Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1)#[CH:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17](I)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([C:2]#[C:1][CH:3]2[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]2)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Reactant: C#CC1CCC2(CC1)OCCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCC(C#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.9 grams (0.022 mole) of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 10.5 grams (0.031 mole) of 3,5-di(trifluoromethyl)phenyl iodide (prepared in Step A of this Example), 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(I) iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred for about 2 hours with 150 mL of aqueous 1N hydrochloric acid. After this time the mixture is extracted with three 100 mL portions of ethyl acetate. The combined extracts are washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4-[3,5-di(trifluoromethyl)phenylethynyl]cyclohexanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:29]([OH:31])=O)=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:32]([O:39][CH2:40][CH2:41][NH:42][CH:43]1[CH2:45][CH2:44]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.CCCCCC.O.C(OCC)(=O)C>[Si:32]([O:39][CH2:40][CH2:41][N:42]([CH:43]1[CH2:44][CH2:45]1)[C:29]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:31])([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: O=C(O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Reaction time: 16 h
Yield: 55.5 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (324) (150.0 mg, 0.34 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (8d) (110.4 mg, 0.51 mmol) were taken up in dimethylformamide (3 ml), HATU (123.3 mg, 0.41 mmol) and N,N-diisopropylethylamine (132.5 mg, 1.03 mmol) were added at room temperature and stirred for 16 h while silica thin layer chromatography was performed (40% ethyl acetate in hexane; Rf=0.4). To the reaction, water (10 ml) was added and stirred for 5 min and the aqueous mixture was extracted with ethyl acetate (2×15 ml). The combined extracts were washed with water (3×10 ml), dried and concentrated under reduced pressure. The obtained crude product was purified by normal silica gel column chromatography (100-200 mesh) using 30% ethyl acetate in hexane as mobile phase to get pure 5-benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (325) (120 mg, 55%) as a yellow sticky solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[CH:27][C:28]=1[Cl:29]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][C:28]([Cl:29])=[C:23]([Cl:22])[CH:24]=4)[CH2:35][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichlorophenyl)piperazine. The crude product was partitioned between dichlorormethane and 2 M aqueous sodium carbonate. The organic layer was washed with water, dried and evaporated. The residue was triturated with ethyl acetate—heptane (1:4) and the precipitate was collected by filtration and dried to give the title compound as white crystals. Yield 28%; m.p. 115-116° C.; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.30-8.20 (dd-like, 1H), 7.48-7.40 (d-like, 1H), 7.31-7.16 (m, 6H), 7.04-6.94 (dd-like, 1H), 3.83-3.47 (br m, 4H), 3.36-3.24 (br s, 4H+water); HPLC-MS: m/z=512 (M+H); IR (KBr): ν 1724,1706 cm−1.
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7](=[O:10])[CH:6](C)[NH:5]1)([CH3:3])[CH3:2].C(N1C(=O)C(=O)C(C2C=CC=CC=2)N1)(C)C.C(N1C(=O)C(=O)C(C2C=CC(Cl)=CC=2)N1)(C)C.C(N1C(=O)C(=O)C(C2C=CC=C(OC)C=2)N1)(C)C.C(N1C(=O)C(=O)C(C2C=CC(OC)=CC=2)N1)(C)C.C(N1C(=O)C(=O)C(C2C=CC=C([N+]([O-])=O)C=2)N1)(C)C.C(N1C(=O)C(=O)C(C2C=CC(C)=CC=2)N1)(C)C.C(N1C(=O)C(=O)C(OC)N1)(C)C.C(N1C(=O)C(=O)C(OCC)N1)(C)C.C(N1C(=O)C(=O)C(N(C)C)N1)(C)C.C(N1C(=O)C(=O)C(N(CC)CC)N1)(C)C.C(N1C(=O)C(=O)C(NC(=O)C)N1)(C)C.C(N1C(=O)C(=O)C(C(O)=O)N1)(C)C.C(N1C(=O)C(=O)C(C(OC)=O)N1)(C)C.C(N1C(=O)C(=O)C(C(OCC)=O)N1)(C)C>>[CH:1]([N:4]1[C:8](=[O:9])[C:7](=[O:10])[CH2:6][NH:5]1)([CH3:3])[CH3:2]
Reactant: CC1NN(C(C)C)C(=O)C1=O
Agent: CC(=O)NC1NN(C(C)C)C(=O)C1=O
Agent: CC(C)N1NC(C(=O)O)C(=O)C1=O
Agent: CC(C)N1NC(N(C)C)C(=O)C1=O
Product: CC(C)N1NCC(=O)C1=O

Procedure:
1-isopropyl-3-methyl-4,5-pyrazolinedione; 1-isopropyl-3-phenyl-4,5-pyrazolinedione; 1-isopropyl-3-(4′-chlorophenyl)-4,5-pyrazolinedione; 1-isopropyl-3-(3′-methoxyphenyl)-4,5-pyrazolinedione; 1-isopropyl-3-(4′-methoxyphenyl)-4,5-pyrazolinedione; 1-isopropyl-3-(3′-nitrophenyl)-4,5-pyrazolinedione; 1-isopropyl-3-(4′-methylphenyl)-4,5-pyrazolinedione; 1-isopropyl-3-(2 ′-furyl)-4,5-pyrazolinedione; 1-isopropyl-3-(2′-thienyl)-4,5-pyrazolinedione; 1-isopropyl-3-(5′-pyrazolyl)-4,5-pyrazolinedione; 1-isopropyl-3-methoxy-4,5-pyrazolinedione; 1-isopropyl-3-ethoxy-4,5-pyrazolinedione; 1-isopropyl-3-dimethylamino-4,5-pyrazolinedione; 1-isopropyl-3-diethylamino-4,5-pyrazolinedione; 1-isopropyl-3-acetamido-4,5-pyrazolinedione; 1-isopropyl-3-carboxy-4,5-pyrazolinedione; 1-isopropyl-3-methoxycarbonyl-4,5-pyrazolinedione; 1-isopropyl-3-ethoxycarbonyl-4,5-pyrazolinedione;
Reaction SMILES: CO[C:3]([C:5]1[C:9]([CH3:10])=[CH:8][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:6]=1)=[O:4].[NH2:17][C:18]([NH2:20])=[NH:19]>CN1C(=O)CCC1.O>[CH3:10][C:9]1[C:5]([C:3]([NH:19][C:18]([NH2:20])=[NH:17])=[O:4])=[CH:6][N:7]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=1
Reactant: COC(=O)c1cn(-c2ncccn2)cc1C
Reactant: N=C(N)N
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cn(-c2ncccn2)cc1C(=O)NC(=N)N
Temperature: 25 °C
Yield: 53.4 %

Procedure:
250 mg 4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carboxylic acid methyl ester was dissolved in 0.3 mL of NMP. After addition of 1 g guanidine (preparation according to known literature) the mixture was heated under argon for 1 h to 90° C. Completion of the reaction was checked by LCMS. The mixture was cooled to room temperature and then diluted with water, followed by extraction with ethyl acetate. The organic layer was washed with water (twice), dried over anhydrous sodium sulfate. After filtration the solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column flash chromatography (eluent: dichloromethane/methanol=5/1) to obtain 150 mg of N-(4-methyl-1-pyrimidin-2-yl-1H-pyrrole-3-carbonyl)-guanidine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].[CH2:27]([SH:31])[CH2:28][CH2:29][SH:30].B(F)(F)F.CCOCC>ClCCl>[CH2:1]([O:3][C:4](=[O:26])[C:5]([CH3:25])([CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[CH3:21])[S:31][CH2:27][CH2:28][CH2:29][S:30]1)[CH3:2]
Reactant: SCCCS
Reactant: CCOC(=O)C(C)(C)CCCCC(=O)CCCCC(C)(C)C(=O)OCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)CCCCC1(CCCCC(C)(C)C(=O)OCC)SCCCS1
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Under N2 atmosphere, to a solution of 2,2,12,12-tetramethyl-7-oxo-tridecanedioic acid diethyl ester (1.0 g, 2.70 mmol) and 1,3-propanedithiol (361 mg, 361 L, 3.24 mmol) in dichloromethane (20 mL; dried with Aluminum oxide, activated, neutral, Brockman I) was added boron trifluoride diethyl etherate (100 L) at rt. The reaction mixture was stirred for 3 h, diluted with dichloromethane (100 mL), and extracted with 5% NaOH solution (100 mL) and water (75 mL). The organic phase was dried over MgSO4, concentrated in vacuo, and dried in high vacuo to furnish 6-[2-(5-ethoxycarbonyl-5-methyl-hexyl)-[1,3]dithian-2-yl]-2,2-dimethyl-hexanoic acid ethyl ester (1.0 g, 80%) as a yellowish oil. 1H NMR (300 MHz, CDCl3/TMS): (ppm): 4.11 (q, 4H, J=7.1), 2.79 (t, 4H, J=5.6), 1.94 (m, 2H), 1.84 (m, 4H), 1.54 (m, 4H), 1.39 (m, 4H), 1.24 (t, 6H, J=7.1), 1.30-1.20 (m, 4H), 1.16 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm): 178.08, 60.33, 53.32, 42.27, 40.69, 38.28, 26.14, 25.67, 25.28, 24.71, 14.41. HRMS (LSIMS, nba): Calcd. for C24H45S2O4 (MH4): 461.2759, found 461.2774.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH:17]1[CH2:19][CH2:18]1)=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([C:32](O)=O)[CH:29]=[N:30][CH:31]=1>>[CH:17]1([C:7]2[N:8]([CH2:12][C:13]3[N:16]=[C:32]([C:28]4[CH:29]=[N:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:35])[CH:27]=4)[O:15][N:14]=3)[C:9]3[C:5]([CH:6]=2)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH2:19][CH2:18]1
Reactant: N#Cc1ccc2c(cc(C3CC3)n2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cncc(C(F)(F)F)c1
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2noc(-c3cncc(C(F)(F)F)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-2-cyclopropyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 364B) and 5-(trifluoromethyl)-3-pyridinecarboxylic acid: MS (ES) m/z 478 (M+1).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1[N:50]=[N:49][C:44]2[CH:45]=[CH:46][CH:47]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1(N)CCCC1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:50][N:49]5[CH2:44][CH2:45][CH2:46][CH2:47]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCC1
Product: COc1cc(C(=O)NN2CCCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and pyrrolidin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.45 (m, 3 H) 1.55-1.90 (m, 7 H) 2.02 (br. s., 4 H) 3.33 (s, 3 H) 3.52 (br. s., 4 H) 3.97 (s, 3 H) 4.14 (t, 2 H) 4.49 (quin, 1 H) 7.48 (d, 1 H) 7.52 (s, 1 H) 8.26 (s, 1 H) 8.31 (d, 1 H) 8.42 (s, 1 H). [M+H] calc'd for C26H33F2N7O3 530; found 530.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:30][CH:29]=1)[C:25]([OH:27])=[O:26])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
Potassium carbonate (23.11 g, 140 mmol) and 4-fluorobenzaldehyde (25.0 mL, 233 mmol) were added to a solution of tert-butoxycarbonylamino-(4-hydroxy-phenyl)-acetic acid (12.5 g, 46.7 mmol) in anhydrous DMF (40 mL). The resulting suspension was refluxed at 75±5° C. under an atmosphere of argon. After 72 hr, the reaction mixture was cooled to room temperature, diluted with water (200 mL) and extracted with EtOAc (2×150 mL). The aqueous layer was collected, acidified with 5.0 M HCl to pH ˜2.0 and extracted with EtOAc (3×150 mL). The resulting EtOAc layer was extracted with water (2×300 mL) and brine (1×300 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to yield the desired aldehyde 29 as a low melting solid (12.0 g, 69%). 1H NMR (400 MHz, DMSO-d6): 12.9 (br, 1H), 9.93 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.65 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.8 Hz, 2H), 7.13 (overlapped d, J=8.8 Hz, 2H), 7.13 (overlapped d, J=8.8 Hz, 2H), 5.16 (d, J=8.0 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [OH-].[Na+].C([O:11][C:12]1[CH:27]=[CH:26][C:15]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[C:14]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=1)(=O)C1C=CC=CC=1.CO.Cl>O1CCCC1>[CH2:29]([O:28][C:14]1[CH:13]=[C:12]([OH:11])[CH:27]=[CH:26][C:15]=1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C(Oc1ccc(C(=O)OCc2ccccc2)c(OCc2ccccc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(OCc1ccccc1)c1ccc(O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (6.39 mL) was added to a mixture of benzyl 4-benzoyloxy-2-benzyloxy-benzoate (2.80 g), methanol (10 mL) and tetra hydrofuran (10 mL), and the mixture was stirred at room temperature for 5 hrs. 2 mol/L hydrochloric acid (6.39 mL) was added to the reaction mixture at room temperature, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to afford benzyl 2-benzyloxy-4-hydroxybenzoate (0.86 g).
Reaction SMILES: [P:1](Cl)([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH3:5])=[S:2].[OH-:13].[K+:14]>C(O)C>[K+:14].[P:1]([O-:13])([O:6][CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:3][CH2:4][CH3:5])=[S:2]
Reactant: [OH-]
Reactant: CCOP(=S)(Cl)OCC(C)(C)C
Agent: [K+]
Solvent: CCO
Product: CCOP([O-])(=S)OCC(C)(C)C
Temperature: 22 °C
Reaction time: 60 h

Procedure:
Sixty One grams (260 mmole) of O-ethyl O-neopentyl chlorothiophosphate and 33.7 g (530 mmole) of 88% potassium hydroxide were mixed in 300 ml of ethyl alcohol and stirred at 22° C. for 60 hours. The precipitated potassium chloride was filtered off and the ethyl alcohol removed in vacuo. The resulting solid was washed with hexanes and diethyl ether yielding the title compound, a white solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH2:11][C@H:10]1[O:30][CH3:31])C1C=CC=CC=1>CO.C(#N)C.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:26]3[C:21](=[C:22]([F:28])[CH:23]=[C:24]([F:27])[CH:25]=3)[CH:20]=[CH:19][C:18]2=[O:29])[CH2:11][C@H:10]1[O:30][CH3:31]
Reactant: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: CO[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@@H]1N
Reaction time: 4 h
Yield: 90.2 %

Procedure:
Cis(±)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one (Intermediate 168, 240 mg, 0.46 mmol) was hydrogenated in methanol/acetonitrile (10 mL, 9:1) over palladium hydroxide on carbon (20%, 120 mg) at room temperature and normal pressure for 4 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to dryness under reduced pressure to give 140 mg (90%) of crude product. This was used without further purification.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][CH2:20][C:21]2[C:22]([NH:29][CH3:30])=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=2)=[C:12]([CH3:31])[CH:11]=1.CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[F:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([N:19]2[CH2:20][C:21]3[C:22](=[N:23][C:24]([S:27][CH3:28])=[N:25][CH:26]=3)[N:29]([CH3:30])[C:4]2=[O:3])=[C:12]([CH3:31])[CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CNc1nc(SC)ncc1CNc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1cc([N+](=O)[O-])c(F)cc1C)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.7 %

Procedure:
To a solution of diphosgene (0.85 mL, 7.2 mmol) in anhydrous dioxane (20 mL) was added a solution of 5-((4-fluoro-2-methyl-5-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (2.2 g, 6.5 mmol) and Et3N (1.32 g, 13 mmol) in anhydrous dioxane (50 ml) at 0° C. After the addition, the resulting mixture was stirred at 50° C. overnight. Water was added and the mixture was neutralized with saturated Na2CO3 solution to pH 8. The dioxane was removed in vacuo, and the aqueous layer was extracted with EtOAc (3×60 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated. The residue was washed with ether and dried in vacuo to afford 3-(4-fluoro-2-methyl-5-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (2 g, 84%). 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1 H), 7.97 (d, J=8 Hz, 1 H), 7.18 (d, J=12 Hz, 1 H), 4.73 (d, J=14.8 Hz, 1 H), 4.42 (d, J=14.8 Hz, 1 H), 3.40 (s, 3 H), 2.52 (s, 3 H), 2.25 (s, 3 H); MS (ESI) m/z: 364.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[C:12]3[NH:13][CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16](=O)[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:27]>>[Cl:27][C:16]1[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[CH:10][C:11]=12
Reactant: CCOC(=O)c1c[nH]c2c(cnn2Cc2ccc(OC)cc2)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Cl

Procedure:
Ethyl 1-(4-methoxybenzyl)-4-oxo-4,7-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carboxylate 2 and POCl3 were heated at 80° C. in a sealed tube for 3 hours. Reaction mixture was concentrated in vacuo, diluted with diethylether, washed with water, dried over sodium sulfate and concentrated in vacuo to afford product 3 as off white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([C:9]#[N:10])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:19]1COCC1>>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[O:8][N:7]=[C:6]([CH:9]([NH2:10])[CH3:19])[CH:5]=1
Reactant: CC(C)(C)Cc1cc(C#N)no1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(N)c1cc(CC(C)(C)C)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
The solution of 5-(2,2-dimethyl-propyl)-isoxazole-3-carbonitrile ([943925-83-5] 16 g, 97.5 mmol) in THF (160 ml) was cooled in an ice bath and under an atmosphere of nitrogen methylmagnesium chloride (3 M solution in THF, 51 ml, 127 mmol) was added slowly so that the reaction temperature did not rise above 10° C. The reaction was stirred for 1 h at rt. LiAlH4 (1 M solution in THF, 110 ml, 110 mmol) was added over 10 min keeping the reaction temperature below 40° C. The reaction was heated at reflux temperature for a few minutes and then stirred at rt for 1 h. The reaction was quenched be the slow addition of water (5 ml) keeping the temperature below 50° C., then cooled with an ice bath and aqueous NaOH (4 M, 5 ml) was added. The reaction mixture was diluted with diethylether (200 ml) and extracted with 1 N aqueous hydrochloric acid. The aqueous layers were combined, basified with concentrated aqueous ammonia and extracted with diethylether. The organic layers were dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound as yellow oil (13.8 g, 77%). [1H-NMR (DMSO-d6, 600 MHz) δ 6.21 (s, 1H), 3.95 (q, 1H), 2.49-2.47 (m, 2H), 1.89 (br s, 2H), 1.25 (d, 3H), 0.90 (s, 9H]
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=C(C=CC=1OC)C=O.ON1C2C=CC=CC=2N=N1.CCN1C2C=CC(S([O-])(=O)=O)=CC=2S/C/1=N\N=C1/SC2C=C(S([O-])(=O)=O)C=CC=2N/1CC.[NH4+].[NH4+]>C(O)C>[C:1]1([CH:7]=[CH:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC=Cc1ccccc1
Agent: CCn1/c(=N/N=c2\sc3cc(S(=O)(=O)[O-])ccc3n2CC)sc2cc(S(=O)(=O)[O-])ccc21
Agent: COc1ccc(C=O)cc1OC
Agent: On1nnc2ccccc21
Solvent: CCO
Product: O=CC=Cc1ccccc1
Reaction time: 0.17 h
Yield: 48 %

Procedure:
213 mg (1.59 mmol) of 3-phenyl-2-propen-1-ol in 1.1 ml of ethanol were treated at 45° C. with stirring into 22 ml of buffer solution (see Example 1) with 24.3 mg (0.180 mmol) of 1-hydroxy-1H-benzotriazole. After approx. 10 minutes, 5 ml of an aqueous solution of 2 mg/ml laccase from Trametes versicolor (specific activity approx. 18 IU/mg, defined with ABTS as the substrate) were added. After 3 hours in contact with the air, 48% of 3-phenyl-2-propenal were formed (GC analysis), and a further 24.3 mg of HOBT and 5 ml of laccase solution were added. GC analysis after 6 hours revealed complete conversion into 3-phenyl-2-propenal.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:25][O:24][C:22]1[CH:21]=[CH:20][C:19]([N+:26]([O-:28])=[O:27])=[C:18]([C@@H:13]([OH:12])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH:23]=1
Reactant: COc1ccc([N+](=O)[O-])c([C@@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c([C@@H](O)C(C)(C)C)c1
Yield: 99.4 %

Procedure:
A mixture of (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (590 mg, 1.4 mmol) and K2CO3 (389 mg, 2.8 mmol) in methanol (MeOH, 25 mL) was heated to reflux for one hour, then cooled down, concentrated in vacuo, and diluted with CH2Cl2 (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield enantiopure (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (333 mg, 99%). 1H NMR was identical with that of the racemic alcohol.