Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H]1[O:12][C:10](=[O:11])[C:9]2[C:4](=[C:5](Cl)[CH:6]=[C:7]([C:14](N[C@H](C(O)=O)CC3C=CC=CC=3)=[O:15])[C:8]=2[OH:13])[CH2:3]1.C[O:30]C(C(C(OC)=O)CC(=O)CC)=O.OC=CC(=O)C.[Na]>>[OH:13][C:8]1[C:9]([C:10]([OH:12])=[O:11])=[C:4]([CH3:3])[CH:5]=[CH:6][C:7]=1[C:14]([OH:15])=[O:30]
Reactant: CCC(=O)CC(C(=O)OC)C(=O)OC
Reactant: C[C@@H]1Cc2c(Cl)cc(C(=O)N[C@@H](Cc3ccccc3)C(=O)O)c(O)c2C(=O)O1
Agent: CC(=O)C=CO
Agent: [Na]
Product: Cc1ccc(C(=O)O)c(O)c1C(=O)O

Procedure:
A method of synthesis of Ochratoxin A comprising: reacting dimethyl-3-oxo-pentane-dicarboxylate with sodium hydroxymethyleneacetone to provide the dimethyl ester of 2-hydroxy-4-methylbenzene-1,3-dioic acid;
Reaction SMILES: [CH2:1]([NH:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:9]2[C:10]([N:16]=1)=[CH:11][N:12]=[N:13][C:14]=2O)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([NH:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][C:9]2[C:10]([N:16]=1)=[CH:11][N:12]=[N:13][C:14]=2[Cl:24])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCNc1nc2cnnc(O)c2cc1C(=O)OCC
Product: CCCCNc1nc2cnnc(Cl)c2cc1C(=O)OCC

Procedure:
5.8 g of 2-butylamino-5-hydroxy-pyrido[2,3-d]pyridazine-3-carboxylic acid, ethyl ester (0.02 mol) are treated with 20 ml of phosphorous oxychloride for 5 days at room temperature with permanent stirring. The excess of phosphorous oxychloride in distilled off in vacuo and the remaining residue is extracted with 20 ml of hot ethyl acetate. 2-butylamino-5-chloro-pyrido[2,3-d]pyridazine-3-carboxylic acid, ethyl ester crystallizes on cooling. Yield 5.5 g (83%); m.p. 126.7° C. (ligroin).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=2[CH:18]=O)[C:13]#[N:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH3:34]>>[CH3:20][O:21][C:22](=[O:35])[CH2:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=2)[C:26]([CH2:18][C:17]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[C:25]1[CH3:34]
Reactant: N#Cc1ccc(C=O)c(S(=O)(=O)c2ccccc2)c1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2ccc(C#N)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 3-benzenesulfonyl-4-formylbenzonitrile and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:28]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[C:18](=[N:20][N:21]([CH3:28])[N:22]=3)[N:19]=2)=[N:6]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.692 mmol) of the compound from example 53 and 190 mg (0.692 mmol) of BEMP were initially charged in 12 ml of dimethylformamide, and a solution of 98 mg (0.692 mmol) of iodomethane in 3 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/aqueous 0.1% ammonia solution=65:35). The residue was stirred with acetonitrile and filtered with suction, and the solids were dried under high vacuum. 50 mg (19% of theory) of the title compound and 78 mg (30% of theory) of example 54 were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8].Br[C:18]1[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[N:22][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[CH:3][C:2]=1[O:1][C:18]1[CH:23]=[N:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cc1O
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)OC(C)(C)C)cc1Oc1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
A mixture of tert-butyl (3-hydroxy-4-methylphenyl)carbamate (3.14 g, 14.1 mmol), 5-bromo-2-nitropyridine (2.38 g, 11.7 mmol), cesium carbonate (5.72 g, 17.6 mmol) and N,N-dimethylformamide (25 mL) was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=80/20→0/100) to give the title compound (1.86 g, 44%) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11](CO)[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O>[C:2]1([C:1]([O:9][CH2:10][CH:11]=[O:12])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC(O)CO)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Product: O=CCOC(=O)c1ccccc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
This known intermediate was prepared by portionwise addition of NaIO4 (80 g) to a mixture of 1-benzoyl glycerol (50 g), CH2Cl2 (500 ml), and H2O (25 ml) under vigorous stirring at room temperature. The resulting solution was stirred for 2 hours, MgSO4 (100 g) was added and the solution stirred for an additional 30 minutes. The mixture was filtered, the filtrate evaporated in vacuo and the residue distilled in vacuo to yield 26 g of pure product.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[C@@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44]Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].[I-].Cl>CC(N(C)C)=O>[CH2:27]([C@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:40](=[O:47])[C@@H:41]([CH3:46])[CH2:42][CH2:43][CH2:44][N:8]([C:7]1[N:6]=[C:5]2[O:13][C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([C:16]([NH:18][CH3:19])=[O:17])[C:4]2=[CH:3][C:2]=1[I:1])[S:9]([CH3:12])(=[O:10])=[O:11])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: C[C@@H](CCCBr)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCC[C@H](C)C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)S(C)(=O)=O)c(I)cc12
Temperature: 100 °C

Procedure:
To 5-iodo-N-methyl-6-(methylsulfonamido)-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide (1 g, 2.061 mmol) was added (S)-4-benzyl-3-((S)-5-bromo-2-methylpentanoyl)oxazolidin-2-one (0.730 g, 2.061 mmol) and CESIUM CARBONATE (2.014 g, 6.18 mmol) and NaI (0.309 g, 2.061 mmol) and DMA (4.12 mL). Heated 100° C. 2 hr (note: done at 1 hr) Added 30 mL 1N HCl and extracted with EtOAc, washed with brine, and conc. on vac. 3.05 g crude brown oil. Taken up in minimum EtOAc 30 mL and triturated into a stirring solution of 200 mL heptanes. to give a white solid which is filtered. Purified on 120 g Silica: 0-20% DCM/ether 15 column volumes 964 mg 6-(N—((S)-5-((S)-4-benzyl-2-oxooxazolidin-3-yl)-4-methyl-5-oxopentyl)methylsulfonamido)-5-iodo-N-methyl-2-p-tolylfuro[2,3-b]pyridine-3-carboxamide
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[O:8])=[CH:3][CH:2]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C1COCC1.O.C(N(CC)CC)C.C(#N)C>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:14]([C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:2][CH:3]=2)=[O:8])=[CH:18][CH:17]=1)=[O:15]
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of 4-(4-biphenylylcarbonylamino)benzoic acid (0.323 g) in THF (15 ml)/acetonitrile (15 ml) were added WSC (0.248 g), HOBt (0.156 g), N,N-dimethylethylenediamine (0.097 g), and triethylamine (0.21 ml). After stirring at room temperature for 18 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous potassium carbonate and saturated aqueous sodium chloride sequentially, dried, and concentrated. The residue was recrystallized from methanol/diethyl ether to obtain the titled compound (0.100 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](OCC)=[O:14]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:13](=[O:14])[CH2:12][Cl:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCl
Solvent: COC(C)(C)C
Product: CC(NC(=O)CCl)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
At room temperature, a solution of 4.67 g (0.03 mol) of racemic 1-(4-chloro-phenyl)ethylamine in 40 ml of methyl tert-butyl ether is admixed successively with stirring with 5.5 g (0.045 mol) of ethyl chloroacetate and 0.4 g of Novozym 435® (=immobilized lipase from Candida antarctica; 7300 U/g). Stirring is continued at room temperature and the progress of the reaction is monitored by gas chromatographic sample analysis. After 1 hour, a conversion of 51% is reached. At this stage, the reaction is terminated by filtering off the enzyme. In the filtrate that remains, the (S)-enantiomer of 1-(4-chloro-phenyl)-ethylamine has an ee value of 89.1%, while the (R)-enantiomer of N-[1-(4-chloro-phenyl)-ethyl]chloroacetamide is obtained with an ee value of 95.5%.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:29][C:28]=1[CH3:40])=[O:25])=[O:18].C(N(C(C)C)CC)(C)C>C1COCC1.CC(N(C)C)=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][C:17]([C:19]1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH:34]2[CH2:39][CH2:38][N:37]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:36][CH2:35]2)=[CH:29][C:28]=1[CH3:40])=[O:25])=[O:18]
Reactant: Cc1cc(OC2CCNCC2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Reactant: CCOC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC(Oc2ccc(NC(=O)c3[nH]cnc3C(=O)Nc3nc4ccccc4[nH]3)c(C)c2)CC1
Reaction time: 0.08 h
Yield: 6.4 %

Procedure:
Ethyl chloroformate (0.1 mmol) in anhydrous THF was slowly added to a solution of N4-(1H-benzo[d]imidazol-2-yl)-N5-(2-methyl-4-(piperidin-4-yloxy)phenyl)-1H-imidazole-4,5-dicarboxamide (0.10 mmol) and diisopropylethylamine (0.20 mmol) in anhydrous DMA (5 mL) at 0° C. LCMS indicated that the reaction was complete in 5 minutes. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative reverse phase HPLC (ammonium acetate/acetonitrile) to give 3.4 mg of ethyl 4-({4-[({4-[(1H-benzimidazol-2-ylamino)carbonyl]-1H-imidazol-5-yl}carbonyl)amino]-3-methylphenyl}oxy)piperidine-1-carboxylate. 1H-NMR (400 MHz, DMSO-d6): δ 12.19 (s, 1H), 8.13 (s, 1H), 7.48 (m, 2H), 7.11 (m, 2H), 6.96 (s, 1H), 6.88 (dd, 1H), 4.60 (m, 1H), 4.05 (m, 2H), 3.70 (m, 2H), 3.30 (m, 1H), 2.26 (s, 3H), 1.91 (m, 2H), 1.57 (m, 2H), 1.19 (t, 3H). MS (EI): 532.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([O:14]C)=[O:13])[CH2:4]1.[OH-].[K+].Cl>CO>[CH3:1][O:2][C@@H:3]1[C@@H:7]([O:8][N+:9]([O-:11])=[O:10])[CH2:6][C@H:5]([C:12]([OH:14])=[O:13])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](OC)[C@@H](O[N+](=O)[O-])C1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CO[C@H]1C[C@@H](C(=O)O)C[C@@H]1O[N+](=O)[O-]
Temperature: 10 °C

Procedure:
A solution of methyl (1R,3S,4S)-3-methoxy-4-(nitrooxy)cyclopentanecarboxylate (0.66 g, 3.0 mmol) in methanol (12 mL) was cooled to 0° C. To this solution was added 4N potassium hydroxide (1.5 mL, 6.0 mmol) dropwise over 10 minutes, and the solution was stirred and allowed to warm to 10° C. over 3 hours. The reaction mixture was acidified by the addition of concentrated hydrochloric acid and extracted with chloroform (3×15 mL). The combined organic layers were washed with brine and dried (sodium sulfate) to give the title compound as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 2.06-2.14 (m, 2H), 2.34 (ddd, J=6.2, 9.1, 14.1 Hz, 1H), 2.54 (ddd, J=6.6, 8.7, 15.0 Hz, 1H), 3.03 (quintet, J=8.4 Hz, 1H), 3.38 (s, 3H), 3.82-3.86 (m, 1H), 5.27-5.32 (m, 1H), 8.5-11.5 (br, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:10]=2)=[C:5]([CH3:25])[CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[CH:10]=3)=[C:5]([CH3:25])[CH:4]=2)[S:26]1
Reactant: Cc1cc(C=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Reactant: O=C1CSC(=O)N1
Product: Cc1cc(C=C2SC(=O)NC2=O)ccc1-c1cccc(CN(C)C(=O)OC(C)(C)C)c1

Procedure:
In a manner similar to that of Example 1(f), by reacting 3.95 g (11.6 mmol) of tert-butyl (4′-formyl-2′-methylbiphenyl-3-ylmethyl)-N-methylcarbamate with 1.4 g (11.6 mmol) of 2,4-thiazolidine dione, and after purification by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (8/2), 3 g (59%) of the expected product are obtained in the form of a yellow solid with a melting point of 156° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>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.C1(C)C=CC=CC=1.O>[F:20][C:16]1[CH:15]=[C:14]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: Fc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cccc(F)c2)cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Into a reaction vessel under an atmosphere of nitrogen, 4-propyl phenylboronic acid (T16; 200.0 g), 1-bromo-3-fluorobenzene (T8; 177.8 g), potassium carbonate (281.9 g), Pd(Ph3P)2Cl2 (7.2 g), toluene (600 ml), and Solmix A-11 (600 ml) were put and heated under reflux for 2 hours. After the reaction mixture had been cooled to 25° C., the solution was poured into water (2,000 ml) and toluene (1,000 ml), and mixed. The mixture was then allowed to stand to be separated into two layers of an organic layer and an aqueous layer. Extraction into an organic layer was carried out and the resulting organic layer was fractionated. The extracts were washed with water, and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure, and the residue was purified by means of fraction-collecting column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The solution was further purified by recrystallization from Solmix A-11 and then dried, whereby 175.5 g of 3-fluoro-4′-propylbiphenyl (T17) was obtained. The yield based on the compound (T8) was 80.3%.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]([NH2:10])[C@H:2]1[OH:11].[C:12]1(=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=O>>[CH2:15]1[CH2:14][C@:13]2([O:11][C@H:2]3[CH2:1][C:9]4[C:4]([C@H:3]3[NH:10]2)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C@@:12]2([O:19][C@H:2]3[CH2:1][C:9]4[C:4]([C@H:3]3[NH:10]2)=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:17][CH2:16]1
Reactant: O=C1CCCCC1=O
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Product: c1ccc2c(c1)C[C@@H]1O[C@]3(CCCC[C@@]34N[C@@H]3c5ccccc5C[C@@H]3O4)N[C@H]21
Yield: 90 %

Procedure:
For example, employing (1R,2S)-cis-1-amino-2-indanol in the acid-promoted reaction with 1,2-cyclohexanedione, bisoxazolidine 1 was obtained in 90% yield and 99% de (FIG. 1B). It was shown that compound 1 was produced with excellent diastereoselectivity and exclusive formation of the (S,S)—N,O-diketal by crystallographic analysis: careful evaporation of a solution of 1 in chloroform gave the single crystal suitable for crystallographic analysis (CDCC602445). (Crystal structure data: C24H26N2O2, monoclinic, space group P21, a=16.9199(16) Å, b=5.5487(5) Å, c=23.585(2) Å, α=90.00°, β=108.5190(10)°, γ=90.00°, V=2099.6(3) Å3, Z=4, ρcalcd=1.367 g cm−3, T=173 K.) It was shown that the ligand possesses a C2-symmetric structure and an averaged separation of 2.35 Å between the nitrogen and oxygen atoms which facilitates bidentate binding to metal ions and organometallic compounds (FIG. 1C). It was envisioned that 1, as well as other bisoxazolidines, would be useful for a variety of asymmetric reactions.
Reaction SMILES: C([C:3]1([CH2:13][O:14][C:15]2[C:27]([CH:28]3[CH2:30][CH2:29]3)=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[C:17]([F:31])[CH:16]=2)[CH:10]2CC3[CH2:7][CH:8]([CH2:12][CH:4]1C3)[CH2:9]2)#N.C12CC1CCC(COC1C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=1)C2>>[CH:12]12[CH2:7][CH:8]1[CH2:9][CH2:10][CH:3]([CH2:13][O:14][C:15]1[C:27]([CH:28]3[CH2:29][CH2:30]3)=[CH:26][C:18]([C:19]([OH:21])=[O:20])=[C:17]([F:31])[CH:16]=1)[CH2:4]2
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2CCC3CC3C2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6, and making variations as required to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-(bicyclo[4.1.0]heptan-3-ylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was obtained as a yellow solid (1.06 g, 99%): MS (ES+) m/z 305.1 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][C:8]=2[C:27]2[N:31](COCC[Si](C)(C)C)[N:30]=[CH:29][CH:28]=2)[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CCOC(C)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:26]=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)=[O:12])=[CH:9][C:8]=2[C:27]2[NH:31][N:30]=[CH:29][CH:28]=2)[CH2:3]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)ccc1N1CC[C@@H](O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
(R)-4-(3-Hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)benzamide (Stage 1.1, 149 mg, 0.2 mmol) was added to a MW vial, which was sealed and flushed with argon. A solution of 1 M TBAF in THF (2.98 mL, 2.98 mmol) was then added and the RM was stirred at 80° C. for 3 days. The RM was diluted with EtOAc (40 mL), washed with sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was purified by preparative SFC (Column DEAP, from 25% to 30% in 6 min) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=0.98 min, m/z=433.3 [M+H]+, m/z=431.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.75 (br. s, 1H) 1.86 (br. s, 1H) 2.70-2.79 (m, 1H) 3.03-3.19 (m, 2H) 3.19-3.28 (m, 1H) 4.20 (br. s, 1H) 4.73-4.92 (m, 1H) 6.34 (d, J=11.00 Hz, 1H) 6.73-6.94 (m, 1H) 7.32 (d, J=8.80 Hz, 2H) 7.65 (d, J=104.42 Hz, 1H) 7.81-7.96 (m, 4H) 10.10 (s, 1H) 12.88 (d, J=81.67 Hz, 1H).
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH3:25])[N:23]=[C:22]([CH:26]=O)[CH:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:26]([C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[N:24]([CH3:25])[N:23]=1)#[CH:1]
Reactant: Cn1nc(C=O)cc1-c1ccc(F)cc1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cc(-c2ccc(F)cc2)n(C)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 93.3 %

Procedure:
To a solution of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (2.27 g, 11.8 mmol) in methanol (100 mL) were added 5-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carbaldehyde (may be prepared in analogy to WO2005014553, 2.00 g, 9.8 mmol) and potassium carbonate (2.84 g, 20.56 mmol) and the resulting yellow suspension was stirred for 19 h at ambient temperature. After extraction with aqueous sodium hydrogencarbonate and ethyl acetate the combined organic layers were washed with brine, dried over sodium sulfate. Concentration and purification by chromatography (SiO2, hexane:ethyl acetate=100:0 to 75:25) afforded the title compound (1.83 g, 93%) as a white solid. MS: m/e=201.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])C=1C(OCC)=O.[C:22]([O:26][C:27](=[O:29])[CH3:28])([CH3:25])([CH3:24])[CH3:23].CC(C)([O-])C.[K+]>>[Br:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[C:28]=1[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:29]
Reactant: CCOC(=O)c1c(Br)c(Cl)c(C)n1COCC[Si](C)(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Cc1c(Cl)c(Br)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
Ethyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 266, 564 mg, 1.42 mmol), t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were mixed together and stirred at room temperature for 10 minutes, concentrated to an oil under vacuum. t-Butylacetate (330 mg, 2.84 mmol) and potassium t-butoxide (0.14 mmol) were added again into the reaction mixture, repeated the same procedure again. The resulting reaction crude was filtered through a short pass silica gel, washed with ethyl acetate, the combined filtrate was concentrated to an oil and purified by column chromatography (2% ethyl acetate in hexanses) to give the desired product as an oil (485 mg).