Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].O.O1CCCC1.OO>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1([CH2:12][CH3:13])[CH2:10][CH2:9][CH:8]=[CH:7][C:6]1=[O:11]
Reactant: CCC1(CC(=O)OC)CCCCC1=O
Agent: OO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC1(CC(=O)OC)CCC=CC1=O
Reaction time: 4 h
Yield: 55.3 %

Procedure:
The ketone, 2-carbomethoxymethyl-2-ethylcyclohexanone (IX) (141 mmol, 28 g) was stirred in 1.25 L of ethyl acetate (dried over 3A molecular sieves) and treated with 169 mmol (32.5 g) of PhSeCL. The reaction was stirred under nitrogen for 4 hours then treated with 250 mL of water. The mixture was shaken vigorously in a separatory funnel and the organic phase was returned to the reaction flask. Tetrahydrofuran (550 mL) was then added followed by 35 mL of 30% H2O2 (aq.) added dropwise. The reaction mixture was stirred for one hour then washed with 500 mL of water and 500 mL of saturated Na2CO3 (aq.). The product was then dried over MgSO4 and concentrated in vacuo. Flash chromatography (4 inches diameter column, 20% ethyl acetate in petroleum ether eluent, 51/2 inches of silica gel) afforded 15.3 g (78.0 mmol, 55%) of the product as a pale yellow oil. Rf =0.9 in 15% ethyl acetate/petroleum ether on TLC.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:23])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OCCCCCCCCCCCCCC)C1OC1.C(CN)O.O1CCCC1.[P:52](=O)([OH:55])([OH:54])[OH:53].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+:72].[Na]>O>[P:52]([OH:55])([O-:54])([O:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:23])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:53].[Na+:72]
Reactant: CCCCCCCCCCCCCCOCC(O)CNCCO
Reactant: O=P(O)(O)O
Agent: CCCCCCCCCCCCCCOCC1CO1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: NCCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCCCOCC(O)CNCCOP(=O)([O-])O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.2 %

Procedure:
A 300-ml flask equipped with a stirrer was charged with 5.13 g (14.8 mmol) of 3-(2-hydroxyethylamino)-1-tetradecyloxy-2-propanol prepared from tetradecyl glycidyl ether and ethanolamine in the same manner as in Preparation Example 14, and 70 mol of tetrahydrofuran, 1.95 g (16.9 mmol) of 85% phosphoric acid and 3.54 g (30.7 mmol) of P2O5 were added thereto. The resultant mixture was stirred at 65° C. for 10 hours. After cooling the mixture to room temperature, 0.56 g of water was added to the mixture, stirring was conducted for 30 minutes, 5.0 g of 48% aqueous NaOH were added further. After concentrating the resultant reaction mixture under reduced pressure, the resultant residue was subjected to extraction with ethanol by means of a Soxhlet's extractor. The resultant extract was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel, thereby obtaining 2.32 g (yield: 34.9%) of the title compound monosodium (IIa-14).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:15]([C:26](OC)=[O:27])[CH2:14]1.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH:15]([CH2:26][OH:27])[CH2:14]1
Reactant: COC(=O)C1CN(C)CCC1c1ccccc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1CCN(C)CC1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106 %

Procedure:
In a nitrogen atmosphere, 152 mg of lithiumaluminium hydride was added to tetrahydrofuran (20 mL) solution of 500 mg of methyl (3RS,4SR)-1-methyl-4-o-tolylpiperidine-3-carboxylate obtained in Production Example 31-1, at 0° C., and stirred at 0° C. for 30 minutes. 0.15 mL of water, 0.15 mL of aqueous 15% sodium hydroxide solution and 0.46 mL of water were added to the reaction liquid in that order, and stirred at room temperature for 1 hour. This was diluted with ethyl acetate, and dried with anhydrous sodium sulfate, and the insoluble substance was removed through filtration through Celite. The filtrate was distilled under reduced pressure, and the residue was separated and purified through silica gel column chromatography (chloroform/methanol=70/30) to obtain 470 mg of the entitled compound as a pale yellow oily substance.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][C:21]=3[Cl:32])[C:14]2=[O:33])[CH2:9][CH2:8]1)(C)(C)C>CO>[Cl:32][C:21]1[CH:22]=[C:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:25][C:20]=1[CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][N:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([OH:6])[CH2:8][CH2:9]2)[C:14]1=[O:33]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2CCCC(Cc3ccc(-c4cccnc4)cc3Cl)C2=O)CC1
Solvent: CO
Product: O=C1C(Cc2ccc(-c3cccnc3)cc2Cl)CCCN1[C@H]1CC[C@H](O)CC1
Temperature: 40 °C

Procedure:
Dissolve trans-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-3-(2-chloro-4-pyridine-3-yl-benzyl)-piperidin-2-one (0.2 g, 0.39 mmol) in methanol containing concentrated hydrochloric acid (5% v/v) and heat at 40° C. for 1 hour. Evaporate the solvent, dissolve the residue in DCM (10 mL) and wash with saturated aqueous NaHCO3 (5 mL). Dry the organic layer over anhydrous Na2SO4, remove the solvent and purify the residue by chromatography over silica gel eluting with EtOAc to obtain the title compound as a white solid (131.4 mg, 84%): MS (ES+) m/z=399 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.Cl[C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[C:21]#[N:22])[NH2:17]>CN1C(=O)CCC1>[C:21]([C:20]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)#[N:22]
Reactant: OCCCN1CCOCC1
Reactant: N#Cc1ccc(N)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1ccc(N)cc1OCCCN1CCOCC1
Temperature: 145 °C
Reaction time: 0.25 h
Yield: 25.5 %

Procedure:
Sodium hydride (2.0 g of an 85% dispersion in mineral oil, 60 mmol) was added to 4-(3-hydroxypropyl)morpholine (4.8 g, 30 mmol), (Tet. Lett. 1994, 35, 1715), in NMP (50 ml) and the mixture was stirred for 15 minutes. 3-Chloro-4-cyanoaniline (4.8 g, 30 mmol) was added and the mixture was heated at 145° C. for 6 hours. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and then brine and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate and then methylene chloride/methanol (9/1) to give 4-cyano-3-(3-morpholinopropoxy)aniline (2.0 g, 26%) as a yellow gum.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[C:9]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([NH2:14])[CH:13]=1>O>[N+:15]([C:11]1[CH:10]=[C:9]([O:18][C:19]([F:20])([F:21])[F:22])[C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][C:12]=1[NH2:14])([O-:17])=[O:16]
Reactant: C1CCNCC1
Reactant: Nc1cc(Cl)c(OC(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Product: Nc1cc(N2CCCCC2)c(OC(F)(F)F)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 99.9 %

Procedure:
Piperidine (1.2 mL) was added to 5-chloro-2-nitro-4-trifluoromethoxy-phenylamine (0.757 g, 2.94 mmol) in a sealed tube and the mixture was heated to 100° C. for 2 h. The mixture was cooled to 23° C., poured into water (50 mL) and extracted with EtOAc (3×80 mL). The combined organic layers were washed with brine (50 mL), dried, filtered, and concentrated under reduced pressure to yield the titled compound (0.900 g, 99.9%). MS (ESI/CI): mass calcd. for C12H14F3N3O3, 305.1; m/z found, 306.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][C:3]=1[CH3:10].C([Mg]Cl)(C)C.C([Li])CCC.C(O)(=O)C[C:23](CC(O)=O)(C(O)=O)[OH:24]>C1COCC1.CN(C=O)C>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([CH:23]=[O:24])=[C:3]([CH3:10])[CH:4]=1
Reactant: Cc1cc(Br)c(C)cc1Br
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(C=O)c(C)cc1Br
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
A solution of 1,4-dibromo-2,5-dimethylbenzene (5.0 g, 18.94 mmol, Aldrich) in anhydrous THF (20 mL) was cooled to about −10° C. Isopropyl magnesium chloride (3.95 mL, 2.0 M in THF, 7.9 mmol) was added. The mixture was allowed to stir at about −10° C. for about 0.25 h. Next n-butyl lithium (6.31 mL, 2.5 M in hexanes, 15.8 mmol) was added dropwise keeping the temperature at or below about 0° C. Once the addition was complete the reaction was stirred at about −10° C. for about 1 h. Next a solution of DMF in 10 mL anhydrous THF (20.52 mmol) was added dropwise keeping the temperature at or below about 0° C. The reaction was stirred at ambient temperature for about 3 hours. The reaction was poured into about 50 mL of about 5 M aqueous citric acid solution (exothermic) and stirred at room temperature for about 10 minutes. The layers were separated and the aqueous layer was extracted once with toluene (50 mL). The combined organic layers were washed with water (20 mL), then concentrated in vacuo. The residue was purified by column chromatography (SiO2, diethyl ether/petroleum ether 5:95) to give 4-bromo-2,5-dimethylbenzaldehyde (3.66 g, 17.18 mmol, 91%) as a pale crystalline solid: 1H-NMR (CDCl3, Bruker 400 MHz) δ 2.43 (3 H, s); 2.60 (3 H, s); 7.47 (1 H, s); 7.63 (1 H, s) 10.2 (1 H, s).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[Cl:11])=[N+:2]=[N-:3].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.C[O-].[Na+]>C(O)C.C(OCC)(=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N:1]1[C:21]([NH2:22])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[N:3]=[N:2]1
Reactant: COc1ccc(CC#N)cc1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nnn(-c3ccc(F)cc3Cl)c2N)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.1 %

Procedure:
To an ice-cooled and stirred mixture of 1-azido-2-chloro-4-fluoro-benzene (0.300 g, 1 eq) and commercial (4-methoxy-phenyl)-acetonitrile (0.309 g, 1.2 eq) in ethanol (5 ml) kept under nitrogen, a solution of sodium methoxide (0.142 g, 1.5 eq) in ethanol (5 ml) is added drop-wise (15 min). After the addition, the reaction mixture is allowed to reach room temperature spontaneously and stirring is then continued overnight at room temperature. The resulting reaction mixture is diluted with ethyl acetate (20 ml), washed with water (2×25 ml), dried over MgSO4 and evaporated to dryness. The yellow semisolid residue (˜0.500 g) is purified by flash chromatography using 60-120 mesh silica gel and eluting with 20% ethylacetate in hexane, to afford the title compound as a white solid (0.190 g, 34% yield). M.p. 136.3-141.2° C.
Reaction SMILES: C([N:4]([CH2:14][C@@H:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[C:23]([F:35])[CH:22]=2)[CH2:16]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])(=O)C.C(Cl)(=O)OCOC(=O)CC>ClCCl>[O:34]=[S:30]1(=[O:33])[CH2:31][CH2:32][CH:27]([C:24]2[CH:25]=[CH:26][C:21]([N:17]3[CH2:16][C@H:15]([CH2:14][NH:4][C:5]([O:7][CH2:8][O:9][C:10](=[O:13])[CH2:11][CH3:12])=[O:6])[O:19][C:18]3=[O:20])=[CH:22][C:23]=2[F:35])[CH2:28][CH2:29]1
Reactant: CCC(=O)OCOC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: CCC(=O)OCOC(=O)Cl
Solvent: ClCCl
Product: CCC(=O)OCOC(=O)NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 75 %

Procedure:
Following general procedure C, (S)-5-aminomethyl-3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-oxazolidin-2-one (2) (500 mg, 1.5 mmol), dichloromethane (14 mL) and propanoyloxymethyl carbonochloridate (7b) gave the titled product in 75% yield (520.9 mg, 1.10 mmol). 1H NMR (400 MHz, CDCl3): δ 7.48 (dd, 1H), 7.24 (t, 1H), 7.16 (dd, 1H), 5.74 (q, 2H), 5.28 (t, 1H), 3.12-3.18 (m, 4.83 (m, 1H), 4.05 (t, 1H), 3.79 (dd, 1H), 3.67 (ddd, 1H), 3.56 (dt, 1H), 3.12-3.18(m, 4H), 3.10 (dt, 1H), 2.32-2.46 (m, 4H), 2.17-2.20 (m, 2H), 1.12 (t, 3H). MS-APCI (m/z+): 473 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:57]([O:59][C:60]([CH2:62][CH:63]1[NH:68][CH2:67][CH2:66][NH:65][C:64]1=[O:69])=[O:61])[CH3:58].ClCl>CN(C=O)C.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:68]1[CH2:67][CH2:66][NH:65][C:64](=[O:69])[CH:63]1[CH2:62][C:60]([O:59][CH2:57][CH3:58])=[O:61])=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)CC1NCCNC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC1C(=O)NCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 37 %

Procedure:
Prepared analogously to Example 1g from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and 3-(ethoxycarbo-nylmethyl)piperazin-2-one in DMF. Yield: 37%; Rf value: 0.49 (silica gel; dichloromethane/ethanol=10:1); C25H25Cl2N5O5 (546.41); mass spectrum: (M+H)+=546/548/550 (chlorine isotope).
Reaction SMILES: [F-:1].[F-:2].[F-].C(N(SN(CC)CC)CC)C.[C:15]([O:18][CH2:19][C:20]1[O:24][C:23]([CH:25]=O)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:15]([O:18][CH2:19][C:20]1[O:24][C:23]([CH:25]([F:2])[F:1])=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: [F-]
Reactant: CC(=O)OCc1ccc(C=O)o1
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C(F)F)o1
Temperature: 20 °C

Procedure:
A solution containing 7.26 cm3 of DAST (diethylamino sulphide trifluoride) and 30 cm3 of methylene chloride is added at 5° C. to a solution containing 10 g of the product prepared in Stage A and 100 cm3 of methylene chloride. The reaction mixture is agitated at 20° C. for half an hour and is taken to reflux for 1 hour. It is maintained under agitation for 18 hours at 20° C. and taken to reflux for 3 hours, then treated with sodium acid carbonate and extracted with methylene chloride. After drying and concentrating, 12 g of a product is obtained which is chromatographed on silica eluting with a hexane--ethyl acetate mixture (8-2). In this way 5.5 g of desired product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH2:18]>C(Cl)Cl.C(#N)C>[C:1]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:14][CH2:13][O:12][S:11]2(=[O:18])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN2CCOS2=O)cc1
Reactant: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN2CCOS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of 2-(4-tert-butylbenzylamino)-ethanol (1190 mg, 5.74 mmol) and triethylamine (3200 μl, 22.96 mmol) in DCM (15 ml) at −15° C. was added a solution of thionylchloride (544 μl, 7.46 mmol) in DCM (4 ml) over 10 min. The reaction mixture was stirred at −10° C. for 30 min, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography to give the desired compound (790 mg, 54%) as a white solid. To a mixture of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2-oxide (790 mg, 3.12 mmol) in DCM (20 ml), acetonitrile (8 ml) and water (8 ml), at 0° C. was added NaIO4 (867 mg, 4.05 mmol) followed by RuO2 (2 mg). The reaction mixture was stirred at 0° C. for 2 h. Water was added and the phases were separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was then purified by flash column chromatography to give the desired product (640 mg, 76%) as an off white solid. MS (ISP) 287.0 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[CH:24]=[C:25]2[N:31]=[N:30][N:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=3)[C:26]2=[N:27][CH:28]=1>>[Cl:1][C:2]1[C:3]([N:8]([C:38]([C:35]2[CH:34]=[CH:33][C:32]([N:29]3[C:26]4=[N:27][CH:28]=[C:23]([CH3:22])[CH:24]=[C:25]4[N:31]=[N:30]3)=[CH:37][N:36]=2)=[O:39])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cnc2c(c1)nnn2-c1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ncccc2Cl)C1
Product: Cc1cnc2c(c1)nnn2-c1ccc(C(=O)N(c2ncccc2Cl)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc1
Yield: 43.2 %

Procedure:
Prepared according to General Procedure A and C starting from Preparation 1 tert-butyl (3R)-3-[(3-chloropyridin-2-yl)amino]piperidine-1-carboxylate (3.22 g, 10.3 mmol) and Preparation 8 5-(6-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxylic acid (2.51 g, 9.83 mmol) to provide 2.33 g (43%) of the product as a solid.
Reaction SMILES: CS(O[CH2:6][C:7]#[C:8][C:9]1[S:29][C:12]2=[N:13][C:14]([CH3:28])=[CH:15][C:16]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])=[C:11]2[C:10]=1[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)(=O)=O.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C1COCC1>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:16]2[CH:15]=[C:14]([CH3:28])[N:13]=[C:12]3[S:29][C:9]([C:8]#[C:7][CH2:6][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:10]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[C:11]=23)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: COc1cccc(-c2c(C#CCOS(C)(=O)=O)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C#CCN3CCOCC3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
A mixture of 3-{4-{[(3-chlorophenyl)sulfonyl]amino}-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-2-yl}-2-propyn-1-yl methanesulfonate (Description 77) (14 mg, 0.024 mmol) and morpholine (21.14 μl, 0.243 mmol) in THF (221 μl) was stirred at 60° C. for 1 h. The mixture was evaporated to dryness and the residue purified on silica, eluting with a gradient of 0-10% 2M NH3 in MeOH in DCM, to afford the title compound (12 mg). LCMS (A) m/z: 568 [M+1]+, Rt 1.02 min (acidic).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].O=S(Cl)Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[CH:25][CH:24]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: CC(=O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(N(C(=O)C(C)=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Pyruvic acid (1.00 g, 11.34 mmol) was placed in a 250 mL three-necked round-bottomed flask fitted with a stirring bar, reflux condenser and a nitrogen inlet, and dissolved in 30 mL anhydrous THF at room temperature. Then, SOCl2 (2.03 g, 17.01 mmol) was added dropwise with stirring in 3 hours at room temperature. Bis(4-methoxyphenyl)amine (2.00 g, 8.72 mmol) was added under nitrogen protection. Pyridine (4.14 g, 52.3 mmol) were added to the mixture at 0° C. The reaction mixture was heated to reflux for 12 hours. The reaction was quenched by adding 30 mL of 2N HCl solution. The mixture was extracted with EtOAc (3×20 mL). The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give a yellow residue. The solvent was removed and residue was subjected to flash column chromatography (silica gel, EtOAc/hexanes=3/7 v/v) to give a white solid product, N,N-bis(4-methoxyphenyl)-2-oxopropanamide, 2.15 g, 82.4% yield. MS: m/z 322 [M+Na]+.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]#[N:10].[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)(C)(C)C>[O:16]1[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]1[C:9]#[N:10]
Reactant: O=C1CCCC1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CC1OC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A 1 M solution of potassium tert-butoxide in tert-butyl alcohol (184.4 mL, 184.4 mmol) is added slowly to a solution of chloroacetonitrile (10.8 mL, 167.6 mmol) and cyclopentanone (15.0 mL, 167.6 mmol) in anhydrous t-butyl alcohol (33 mL). The reaction is stirred at room temperature for 16 h. The mixture is filtered through diatomaceous earth, the solvent is removed, and the residue is diluted with water. The mixture is neutralized with 30% aq.sodium dihydrogen phosphate solution and extracted with diethyl ether. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed. The residue is purified by flash chromatography over silica gel to obtain 14.1 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 3.46 (s, 1H), 1.65-2.20 (m, 8H).
Reaction SMILES: [NH:1]([C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=2)[N:4]=1)[NH2:2].[CH:20]([O-])([O-])OCC.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)C>[C:13]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([Cl:19])[CH:9]=3)[N:4]3[CH:20]=[N:2][N:1]=[C:3]3[N:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC([O-])[O-]
Reactant: NNc1nc(-c2ccccc2)c2cc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Clc1ccc2c(c1)c(-c1ccccc1)nc1nncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.0 g of 2-hydrazino-4-phenyl-6-chloroquinazoline in 50 ml of ethanol were added 5.5 g of ethyl orthoformate and 1 ml of concentrated sulfuric acid. The resulting mixture was stirred at room temperature for 1 hour and then 30 ml of dilute sodium bicarbonate solution was added thereto. The resulting crystals were collected by filtration and recrystallized from ethanol to give 5-phenyl-7-chloro-s-triazolo[4,3-a]quinazoline as colorless needles, m.p. 295° - 297° C.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[CH2:13][CH2:12]3)[CH2:9][C@H:8]1[C:28]#[N:29])(=O)C.Cl>>[C:28]([C@@H:8]1[CH2:9][C@@H:10]2[C@:24]([CH3:25])([CH2:23][C@H:22]([OH:26])[C@H:21]3[C@H:11]2[CH2:12][CH2:13][C:14]2[C@:19]3([CH3:20])[CH:18]=[CH:17][C:16](=[O:27])[CH:15]=2)[C@H:7]1[C:6](=[O:30])[CH2:5][OH:4])#[N:29]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C#N)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Cl
Product: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1C[C@@H](C#N)[C@@H]2C(=O)CO

Procedure:
The process of claim 7 which additionally comprises reacting (V) with hydrogen chloride to produce (VI) 16α-cyano-11β,21-dihydroxy-3,20-dioxo-1,4-pregnadiene.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([F:9])([F:8])[F:7])C.O.[NH2:12][NH2:13]>>[F:7][C:6]([F:9])([F:8])[CH2:5][C:4]([NH:12][NH2:13])=[O:3]
Reactant: NN
Reactant: CCOC(=O)CC(F)(F)F
Solvent: O
Product: NNC(=O)CC(F)(F)F

Procedure:
Ethyl-3,3,3-trifluoropropanoate (2.5 g, 0.016 mol) and hydrazine monohydrate (1.2 g, 0.024 mol) were heated to reflux for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue was treated with toluene (100 ml×3) to azeotrope hydrazine in excess.