Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][C:4]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])([CH2:30][CH2:31][C:32]([OH:34])=[O:33])[CH2:3]1.N12CCCN=C1CCC[CH2:42][CH2:41]2.ICC>CN(C)C=O>[CH2:41]([O:33][C:32](=[O:34])[CH2:31][CH2:30][C:4]1([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:3][C:2](=[O:1])[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:29]4[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=4[CH:23]=[CH:22][CH:21]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5]1)[CH3:42]
Reactant: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCI
Product: CCCc1c(OCCCOc2cccc3c2CCCC3)ccc2c1OC(CCC(=O)O)(CCC(=O)OCC)CC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the titled product of Example 43 (676 mg, 1.25 mmol) in 5 ml of dimethylformamide (DMF) was added 190 mg (1.25 mmol) of 1,8-diazabicyclo (5.4.0)undec-7-ene followed by 585 mg (3.75 mmol) of iodoethane. After stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2. The solution was then washed with 3N hydrochloric acid, dried (Na2SO4), filtered, and the solvent removed on a rotary evaporator. The residue was chromatographed on a silica gel column. Elution with 35% ethyl acetate/61.5% hexane/2.5% acetic acid as eluent produced the title product which was crystallized from 3:1 hexane:ethyl acetate to give 183 mg, m.p. 83.5°-84.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH2:25])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([O:23][CH3:24])=[CH:21][C:20]([NH:25][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ncc(N)cc3OC)cc2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CC1CCC(c2ccc(-c3ncc(Nc4ccccc4)cc3OC)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-Amino-3-methoxy-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.12 g, 0.3 mmol, 1.0 equiv) and phenyl boronic acid (0.082 g, 0.67 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.054 Ml, 0.67 mmol, 2.0 equiv), copper (II) acetate (0.092 g, 0.50 mmol, 1.5 equiv), and 4 Å molecular sieves. The heterogeneous reaction mixture was allowed to stir open to atmosphere for 18 h. Removal of solvent and purification by silica gel chromatography (40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.31 (m, 2H) 1.50 (br. S., 1H) 1.55 (dd, J=12.51, 2.40 Hz, 2H) 1.87 (d, J=12.38 Hz, 5H) 2.31 (d, J=6.57 Hz, 2H) 3.66 (s, 3H) 3.86 (s, 3H) 6.96 (t, J=7.33 Hz, 1H) 7.20-7.38 (m, 7H) 7.82 (d, J=8.34 Hz, 2H) 8.11 (d, J=2.02 Hz, 1H) 8.53 (s, 1H); (M+H)+431.2.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13](Cl)[N:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(SC1C(C(OC)=O)=C(SCC2C=CC=CC=2)N=C(Cl)N=1)C1C=CC=CC=1.[OH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:1]([S:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N:52]2[CH2:53][CH2:54][CH:49]([OH:48])[CH2:50][CH2:51]2)[N:12]=[C:11]([Cl:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1c(Cl)nc(Cl)nc1SCc1ccccc1
Agent: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1SCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)c1c(SCc2ccccc2)nc(Cl)nc1N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-benzylthio-5-methoxycarbonyl-2,6-dichloropyrimidine and 4,6-dibenzylthio-5-methoxycarbonyl-2-chloropyrimidine (prepared in the above (3)) 97 mg, 4-hydroxypiperidine 29 mg, triethylamine 29 mg and toluene 2.5 mg is stirred at room temperature for 4 hours. Further, 4-hydroxypiperidine 3 mg and triethylamine 3 mg are added thereto, and the mixture is stirred for 30 minutes. The reaction mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo to give 4-benzylthio-5-methoxycarbonyl-6-(4-hydroxypiperidine-1-yl)-2-chloropyrimidine as a colorless caramel, 120 mg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14]O)[C:9]=1[CH3:16].S(Cl)([Cl:19])=O>ClCCl>[ClH:19].[Cl:19][CH2:14][C:10]1[C:9]([CH3:16])=[C:8]([S:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1c(SCc2ccco2)ccnc1CO
Solvent: ClCCl
Product: Cc1c(SCc2ccco2)ccnc1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10.0 g (0.042 mol) of 4-(2-furylmethylthio)-2-hydroxymethyl-3-methylpyridine are dissolved in dichloromethane (100 ml), 1.2 equivalents of thionyl chloride are added dropwise at RT, and the mixture is stirred at RT for 20 h. The mixture is concentrated fully, which gives the title compound as an oily residue which crystallizes slowly and which, if desired, can also be used directly as a solution in ethanol for the reaction with substituted 2-mercaptobenzimidazoles. For purification, it is recrystallized from hot isopropanol with an addition of active charcoal. This gives 9.0 g (74% of theory) of the title compound as colorless crystals of m.p. 159°-161° C. (decomp.).
Reaction SMILES: [OH-].[Na+].[CH2:3]1[C:10](=[O:11])[NH:9][C:7](=[S:8])[NH:6][C:4]1=[O:5].[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br>C(O)C.O.C(O)C.O>[F:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][S:8][C:7]1[NH:6][C:4](=[O:5])[CH2:3][C:10](=[O:11])[N:9]=1
Reactant: O=C1CC(=O)NC(=S)N1
Reactant: Fc1cccc(CBr)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CC(=O)NC(SCc2cccc(F)c2F)=N1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
Sodium hydroxide (6.1 g) in ethanol (20 ml) and water (20 ml) was added to a suspension of 4,6-dihydroxy-2-thiopyrimidine in ethanol/water (120 ml/120 ml). 2,3-difluorobenzyl bromide (28.4 g) was added dropwise to this solution. The mixture was heated at 60° C. for 2 h and stirred at room temperature for 20 h. The solids were filtered and washed with water (200 ml), isopropanol (20 ml) and dried in vacuo at 40° C. for 24 h to yield the subtitle compound. Yield 31.0 g.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][C:32]#[C:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:11][C:10]1([CH3:12])[S:9][CH2:8][CH2:7][N:6]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:34][C:33]#[C:32][CH2:31][CH2:30][O:29][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:5]1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCCOC1CCCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCOC3CCCCO3)cc2)CCSC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.7 %

Procedure:
To a solution of 3.31 g (9.6 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.12 g (11.5 mmol) of 5-(tetrahydro-2H-pyran-2-yloxy)-2-pentyn-1-ol in 15 mL of THF was added 3.0 g (11.5 mmol) of triphenylphosphine, followed by dropwise addition of 1.8 mL (11.5 mmol) of diethyl azodicarboxylate. The resulting solution was stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:9) to provide 3.03 g (62%) of methyl 2,2-dimethyl-4-[(4-{[5-(tetrahydro-2H-pyran-2-yloxy)-2-pentynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[N:4]1.[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][N:3]([CH2:2][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[CH:7]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: FC(F)(F)c1cnn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C(F)(F)F)cn1
Yield: 18.8 %

Procedure:
0.60 g of 1-(chloromethyl)-4-(trifluoromethyl)-1H-pyrazole and 0.54 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.99 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-chloroform to obtain 0.19 g of {[4-(trifluoromethyl)-1H-pyrazole-1-yl]methyl}(3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (22), hereinafter) shown by below formula.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:10]=[N:11][C:12](=[O:14])[CH:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].S(O[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]([C:37]1[CH:38]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=2[Cl:56])[C:39]([C:45]([O:47][CH3:48])=[O:46])=[C:40]([CH3:44])[NH:41][C:42]=1[CH3:43])=[O:36])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:3]1([C:9]2[NH:10][N:11]=[C:12]([O:14][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]([C:37]3[CH:38]([C:49]4[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[C:50]=4[Cl:56])[C:39]([C:45]([O:47][CH3:48])=[O:46])=[C:40]([CH3:44])[NH:41][C:42]=3[CH3:43])=[O:36])[CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C=C(c2ccccc2)N=N1
Reactant: [H][H]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOS(=O)(=O)c2ccc(C)cc2)C1c1cccc(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCOc2cc(-c3ccccc3)[nH]n2)C1c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
0.51 g (12 mmole) of 55% sodium hydride in mineral oil was suspended in 10 ml of N,N-dimethylformamide, to which was added gradually 2.40 g (15 mmole) of 3-phenyl-5-pyrazolone with stirring at room temperature. After evolution of hydrogen had ceased, to this solution was added dropwise 20 ml of a solution of 6.10 g (10 mmole) of the 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-tosyloxyhexyl ester obtained in the above Step i in N,N-dimethylformamide, and stirring with heating at 60° C. was continued for 4 hours. The resultant reaction mixture was poured into 150 ml of ice water, and the separated product was extracted with 50 ml of ethyl acetate. This ethyl acetate solution was washed with 50 ml of water three times, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a brown oily residue. This residue was chromatographed on a silica gel column using a chloroform-methanol mixed solution as an eluent, and the eluate fractions containing the intended compound were concentrated under reduced pressure to obtain crystals. These crystals were recrystallized from a mixed solution of benzene-hexane to obtain 2.63 g (yield 43.9%) of the 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3-methoxycarbonylpyridine-5-carboxylic acid 6-(5-phenyl-3-pyrazolyloxy)hexyl ester.
Reaction SMILES: [C:1]1([N:7](C2C=CC=CC=2)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:19])=O.CN(C=O)C.S([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)([O-])(=O)=O.C[N+]1C2C=CC=CC=2SC=1C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl-:19].[C:1]1([N+:7]2[C:36]3[C:34](=[CH:33][CH:32]=[CH:31][CH:37]=3)[CH:35]=[CH:9][C:8]=2[Cl:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CN(C)c1ccncc1
Agent: Cc1sc2ccccc2[n+]1C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1ccc2ccccc2[n+]1-c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The intermediate N-phenyl-2-chloroquinolinium chloride is prepared according to the literature method (Marson, TETRAHEDRON, 48, 3659 (1992)). Thus 1.06 g (5 mmoles) of N, N-diphenyl acetamide is heated with 1.69 g (11 mmoles) of phosphorous oxychloride and 0.44 g (6 mmoles) of DMF at 120° C. for 2 hours. The reaction mixture is cooled to room temperature and 15 mL of methylene chloride is added to dissolve the residue. To the solution is added 1.68 g (5 mmoles) of N,2-dimethylbenzothiazolium tosylate and 1.46 g (12 mmoles) of 4-dimethylaminopyridine, and the reaction is stirred overnight (Elderfield, supra). The crude product is first purified on a silica gel column eluting with 2:2:1 ethyl acetate/chloroform/methanol and then metathesized to the iodide salt and recrystallized from methanol to obtain the pure product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>C1CCCCC1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:26])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: C1CCCCC1
Product: CCOC(=O)CC(=Nc1ccc(C(=O)OCC)cc1)c1ccccc1

Procedure:
4-Amino-benzoic acid ethyl ester (66 g, 0.4 mol) and 3-oxo-3-phenyl-propionic acid ethyl ester (0.4 mol, 1 eq.) were dissolved in 500 mL cyclohexane and refluxed for 2 days using a Dean-Stark trap. The solution was filtered, the solvent evaporated and the residue recrystallized to give 4-(2-ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester (Compound 481a) MS: 340.18 (M+H+). 4-(2-Ethoxycarbonyl-1-phenyl-ethylideneamino)-benzoic acid ethyl ester was dissolved in diphenyl-methanone (250 mL) and heated to 250° C. for 4 hr. The resulting solution was diluted with diethyl ether and filtered to give 48.6 g of the title intermediate as a white crystalline solid.
Reaction SMILES: CC1N(C(C(Cl)Cl)=O)[C:10]2C=CC=[CH:6][C:5]=2[O:4]C1.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([O-:19])=[O:18].ClCC(=O)C>>[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:10][C:5](=[O:4])[CH3:6])([O-:19])=[O:18]
Reactant: CC1COc2ccccc2N1C(=O)C(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: CC(=O)CCl
Product: CC(=O)COc1ccccc1[N+](=O)[O-]

Procedure:
The preparation of benoxacor, a safener in the use of herbicides, is a three-stage process: in the first stage, o-nitrophenol is reacted with chloroacetone to give o-nitrophenoxyacetone; in the second stage, the compound is hydrogenated so as to obtain a benzoxazine, which is then acylated. This process is described in EP1283829.
Reaction SMILES: [Na].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].Cl>CO>[O:8]([C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: [Na]
Solvent: CO
Product: O=C(O)c1cccnc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
55.2 g of sodium was added portionwise to 1500 ml of anhydrous methanol. When the reaction was complete 120 g of phenol and 200 g of 2-chloronicotinic acid were added, and the mixture was heated until completely solubilized. The methanol was removed by distillation, and the residue heated to 180°-200° C. for 5 minutes. The molten mass was cooled to about 100° C., and water was added slowly. The solution obtained was acidified with hydrochloric acid. After standing for about 16 hours, the solid obtained was filtered and dried, giving 237.4 g of 2-phenoxynicotinic acid, as white crystals, m.p. 179-181° C. (Kofler micro hot-stage); neutralization equivalent: 215.20 (calculated 216.55).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.CC#N.O>C(O)CCC>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:17]2)[NH:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: O
Solvent: CC#N
Solvent: CCCCO
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 155 °C
Yield: 81.7 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (400 mg, 1.47 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.0 g, 5.15 mmol) were placed in n-butanol (4 mL) and heated to 155° C. in a sealed tube for 18 hours. The reaction was then cooled and concentrated. The resulting residue was purified by C-18 reverse phase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-85% CH3CN/water) to give (R)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (543 mg, 77% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.[CH3:17][O:18][C:19](Cl)=[O:20]>CN(C=O)C.C(OCC)(=O)C.O>[CH3:17][O:18][C:19]([N:10]1[C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[CH:6][C:5]=2[CH:8]=[C:9]1[C:11]1[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=1)=[O:20]
Reactant: COC(=O)Cl
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)n1c(-c2cnn(C)c2)cc2cnc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.36 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.55 ml of a 1M solution in THF, 0.55 mmol) was added. After 20 minutes reaction, methylchloroformate (52 mg, 0.55 mmol) was added and the reaction stirred for 2 hours at room temperature. The reaction was diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate followed by 2% methanol in ethyl acetate to afford the title compound as a white powder (95 mg, 79%). 1H NMR (500 MHz, CDCl3) 3.96 (s, 3H), 4 (s, 3H), 6.57 (s, 1H), 7.63 (s, 1H), 7.64 (s, 1H), 8.1 (s. 1H), 8.53 (s, 1H)
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[N:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=4)[CH:13]=3)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.O.O.O.P([O-])([O-])([O-])=[O:44].[K+].[K+].[K+]>COCCOC.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>[Br:24][C:21]1[CH:20]=[N:19][C:18]([C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[CH2:11][N:8]2[C:6]3=[N:7][C:2]([O:44][C:29]4[CH:28]=[N:27][N:26]([CH3:25])[CH:30]=4)=[CH:3][N:4]=[C:5]3[N:10]=[N:9]2)=[N:23][CH:22]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnc(-c2cccc(Cn3nnc4ncc(Br)nc43)c2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(Oc2cnc3nnn(Cc4cccc(-c5ncc(Br)cn5)c4)c3n2)cn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
500 mg (0.932 mmol) of 6-bromo-1-[3-(5-bromopyrimidin-2-yl)benzyl]-1H-1,2,3-triazolo[4,5-b]pyrazine, 213 mg (1.03 mmol) of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 396 mg (1.86 mmol) of tripotassium phosphate trihydrate are suspended in 20 ml of ethylene glycol dimethyl ether, degassed, evacuated and flushed with nitrogen a number of times. 65.4 mg (0.093 mmol) of bis(triphenylphosphine)palladium(II) chloride (15.2% of Pd) are added, and the mixture is again evacuated and flushed with nitrogen. The reaction mixture is stirred at 80° C. for 24 h. The reaction mixture is filtered, water is added to the filtrate, and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate, evaporated under reduced pressure in a rotary evaporator and purified column-chromatically on silica gel.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(OO)(=[O:26])C.CC(O)C>C(O)=O.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:26])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: CC(=O)OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: [Pd]
Solvent: O=CO
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 16 h

Procedure:
Thebaine (100 g, 0.321 mol) was dissolved in formic acid (100 g) and acetic acid (100 g); volume 253 ml. Solution 2: Peracetic acid (39% in acetic acid, 63.25 g, 0.325 mol) was diluted with acetic acid to give a solution of 85 ml volume. The two solutions were pumped through the continuous flow reactor in the ratio 6 ml/min solution 1 to 2 ml/min solution 2 at 20° C. (4 min residence time). An analytical control after the continuous reactor showed less than 4% Thebaine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (60 g), formic acid (98-100%, 10 g) and 5% Pd/C (2.5 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The yields were 74% for the base and 73% for the HCl salt. The 14-hydroxy-codeinone content of the base was 27 ppm and of the HCl salt <10 ppm.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3](=[O:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[CH:13]=[CH:14][CH2:15][Mg]Cl.[CH2:18]1COCC1>>[CH2:7]([O:6][C:4](=[O:5])[C:3]([OH:9])([C:2]([F:10])([F:11])[F:1])[CH2:18][C:14]([CH3:15])=[CH2:13])[CH3:8]
Reactant: CC=CC[Mg]Cl
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C1CCOC1
Product: C=C(C)CC(O)(C(=O)OCC)C(F)(F)F
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of ethyl trifluoropyruvate (124.84 g, 0.734 mol) in 2.0 L of THF was treated with methylallyl magnesium chloride (0.5 M in THF, 1.90 L, 0.954 mol) over 4 hours while the internal temperature was maintained below −60° C. The reaction mixture was allowed to reach room temperature overnight, concentrated in vacuo to remove THF, quenched with 1 L of saturated ammonium chloride solution, and extracted with three 1 L portions of diethyl ether. The combined organic phases were washed with 100 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Vacuum distillation at 60 mmHg afforded 100.1 g of 2-hydroxy-4-methyl-2-trifluoromethylpent-4-enoic acid ethyl ester as a clear oil (b.p. 97° C.-103° C., 60% yield).