Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2.CC(C)([O-])C.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:29][C:30]1[N:31]([C:2]2[N:3]=[C:4]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:20])[CH3:21])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)[C:32]2[C:37]([CH:38]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Cc1cc2ccccc2[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1cc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 (0.1 g) was reacted with 2-methylindole and sodium-tert-butoxide (instead of cesium carbonate) via General Procedure C to afford 19 mg of 135 following reverse phase HPLC purification. MS (Q1) 501.3 (M)+
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:14]1[C:18]2[CH2:19][NH:20][CH2:21][C:17]=2[CH2:16][N:15]1[C:22]1[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=1.FC(F)(F)C(O)=O.C(N(CC)CC)C>C(Cl)Cl.N1C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:20]1[CH2:21][C:17]2[CH2:16][N:15]([C:22]3[S:23][C:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][N:26]=3)[CH2:14][C:18]=2[CH2:19]1)=[O:6]
Reactant: CCOC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Reaction time: 3 h

Procedure:
2-Trifluoromethylbenzoyl chloride (50.4 mg, 0.24 mmol) was added at RT to ethyl 2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxylate; trifluoroacetic acid salt (60 mg, 0.16 mmol) and triethylamine (64 μl, 0.46 mmol) in 4 ml of methylene chloride and 2 ml of pyridine. After 3 h at RT, the mixture was concentrated, water and ethyl acetate were added, and the organic phase was removed, concentrated by evaporation and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 63 mg (91%), M+H+: 438.04.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:4][CH3:5])[CH3:2].O[CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21]>>[CH2:1]([CH:3]([C:6]1[C:15]2[C:10](=[C:11]([CH2:17][NH:18][C:19](=[O:23])[CH:20]([Cl:22])[Cl:21])[CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1nccc2ccccc12
Reactant: O=C(NCO)C(Cl)Cl
Product: CCC(CC)c1nccc2c(CNC(=O)C(Cl)Cl)cccc12

Procedure:
1-(1-Ethylpropyl)isoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-(1-ethylpropyl)-5-dichloroacetylaminomethylisoquinoline. The product was successively reacted in the same way as in steps (c), (d), (e) and (f) of Example 18 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-(1-ethylpropyl)-isoquinoline-5-acetic acid as an oil. The hydrochloride of the product was in the form of colorless prisms having a melting point of 107° to 109° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([C:10]2[O:14][C:13]([C:20](=[O:36])[CH:21]([O:34][CH3:35])[C:22]3[CH:23]=[CH:24][C:25]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[CH:26][CH:27]=3)=[N:12][CH:11]=2)=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(-c2cnco2)cc(OC)c1Br
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: COc1cc(-c2cnc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)oxazol-2-yl)-2-methoxy-2-(4-morpholinophenyl) ethanone was prepared from 5-(4-bromo-3,5-dimethoxyphenyl)oxazole and N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure used in Example 30. Recrystallization from EtOAc gave the product as a yellow solid (0.308 g, 56% yield). MS: m/z 517.3 [M+H]+.
Reaction SMILES: O1CCOCC1.[CH3:7][O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([CH3:18])=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1.Br[C:29]1[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[N+:15]([C:14]1[C:9]([O:8][CH3:7])=[C:10]([C:29]2[O:33][C:32]([C:34]([OH:36])=[O:35])=[CH:31][CH:30]=2)[CH:11]=[C:12]([CH3:18])[CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: COc1c(B2OC(C)(C)C(C)(C)O2)cc(C)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C(=O)O)o2)cc(C)cc1[N+](=O)[O-]
Yield: 27.7 %

Procedure:
To a solution of the solvent mixture of 30 mL of 1,4-dioxane and 15 mL of water was added 2-(2-methoxy-5-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 24a (3.1 g, 7.5 mmol) followed by 5-bromofuran-2-carboxylic acid (1.3 g, 6.8 mmol), tetrakis(triphenylphosphine)palladium (0.43 g, 0.4 mmol) and sodium carbonate (1.6 g, 15.1 mmol). The reaction mixture was heated to reflux for 1 hour. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was cooled and filtered. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was diluted with 50 mL of water and adjusted to pH 3 with concentrated hydrochloric acid and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound 5-(3-nitro-2-methoxy-5-methyl-phenyl)-furan-2-carboxylic acid 46a (522 mg, 29%) as a yellow solid.
Reaction SMILES: [CH2:1]=[C:2]=[O:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28]N=O>>[CH3:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:2]([CH3:1])=[O:3]
Reactant: CCCCCON=O
Reactant: C=C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCOC(C)=O
Reaction time: 3 h
Yield: 12.8 %

Procedure:
The procedures of Example 11 were followed, except that ketene was introduced at the rate of 32.0 ml/min (1.43 mmole/min) and that triphenylphosphine (0.066 g, 0.25 mmole) was dissolved in the further added n-amyl nitrite (50 ml). The reaction proceeded smoothly for three hours, during which no deactivation of the catalyst was observed. The reaction product was analyzed by gas chromatography, revealing that n-di-amyl malonate (165.6 mmoles, 64.5%) and n-amyl acetate (32.9 mmoles, 12.8%) were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=3)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=2[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=1.[CH3:30][CH:31]1[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:30][CH:31]1[N:35]([C:2]2[CH:7]=[C:6]([C:8]3[C:17]4[C:12](=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=4)[CH:11]=[C:10]([C:22]([O:24][CH3:25])=[O:23])[C:9]=3[C:26]([O:28][CH3:29])=[O:27])[CH:5]=[CH:4][N:3]=2)[C:34](=[O:36])[CH2:33][CH2:32]1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(Br)c2)c1C(=O)OC
Reactant: CC1CCC(=O)N1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(N3C(=O)CCC3C)c2)c1C(=O)OC

Procedure:
1-(2-Bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene and 5-methyl-2-oxopyrrolidine are treated in the same manner as in Example 6-(2) to give 1-[2-(5-methyl-2-oxopyrrolidin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])=[N:19][N:18]=[C:17]1[CH2:33][SH:34].C(N(CC)CC)C.C(Cl)Cl.[C:46](Cl)(=[O:50])[O:47][CH2:48][CH3:49]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH:22][C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24])=[N:19][N:18]=[C:17]1[CH2:33][S:34][C:46]([O:47][CH2:48][CH3:49])=[O:50]
Reactant: CCOC(=O)Cl
Reactant: O=C(NCc1nnc(CS)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)SCc1nnc(CNC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To a solution of 2',5-dichloro-2-(5-carbobenzoxyaminomethyl-3-mercaptomethyl-1,2,4-triazol-4-yl)-benzophenone (0.5 g), triethylamine (0.5 ml) and methylene chloride (10 ml) is added a solution of ethyl chlorocarbonate (0.5 ml) in tetrahydrofuran (8 ml) at 15° C. with stirring. The reaction mixture is stirred for 1 hour and poured into water. The organic layer is washed with water, dried over sodium sulfate and evaporated to remove the solvent. The residual oily material is chromatographed on a column of silica gel, whereby 2',5-dichloro-2-(5-carbobenzoxyaminomethyl-3-ethoxycarbonylthiomethyl-1,2,4-triazol-4-yl)benzophenone (0.5 g) is obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[Na+]>O>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[N:3][S:4][N:5]=1
Reactant: O=c1c(Cl)nsnc1Cl
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1c(Cl)nsnc1Oc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
A suspension of 1.83 g of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one in 100 ml of water is stirred mechanically at room temperature while a solution of 1.29 g of p-chlorophenol, 20 ml of H2O and 5 ml of 2N aqueous sodium hydroxide solution is added dropwise to it. The mixture is stirred an additional 1 hour. The resulting precipitate is collected and recrystallized from alcohol. The white crystals melt at 142°-145°. The compounds described in Table II can be prepared by the same procedure as Example 2 substituting the appropriate phenol for p-chlorophenol.
Reaction SMILES: [CH2:1]([N:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:30])([CH3:29])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)[CH2:4][CH2:5][OH:6])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(=[O:48])[CH2:46][CH3:47]>C(Cl)Cl>[C:45]([O:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:16]3[O:17][C:18]4([C:28]([CH3:29])([CH3:30])[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]4[CH3:31])[CH:19]=[N:20][C:15]=3[CH:14]=2)=[CH:9][CH:8]=1)(=[O:48])[CH2:46][CH3:47]
Reactant: CCC(=O)Cl
Reactant: CCN(CCO)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCCN(CC)c1ccc(-c2cc3c(c4ccccc24)OC2(C=N3)N(C)c3ccccc3C2(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethanol (Example 8, Step 3) (0.085 g, 0.17 mmol) in DCM (5 ml) was treated with triethylamine (0.026 g, 0.26 mmol) in one portion followed by propionyl chloride (0.019 g, 0.21 mmol) and stirred at RT for 18 hrs. The solvent was then evaporated in vacuo and the crude residue purified by column chromatography (silica gel) eluting with 0-10% EtOAc/Petroleum ether, which gave the pure product, 2-(ethyl(4-(1,3,3-trimethylspiro[indoline-2,2′-naphtho[1,2-b][1,4]oxazine]-6′-yl)phenyl)amino)ethyl propionate, as a pale green foam upon evaporation of the solvent in vacuo (0.08 g, 84%).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:21])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[NH:10][CH2:9]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)[C@@H](N)CNc2ccccc21
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 5.0 g (18 mmol) (S)-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester in 80 ml of tetrahydrofuran at −75° C. 18 ml (18 mmol) of lithium bis(trimethylsilyl)amide solution (1M in tetrahydrofurane) was added. After stirring for 30 min at −75° C. the mixture was allowed to reach room temperature and 3.07 g (21.6 mmol) of methyl iodide was added. The mixture was stirred for 2.5 hours at room temperature and concentrated in vacuo. The residue was distributed between 1M NaHSO4 solution and ethyl acetate. The combined organic layers were reextracted with water and dried (MgSO4). After evaporation of the solvent 20 ml of dichlorometane and 20 ml of trifluoracetic acid was added and the mixture was stirred for 2.5 h at room temperature. For workup the mixture was concentrated in vacuo, then ethylacetate was added and the mixture was extracted two times with water. The aqueouos phase was basified with sodium hydroxide and extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated. The residue was purified by column chromatography (dichloromethane/methanol=9:1) to yield 2.1 g (65%) of (S)-3-amino-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4] diazepin-2-one.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[CH:10][NH2:11])[C:8]2[CH:12]=[CH:13][S:14][C:7]=2[N:6]=[C:5]1[O:15][CH2:16][CH2:17][CH3:18])[CH2:2][CH3:3].[Br:19]N1C(=O)CCC1=O>N1C=CC=CC=1>[Br:19][C:13]1[S:14][C:7]2[N:6]=[C:5]([O:15][CH2:16][CH2:17][CH3:18])[N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[CH:10][NH2:11])[C:8]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCOC1=Nc2sccc2C(=CN)N1CCC
Solvent: c1ccncc1
Product: CCCOC1=Nc2sc(Br)cc2C(=CN)N1CCC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In a sulfonation flask, 1.2 g (0.0045 mol) (3-propyl-2-propoxy-3H-thieno[2,3-d]-pyrimidine-4-ylidene)methylamine are dissolved in 15 ml of absolute pyridine. Then the internal temperature is raised to 60° C. and 1.2 g (0.0068 mol) N-bromosuccinimide are added in three portions. After stirring for 3 hours at 60° C., the pyridine is distilled off in a water jet vacuum and the residue taken up in ethylacetate. The organic phase is washed three times with water and after drying the organic phase over Na2SO4 the solvent is removed in a water jet vacuum. The raw material is purified by column chromatography over silica gel (eluant: hexane/ethylacetate 3:1). Yield: 1.2 g of (6-bromo-3-propyl-2-propoxy-3H-thieno[2,3-d]pyrimidine-4-ylidene)methylamine in the form of a brownish oil (1H-NMR-data see table 5).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[OH:37].[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[F:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[O:37][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Oc1cc(F)ccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cc(F)ccc2F)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 52.1 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 2,5-difluorophenol (0.23 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.29 g, 52%).
Reaction SMILES: [C:1]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl[CH2:19][C:20]([O-:22])=[O:21].[Na+]>>[C:1]([C:6]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][N:9]([CH2:19][C:20]([OH:22])=[O:21])[CH2:10][CH2:11]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C([O-])CCl
Agent: [Na+]
Product: CCOC(=O)C1(c2ccccc2)CCN(CC(=O)O)CC1
Reaction time: 7 h
Yield: 58 %

Procedure:
4-Carbethoxy-4-phenylpiperidine (4.01 g.) was dissolved in 13 ml. absolute alcohol and refluxed together with 2.01 g. sodium chloroacetate. After 7 hours no starting material was present as evidenced by TLC. The precipitated sodium chloride was removed by filtration and washed with 3 ml. ethanol. On cooling of the filtrate white crystals appeared. Filtration and drying gave 2.9 g. (58%) of the title compound. m.p. 148°-150°C. Evaporation of the mother liquor gave a glass which did not crystallize from acetone/hexane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:33]1([CH3:42])[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>O1CCOCC1.O.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:36]4[CH:37]=[CH:38][C:33]([CH3:42])=[CH:34][CH:35]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.179 mmol) in dioxane (20 mL) and water (10 mL) were added K2CO3 (488 mg, 3.537 mmol) and 4-tolyl boronic acid (179 mg, 1.297 mmol) in a sealed tube. The reaction mixture was degassed with N2 for 20 min, then Pd(PPh3)4 (136 mg, 0.118 mmol) was added to the reaction mixture at RT. The reaction mixture temperature was raised to 100° C., stirred for 18 h at 100° C. The reaction mixture was diluted with water (30 mL) extracted with ethyl acetate (3×30 mL) and organic layer was washed with brine, dried the organic layer over anhydrous sodium sulphate and concentrated under reduced pressure to affords the crude product. Crude was purified by column chromatography using 100-200 mesh silica gel compound eluted with 35% ethyl acetate in petroleum ether to afford the title compound as a white solid.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[CH2:12](O)[CH3:13]>OS(O)(=O)=O>[NH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:12][CH3:13])=[O:8])=[CH:10][CH:11]=1)[NH2:2]
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(NN)cc1

Procedure:
5.0 g of 4-hydrazinobenzoic acid are dissolved in 70 ml of ethanol and 3 ml of concentrated H2SO4. The mixture is heated at reflux for five hours, the ethanol is evaporated, the residue is then taken up in a saturated K2CO3 solution and then extraction is carried out with AcOEt. 5.9 g of the expected compound are obtained in the form of a powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([CH:14]1[CH2:17][NH:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:19]1[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1.O>CN(C=O)C.CCOC(C)=O>[CH3:25][C:23]1[N:24]=[C:19]([N:16]2[CH2:17][CH:14]([O:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:15]2)[C:20]([NH2:26])=[N:21][CH:22]=1
Reactant: c1ccc(OC2CNC2)cc1
Reactant: Cc1cnc(N)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N)c(N2CC(Oc3ccccc3)C2)n1
Temperature: 120 °C
Reaction time: 4 h
Yield: 35.2 %

Procedure:
Potassium carbonate (18.53 mg) was added to a mixture of 3-phenoxyazetidine (20 mg) and 3-bromo-5-methylpyrazin-2-amine (25 mg) in DMF (dry) (1 mL). The mixture was stirred at 120° C. for 4 hr. Water and EtOAc were added and the extracted organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (12 mg) as white solid.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([Si](C)(C)C)([F:12])[F:11].O>CCCCCC>[C:2]1([CH:1]([OH:8])[C:10]([F:12])([F:11])[F:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: OC(c1ccccc1)C(F)(F)F
Temperature: 80 °C
Yield: 88 %

Procedure:
Benzaldehyde was reacted with trifluoromethyltrimethylsilane as in Example 10. After a reaction time of 5 hours, 20 ml of water were added, and the reaction mixture was heated briefly to 80° C. 50 ml of hexane were then added. The reaction mixture was then extracted twice with 100 ml of water, and the resultant organic phase was dried over Na2SO4. On distillation of the crude product, 15.4 g (88% yield) of 1-phenyl-2,2,2-trifluoroethanol (boiling point 68°-69° C./6 mbar) were obtained.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([O:9]C)=[O:8])[CH2:2]1.CO.[OH-].[Li+].Cl>O.C1COCC1>[S:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]([OH:9])=[O:8])[CH2:2]1
Reactant: COC(=O)C1=CCCSC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1=CCCSC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 5,6-dihydro-2H-thiopyran-3-carboxylate (1.0 g, 6.32 mmol) in 10:1 MeOH:THF (16.5 mL) was added lithium hydroxide (0.30 g, 13 mmol) in water (15 mL). The resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was carefully acidified with 1N aqueous HCl, and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].Br.[CH2:11]([NH:13][CH2:14][CH2:15][CH2:16]Br)[CH3:12]>>[Cl:9][C:7]1[CH:6]=[CH:5][C:3]([NH:4][CH2:16][CH2:15][CH2:14][NH:13][CH2:11][CH3:12])=[C:2]([CH3:1])[CH:8]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: CCNCCCBr
Agent: Br
Product: CCNCCCNc1ccc(Cl)cc1C

Procedure:
Prepared in the manner of Example 1, Step A using 2-methyl-4-chloroaniline and the N-ethyl-1-amino-3-bromopropane hydrobromide salt of Step C (12.7 g).