Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[N+:16]([CH:19]([CH3:21])[CH3:20])([O-:18])=[O:17]>CO.C(O)(=O)C>[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[C:19]([CH3:21])([N+:16]([O-:18])=[O:17])[CH3:20]
Reactant: COc1ccc(C=O)c(OC)c1OC
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(C(O)C(C)(C)[N+](=O)[O-])c(OC)c1OC
Temperature: 15 °C
Reaction time: 0.67 h
Yield: 86.7 %

Procedure:
6.4 g of sodium are added to 250 ml of anhydrous methanol, and 50 g of 2,3,4-trimethoxybenzaldehyde and 54.4 g of 2-nitropropane are added dropwise thereto at 15° C. for 40 minutes under stirring. The mixture is stirred at 25° C. for 24 hours, and 17 ml of acetic acid and 20 ml of methanol are added to said mixture under ice-cooling. The mixture is evaporated to remove solvent, and the residue is extracted with benzene. The extract is washed with water, an aqueous sodium bisulfite solution, water and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 63 g of 1-(2,3,4-trimethoxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a pale yellow oil.
Reaction SMILES: ClC1C=NC=C(Cl)C=1C(O)=O.[CH2:12]([N:19]([C:41]1[CH:46]=[CH:45][C:44]([S:47](=[O:60])(=[O:59])[NH:48]C(C2C(Cl)=CN=CC=2Cl)=O)=[CH:43][CH:42]=1)[CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30](=[O:39])[C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:38])[CH2:22][CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]([C:41]1[CH:42]=[CH:43][C:44]([S:47](=[O:60])(=[O:59])[NH2:48])=[CH:45][CH:46]=1)[CH:20]1[CH2:21][CH2:22][N:23]([CH:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30](=[O:39])[C:31]2[C:36]([Cl:37])=[CH:35][N:34]=[CH:33][C:32]=2[Cl:38])[CH2:24][CH2:25]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(CCNC(=O)c1c(Cl)cncc1Cl)N1CCC(N(Cc2ccccc2)c2ccc(S(=O)(=O)NC(=O)c3c(Cl)cncc3Cl)cc2)CC1
Agent: O=C(O)c1c(Cl)cncc1Cl
Product: CC(CCNC(=O)c1c(Cl)cncc1Cl)N1CCC(N(Cc2ccccc2)c2ccc(S(N)(=O)=O)cc2)CC1

Procedure:
Using general procedure F, 3,5-dichloroisonicotinic acid (87 mg, 0.45 mmol) and the above amine (58 mg, 0.14 mmol) afforded the desired product and N-{3-[4-(benzyl-{4-[(3,5-dichloro-pyridine-4-carbonyl)-sulfamoyl]-phenyl}-amino)-piperidin-1-yl]-butyl}-3,5-dichloro-isonicotinamide.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].Br[CH:13]([CH3:22])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]>>[C:2]([CH:3]([CH:13]([CH3:22])[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH3:9]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(C)=O)C(C)C(=O)c1ccccc1
Yield: 89.9 %

Procedure:
Using ethyl 3-oxobutanoate (12.2 g), sodium hydride (60% in oil, 4.24 g) and 2-bromopropiophenone (22.0 g), a procedure as in Reference Example 13 was performed to give the title compound as a brown oil (yield 22.1 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.[C:23](Br)#[N:24].ClCCl.[OH-].[Na+]>C(O)C>[NH2:24][C:23]1[N:9]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)[CH2:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:1]=1
Reactant: N#CBr
Reactant: Nc1ccccc1CNC1CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: NC1=Nc2ccccc2CN1C1CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
A solution of 10.0 g (33.85 mmol) of N-[(2-aminophenyl)methyl]-1-(phenylmethyl)-4-piperidineamine in 150 ml of anhydrous ethanol was combined with 4.0 g (37.76 mmol) of bromocyanogen added batchwise. The mixture was left to stand overnight at ambient temperature, the ethanol was eliminated in vacuo and the residue was distributed between dichloromethane and 1N sodium hydroxide solution. After working up in the conventional way, 9.3 g (86% of theoretical) of colourless crystals were obtained, Rf 0.4 (El D), which were further processed without any additional purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14]([O:16]CC)=O)=[N:11]2)=[CH:6][CH:5]=1.[C:20](#[N:22])[CH3:21].O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14](=[O:16])[CH2:21][C:20]#[N:22])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1nc2cc(F)ccc2nc1C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2ccc(F)cc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.0 g, 300 mmol) in toluene (450 mL) was added a solution of ethyl 7-fluoro-3-methylquinoxaline 2-carboxylate (35.1 g, 150 mmol) and acetonitrile (19.6 mL, 375 mmol) in toluene (40 mL) dropwise over 35 min at 85° C. After being stirred for 5 min at the same temperature, the reaction mixture was cooled to 0° C., and then added water (175 mL). The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide (200 mL). The combined aqueous layer was acidified to pH 2 with conc. Hydrochloric acid (45.0 mL) at 0° C., and the resulting precipitate was collected and washed with water (150 mL). The solid was dissolved with chloroform (1000 mL) and water (500 mL). The aqueous layer was extracted with chloroform (300 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was triturated with ethanol to give 3-(7-fluoro-3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 230 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][P:7](=[O:18])([O:13]CCCC)[O:8]CCCC)=[CH:4][CH:3]=1>Cl>[OH:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][P:7](=[O:8])([OH:18])[OH:13])=[CH:4][CH:3]=1
Reactant: CCCCOP(=O)(Cc1ccc(O)cc1)OCCCC
Agent: Cl
Product: O=P(O)(O)Cc1ccc(O)cc1

Procedure:
A mixture of dibutyl 4-hydroxybenzylphosphonate (1.77 g) in 18% aqueous hydrochloric acid (30 ml) is heated at reflux for about 18 hours, then is concentrated in vacuo. The residue is triturated in hexanes to give 4-hydroxybenzyl phosphonic acid.
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:11]C(Cl)(Cl)Cl>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:11][C:2]([CH3:1])([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: ClC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: COC(=O)C(C)(Cl)C(=O)OC
Yield: 63.1 %

Procedure:
In a 10 mL round-bottom flask, a mixture of 1.46 g dimethyl methylmalonate (10 mmol), 1.69 g tetrachloromethane (11 mmol), and 63 mg tetra-n-butylammonium fluoride (0.2 mmol) was mixed by a magnetic stirrer for 15 min at 24° C. Gas chromatographic analysis of the product mixture showed that the solution contained 1.14 g of dimethyl α-chloro-α-methylmalonate (63% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:16]([N:22]3[CH:26]=[C:25]([C:27]([OH:29])=O)[CH:24]=[N:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:36]1[CH:40]=[CH:39]N=N1.C([O-])([O-])=O.[K+].[K+].S1(CCCC1)(=O)=O>C(O)(=O)C.ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:16]([N:22]3[CH:26]=[C:25]([C:27]4[O:29][CH:39]=[CH:40][N:36]=4)[CH:24]=[N:23]3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: c1c[nH]nn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(C(=O)O)cn2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(Cl)cnc2-n2cc(-c3ncco3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 mL scintillation vial was charged with 1-[3-(4-tert-butyl-benzenesulfonylamino)-5-chloro-pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (87 mg, 0.2 mmol), oxalyl chloride (2 mL, 1.0 M solution in dichloromethane), and dichloromethane (3 mL). The mixture was stirred at room temperature for 2 hours, the volatiles removed in vacuo, and the residue further dried at reduced pressure for 4 hours. The scintillation vial containing the crude acid chloride was subsequently charged with 1H-1,2,3-triazole (34 mg, 0.5 mmol), K2CO3 (138 mg, 1.0 mmol), and sulfolane (2 mL). The vial was sealed and stirred at 80° C. for 16 hours. The reaction solution was neutralized to pH=7 with glacial acetic acid. The mixture was extracted with ethyl acetate (2×10 mL) and the combined organics were concentrated in vacuo. The residue was purified via preparative HPLC to afford 4-tert-butyl-N-[5-chloro-2-(4-oxazol-2-yl-pyrazol-1-yl)-pyridin-3-yl]-benzenesulfonamide as a white powder: MS (ES) M+H expected 458.1, found 458.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)=[S:11])[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:17][CH:18]=1)=[S:11])[CH2:28][CH3:29]
Reactant: CCCN(CCC)CCCCNC(=S)Nc1ccc(CNCc2ncc[nH]2)cc1
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=S)Nc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 13.5 h

Procedure:
The compound (93.8 mg) obtained in Example 35-2 was dissolved in anhydrous methanol (3.8 ml) and added with 1-methyl-2-imidazole carboxaldehyde (38.5 mg) and sodium cyanoborohydride (43.4 mg). The solution was adjusted to pH 5 with acetic acid and stirred at room temperature for 13.5 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The resultant was dried with magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (86.6 mg) of the subject compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].Cl.Br[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][N:53]=1.C([O-])([O-])=O.[K+].[K+]>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>[C:16]1([C:8]2([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:7][C:6]3[CH:22]=[C:2]([C:56]4[CH:55]=[CH:54][N:53]=[CH:52][CH:57]=4)[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]=3[O:9]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Brc1ccccn1
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: COC(=O)c1cc(-c2ccncc2)cc2c1OC(c1ccccc1)(c1ccccc1)O2

Procedure:
Methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (400 mg, 0.973 mmol, 1 eq.), Pd(PPh3)4 (100 mg, 0.087 mmol, 0.09 eq.), bis(pinacolato)diboron (320 mg, 1.26 mmol, 1.3 eq.) and KOAc (150 mg, 1.5 mmol, 1.5 eq.), then Pd(PPh3)4 (112 mg, 0.097 mmol, 0.1 eq.), 2-bromo-pyridine hydrochloride (265 mg, 1.36 mmol, 1.4 eq.) and K2CO3 (680 mg, 4.9 mmol, 5 eq.) were used according to GP6 to yield the title product as a colorless solid.
Reaction SMILES: C[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([C:9]#[C:10]CO)[C:3]=1C.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:8][C:7]1[CH:2]=[CH:3][C:4]([C:9]#[CH:10])=[N:5][CH:6]=1
Reactant: Cc1c(F)cnc(C#CCO)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(F)cn1
Temperature: 120 °C
Yield: 63.1 %

Procedure:
820 mg (4.58 mmol) of Dimethylhydroxymethyl-5-fluoro-2-pyridylacetylene and 192 mg (4.81 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 50 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 23 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.25 hour. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure at 90 mmHg/70° C. to give 5-fluoro-2-pyridylethyne as an orange-color liquid (0.35 g, yield: 63%).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:11][NH:12][CH:13]1[CH2:17][C:16]2([O:21][CH2:20][CH2:19][O:18]2)[CH:15]=[CH:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:27][C:28]#[N:29].[K+].Cl>C(O)C.O>[CH2:1]([O:8][CH:9]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:10][CH2:11][N:12]([CH:13]1[CH2:17][C:16]2([O:18][CH2:19][CH2:20][O:21]2)[CH:15]=[CH:14]1)[C:28]([NH2:29])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[O-]
Reactant: CCCCCC(CCNC1C=CC2(C1)OCCO2)OCc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCC(CCN(C(N)=O)C1C=CC2(C1)OCCO2)OCc1ccccc1
Reaction time: 18 h

Procedure:
N-(3-Benzyloxyoctyl)-4,4-ethylenedioxycyclopent-2-enamine (972 mg) in ethanol (60 ml) was treated with potassium cyanate (360 mg) in water (4.0 ml) then 1.0N aqueous hydrochloric acid (3.0 ml) at room temperature. After 18 hours, the mixture was diluted with water and extracted with chloroform. The extract was dried then decolourised and the solvent was removed in vacuo to give crude N-(3-benzyloxyoctyl)-N-(4,4-ethylenedioxycyclopent-2-enyl)urea as a yellow glass. This material was dissolved in tetrahydrofuran (11.0 ml) and 2.0N aqueous hydrochloric acid (11.0 ml) and the solution set aside at room temperature for 1.25 hours. After dilution with water, the product was extracted into chloroform, and the solvent removed from the dried extract to give the mixture of diastereomers of 2-(3-benzyloxyoctyl)-cis-2,4-diazabicyclo[3.3.0]octane-3,7-dione as a colourless glass, δ (CDCl3) 0.95 (3H, bt, --CH3), 2.41 (4H, m, ##STR13## 3.40 (2H, m, --N--CH2 --), 4.24 (2H, m, 1-H, 5-H), 4.48 and 4.50 (total 2H, both s, --CH2Ph from each isomer), 7.31 (5H, bs, --Ph).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH2:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:18])=[O:19])[N:7]([C:21]([NH:45][C:46]([CH3:50])([CH3:49])[CH2:47][OH:48])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:41])[F:42])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(N)CO
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)NC(C)(C)CO)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (75.0 mg, 0.120 mmol; Example 6A) was reacted with 2-amino-2-methylpropanol (32.1 mg, 0.360 mmol) in acetonitrile (0.96 ml) to give the target compound (51 mg, 74% of theory).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH:26]=[O:27])[N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:6][C:7]1[N:8]=[C:9]2[N:10]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[CH:26]2[OH:27])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc(C=O)n(CCc2ccccc2)c1-c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2n(c1-c1ccccc1)CCc1ccccc1C2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methanesulfonic acid (10 mL) in CHCl3 cooled at 0° C. is added a solution of 4-methyl-1-phenethyl-5-phenyl-imidazole-2-carbaldehyde (example 123C) (290 mg, 1 mmole) in CHCl3 (2 mL) dropwise. The reaction mixture is allowed to slowly reach room temperature and is stirred at room temperature for 1 h. The reaction mixture is poured into a solution of saturated Na2CO3 (final pH 9-10). The precipitate is filtered, washed with water and filter-dried. The residual solid is re-crystallized from hot ACN to give 2-methyl-1-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-4-ol.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].O.[OH-].[Na+:18]>C1(C)C=CC=CC=1>[Na+:18].[O-:3][C:2]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(C(C)C(=O)[O-])cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A solution of (S)-enriched ibuprofen having an enantiomeric purity of 95.5% (211 kg) in toluene (797 kg) was heated to 60° C. with water (300 l) and aqueous sodium hydroxide solution (52 l--specific gravity 1.5) and allowed to settle for four hours. The aqueous layer was separated and the toluene layer washed with water. The aqueous washings and the aqueous layer were combined and residual toluene removed by distillation. Acetone (1684 kg) was added and the mixture cooled to 20° C. The sodium salt of (S)-enriched ibuprofen dihydrate (having an enantiomeric purity of 99.9%) separated, was collected by filtration and dried in vacuo. (Yield 143.5 kg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([O:15]CC)=[O:14])=[C:11]([O:18][CH3:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[C:12]([C:13]([OH:15])=[O:14])=[C:11]([O:18][CH3:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CCOC(=O)c1c(OC)nc2ccccc2c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1nc2ccccc2c(OC)c1C(=O)O
Yield: 50.4 %

Procedure:
Ethyl 2,4-dimethoxyquinoline-3-carboxylate (1.5 g, 5.7 mmol) was heated at reflux in NaOH solution (10%, 100 mL) for 1 h. After cooling, the mixture was acidified with concentrated HCl to pH 4. The resulting precipitate was collected via filtration and washed with water and ether to give 2,4-dimethoxyquinoline-3-carboxylic acid (A-17) as a white solid (670 mg, 50%). 1H NMR (CDCl3) δ 8.01-8.04 (d, J=12 Hz, 1H), 7.66-7.76 (m, 2H), 7.42-7.47 (t, J=22 Hz, 2H), 4.09 (s, 3H). 3.97 (s, 3H); ESI-MS 234.1 m/z (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][C@@H:9]([CH2:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].CO>[CH2:10]([C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12)[CH3:11]
Reactant: [H][H]
Reactant: CC[C@@H]1CN(C(=O)OCc2ccccc2)[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Pd]
Solvent: CO
Product: CC[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 1.25 h

Procedure:
Methanol (2.0 mL) was added dropwise to a mixture of 10% palladium on charcoal (10 mg) and alcohol (113) (105 mg, 0.36 mmol) wider an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 75 mins before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol (3×10 mL) then the solvents removed in vacuo from the filtrate. The residue was azeotroped with toluene (2×3 in L) to obtain free base which was used without further purification.
Reaction SMILES: [CH:1]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][O:5][C:3](=[O:4])[CH:2]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C1COCC1.CN(C)C1C=CN=CC=1>[O:4]=[C:3]1[CH:2]=[CH:1][C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:6][O:5]1
Reactant: O=C(O)c1ccc(=O)oc1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(=O)oc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of coumalic acid (1.2 g, 8.57 mmol) in DCM (20 mL) and THF (20 mL) was treated with 4-dimethylaminopyridine (0.105 g, 0.857 mmol). The reaction was stirred under nitrogen at 23° C. After 15 min, benzyl alcohol (0.886 mL, 8.57 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.642 g, 8.57 mmol) were added, and the stirring was continued. After 5 h, the solution was diluted with DCM (200 mL) and the mixture was washed with water (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 5-25% EtOAc/hexane), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.32 (s, 1H), 7.80 (dd, J=9.78, 2.15 Hz, 1H), 7.33-7.48 (m, 5H), 6.33 (d, J=9.78 Hz, 1H), 5.31 (s, 2H). MS (ESI, positive ion) m/z: 231.1 (M+H).
Reaction SMILES: [C:1]([O:12][CH2:13][CH3:14])(=[O:11])[C:2]1[CH:10]=[C:8]([OH:9])[C:6]([OH:7])=[C:4]([OH:5])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:21](Br)[CH:22]=[CH2:23]>CN(C=O)C>[CH2:21]([O:9][C:8]1[CH:10]=[C:2]([CH:3]=[C:4]([O:5][CH2:8][CH:6]=[CH2:4])[C:6]=1[O:7][CH2:3][CH:2]=[CH2:1])[C:1]([O:12][CH2:13][CH3:14])=[O:11])[CH:22]=[CH2:23]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(C(=O)OCC)cc(OCC=C)c1OCC=C

Procedure:
Ethyl gallate (7.92 g, commercially available, Fluka), and K2CO3 (27.6 g) in DMF (40 ml) were treated with allyl bromide (13.5 ml) as above, to give ethyl 3,4,5-triallyloxybenzoate (14 g): NMR (CDCl3) 1.49 (t, 3H); 4.35 (q, 2H); 4.62 (m, 6H); 5.15-5.48 (m, 6H); 6.00-6.28 (m, 3H); 7.29 (s, 1H). This crude ester was hydrolysed essentially as above to give 3,4,5-triallyloxybenzoic acid(10.4 g): NMR (CDCl3) 4.64 (m, 6H); 5.15-5.51 (m, 6H); 6.00-6.20 (m, 3H); 7.35 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C@H:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:12]=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)(C)C>[OH:8][C:9]1[CH:10]=[C:11]([C@H:23]2[O:27][C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:25][C@@H:24]2[C:34]([O:36][CH3:37])=[O:35])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: COC(=O)[C@H]1N=C(c2ccccc2)O[C@@H]1c1ccc(O)c(O)c1
Yield: 84 %

Procedure:
A mixture of methyl (4S,5R)-5-(3,4-dibenzyloxyphenyl)-2-phenyl-2-oxazoline4-carboxylate (494 mg, 1.00 mmol), 5%-palladium-carbon (64 mg) and isopropanol (5 g) was reduced with hydrogen at room temperature under atmospheric pressure for 15 hours. The reaction mixture was filtered and then the filtrate was concentrated under reduced pressure. The residue was treated with silica gel chromatography to obtain 263 mg (0.84 mmol, yield: 84%) of methyl (4S,5R)-5-(3, 4-dihydroxyphenyl)-2-phenyl-2-oxazoline-4-carboxylate.