Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:21]=[C:22]([CH:36]=[CH:37][CH:38]=1)[C:23]([C:25]1[CH:35]=[CH:34][CH:33]=[CH:32][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24].C(N(CC)CC)C.C(#N)C>O1CCOCC1>[CH2:30]([O:29][C:27]([C:26]1[CH:32]=[CH:33][CH:34]=[CH:35][C:25]=1[C:23]([C:22]1[CH:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:38]=[CH:37][CH:36]=1)=[O:24])=[O:28])[CH3:31]
Reactant: CCOC(=O)c1ccccc1C(=O)c1cccc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1C(=O)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 14.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (5.1 g) is added, at a temperature between 70° and 78° C., to a solution of ethyl 2-(3'-aminobenzoyl)benzoate (4.6 g) and triethylamine (3.45 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 70° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 45 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with a saturated aqueous sodium bicarbonate solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (9 g) is thereby obtained, which is chromatographed on an 8 cm diameter column containing silica (0.02-0.045 mm; 640 g). Elution is carried out with ethyl acetate at a pressure of 0.45 bar (45 kPa), collecting 300 cm fractions. The first 12 fractions are discarded. The following 6 fractions are combined and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (5.1 g) is thereby obtained, which is dissolved in boiling acetonitrile (30 cc). The solution obtained is filtered in the heated state. The filtrate obtained is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed 3 times with acetonitrile cooled to a temperature in the vicinity of 4° C. (30 cc in total) and 3 times with diethyl ether (90 cc in total) and the dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(2-ethoxycarbonylbenzoyl)phenyl]-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (1.2 g) in the form of cream-coloured crystals, m.p. 150° C., is thereby obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[C@@H:26]([CH3:27])[CH2:25][CH2:24][C@@H:23]1[CH3:28].C([O-])([O-])=O.[K+].[K+].N>CO.C(Cl)Cl.CN(C=O)C>[CH3:28][CH:23]1[CH2:24][CH2:25][CH:26]([CH3:27])[N:22]1[CH2:21][CH2:20][CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]2)=[CH:12][CH:13]=1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: C[C@H]1CC[C@H](C)N1CCCCl
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC1CCC(C)N1CCCOc1ccc(C2(CN(C)C)CCOCC2)cc1
Yield: 38.1 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (330 mg, 1.43 mmol), 1-(3-chloro-propyl)-2,5-trans-dimethyl-pyrrolidine (221 mg, 1.26 mmol), DMF (7.6 ml) and K2CO3 (790 mg, 5.72 mmol) were reacted together according to general procedure B. The isolated material was subjected to chromatography on silica, eluant 95:4:1 (DCM, MeOH, NH3) to give the title compound as a yellow oil (180 mg, 34%). 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.87 (d, 2H), 4.08-3.95 (m, 2H), 3.79-3.70 (m, 2H), 3.59-3.49 (m, 2H), 3.11-3.00 (m, 2H), 2.77 (m, 1H), 2.54 (m, 1H), 2.40 (s, 2H), 2.14-1.81 (m, 8H), 1.96 (s, 6H), 1.44-1.31 (m, 2H), 0.97 (d, 6H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].I[CH2:15][CH2:16][CH2:17][C:18]1[C:19]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[N:20][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]3[N:33]=[C:34]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[O:35][C:36]=3[CH3:37])=[CH:26][CH:25]=2)[CH:22]=1.Cl>O1CCCC1>[CH3:37][C:36]1[O:35][C:34]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[N:33][C:32]=1[CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:21]2[CH:22]=[C:18]([CH2:17][CH2:16][CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:19]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[N:20]2)=[CH:25][CH:26]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CCCI)c(-c3ccccc3)n2)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1)C(=O)OCC
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
Sodium hydride (60%, oily, 476 mg) was added to a solution of diethyl malonate (2.37 g) in tetrahydrofuran (50 ml) at 0° C., and the mixture was stirred for 30 minutes. A solution of 1-iodo-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propane (1.75 g) in tetrahydrofuran (15 ml) was added dropwise to the above mixture, which was stirred at room temperature for 13 hours. The reaction mixture was acidified with diluted hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The residue was subjected to silica gel column chromatography, and diethyl 2-[3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propyl]malonate (1.63 g, yield: 88%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=[C:10]2[CH:9]1[CH2:21][O:22]CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[N:14]=[C:15]([C:17]([F:19])([F:18])[F:20])[N:16]=[C:10]2[CH:9]1[CH2:21][OH:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCn2nc(C(F)(F)F)nc2C1CO
Reaction time: 29 h

Procedure:
To a solution of 733 mg (1.8 mmol) of 7-N-(tert-butoxycarbonyl)-8-[(benzyloxy)methyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-α]pyrazine in 8.0 mL of ethanol was added 400 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for 29 h. TLC analysis indicated that starting material was present. Thus 400 mg of 10% palladium on carbon was added and the mixture shaken on a Parr apparatus under 42 psi hydrogen for 12 h. The reaction mixture was filtered through Celite and concentrated. Flash chromatography (silica gel, 7% to 50% ethyl acetate/hexane gradient) gave the title compound as a white solid. LC/MS 267 (M+1-tBu).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)(=O)C.O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])[CH3:36]
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 40 °C
Yield: 44.1 %

Procedure:
A mixture of 7-benzyl-3,7-dihydropurine-2,6-dione (3.0 g), anhydrous potassium carbonate (2.0 g), and N,N-dimethylformamide (60 ml) was stirred with heating in an oil bath of 40° C., and ethyl bromoacetate (1.5 g) was added thereto. The mixture was stirred by heating at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 20–40% (20% 2-propanol/ethyl acetate)/hexane to give 1.3 g of the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.[CH3:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=1Br)=[O:25].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.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>[OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:28]2[CH:29]=[C:30]([C:33]([F:36])([F:35])[F:34])[CH:31]=[CH:32][C:27]=2[NH:26][C:24](=[O:25])[CH3:23])=[CH:7][CH:6]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Reactant: CC(=O)Nc1ccc(C(F)(F)F)cc1Br
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: CCO
Product: CC(=O)Nc1ccc(C(F)(F)F)cc1-c1ccc(O[C@@H](C)[C@H](O)CCc2cccnc2)cc1
Yield: 70.1 %

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.15 g, Example 33), 2-bromo-4-(trifluoromethyl)acetanilide (0.28 g), 2M aqueous sodium carbonate (0.57 ml) and tetrakis(triphenylphosphine)palladium (0) (0.014 g) in ethanol (5 ml) with heating at reflux for 2 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-5% ethanol in dichloromethane to give the title compound as a solid (0.16 g).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([Cl:21])[C:10]=1[CH:11]=[O:12].COB(OC)OC.Cl>O1CCCC1.[Zn].C(O)(=O)C>[Cl:8][C:9]1[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=[C:13]([Cl:21])[C:10]=1[CH:11]([OH:12])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)CBr
Agent: COB(OC)OC
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
Ethyl bromoacetate (13.7 ml) was added to a suspension of 30.0 g of 2,6-dichloro-4-trifluoromethylbenzaldehyde (7), 50 ml of trimethoxyborane and 8.5 g of zinc powder in 50 ml of anhydrous tetrahydrofuran with vigorous stirring at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into a mixture of 100 ml of 10% hydrochloric acid and 10 ml of acetic acid, and the resulting mixture was filtered through Celite. The aqueous filtrate was neutralized with a 5% aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate, drying over anhydrous magnesium sulfate and concentration under reduced pressure, affording 40.7 g of the desired compound in the form of a pale green oil (quantitative crude yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[C@@H:16]([CH3:18])[NH2:17].C(=O)([O-])[O-].[K+].[K+]>CCOCC.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C@@H:16]([C:15]([O:14][CH3:13])=[O:19])[CH3:18])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)[C@@H](C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
To a stirred solution of 2,4-dichloro-5-nitropyrimidine (17.5 g, 90 mmol) in ether (100 mL) at —OC was added a solution of D-alanine methyl ester hydrochloride (12 g, 85.96 mmol) in water (50 mL). To the resulting mixture was added potassium carbonate (71.2 g, 515.5 mmol) in portions with vigorous stirring. Then the reaction was allowed to warm up to rt and stirred for 16 h. The precipitated solid was filtered to afford desired product as yellow solid (4 g). Ether layer was separated from filtrate, the aqueous layer was extracted with ether (50 mL×3). Combined ether layers were dried (Na2SO4), evaporated to give a crude residue, which was then purified by silica gel flash chromatography to give another 2.7 g of desired product. 1HNMR (300 MHz, CDCl3): δ 1.61 (d, J=7.2 Hz, 3H), 3.82 (s, 3H), 4.90-5.0 (m, 1H), 8.75 (br s 1H) and 9.07 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][NH:8][CH2:9][CH:10]([CH2:13][OH:14])[CH2:11]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl>[CH:1]1([CH2:7][N:8]2[CH2:9][CH:10]([CH2:13][OH:14])[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(CO)CNCC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: OCC1CN(CC2CCCCC2)C1

Procedure:
To 100 mL of carbon tetrachloride add 19.2 g (0.1 mol) of 2-[(cyclohexylmethylamino)methyl]-1,3-propanediol, 26.2 g (0.1 mol) of triphenylphosphine, and 11 g (0.1 mol) of triethylamine. Monitor the reaction by thin-layer chromatography. Upon completion extract twice with 50 mL of 1N aqueous HCl. Add 1N NaOH to the aqueous portion until basic and extract twice with 100 mL of ether. Dry the organic phase over Na2SO4. Filter off the drying agent and evaporate the solvent in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:22][OH:21])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)occ1O
Product: O=c1cc(CNS(=O)(=O)c2cccc(Cl)c2)oc(CO)c1O
Yield: 47.5 %

Procedure:
3-Chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-05) (7.3 g, 47.50%) was synthesized as a white solid from 3-chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-05) (14.0 g, 44.44 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:20])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][NH:17][C:16](=O)[CH2:15]2)[CH2:10][CH2:9]1>C1COCC1>[F:20][C:8]1([F:7])[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18]2)[CH2:12][CH2:13]1
Reactant: O=C1CC(C2CCC(F)(F)CC2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: FC1(F)CCC(C2CCNC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium aluminium hydride (397.6 mg, 10.49 mmol, 2 eq) is added portionwise at 0° C. to a solution of 4-(4,4-difluorocyclohexyl)pyrrolidin-2-one a1-26 (assumed quantitative from previous step, 5.24 mmol, 1 eq) in dry THF (10 ml). The reaction mixture is allowed to warm to room temperature and stirred overnight, then quenched by water at 0° C. and filtered on celite. The solvent is evaporated under reduced pressure to afford 3-(4,4-difluorocyclohexyl)pyrrolidine a1-34.
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:13][C:14]1[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([F:27])[CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)C.C1(C)C=CC=CC=1>[F:13][C:14]1[C:22]([C:23]([F:24])([F:25])[F:26])=[C:21]([F:27])[CH:20]=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(F)c(C(F)(F)F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.15 g (0.09 mol) of magnesium filings are introduced into 4.8 ml of ethanol, the reaction is started up using a few drops of carbon tetrachloride, and a solution of 12.8 g (0.075 mol) of diethyl malonate in 9 ml of ethanol and 35 ml of toluene is subsequently added dropwise in such a manner that the internal temperature is between 50 and 60° C. Stirring is then continued for one hour at 60° C. A solution of 20.0 g (0.082 mol) of 2,4-difluoro-3-trifluoromethylbenzoyl chloride in 9 ml of toluene is added dropwise at -10° to -5° C., and stirring is continued for one hour at 0° C. and subsequently while the mixture comes to room temperature. The batch is poured into 35 ml of ice-water, treated with 5.7 ml of concentrated sulphuric acid, and the mixture is extracted using toluene. The toluene phase is washed using saturated sodium chloride solution, and the solvent is removed in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:8]2(C(O)=O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1(C(=O)O)CCOCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Br)cnc1C1CCOCC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 4-(5-bromo-3-methylpyridin-2-yl)tetrahydro-2H-pyran-4-carboxylic acid (420 mg) in dimethylsulfoxide (1 ml) was stirred at 150° C. for 1.5 hours. After completion of the reaction, the mixture was cooled to room temperature, water was added thereto, and extracted with chloroform. The organic layer was washed with water and saturated brine sequentially, then dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (316 mg) as a white solid. MS (ESI) m/z: 256, 258 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:22][C:18]1[CH:17]=[C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)CBr
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Temperature: 145 °C
Reaction time: 3.5 h

Procedure:
4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 119, 158 mg) was dissolved in toluene (5 mL), and treated with bromo-acetic acid methyl ester (0.03 mL) and silver carbonate (53 mg). The reaction mixture was then stirred at 145° C. (Bath-temperature) for 3.5 h, cooled down to r.t., filtered-off and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 1:9) to give the title compound as colorless oil (30 mg). MS (m/e)=438.3 (MH+).
Reaction SMILES: Br[C@H:2]1[C:28](=[O:29])[C@@:27]2([CH3:30])[C@@H:13]([CH2:14][C@@H:15]3[O:20][C@@:19]4([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]4)[C@@H:17]([CH3:18])[C@@H:16]32)[C@H:12]2[C@H:3]1[C@:4]1([CH3:32])[C@@H:9]([CH2:10][CH2:11]2)[CH2:8][C@@H:7]([OH:31])[CH2:6][CH2:5]1.[OH-:33].[Na+]>O>[CH3:18][C@@H:17]1[C@:19]2([O:26][CH2:25][C@H:23]([CH3:24])[CH2:22][CH2:21]2)[O:20][C@H:15]2[CH2:14][C@@H:13]3[C@@:27]([CH3:30])([C@@H:16]12)[C@H:28]([OH:29])[C:2](=[O:33])[C@H:3]1[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@:4]1([CH3:32])[CH2:5][CH2:6][C@H:7]([OH:31])[CH2:8]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](Br)C(=O)[C@]3(C)[C@H]1[C@@H]2C
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Temperature: 83 °C

Procedure:
A glass lined reactor was charged with 12.4 Kg of (3β,5α,11β,25R)-11-bromospirostan-3-ol-12-one (24.34 mole), 33 gallons of 33 gallons of water and 7.5 Kg (189 mole, 7.75 eq) of sodium hydroxide pellets. The reaction was heated to reflux over 1.5 hours, maintained at reflux for 4.5 hours (pot temperature was 83° C.), then cooled to room temperature. TLC at this point indicated complete reaction.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[CH:6]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:6]([N:19]1[CH2:22][C:21]([CH:1]([CH3:3])[CH3:2])([OH:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a 1.0 M isopropylmagnesium bromide in THF (5.0 mL, 5.0 mmol), 1-benzhydryl-azetidin-3-one (237 mg, 1 mmol) in THF (5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. Then it was added 10% NaHCO3 solution and extracted with ether (2×30 mL). The organic layers were combined, dried (MgSO4) and concentrated to give an orange oil. The crude product was purified by Prep. HPLC column using CH3CN—H2O-ammonium acetate solvent system. Fractions were collected and concentrated. Then it was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a light yellow oil as Grignard reaction product. (80 mg, 28% yield). MS m/z 282(MH+), Retention time: 1.485 min. 1H NMR (300 MHz, MeOD) δ ppm 0.93 (d, J=6.95 Hz, 6 H) 1.90-2.04 (m, 1 H) 3.00 (d, J=9.15 Hz, 2 H) 3.28 (d, J=9.15 Hz, 2 H) 4.49 (s, 1 H) 7.14-7.22 (m, 2 H) 7.23-7.33 (m, 4 H) 7.37-7.46 (m, 4 H).