Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:8]2[S:12][C:11]([N:13]=[C:14]=[O:15])=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][NH:17][CH2:18][CH:19]=[O:20]>C1C=CC=CC=1>[CH3:16][N:17]([CH2:18][CH:19]=[O:20])[C:14]([NH:13][C:11]1[S:12][C:8]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[N:9][N:10]=1)=[O:15]
Reactant: CNCC=O
Reactant: O=C=Nc1nnc(C2CCCCCC2)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(C2CCCCCC2)s1

Procedure:
A mixture of 5-cycloheptyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cycloheptyl-1,3,4-thiadiazol-2-yl)ureido]acetaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[OH:13][C:14]1([CH3:21])[CH2:19][CH2:18][CH:17]([NH:1][C:2]2[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:16][CH2:15]1
Reactant: CC1(O)CCC(=O)CC1
Reactant: COC(=O)c1cccc(N)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cccc(NC2CCC(C)(O)CC2)c1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of methyl 3-amino-2-methylbenzoate (1.5 g, 9.1 mmol) and 4-hydroxy-4-methylcyclohexanone (1.51 ml, 11.8 mmol) in 10 ml of dichloroethane was added acetic acid (3.2 mL, 55 mmol) and the reaction mixture stirred at room temperature for 20 minutes. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (5.78 g, 27.3 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was neutralized with sat. NaHCO3, extracted with DCM, dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the title compound which was carried forward as a mixture of cis and trans isomers (1.4 g, 56%).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([CH2:23][NH2:24])[OH:22].O>CCCCCC>[C:1]([NH:24][CH2:23][CH2:21][OH:22])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: NCCO
Solvent: O
Solvent: CCCCCC
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NCCO

Procedure:
In an exemplary embodiment, 1 mmol oleic acid was reacted with 1 mmol ethanolamine in 1.5 mL hexane at 65° C. for 3 hours in the presence 30% lipase and 10 μL water. N-oleoyl ethanolamine with 96.6% purity was obtained and all oleic acid was consumed. In another exemplary embodiment, when the synthesis was conducted on a large scale (50 mmol of each of the reactants), the purity of N-oleoyl ethanolamine after crystallization purification was 96.1%. More examples of reacting the alkanolamine and the fatty acid to prepare the high-purity fatty acid N-acylalkanolamine in a high yield are described in Examples 9-18.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH:17]([OH:19])[CH:16]([OH:20])[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>O.C1COCC1>[C:7]([O:11][C:12](=[O:13])[N:14]([CH2:18][CH:17]=[O:19])[CH2:15][CH:16]=[O:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(O)C1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(CC=O)CC=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium periodate (20.31 g, 94.96 mmol) in H2O (118 mL) was added to a cooled solution of 3,4-dihydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (19.3 g, 94.6 mmol) in THF (158 mL) over a 30 minute period. The resulting white suspension was allowed to stir at room temperature for 3 h. The suspension was filtered and the filtrate concentrated under vacuum to remove the THF. The resulting aqueous solution was used directly in the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)[C:5]([CH3:18])=[CH:4][N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1>C(Cl)Cl.CO>[CH3:18][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=2)=[N:7][C:2]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][N:23]3[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]3)=[CH:33][CH:32]=2)=[N:3][CH:4]=1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1-c1cccc(S(C)(=O)=O)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(S(C)(=O)=O)c1
Yield: 63 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-5-methyl-4-(3-(methylsulfonyl)phenyl)pyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 63% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.23 (s, 1H), 8.03 (d, 1H, J=7.8 Hz), 7.93 (d, 1H, J=7.8 Hz), 7.70 (t, 1H, J=7.8 Hz), 7.56 (d, 2H, J=8.2 Hz), 7.26 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 3.09 (s, 3H), 2.43 (bs, 8H), 2.26 (s, 6H). MS (ESI): 452.3 [M+H]+, 226.8 [M+2H]2+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][NH:8]3)=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Temperature: 25 °C
Yield: 38.2 %

Procedure:
A degassed solution of 6-bromoindole (1.0 g, 5.1 mmol), 4-fluorobenzeneboronic acid (0.928 g, 6.63 mmol), potassium phosphate (2.7 g, 153 mmol) and palladium(0)tetrakis-(triphenylphosphine) (0.294 g, 0.255 mmol) in dimethylacetamide (50 mL) was heated at 120° C. for 14 hours. After cooling to room temperature, the mixture was diluted with water. The suspension was filtered, the solid washed with water and then dissolved in ethyl acetate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with ethyl acetate:hexane (1:4) to give 0.411 g (38.2%) of the title compound as a white crystalline solid.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24].C(Cl)(Cl)Cl>ClCCl>[CH2:21]([NH:25][S:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]=[CH:1][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:13])=[O:12])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CCCCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 12 h
Yield: 71.8 %

Procedure:
In 100 ml of dichloromethane was dissolved 2.28 g of 5-isoquinolinesulfonyl chloride, and to the solution were added 1.38 g of anhydrous potassium carbonate and 1.46 g of n-butylamine, and the mixture thus obtained was stirred at a temperature of 20° C. to 25° C. for 12 hours. The reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the dichloromethane was distilled therefrom under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 1.90 g of N-n-butyl-5-isoquinolinesulfonamide, i.e., Compound (27) in a yield of 72%.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[O:22]([CH2:29][CH2:30]Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:30][CH2:29][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Reactant: BrCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture containing 3-(R)-(1-cyano-1,1-diphenylmethyl)piperidine (0.3 g), 2-phenoxyethyl bromide (0.24 g--commercially available), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 5 hours. The mixture was then partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 2%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a gum, yield 0.254 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][NH:39][CH2:40][C:41]#[CH:42]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:39]([CH3:38])[CH2:40][C:41]#[CH:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: C#CCNC
Product: C#CCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and methyl-prop-2-ynylamine according to conditions described in general procedure C. Mp: 116-117° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.58-1.61 (m, 6 H), 2.85 (m, 3 H), 3.27-3.30 (m, 5 H), 4.22 (s, 2 H), 6.30 (d, J=5.5 Hz, 1 H), 6.94-6.98 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.43 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82-7.84 (m, 1 H), 7.98 (d, J=7.4 Hz, 1 H), 8.30 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[CH2:4][CH:5]=[CH2:6].C(OC)(OC)OC.[CH3:19][C:20]([CH3:22])=O>S(=O)(=O)(O)O>[CH2:4]([C:3]1([CH2:7][CH:8]=[CH2:9])[CH2:10][O:11][C:20]([CH3:22])([CH3:19])[O:1][CH2:2]1)[CH:5]=[CH2:6]
Reactant: C=CCC(CO)(CO)CC=C
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: COC(OC)OC
Product: C=CCC1(CC=C)COC(C)(C)OC1

Procedure:
There were put 15.2 g of 4,4-bis(hydroxymethyl)-1,6-heptadiene prepared above, 42.5 mL of trimethyl orthoformate manufactured by Tokyo Chemical Industry Co., Ltd., and 97 mL of dry acetone manufactured by Kanto Chemical Co., Inc. in a 200 mL round-bottom flask. To the resultant mixture, a few drops of concentrated sulfuric acid were added gradually, and the mixture was refluxed for 4 hours. The reaction mixture was extracted with ether, and the extract was washed with saturated aqueous sodium bicarbonate, and was further washed with a saturated sodium chloride solution. The washed extract was dried over anhydrous magnesium sulfate manufactured by Nacalai Tesque, Inc. The dried ether solution was subjected to evaporation to remove ether contained therein. The obtained liquid was distilled in vacuo, thereby obtaining 16.2 g of 5,5-diallyl-2,2-dimethyl-1,3-dioxane as a colorless and oily fraction at 45° C. under a pressure of 4 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3C(=O)C4=CC=CC=C4C3=O)=[CH:8][C:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=3)=[N:6]2)[CH2:3][CH2:2]1.O.NN>CO>[NH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=2)[CH:8]=1
Reactant: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Agent: NN
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(CN)c(=O)n(CC3CC3)n2)cc1F
Yield: 99.7 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxypheyl)-4-phthalimidomethyl-2H-pyridazin-3-one (190 mg, 0.43 mmol) in methanol (5 mL) was added hydrazine monohydrate (110 mg, 2.20 mmol), and the mixture was heated under reflux for 2 hours. Methanol was distilled off, and chloroform (20 mL) was added to the residue. The mixture was successively washed with water (10 mL) and brine (10 mL) in this order, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/10% w/v solution of methanol in ammonia (20/1)] to yield the title compound as yellow crystals (130 mg, 97.8%).
Reaction SMILES: [CH2:1]([CH:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18](Cl)([Cl:20])=[O:19].C(=O)=O>CC(C)=O>[Cl:20][C:18]([O:9][CH2:8][CH:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:19]
Reactant: CCCCCCCCC(CO)CCCCCC
Reactant: O=C(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Product: CCCCCCCCC(CCCCCC)COC(=O)Cl
Reaction time: 0.5 h

Procedure:
2-Hexyldecyl chloroformate was prepared by adding 2-hexyldecanol (540 g) during 3 hours to liquid phosgene (500 g) which was refluxing below a condenser cooled with a mixture of solid carbon dioxide and acetone. After addition was complete the mixture was stirred for 30 minutes, and excess phosgene was then allowed to evaporate into a scrubbing device charged with 20% aqueous sodium hydroxide. The last traces of phsogene were removed by bubbling nitrogen through the liquid product while it was heated to 120°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[CH:6][CH:5]=1.[C:35]1([N:41]=[C:42]=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:33]=[CH:34][C:25]=1[CH2:24][O:23][CH:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][O:1][C:42](=[O:43])[NH:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:12]1
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCO)cc2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCOC(=O)Nc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24(m), by reacting tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethyl)-phenyl]-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate with phenyl isocyanate there was obtained tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-[4-(2-phenylcarbamoyloxy-ethyl)-phenyl]-piperidine-1-carboxylate as a colourless oil, MS: 481 (M+H)+.
Reaction SMILES: N1(C2CC[N:8]([CH2:11][C:12]3[S:13][C:14]4[N:15]=[C:16]([Cl:27])[N:17]=[C:18]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:19]=4[N:20]=3)[CH2:7]C2)CCC1.[N:28]1([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:33]CN[CH2:30][CH2:29]1>>[Cl:27][C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:19]2[N:20]=[C:12]([CH2:11][N:8]3[CH2:30][CH2:29][N:28]([C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36])[CH2:33][CH2:7]3)[S:13][C:14]=2[N:15]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CN3CCC(N4CCC4)CC3)sc2n1
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-(4-azetidin-1-ylpiperidin-1-ylmethyl)-5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine using 2-piperazin-1-ylisobutyramide in place of 4-azetidin-1-ylpiperidine. The title compound was obtained as a white solid (70 mg, 46%).
Reaction SMILES: C([O:8][C:9]([C:11]1([C:24]([O:26]CC2C=CC=CC=2)=[O:25])[CH2:16][CH2:15][P:14](=[O:23])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[O:23]=[P:14]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16][C:11]([C:9]([OH:10])=[O:8])([C:24]([OH:26])=[O:25])[CH2:12][CH2:13]1
Reactant: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCP(=O)(c2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCP(=O)(c2ccccc2)CC1
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a 500 mL Parr flask was added 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid dibenzyl ester (8.5 g, 18 mmol), ethanol (250 mL), and palladium on carbon (10%, 1.1 g). The flask was charged with hydrogen (51 psi), and agitated on a mechanical shaker. After 1 hour, the ballast was re-charged to 50 psi (from 40 psi) and shaking continued overnight (14 hours). The reaction mixture was filtered and the solvent removed in vacuo to provide 1-oxo-1-phenyl-1λ5-phosphinane-4,4-dicarboxylic acid (1.8 g, 35%) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 7.9-7.4 (m, 5H), 2.6 -1.4 (m, 8H); ESMS m/z: found, 283 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[C:6]([N:8]1[CH2:24][CH2:23][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH:12]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:34]I>>[F:31][C:28]([F:29])([F:30])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:34])[CH2:13][CH:12]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:23][CH2:24]1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCC2c1ccccc1
Reactant: CI
Product: CN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=485.3 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decan-1-one and methyl iodide.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: CCOC(=O)CBr
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reaction time: 8 h
Yield: 90 %

Procedure:
To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), ethyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.), and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of the solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 90% yield.
Reaction SMILES: Br[C:2]1[C:3]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[C:3]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[CH:4][C:5]2[N:6]([C:9](=[O:23])[N:10]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:18]=3)[N:11]=2)[C:7]=1[CH3:8]
Reactant: Cc1c(Br)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Reactant: OB(O)c1ccccc1Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)cc2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 95 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
Into a flame-dried 25 mL round bottom flask was placed 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (25 mg, 0.05 mmol), 2-chlorophenylboronic acid (16 mg, 0.1 mmol), K3PO4 (43 mg, 0.2 mmol), Pd(dba)3 (4.6 mg, 0.005 mmol), and S-Phos (dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, 4.2 mg, 0.01 mmol). The reaction flask was purged with argon three times before toluene (1 mL) was added. The reaction mixture was stirred at 95° C. for 16 h. Analysis by HPLC/MS indicated the starting 6-bromo-7-(4-chlorophenyl)-5-methyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one had been consumed. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (15 mL×2). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (4 g) eluted with a gradient of EtOAc (30-70%) in hexanes to afford the desired product (86% pure). The product was further purified by preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 70% to 100% B over 10 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue obtained was dissolved in acetonitrile, frozen and lyophilized to afford 10 mg (40%) of the title compound as a light yellow powder. HPLC/MS: retention time=4.13 min, [M+H]+=529.3.
Reaction SMILES: [CH:1]1([C:4]([O:6][CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)=O)=O)[CH2:3][CH2:2]1.C([NH2:20])(=O)C.B(F)(F)F.CCOCC>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:20]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:6][CH:7]=2)=[CH:11][CH:12]=1
Reactant: CC(N)=O
Reactant: O=C(COC(=O)C1CC1)c1ccc(Br)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: Brc1ccc(-c2coc(C3CC3)n2)cc1
Yield: 64.5 %

Procedure:
To a mixture of 2-(4-bromophenyl)-2-oxoethyl cyclopropane carboxylate (6.00 g, 21.19 mmol) and acetamide (6.60 g, 111.73 mmol) was added BF3/Et2O (4 ml). The mixture was heated to 140C for 2.5 h. Upon cooling, water was added, and the mixture was extracted with Et2O (4×125 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (CH2Cl2/hexanes, 7:3) to provide the title compound as a yellow solid (3.61 g, 64%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(Cl)(Cl)Cl>[C:17]([O:1][CH2:2][CH2:3][N:4]1[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[C:7]([CH3:15])[S:6][C:5]1=[S:16])(=[O:19])[CH3:18]
Reactant: Cc1sc(=S)n(CCO)c1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1c(-c2ccccc2)c(C)sc1=S

Procedure:
Intermediate 3-(2-hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thione was treated with acetic anhydride (1 equiv) and TEA (2 equiv) in CHCl3. After 12 h the product mixture was concentrated and chromatographed (silica gel, 0–40% EtOAc/Hex) to afford the title compound. 1H-NMR (CDCl3): δ 7.50–7.55 (3H, m), 7.28–7.32 (2H, m), 4.32 (2H, t), 4.26 (2H, t), 2.03 (3H, s), 1.93 (3H, s).