Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:20]([CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23](OCC)=[O:24])=[O:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13]>CCOC(C)=O>[Cl:13][C:12]1[CH:11]=[C:10]2[C:9](=[CH:8][C:7]=1[Cl:6])[C:14]1([CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:20](=[O:21])[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]2[OH:24]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccc(Cl)c(Cl)c2)CCOCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C2(CCOCC2)C1=O
Temperature: 50 °C

Procedure:
Concentrated H2SO4 (4203 μL) was added to solid diethyl 2-(4-(3,4-dichlorophenyl)-tetrahydro-2H-pyran-4-carbonyl)malonate (3.29 g, 7884 μmol) at ambient temperature. The reaction was heated at 50° C. for 6 hours and then poured into a flask of ice, diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the purified title compound (375 mg) after flash chromatography as a pale yellow solid. MS (m/z)=371 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH:36]1([CH2:39][N:23]2[C:24]3[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=3)[C:30](=[O:31])[N:21]([CH:18]3[CH2:19][CH2:20][N:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)[C:22]2=[O:35])[CH2:38][CH2:37]1
Reactant: BrCC1CC1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(CC5CC5)c4=O)CC3)c2cc1OC
Yield: 27 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and cyclopropylmethyl bromide was used in place of methyl iodide. As a result, 89 mg (yield: 27%) of Compound 26 was obtained as pale yellow crystals.
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:12]([CH2:13][S:14][C:15](=N)N)=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6])[CH3:3].[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:20]=1CBr.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH2:2]([O:4][C:5]([C:7]1[C:12]([CH2:13][S:14][CH2:15][C:20]2[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:19]=2[Cl:18])=[N:11][CH:10]=[CH:9][N:8]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1nccnc1CSC(=N)N
Reactant: FC(F)(F)c1ccc(Cl)c(CBr)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1nccnc1CSCc1cc(C(F)(F)F)ccc1Cl
Temperature: 120 °C

Procedure:
To a solution of 3-carbamimidoylsulfanylmethyl-pyrazine-2-carboxylic acid ethyl ester hydrobromide (0.367 g) in acetonitrile (2 ml) was added 2-chloro-5-trifluoromethyl-benzylbromide (commercially available) (0.294 g), potassium carbonate (0.316 g) and water (3 drops). The reaction mixture was heated to 120° C. for 10 minutes in the microwave. The reaction mixture was filtered and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluent: 0-10% v/v ethyl acetate in iso-hexane) to give Compound No. A2 of Table A.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[F:12][C:13]([F:23])([F:22])[C:14]([C:18]([F:21])([F:20])[F:19])([OH:17])[CH2:15]O.Cl.C1(C)C=CC=CC=1>N1C=CC=CC=1>[F:12][C:13]([F:22])([F:23])[C:14]([C:18]([F:19])([F:21])[F:20])([OH:17])[CH2:15][O:9][S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)(=[O:11])=[O:10]
Reactant: OCC(O)(C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
Under ice cooling, a solution of 54 g of p-toluene sulfonate in 140 g of pyridine was added dropwise to a mixture of 93 g of the 61 wt % IPE solution of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol prepared in Reference Synthesis Example and 140 g of pyridine. Stirring was continued for 48 hours at room temperature. The reaction solution was ice cooled and poured into a mixture of 678 g of 20 wt % hydrochloric acid aqueous solution and 100 g of ice to quench the reaction. Toluene, 500 g, was added to the reaction solution, which was separated into layers. The organic layer was washed with water, concentrated, and recrystallized from heptane, obtaining 74 g of 3,3,3-trifluoro-1-(p-toluene-sulfonyloxy)-2-trifluoromethylpropan-2-ol (yield 74%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].OC1C=CC([C:22]([NH:28]C)(C)C(OC)=O)=CC=1>>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([CH:2]([NH:28][CH3:22])[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)C(Br)c1cccc(OC)c1
Reactant: CNC(C)(C(=O)OC)c1ccc(O)cc1
Product: CNC(C(=O)OC)c1cccc(OC)c1

Procedure:
Starting from 14.5 g of methyl 2-bromo-2-(3-methoxyphenyl)acetate, 7.5 g of product are prepared by the process used above when preparing methyl 2-(4-hydroxyphenyl)-2-methylaminopropionate (yellow oil; Yd=65%).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([C:14]([OH:16])=O)=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:38][C:39]1[CH:56]=[C:55](/[C:57](=[N:59]/O)/[NH2:58])[CH:54]=[CH:53][C:40]=1[CH2:41][N:42]1[CH2:45][CH:44]([C:46]([O:48]C(C)(C)C)=[O:47])[CH2:43]1>CN(C=O)C>[Br:38][C:39]1[CH:56]=[C:55]([C:57]2[N:59]=[C:14]([C:4]3[C:3]([CH2:1][CH3:2])=[C:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[O:6][N:5]=3)[O:16][N:58]=2)[CH:54]=[CH:53][C:40]=1[CH2:41][N:42]1[CH2:43][CH:44]([C:46]([OH:48])=[O:47])[CH2:45]1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2Br)C1
Reactant: CCc1c(C(=O)O)noc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)c(Br)c3)no2)noc1-c1ccccc1
Temperature: 55 °C

Procedure:
A solution of 4-ethyl-5-phenylisoxazole-3-carboxylic acid, Int.5-D (7.83 mg, 0.036 mmol), EDCI (6.91 mg, 0.036 mmol), and HOBt (5.52 mg, 0.036 mmol) in DMF (2 mL) was stirred at RT for 5 minutes before being transferred to a flask containing (Z)-tert-butyl 1-(2-bromo-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.5-B (12.60 mg, 0.033 mmol). The reaction was placed in an oil bath and heated overnight at 55° C. then the temperature was raised to 90° C. for 3 hours. The solution was cooled and the volatiles were removed under vacuum. The resulting residue was treated with TFA (2 mL) at RT for 3 hours. The TFA was evaporated and the residue was treated with triethylamine (3-4 mL) before again being evaporated to dryness. The residue was loaded onto a 4 g silica gel Isco cartridge (which had been pre-equilibrated with DCM) and purified by flash chromatography. Eluent: 0-20% MeOH in DCM (plus 5% NH4OH). The product containing fractions were evaporated and placed under high vacuum to afford 1-(2-bromo-4-(5-(4-ethyl-5-phenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid as a pale yellow solid (13.1 mg, 0.024 mmol). The compound had an HPLC retention time=3.97 min.−Column: PHENOMENEX® Luna 3 u C18 4.6×30 mm (5 min. gradient; 4 mL/min); Solvent A=10% MeOH, 90% H2O, 0.05% TFA; Solvent B=90% MeOH, 10% H2O, 0.05% TFA. LC/MS M+1=509/511. 1H NMR (500 MHz, MeOD) δ ppm 1.39 (t, J=7.5 Hz, 3H), 3.11 (q, J=7.5 Hz, 2H), 3.36-3.44 (m, 1H), 3.92 (dd, J=8.5 Hz, 8.5 Hz 2H), 4.01 (dd, J=8.8 Hz, 9.0 Hz 2H), 4.26 (s, 2H), 7.56-7.72 (m, 4H), 7.81-7.83 (m, 2H), 8.22 (dd, J=6.3, 1.8 Hz, 1H), 8.42 (d, 1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][CH:13]3[N:15](C)[CH:10]([CH2:11][CH2:12]3)[CH:9]=2)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27]>ClCCCl.C(O)C>[C:24]([OH:30])(=[O:29])[CH2:25][C:26]([OH:28])=[O:27].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH:10]3[NH:15][CH:13]([CH2:12][CH2:11]3)[CH:14]=2)=[CH:6][CH:7]=1
Reactant: CN1C2C=C(c3ccc(Cl)cc3)CC1CC2
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(O)CC(=O)O
Solvent: ClCCCl
Solvent: CCO
Product: Clc1ccc(C2=CC3CCC(C2)N3)cc1

Procedure:
To a stirred solution of 3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene (2 g, 8.5 mmol) in anhydrous 1,2-dichloroethane (20 mL) under a nitrogen atmosphere was added 1-chloroethyl chloroformate (1.25 mL, 11.6 mmol). The reaction mixture was heated at reflux overnight, then added 1-chloroethyl chloroformate (1 mL, 9.3 mmol), once again the reaction mixture was heated at reflux overnight. The reaction mixture was concentrated to an oil, the oil was dissolved in methanol (25 mL), this solution was heated at reflux for 2 hours and then concentrated to an oil. The residue was dissolved in water and added concentrated NH4OH until pH=10, the water phase was extracted with diethyl ether. The organic phase was dried with magnesium sulphate and concentrated to dryness. The residue was chromatographed over silica gel (dichloromethane/acetone/methanol, 4/1/1 (v/v)). The product fractions was concentrated to an oil, the oil was dissolved in ethanol (96%) and malonic acid (0.55 g, 5.3 mmol) in ethanol (96%) was added, this solution was concentrated to an oil, the oil was trituated in diethyl ether, the title compound precipitated as powder and was isolated by filtration. Yield (1.32 g, 48%), m.p. 136.1-138° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1[CH2:8]Br.[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11]>O1CCOCC1>[C:10]([N:14]1[CH2:8][C:7]2[S:6][CH:5]=[N:4][C:3]=2[CH2:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)N
Reactant: BrCc1ncsc1CBr
Solvent: C1COCCO1
Product: CC(C)(C)N1Cc2ncsc2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4,5-bis(bromomethyl)thiazole (1.50 g) synthesized in 1) of Referential Example 109 was dissolved in dioxane (30 ml), and a dioxane solution (10 ml) of tert-butylamine (2.03 ml) was added dropwise to the solution over 1 hour at room temperature. After stirring at room temperature for 5 hours, the reaction mixture was concentrated, and dichloromethane and a saturated aqueous solution of sodium hydrogencarbonate were added to the residue to separate an organic layer. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (methanol:dichloromethane=1:19) to obtain 5-tert-butyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazole (407 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][C:17]=2Cl)[N:12]=1.C(O)(=[O:23])C>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:17](=[O:23])[NH:16][CH:15]=[N:14][C:13]=2[N:12]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nc3ncnc(Cl)c3[nH]2)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc3nc[nH]c(=O)c3[nH]2)c(OC)c1

Procedure:
One-half gram of 8-(2,4-dimethoxy-phenyl)-6-chloro-purine is refluxed for seven hours in 30 ml of 2N sodium hydroxide solution. The mixture is acidified with glacial acetic acid, and the precipitate obtained is recrystallized from methanol.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]([CH3:36])([CH3:35])[CH2:28]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)=O)C.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:27]2[CH2:28][C:29]([CH3:36])([CH3:35])[CH2:30][C:31]([CH3:34])([CH3:33])[CH2:32]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)C#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(OC(=O)OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.1 %

Procedure:
To a solution of ethyl 3-{4-[(4-{[(ethyloxy)carbonyl]oxy}phenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-2-propynoate (148) (88 mg, 0.18 mmol) in a mixture of EtOH (4 mL) and THF (4 mL) was added an aqueous solution of 1 N NaOH (5 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with water, brine and dried over Na2SO4. Upon concentration and trituration with hot 1:1 hexanes/ether (contained 1% of methanol), (35 mg (50%) of compound 149 was obtained as white solid. mp 172-174° C. (dec.). 1H NMR (400 MHz, DMSO-d6): δ 0.86 (s, 6H), 0.87 (s, 6H), 1.24 (s, 2H), 1.85 (s, 2H), 1.91 (s, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.19 (d, J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 9.31 (s, 1H), 13.73 (s, 1H). HRMS (EI) Calcd for C32H44O3Si2: 532.2829 (M+.); Found: 532.1591.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].OC1C=CC([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=CC=1>>[OH:9][C:3]1[C:4]([CH3:8])=[CH:5][C:6]([N:17]2[C:21](=[O:22])[N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:29])[NH:18]2)=[CH:7][C:2]=1[CH3:1]
Reactant: O=c1[nH]n(-c2ccc(O)cc2)c(=O)n1-c1ccccc1
Reactant: Cc1cccc(C)c1O
Product: Cc1cc(-n2[nH]c(=O)n(-c3ccccc3)c2=O)cc(C)c1O

Procedure:
Compound 30 was prepared from 2,6-dimethylphenol in the same manner of compound 27, and was obtained as white solids (61%). 1H NMR (300 MHz, DMSO-d6): δ 11.32 (br s, 1H), 8.42 (s, 1H), 7.53-7.39 (m, 5H), 7.14 (d, J=1.8 Hz, 1H). 13C NMR (75 MHz, DMSO-d6): δ 152.07, 151.38, 129.58, 127.13, 125.61, 121.94, 121.48, 17.43. HRMS: calcd for C16H15N3O3 (MH+) 298.1186. found 298.1184.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1([CH3:17])[C@@H:7]2[CH2:8][C:9]3[C:13]([C@H:6]12)=[C:12]([CH3:14])[S:11][C:10]=3[C:15]#[N:16]>CO>[OH:3][NH:2][C:15]([C:10]1[S:11][C:12]([CH3:14])=[C:13]2[C:9]=1[CH2:8][C@H:7]1[C:5]([CH3:17])([CH3:4])[C@H:6]12)=[NH:16]
Reactant: Cc1sc(C#N)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1sc(C(=N)NO)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
To a stirred suspension of K-tert.-butylate (281 mg, 2.5 mmol), hydroxylamine hydrochloride (208 mg, 3.0 mmol) in methanol (4 mL) is added (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopro-pa[a]pentalene-4-carbonitrile (203 mg, 1.0 mmol). The reaction mixture is stirred at rt for 5 h before it is filtered. The filtrate is purified by prep. HPLC (Water XTerrra Prep MS C18 30×75 mm, 10% to 95% acetonitrile in water containing 0.5% sat. aq. NH3) to give (1aS,5aR)-N-hydroxy-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxamidine (200 mg) as a colourless solid; LC-MS: tR=0.72 min, [M+1]+=237.09.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: 130 °C

Procedure:
20 g (161 mmol) of 4-fluorobenzaldehyde, 48.4 g (483 mmol) of 1-methylpiperazine and 22.3 g (161 mmol) of potassium carbonate were added to 50 ml of dimethylformamide, and the mixture was heated at 130° C. for 36 hours. The mixture was subsequently concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 2 M hydrochloric acid. The aqueous phase was separated off and made alkaline using aqueous sodium bicarbonate solution. This aqueous phase was extracted with ethyl acetate, and the organic phase was separated off, dried and concentrated under reduced pressure. This gave 48.7 g of the intermediate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:10](=[O:11])[O:12][CH2:13][CH3:14])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cccc(Cl)c1
Reaction time: 1 h

Procedure:
3-Chloroaniline (2.510 g) was dissolved in pyridine (20 ml), and to the solution was added dropwise ethyl chloroformate (2.257 ml) under ice-cooling. After the mixture was stirred for 1 hour, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (3.9287 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21]C(=O)C)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1>[OH-].[Na+]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[N:5]=2)(=[O:13])=[O:14])=[CH:16][CH:17]=1
Reactant: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(NC(C)=O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 89.5 %

Procedure:
2.88 g (0.0075 mol) of N-[4-(6-chloro-2-ethylamino-pyrimidin-4-ylsulfamoyl)-phenyl]-acetamide were dissolved in 76 ml of 1N NaOH and boiled at reflux for 3 hours. The mixture was extracted with ethyl acetate, the aqueous phase was saturated with sodium chloride and the residual ethyl acetate was distilled on a rotary evaporator. Then, the aqueous phase was made acid with 3N HCl and the precipitate which separated was filtered off under suction. After drying there were obtained 2.2 g (90%) of 4-amino-N-(6-chloro-2-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as white crystals; m.p.: 172-173° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:4]([CH:3]=1)[C:5]([OH:7])=[O:6]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
3-Fluorobenzoic acid (1 g, 7.13 mmol) was dissolved in concentrated H2SO4 (2 ml) by warming slightly above room temperature. The solution was cooled to 0° C. Fuming nitric acid (539 mg, 8.56 mmol) was added slowly to the solution while keeping the temperature below 0° C. The solution was stirred at 0° C. for 3 h. The solution was poured into ice water, the solid formed were filtered, washed by cold water, and dried to yield 1.2 g (92%) of white solids. M.P. 122° C. 1H NMR (DMSO-d6): 7.60 (dt, J=2.9, 8.5 Hz, 1H), 7.71 (dd, J=2.9, 8.6 Hz, 1H), 8.13 (dd, J=4.8, 8.8 Hz, 1H). EIMS m/z 186 (M+1).
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[C:18]([CH3:23])[N:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>>[CH3:23][C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[CH:14]([NH2:13])[CH2:15][O:16][C:17]=12
Reactant: CON=C1COc2c1ccnc2C
Agent: NC1COc2nnccc21
Product: Cc1nccc2c1OCC2N

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 7-methylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][C@@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C.C(Cl)Cl>[F:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:17]([C@@H:9]3[NH:8][CH2:13][CH2:12][N:11]([CH:14]([CH3:15])[CH3:16])[CH2:10]3)=[O:19])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(c3ccc(F)cc3)CC2)C1
Temperature: 25 °C

Procedure:
To a stirred solution of (2R)-1-(tert-butoxycarbonyl)-4-isopropylpiperazine-2-carboxylic acid (0.078 g, 0.29 mmol, 50% strength by NMR), 1-(4-fluorophenyl)-piperazine (0.031 g, 0.174 mmol), HOBT (0.024 g, 0.174 mmol) and DIPEA (0.091 ml, 0.52 mmol) in DMF (2 ml) was added EDCI (0.033 g, 0.174 mmol) and the reaction allowed to stir at room temperature over weekend. The solvents were then removed in vacuo and the residue partitioned between DCM/water, extracted twice with DCM, the organics passed through phase separating cartridge and concentrated under reduced pressure to give a colourless gum. This was then purified by prep HPLC (basic, high throughput machine) to give a white solid. This was then dissolved in DCM (2 ml), TFA (2 ml) added and reaction allowed to stir overnight at room temperature. The solvents were then removed under reduced pressure to give a brown gum. This was partitioned between DCM and 2M NaOH, extracted twice with DCM, the combined organics passed through a phase separating cartridge and concentrated in vacuo to give the title compound, as a yellow gum (12 mg, 0.036 mmol, 12% over 2 steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16](OS(C(F)(F)F)(=O)=O)=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH3:32]B1OB(C)OB(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:31])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:32])=[C:17]([Cl:20])[CH:18]=3)[C:13]([C:29]#[N:30])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OS(=O)(=O)C(F)(F)F)c(Cl)cc32)cc1
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C)c(Cl)cc32)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(6-chloro-3-cyano-5-trifluoromethanesulfonyloxyindol-1-yl)benzoic acid ethyl ester (0.103 g), trimethylboroxine (0.033 g) and tripotassium phosphate (0.070 g) in dioxane (2.0 mL) was added tetrakis(triphenylphosphine) palladium catalyst (0.038 g), and this mixture was stirred at 80° C. for 1 day. The reaction mixture was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0568 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]>[Ru+3].CO>[OH:14][C:12]([CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])=[CH:10][CH:9]=1)[CH3:15])=[O:13]
Reactant: C=C(C(=O)O)c1ccc(CC(C)C)cc1
Agent: [Ru+3]
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Temperature: 24 °C
Reaction time: 21 h

Procedure:
A 1.05 mmole portion of 2-(4- isobutylphenyl)acrylic acid (UA) was combined with 0.050 mmoles of ruthenium(III) (2,4-pentanedionate) and 30 ml of methanol in a 50-ml Hastelloy C pressure reactor. The reactor was flushed with hydrogen (3×300 psi) and then sealed with 1000 psi hydrogen. After stirring the mixture at 300 rpm for 21 hr at 24° C., a GC analysis of the red solution showed a product composition of 8% ibuprofen and 92% UA. The mixture was then stirred (300 rpm) at 100° C. for 8 hr with 1000 psi H2 to obtain complete conversion of the UA to ibuprofen. HPLC analysis showed the ibuprofen was racemic (0% ee).