Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24].[C:26]1([C:37]2CCCCCCCCCC=2)[CH2:36]CCCCCCCNN=1.C(I)CC>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([OH:25])/[CH:7]=[CH:8]/[C@@H:9]1[C@@H:13]([CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH:26]([CH3:37])[CH3:36])=[O:21])[C@@H:12]([OH:23])[CH2:11][C@H:10]1[OH:24]
Reactant: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@H]1O
Solvent: CC(C)=O
Solvent: CCCI
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC(C)C)[C@@H](O)C[C@H]1O
Reaction time: 8 h

Procedure:
20 mg (0,056 mmol) of 11 epi PGF2alpha (Cayman Chemicals, U.S.) were dissolved in acetone at room temperature. To this solution were added 54.5 mg (0.336 mmol) of diazabicycloundecene (DBu) and 76.15 mg (0.448 mmol) of propyl iodide, whereupon the mixture was left to stand at room temperature for 8 hours. The solvent was removed in vacuo, the residue then being dissolved in 50 ml of ethyl acetate, washed with 20 ml of water, 20 ml of 3% citric acid and 5% sodium hydrogen carbonate; thereafter the organic phase was dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by means of column chromatography on silica gel, with ethyl acetate-acetone (1:1) as the eluent. The yield of the product was about 76%, and its purity was tested by means of thin layer chromatography and NMR.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12](Cl)=[O:13].Cl>C1COCC1.CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CNC(=O)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Glycine (8.26 g, 110 mmol) was dissolved in 2M NaOH (125 ml, 250 mmol). The resulting colorless solution was cooled to 0° C. and 3,4-difluorobenzoyl chloride (12 mL, 95 mmol) in 60 mL of THF was added dropwise over 10 minutes. The reaction was stirred for 1 hour at 0° C. and allowed to warm to room temperature over 2 hours. The reaction was acidified to pH 1 with concentrated HCl while cooling in an ice bath. 100 mL of EtOAc was added and the mixture was poured into a separatory funnel and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water and brine (50 mL each), dried with sodium sulfate, filtered and concentrated in vacuo to about 30 mL whereupon a solid began to crystallize. The mixture was allowed to stand overnight. The solid residue was concentrated on a rotary evaporator to remove the remaining EtOAc and then dried in a vacuum oven at 40° C. to provide the desired product, 2-(3,4-difluorobenzamido)acetic acid as an off-white solid (20.73 grams, 96%). LCMS (+ESI) m/z 216.2 [M+H]+. 1H-NMR (CDCl3) δ 12.70 (br s, 1H), 9.00 (t, 1H), 7.90 (m, 1H), 7.75 (m, 1H), 7.55 (m, 1H), 3.90 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17](Br)=[N:16][C:15]=4[N:14]([CH3:27])[C:12]3=[O:13])=[N:7][C:6]=2[CH:28]=1.[C:29]([O:33][C:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][N:38](N)[CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].O.C[N:51](C)C=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][N:11]3[C:20](=[O:21])[C:19]4[N:18]([CH2:22][C:23]#[C:24][CH3:25])[C:17]([N:38]5[CH2:39][CH2:40][CH2:41][CH:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[C@@H:37]5[NH2:51])=[N:16][C:15]=4[N:14]([CH3:27])[C:12]3=[O:13])=[N:7][C:6]=2[CH:28]=1
Reactant: CC#CCn1c(Br)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN(N)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC#CCn1c(N2CCCC(C(=O)OC(C)(C)C)[C@@H]2N)nc2c1c(=O)n(Cc1nc3cc(Cl)ccc3s1)c(=O)n2C
Temperature: 25 °C
Yield: 72.6 %

Procedure:
By utilizing the well known method, 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine 3b (460 mg, 0.96 mmol) was dissolved in N,N-dimethylformamide (12 ml). (R)-3-tert-butoxycarbonyl-aminopiperidine (193 mg, 0.96 mmol) and potassium carbonate (200 mg, 1.44 mmol) were added to give a reaction mixture. The reaction mixture was reacted at 75° C. for 2 hours, and TLC was used to monitor the reaction progress. After the reaction was completed, the obtained reaction mixture was cooled to room temperature. The cooled reaction solution was poured into cool water, suction filtered, and the obtained solid was washed with water, dried to give 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-tert-butoxycarbonyl-amino-piperidin-1-yl]-xanthine 3c (417 mg, grey solid), yield: 72.6%.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH:30][C:20]([C:3]1[CH:4]=[N:5][N:6]([C:7]2[CH:12]=[C:11]([C:13](=[O:18])[NH:14][CH:15]3[CH2:17][CH2:16]3)[CH:10]=[CH:9][C:8]=2[CH3:19])[C:2]=1[NH2:1])=[O:22]
Reactant: CC1CCCCC1N
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)O)c1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)NC2CCCCC2C)c1N
Yield: 68.7 %

Procedure:
A solution of 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (21 mg), 2-methylcyclohexylamine (10 mg), EDCI (28 mg) and HOBt (12 mg) in DMF (0.75 ml) was reacted at room temperature for 24 h. Water (4 ml) was added and the solution was extracted with ethyl acetate (3 mL×2). The organic phase was then washed with water (3 mL), dried over Na2SO4 and evaporated. The residue was purified by preparative TLC plate to give the desired product 5-amino-1-(5-cyclopropylcarbamoyl-2-methylphenyl)-1H-pyrazole-4-carboxylic acid (2-methylcyclohexyl)-amide (19 mg, 70%). HPLC (4 minute gradient) tR 2.34 min; MS m/z 396.31 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 21.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzoxazole (81.2 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in 1,4-dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (11.3 mg, 21.2%) as white solid. 1HNMR (CDCl3) 500 MHz δ: 8.27 (dd, J=7.7, 1.7 Hz, 1H), 8.08-8.02 (m, 1H), 7.75-7.68 (m, 1H), 7.52-7.38 (m, 5H), 7.37-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.92-6.81 (m, 1H), 6.63 (dd, J=8.0, 4.6 Hz, 1H), 6.45 (s, 1H), 5.20 (s, 1H), 2.68-2.25 (m, 4H), 2.22-2.09 (m, 1H), 1.97-1.86 (m, 1H), 1.54-1.11 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].[Br:14]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(OCC)(=O)C>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CBr)c(OC)c1
Yield: 89 %

Procedure:
A mixture of methyl 3-methoxy-4-methylbenzoate (10.0 g, 55.5 mmol), N-bromosuccinimide (10.7 g, 60.9 mmol), 2,2′-azobis(isobutyronitrile) (1.6 mg) and ethyl acetate (200 ml) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and hexane was added to the residue. The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (9:1-7:3, v/v) to give the title compound (12.8 g, 92%) as a colorless oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:11][N:10]=1.C(N(CC)CC)C.ClCCl>O1CCCC1>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:13]2[C:12]([O:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCNCC2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2nc(N)ncc2Oc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 59.9 %

Procedure:
Acetic anhydride (Aldrich) (0.318 g, 3.11 mmoles) in tetrahydrofuran (1.5 mL) was added to a solution of 2-amino-5-(4-chlorophenoxy)-4-(piperazino)pyrimidine (0.511 g, 1.67 mmoles) and triethylamine (0.526 g, 5.20 mmoles) in tetrahydrofuran (13 mL). After 0.5 hours the solution was diluted with ice water (40 mL) and poured into dichloromethane (75 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (40 mL), brine (40 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give a white foam. The foam was recrystallized from hexanes-ethyl acetate to give 0.348 g (60% yield) of 4-(4-acetylpiperazino)-2-amino-5-(4-chlorophenoxy)pyrimidine as beige pins, mp 153-157° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:9]([OH:10])=[CH:8][C:7]([OH:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[Cl:14][CH2:15][CH2:16][CH2:17]Br.CC(C)=O>O>[Cl:14][CH2:15][CH2:16][CH2:17][O:11][C:7]1[C:6]([O:12][CH3:13])=[CH:5][C:4]([C:2](=[O:3])[CH3:1])=[C:9]([OH:10])[CH:8]=1
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)c(O)cc1O
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C(C)=O)c(O)cc1OCCCCl
Yield: 70.3 %

Procedure:
A mixture of 2,4-dihydroxy-5-methoxyacetophenone (1.4 g, 7.7 mmol), K2O3 (1.4 g, 10.0 mmol), 3chlorobromopropane (1.6 g, 10.0 mmol) and acetone (25 mL) was stirred and refluxed under N2 for 16 hours. The reaction was poured into H2O, and the aqueous suspension was extracted with ethyl acetate. The extract was washed (H2O, brine) dried (MgSO4) and concentrated to yield 1.4 g of an off-white solid. Recrystallization twice from ethanol afforded 0.4 g of the alkylated phenol as a solid, m.p. 99°-101° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:69])[C:43]=1[C:44](=[O:68])[NH:45][C@H:46]([C:65]([OH:67])=[O:66])[CH2:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=2[CH3:60])=[CH:50][CH:49]=1)[CH2:5][NH:6][CH2:7][C:8]1[CH:38]=[C:37]([F:39])[C:11]([C:12]([NH:14][C@@H:15]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[C:27](=[O:36])[N:28]([CH3:35])[C:29](=[O:34])[N:30]([CH3:33])[C:31]=3[CH3:32])=[CH:22][CH:21]=2)[C:16](O)=[O:17])=[O:13])=[C:10]([F:40])[CH:9]=1.[CH3:70][OH:71].[CH3:72]C(=O)OCC>C(Cl)Cl>[CH3:70][O:71][C:16](=[O:17])[C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[C:37]([F:39])=[CH:38][C:8]([CH2:7][NH:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[C:43]([C:44](=[O:68])[NH:45][C@H:46]([C:65]([O:67][CH3:72])=[O:66])[CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]4[C:55](=[O:64])[N:56]([CH3:63])[C:57](=[O:62])[N:58]([CH3:61])[C:59]=4[CH3:60])=[CH:52][CH:53]=3)=[C:42]([F:69])[CH:41]=2)=[CH:9][C:10]=1[F:40])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[C:27](=[O:36])[N:28]([CH3:35])[C:29](=[O:34])[N:30]([CH3:33])[C:31]=2[CH3:32])=[CH:24][CH:25]=1
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cc(CNCc4cc(F)c(C(=O)N[C@@H](Cc5ccc(-c6c(C)n(C)c(=O)n(C)c6=O)cc5)C(=O)O)c(F)c4)cc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Reactant: CO
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cc(CNCc2cc(F)c(C(=O)N[C@@H](Cc3ccc(-c4c(C)n(C)c(=O)n(C)c4=O)cc3)C(=O)OC)c(F)c2)cc1F
Reaction time: 8 h

Procedure:
To a flask containing (S)-2-[4-[[3,5-difluoro-4-[(S)-1-carboxy-2-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]ethylcarbamoyl]benzylamino]methyl]-2,6-difluorobenzoylamino]-3-[4-[1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]phenyl]propionic acid (560 mg, 0.59 mmol) was added methanol (50 mL) and TMSCI (398 mg, 460 mL, 3.66 mmol) and the reaction was stirred overnight. Reaction was diluted with EA (10 mL), DCM (140 mL) and was washed with aqueous NaHCO3 solution (water:saturated solution 50 mL:50 mL, 10 mL brine) and brine (100 mL). The organic layer was dried over MgSO4, filtered and concentrated yielding the title compound as a white solid and used directly as is. ES(+)-LRMS m/e calcd. for C50H49F4N7O10 (M+H)+ 984, obsd 984.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=O.[CH3:10][CH2:11]C(=O)CC.B(F)(F)F.CCOCC.O>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:10]/[CH3:11]
Reactant: O=Cc1ccccc1Cl
Reactant: CCC(=O)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: C/C=C/c1ccccc1Cl
Yield: 59.3 %

Procedure:
48 ml of 2-chlorobenzenaldehyde (0.42 mol) and 49.7 ml of 3-pentanone (0.47 mol) were dissolved in 600 mL of hexane in flask, and then stirred with raising the temperature. 53.6 ml of Boron trifluoride etherate (BF3OEt2, 0.42 mol) was added to the resultant under reflux conditions. When the reaction was completed, water was added thereto. After layer separation, the obtained organic layer was washed twice with 1M sodium hydroxide solution (1M NaOH), and then the separated organic layer was washed with water. The separated organic layer was dehydrated with anhydrous magnesium sulfate (MgSO4) and concentrated. The concentrated residue was purified by a silica gel column chromatography to produce the title compound (38 g, yield 58%). 1H NMR(400 MHz, CDCl3)δ1.94(d, J=4.8 Hz, 3H), 6.24(m, 1H), 6.78(d, J=14 Hz, 1H), 7.11˜7.51(m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([N+:11]([O-])=O)=[CH:5][N:4]=1>[Pd].CCOC(C)=O>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([NH2:11])[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc([N+](=O)[O-])cnc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(N)cnc1OC
Temperature: 50 °C

Procedure:
A stainless steel bomb was charged with 2,3-dimethoxy-5-nitropyridine (430 mg, 2335 μmol), 10% Pd/C (124 mg, 1168 μmol) and 4.7 mL EtOAc. The vessel was sealed and was purged with hydrogen once, before filling with hydrogen at a pressure of 2 atm. The reaction mixture was heated at 50° C. for 3 h. Upon cooling, the mixture was filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated and passed through a silica plug using 5% MeOH/DCM. The filtrate was concentrated to provide 5,6-dimethoxypyridin-3-amine as a peach colored oil that crystallized upon standing. GC/MS confirmed the correct mass to be [M+H]=155.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[C:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)([OH:14])=[O:13].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)C>[NH2:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1)(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccccc1-c1ccc(C(=O)O)cc1
Yield: 57.4 %

Procedure:
2-Bromobenzenesulfonamide (800 mg) and 4-carboxyphenyl boronic acid (563 mg) were suspended in a solvent mixture of toluene (5 mL) and water (5 mL). To the reaction mixture, tetrakis(triphenylphosphine)palladium (392 mg) and sodium carbonate anhydrate (1.08 g) were sequentially added, and the resultant mixture was heated under reflux overnight. The resultant mixture was cooled to room temperature, and diethyl ether and water were added thereto for partitioning the mixture. The organic layer was extracted twice with water. All the resultant aqueous layers were combined together, and 12N aqueous hydrochloric acid was added thereto to acidfy. The mixture was concentrated to about 20 mL under reduced pressure, and the precipitated colorless powder was recovered by filtration, followed by drying under reduced pressure, to thereby give the title compound (539 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:18]([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19](=[O:20])[CH:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[CH3:24])[CH3:23]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc2c(c1)OCO2
Temperature: 90 °C
Reaction time: 16 h

Procedure:
5-Hydroxybenzo[1,3]dioxole (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine, The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[N:14]=[CH:13][NH:12][N:11]=2)=[CH:5][CH:4]=1.OO.[OH2:19].S([O-])([O-])(=[O:22])=S.[Na+].[Na+]>C(O)(=O)C>[F:16][C:2]([F:15])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:10]2[N:14]=[CH:13][NH:12][N:11]=2)(=[O:22])=[O:19])=[CH:5][CH:4]=1
Reactant: O=S([O-])([O-])=S
Reactant: O
Reactant: FC(F)(F)c1ccc(Sc2nc[nH]n2)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)c1nc[nH]n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
76.4 g of 3-[4-(trifluoromethyl)phenylthio]-1,2,4-triazole synthesized by a method similar to that employed to prepare the precursor according to Reference Example 4 was dissolved in 400 ml of acetic acid, and 140 g of 30% hydrogen peroxide solution was added. Then, the temperature was gradually raised, and the solution was stirred at 100° C. for three hours. Then, the reactant solution was cooled to room temperature, and a water solution of sodium thiosulfate was added. Then, precipitate was filtered, so that 66.4 g of the titled compound was obtained (at a yield of 77%).
Reaction SMILES: [CH2:1]([O:3][NH:4][C:5](=[O:8])[CH2:6][Cl:7])[CH3:2].[CH:9]([N:12]=[C:13]=[O:14])([CH3:11])[CH3:10]>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:7][CH2:6][C:5]([O:8][C:13](=[O:14])[NH:12][CH:9]([CH3:11])[CH3:10])=[N:4][O:3][CH2:1][CH3:2]
Reactant: CCONC(=O)CCl
Reactant: CC(C)N=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCON=C(CCl)OC(=O)NC(C)C
Temperature: 25 °C

Procedure:
N-Ethoxychloroacetamide (6.9 grams; 0.05 mole), benzene (70 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. Isopropylisocyanate (5.1 grams; 0.06 mole) dissolved in benzene (20 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-isopropylcarbamoyloxy)-2-ethoxyiminoethane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10](O)[CH2:11][CH2:12][OH:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:13][CH2:12][CH2:11][CH2:10][O:6]2)[CH:7]=[CH:8][CH:9]=1
Reactant: OCCCO
Reactant: O=Cc1cccc(Cl)c1
Product: Clc1cccc(C2OCCCO2)c1

Procedure:
The title compound was prepared as a colourless oil, bp 95°-102° C./0.2 mm, from 3-chlorobenzaldehyde (24 g) and 1,3-propanediol (20 g) by an analogous procedure to that described in Example X 1.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)[CH:9]=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([C:29](=O)[CH3:30])[CH:16]=[CH:17][C:18]=1[CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]1.[O-]CC.[Na+]>ClCCl>[Cl:4][C:29]([C:15]1[CH:16]=[CH:17][C:18]([CH:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH2:20]2)=[C:13]([Cl:12])[CH:14]=1)=[CH:30][CH:9]=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(Cl)c1
Reactant: CN(C)C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CC(c2ccc(C(Cl)=CC=O)cc2Cl)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.51 ml of oxalyl chloride are added dropwise at a temperature of between −5° C. and 2° C. to a solution of 3.72 ml of dimethylformamide and 20 ml of anhydrous dichloromethane and the reaction mixture is then stirred at room temperature for 30 minutes. 3.92 g of 1-[3-chloro-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]ethanone (compound V.6) dissolved in 10 ml of dichloromethane are then added rapidly, after which the reaction mixture is stirred at room temperature for 12 hours. The reaction mixture is poured into a water/ice mixture and 20 ml of aqueous 2.84 M sodium ethoxide solution are then added. The resulting mixture is washed with 50 ml of sodium hydrogen carbonate solution and 50 ml of water, the phases are separated after settling has taken place, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The oil obtained is purified by chromatography on a column of silica gel, eluting with a 97/3 (v/v) cyclohexane/ethyl acetate mixture.