15]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(O)C1CCC1
Reactant: NNC(N)=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C2CCC2)[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a 0° C. solution of cyclobutane carboxylic acid (7.50 g, 74.9 mmol) in DCM (100 mL) was added oxalyl chloride (12.00 g, 95 mmol) followed by catalytic amount of DMF. The resultant mixture was stirred at RT for 1 h. The solvent from the reaction mixture was completely evaporated to a light coloured viscous mass. In a different RB flask, a suspension of semicarbazide hydrochloride (9.00 g, 81 mmol) in DCM (100 mL) was treated with triethylamine (18.00 g, 178 mmol) and stirred at −10° C. for 30 minutes. To the reaction mixture was added the acid chloride dissolved in DCM (20 mL) at the same temp and the resultant mixture was stirred at RT over night. The solvent from the reaction mixture was completely removed and the residue was stirred in MeCN (100 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was transferred to a RB flask and was treated with sodium hydroxide (7.50 g, 188 mmol) and water (20 mL). The resulting reaction mixture was heated at 100° C. for 3 h, cooled to RT, and acidified with conc. sulfuric acid. The solids were collected, washed sparingly with cold water, and dried to provide 3-cyclobutyl-1H-1,2,4-triazol-5(4H)-one, (6.40 g, 61.4% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.27 (s, 1H), 11.10 (s, 1H), 2.15 (m, 7H); MS (ESI) m/z: 140.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([C:12]([F:23])([F:22])[F:11])[CH:18]=2)[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc(N)c1I
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Yield: 163.5 %

Procedure:
5-Bromo-3-iodo-4-methyl-pyridin-2-ylamine (20.0 g, 63.9 mmol) and 3-(trifluoromethyl)benzene boronic acid (12.73 g, 67.0 mmol) were mixed with sodium carbonate (2 M, 160 mL, 320 mmol), toluene (570 mL) and IMS (190 mL) and degassed. 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane (3.13 g, 36.83 mmol) was added and the reaction mixture was degassed again before heating to reflux for 2 hrs. A second reaction was carried on 1.08 times the scale. The two batches were combined and the solvent was removed in vacuo and the resulting mixture was partitioned between DCM and water. The organic phase was separated and was washed with water, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography through a pad of silica, eluting with a gradient of 5-30% EtOAc in cyclohexane to give the title compound as a beige solid (34.6 g).