Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].Cl([O-])=O.[Na+].[OH:11]O.[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([CH:25]=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1>O.C(#N)C>[CH3:13][O:14][C:15]1[C:16]([CH3:44])=[C:17]([C:35]([O:42][CH3:43])=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[CH2:18][C:19]1[C:24]([C:25]([OH:11])=[O:26])=[C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OO
Reactant: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C=O)c(OC)c(OC)c1OC
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1c(C)c(Cc2cccc(OCc3ccccc3)c2C(=O)O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
An aqueous solution (1 ml) of sodium dihydrogenphosphate (24 mg, 0.20 mmol), an aqueous solution (3.5 ml) of sodium chlorite (123 mg, 80%, 1.09 mmol) and aqueous hydrogen peroxide (0.08 ml, 30%) were added to an acetonitrile solution (2.5 ml) of 6-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-benzyloxybenzaldehyde (112 mg, 0.26 mmol) and the resulting solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with an aqueous 10% sodium hydrosulfite (Na2S2O4) solution and saturated brine, then dried and concentrated to obtain the titled compound (106 mg, 0.23 mmol, 91%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[C:1]1([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][N:8]2[C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(c2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCNCC1c1ccccc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To 1-benzyl 4-tert-butyl 2-phenylpiperazine-1,4-dicarboxylate (0.84 g, 2.12 mmol) in dichloromethane (5.0 mL) added drop wise trifluoroacetic acid (5.0 mL) and maintained at 25° C. for 90 minutes. The reaction mixture was concentrated, and the residue dissolved in ethyl acetate (60 mL). The solution was washed with saturated aqueous sodium carbonate (30 mL) and brine (20 mL), and then dried over anhydrous sodium sulfate, filtered and concentrated to yield benzyl 2-phenylpiperazine-1-carboxylate (0.59 g, 94% yield). MS (EI) for C18H20N2O2: 297 (MH+).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]=[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1.I([O-])(=O)(=O)=[O:23].[Na+].CCOC(C)=O>C1COCC1.O>[N+:11]([C:10]1[C:5]([CH:4]=[O:23])=[CH:6][C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]=1)([O-:13])=[O:12]
Reactant: CN(C)C=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of dimethyl-[2-(5-nitro-2-phenoxy-pyridin-4-yl)-vinyl]-amine (0.2 g, 0.7 mmol) in THF (2 mL) and water (2 mL) was added sodium periodate (0.46 g, 2.1 mmol). The reaction mixture was stirred for 30 min, treated with EtOAc and the solids filtered. The filtrate was washed with sat NaHCO3, dried (Na2SO4), and concentrated to yield 5-nitro-2-phenoxy-pyridine-4-carbaldehyde, the title compound, as a bright yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([NH:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[C:16](O)=[O:17])[C:7]=1[Cl:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].OP(O)(O)=O>C1COCC1>[Cl:8][C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]([Cl:19])[C:6]=1[NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)O)c1Cl
Agent: O=P(O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c(Nc2ccccc2CO)c1Cl
Yield: 55.5 %

Procedure:
To a stirred solution of meclofenamic acid (4.27 g, 13.4 mmol) in THF (75 mL) at 0° C. was added LiAlH4 (1.02 g, 26.8 mmol) in portions over 0.5 hour. The mixture was maintained cold for 2 hrs after which it was slowly added to a cold solution of H3PO4 (1M, 100 mL) and extracted with ethyl ether (3×75 mL). The combined organic layers were washed with water and brine, dried over MgSO4. filtered, and evaporated in vacuo. Purification by chromatography on silica gel (9:1 hexanes/ethyl acetate) afforded 2.1 g (56%) of 2-[(2,6-dichloro-3-methylphenyl)amino]phenylmethanol as an off white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([O:10][CH3:14])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=Cc1cc(F)cc(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(Cl)cc(F)cc1C=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5-Fluoro-2-hydroxy-3-chlorobenzaldehyde (2.0 g, 11.01 mmol) was dissolved in N,N-dimethylformamide (30 mL) and to the solution was added methyl iodide (1.1 mL, 18.11 mmol) and potassium carbonate (4.4 g, 30.21 mmol). The mixture was stirred at 100° C. for one hour, cooled to room temperature and then diluted with water (40 mL). After extraction twice with ethyl acetate (40 mL) the combined organic layer was washed with brine and then dried over Na2SO4. The solvent was removed and the solid residue was treated with methanol. After filtration and drying desired compound was obtained 2.0 g (99%). 1H NMR (400 MHz, CDCl3): δ10.21 (s, 1H), 7.25 (dd, 1H), 7.12 (dd, 1H), 3.75 (s, 3H).
Reaction SMILES: C(Br)CCCCCO.[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH:20][CH2:21][CH2:22][CH:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:11])[CH3:10]>C1COCC1>[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][CH2:21][CH2:22]/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH3:28])(=[O:11])[CH3:10]
Reactant: CCCCC=CCCC=CCCCCCCOC(C)=O
Agent: OCCCCCCBr
Solvent: C1CCOC1
Product: CCCC/C=C/CCC#CCCCCCCOC(C)=O
Yield: 55 %

Procedure:
The THP derivative of hexamethylene bromohydrin in THF is added and the reaction mixture is worked up as described for 7,11-hexadecadienyl acetate. Vacuum distillation of the residue affords (E)-11-hexadecen-7-ynyl acetate, bp 134°-136°/1 mm, nD21 1.4655, in about 55-60% yield, contaminated with 0-5% of 7,11-hexadecadiynyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([S:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19](=O)[CH3:20]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([S:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)=[C:19]([CH3:20])[NH:13]2
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Reactant: COC(=O)C(Sc1ccc(Cl)cc1)C(C)=O
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Sc3ccc(Cl)cc3)c(=O)c12
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (2.1 g), 2-(4-chlorophenylsulfanyl)-3-oxobutyric acid methyl ester (2.5 g), polyphosphoric acid (10 g) and dioxane (30 mL) was heated at 130° C. for 2 days. The mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was diluted with water and the resulting precipitate collected by filtration, washed with water and dichloromethane and dried to afford title compound, 1.6 g.
Reaction SMILES: [CH3:1][C:2]([O:14][Si](C)(C)C)([CH3:13])[C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[OH:14][C:2]([CH3:13])([CH3:1])[C:3]#[C:4][C:5]([C:7]1[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C#CC(=O)c1ccncc1)O[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(O)C#CC(=O)c1ccncc1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a stirred solution of 4-methyl-1-(pyridin-4-yl)-4-(trimethylsilyloxy)pent-2-yn-1-one (3.0 g, 11.0 mmol) in DCM (60 mL) was added PTSA (2.62 g, 13.0 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (10 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 4-hydroxy-4-methyl-1-(pyridin-4-yl) pent-2-yn-1-one (1.5 g, 69%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=1.[OH-].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[NH:4][C:5]1[NH:6][C:7](=[O:16])[C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(Nc2ccccc2F)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnc(Nc2ccccc2F)[nH]c1=O
Reaction time: 1 h
Yield: 69 %

Procedure:
Ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (5 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic aicd, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (70 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.1 g). M.p. 300° C.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1.CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH3:12])=[CH:20][CH:19]=2)[C:3]2[N:4]([CH:9]=[CH:10][N:11]=2)[N:5]=1
Reactant: CCOc1ccc(N)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(Nc2cc(Cl)nn3ccnc23)cc1
Temperature: 50 °C

Procedure:
(1c variation 1) To a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (257 mg, 0.956 mmol) from 1b in THF (2.0 ml) was added p-phenetidine (131 mg, 0.956 mmol) and a 1.0 M solution of KOt-Bu in THF (2.5 eq, 2.4 ml, 2.39 mmol). The mixture was allowed to heat at 50° C. for 1 hour. The solution was then concentrated in vacuo to provide crude 6-chloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine as a solid. The solid was then used as is in the following step.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[Na])(C)(C)C.CCOC(C)=O>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:1]1([N:4]([CH:20]2[CH2:21][CH2:22][N:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:24][CH2:25]2)[C:5](=[O:19])[C:6]2[CH:11]=[CH:10][C:9]([C@@:12]([OH:18])([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=2)[CH2:2][CH2:3]1
Reactant: Brc1ccccc1
Reactant: C[C@](O)(c1ccc(C(=O)N(C2CCNCC2)C2CC2)cc1)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@](O)(c1ccc(C(=O)N(C2CC2)C2CCN(c3ccccc3)CC2)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A solution of (S)-N-cyclopropyl-N-(piperidin-4-yl)-4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzamide prepared above in step c in Example 1 (43 mg, 0.12 mmol, 1.0 equiv.), bromobenzene (15 μL, 0.14 mmol, 1.2 equiv.), (±)-BINAP (6.7 mg, 0.011 mmol, 0.09 equiv.), and t-BuONa (28 mg, 0.29 mmol, 2.4 equiv.) in toluene (150 μL, degassed by Argon for 10 min) was treated with Pd2(dba)3 (3.3 mg, 0.0036 mmol, 0.03 equiv.) under Argon. After being stirred for 17 h at 80° C. under argon, the reaction was diluted (EtOAc) and washed (brine). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification of the residue by flash chromatography (SiO2, 20-50% EtOAc/Hexanes, gradient elution) gave the title compound as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) δ 7.59 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.5 Hz, 2H), 7.28-7.25 (m, 2H), 6.98-6.96 (m, 2H), 6.88-6.85 (m, 1H), 4.35-4.25 (m, 1H), 3.80-3.75 (m, 2H), 2.87-2.82 (m, 2H), 2.62-2.54 (m, 1H), 2.52 (s, 1H), 2.28-2.21 (m, 2H), 2.04-2.00 (m, 2H), 1.80 (s, 3H), 0.60-0.57 (m, 2H), 0.49-0.45 (m, 2H); MS(ESI) 433 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:4]([C:6]1[O:10][N:9]=[C:8]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[N:7]=1)=[O:5]
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Reactant: CCOC(=O)c1nc(CNC(=O)c2ccc(Cl)s2)no1
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1F)c1nc(CNC(=O)c2ccc(Cl)s2)no1

Procedure:
In analogy to example 1E 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid ethyl ester (example 1D) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 742073-22-9) to give 3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-[1,2,4]oxadiazole-5-carboxylic acid [2-fluoro-4-(3-oxo-morpholin-4-yl)-phenyl]-amide. Light yellow solid. MS 480.0 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10](C)[C:11](=O)C(F)(F)F)=[O:4]>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH3:11])=[O:4]
Reactant: COC(=O)c1sccc1N(C)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CNc1ccsc1C(=O)OC
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A solution of 2.05 g of 3-[methyl-(2,2,2-trifluoro-acetyl)-amino]-thiophene-2-carboxylic acid methyl ester (7.67 mmol) in a mixture of methanol (100 ml) and 1N NaOH (15.4 ml) was stirred at RT over night. The methanol was then removed in vacuo and the remaining mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give 1.236 g (94%) of 3-methylamino-thiophene-2-carboxylic acid methyl ester as a light brown solid. MS (ISP) 172.2 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30][CH3:31])=[N:25][CH:26]=2)[N:21]1[CH3:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:28](=[O:29])[C:27]2[C:22](=[N:23][C:24]([S:30]([CH3:31])=[O:9])=[N:25][CH:26]=2)[N:21]1[CH3:32]
Reactant: COc1ccccc1-n1c(=O)c2cnc(SC)nc2n1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccccc1-n1c(=O)c2cnc(S(C)=O)nc2n1C
Reaction time: 1 h

Procedure:
At 0° C., 68 mg of m-chloroperbenzoic acid was added to a chloroform solution of 91 mg of 2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, and stirred for 1 hour. Aqueous saturated sodium hydrogencarbonate solution was added thereto, and extracted with chloroform to obtain crude 2-(2-methoxyphenyl)-1-methyl-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH:22]([F:33])[F:21])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-difluoromethoxy-pyridine-2-carboxylic acid (CAS1174323-34-2, WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=459.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:22])=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]1.CC([O-])(C)C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:22][C:3]1[C:2]([NH:31][CH2:30][CH:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[N:7][N:6]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:21])([F:20])[F:19])[CH:12]=3)=[CH:9][N:10]=[C:5]2[CH:4]=1
Reactant: Cc1cc2ncc(-c3cccc(OC(F)(F)F)c3)n2nc1Cl
Reactant: CN1CCC(CN)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc2ncc(-c3cccc(OC(F)(F)F)c3)n2nc1NCC1CCN(C)CC1
Temperature: 150 °C
Yield: 7.3 %

Procedure:
To the toluene (5 mL) solvent was added Compound 11 (57 mg, 0.174 mmol), (1-methylpiperidine-4-yl)methanamine 17 (26.8 mg, 0.209 mmol), ligand (10.27 mg, 0.026 mmol), NaOtBu (23.40 mg, 0.244 mmol) and Pd2(dba)3 (11.95, 0.013 mmol). The resulting reaction mixture was degassed for 10 min under argon and then was heated with microwave at 150° C. for 1 h. Concentration and preparative TLC (10% MeOH/DCM) afforded 5.3 mg (7.26%) of Compound 7-37.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH:25]([CH3:27])[CH3:26]>>[CH:25]([N:10]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[C:17]2[C:12]([C:13]([C:18]([F:21])([F:19])[F:20])=[CH:14][CH:15]=[CH:16]2)=[N:11]1)([CH3:27])[CH3:26]
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(C(F)(F)F)c3nn2C(C)C)cc1
Yield: 23.8 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (1.0 g, 3.4 mmol), sodium hydride (60% in oil, 0.136 g, 3.4 mmol) and 2-iodopropane (0.34 mL, 3.4 mmol) to give the title compound (0.27 g) as a white solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH:13][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(=O)N1CCc2c(sc(NC(=O)c3ccccc3)c2C#N)C1

Procedure:
Prepared according to general procedure A starting from 6-acetyl-2-amino-3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (compound A3) and benzoyl chloride.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][NH:14][C@H:13]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:18]1([C@H:13]2[C:12](=[O:11])[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O[C@H]1CCCN[C@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCN[C@H]1c1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
A solution of dimethyl sulfoxide (4.2 ml, 59 mmol) in dichloromethane (10 ml) was added dropwise to a stirred solution of oxalyl chloride ( 4.4 ml, 51 mmol) in dichloromethane (100 ml) at −70° C. over 10 min. After 10 min a solution of (2S,3S)-3-hydroxy-2-phenylpiperidine (10.5 g, 38.5 mmol) in dichloromethane (30 ml) was added dropwise at −70° C. over 10 min. The mixture was stirred an additional 10 min and triethylamine (15 ml, 108 mmol) added dropwise over 15 min. The reaction mixture was allowed to warm to −10° C. over 90 min and poured into a 10% aqueous solution of citric acid (200 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (2×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give crude (2S)-2-phenyl-3-piperidone which was immediately used in the next step.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[NH3:6]>>[N:6]([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])([CH2:3][CH2:2][C:1]([NH2:5])=[O:4])[CH2:3][CH2:2][C:1]([NH2:5])=[O:4]
Reactant: C=CC(N)=O
Reactant: N
Product: NC(=O)CCN(CCC(N)=O)CCC(N)=O
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A Parr autoclave was charged with an aqueous solution of acrylamide and a 10% molar excess of aqueous ammonia. The resulting mixture was warmed to 65° C. and autogenous pressure (<50 psi) and stirred at these conditions for three hours. At the end of this period, the reaction mass was allowed to cool to room temperature and white, crystalline nitrilotripropionamide (melting range 184°-186° C.) was recovered. NMR spectroscopy confirmed the structure.
Reaction SMILES: O[CH2:2]/[C:3](=[CH:5]\[CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])/[CH3:4].CC(CC=O)CCCC(O)(C)C.CC(=CCC/C(=C/CO)/C)C.OC/C=C(/C)\CCC=C(C)C.CC1(C)C2CC1CCC2=C.CC(C)=CCCC(C=C)=C.Cl>>[CH3:2][C:3](=[CH:5][CH2:6][CH2:7][CH:8]([CH2:10][CH2:11][OH:12])[CH3:9])[CH3:4]
Reactant: C/C(=C/CCC(C)CCO)CO
Agent: C=C1CCC2CC1C2(C)C
Agent: C=CC(=C)CCC=C(C)C
Agent: CC(C)=CCC/C(C)=C/CO
Product: CC(C)=CCCC(C)CCO

Procedure:
A primary use for hydroxycitronellol is as an intermediate in the synthesis of hydroxycitronellal, (7-hydroxy-3,7-dimethyloctan-1-al), a widely used perfumery material. Conventionally, in this synthesis, a mixture of geraniol and nerol is prepared from beta-pinene via myrcene hydrochloride and is partially hydrogenated to produce citronellol. Citronellol is then hydrated under acid conditions to produce hydroxycitronellol. It has also been made from myrcene by preparing the dihydrochloride and then chlorodihydrogeranyl acetate, followed by saponification and hydrogenation.1
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH3:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:11](=[O:13])[CH:10]([CH3:14])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:19][CH:18]=1)#[N:15]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CC(CNC(=O)OC(C)(C)C)C(=O)NCc1ccc(C#N)cc1
Yield: 71 %

Procedure:
A solution of 3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (200 mg, 0.98 mmol), 4-(aminomethyl)benzonitrile (130 mg, 0.98 mmol), HATU (486 mg, 1.28 mmol) and TEA (0.411 mL, 2.95 mmol) in DMF (5 mL) was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20 to 67% ethyl acetate/hexane) to give tert-butyl (3-((4-cyanobenzyl)amino)-2-methyl-3-oxopropyl)carbamate (221 mg, 0.696 mmol, 70.8%) as a white powder.