Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1[C:9]2[C:4](=[C:5](C3N=C(N4CCOCC4)C4SC(COC)=CC=4N=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=N1.[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[C:32]2[S:37][C:36]([CH2:38][OH:39])=[CH:35][C:33]=2[N:34]=1.C(Br)C1C=CC=CC=1>CN(C=O)C.[H-].[Na+]>[Cl:28][C:29]1[N:30]=[C:31]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)[C:32]2[S:37][C:36]([CH2:38][O:39][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:35][C:33]=2[N:34]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: COCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(COCc3ccccc3)cc2n1

Procedure:
Following the procedures for compound 314, (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol in DMF and sodium hydride was alkylated with benzyl bromide to give 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine. Suzuki coupling of 2-chloro-6-benzyloxymethyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine and 7 was carried out via General Procedure A. Purification using column chromatography gave 315. NMR: CDCl3: 3.88-3.94 (4 H, m, CH2), 4.09-4.14 (4 H, m, CH2), 4.69 (2 H, s, CH2), 4.86 (2 H, s, CH2), 7.31-7.46 (6 H, m, Ar), 7.53 (1 H, t, J 8.22, Ar), 7.56 (1 H, t, J 8.24, Ar), 8.30 (1 H, d, J 6.94, Ar), 9.03 (1 H, s, Ar) and 10.1 (1 H, s, NH). MS: (ESI+): MH+ 458.16
Reaction SMILES: O.[NH2:2][NH2:3].[C:4](Cl)([O:6][CH2:7][CH:8]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5]>CC#N.O.CC#N>[C:4]([O:6][CH2:7][CH:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)(=[O:5])[NH:2][NH2:3]
Reactant: NN
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: CC#N
Product: NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a well-stirred solution of hydrazine hydrate (19 g, 386 mmol) in 150 mL of CH3CN/H2O (1/1, v/v), a solution of FmocCl (10 g, 38.65 mmol) in 600 mL CH3CN was added dropwise at 0° C. over 2 h. The reaction mixture was then allowed to warm to room temperature and stirred for an additional 12 hours, concentrated in vacuo to 150 mL and filtered to yield the title compound as a white solid, which was washed with water and hexane and dried to a constant weight in vacuo (9.74 g, 99%): mp 172-173° C.; 1H NMR (DMSO) δ 4.08 (brs, 2H), 4.21 (t, J=7.2 Hz, 1H), 4.28 (d, J=7.2 Hz, 2H), 7.32 (t, J=7.4 Hz, 2H), 7.42 (t, J=7.4 Hz, 2H), 7.69 (d, J=7.4 Hz, 2H), 7.89 (d, J=7.4 Hz, 2H), 8.36 (brs, 1H); 13C NMR (DMSO) δ 47.7, 66.7, 121.1 (2C), 126.3 (2C), 128.1 (2C), 128.7 (2C), 141.7 (2C), 144.9 (2C), 159.2.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:4][CH2:3]1.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C>[N:19]([CH2:7][C@H:5]1[NH:6][C:2](=[O:1])[CH2:3][CH2:4]1)=[N+:20]=[N-:21]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCC(=O)N2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CCC(=O)N1
Temperature: 55 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A round bottom flask was charged with (S)-(5-oxopyrrolidin-2-yl)methyl-4-methylbenzenesulfonate (18.4 g, 68.5 mmol), DMF (400 mL), and NaN3 (17.8 g, 274 mmol). The resulting mixture was stirred at 55° C. for overnight. Removal of solvent under reduced pressure followed by flash chromatography purification (7% MeOH in CHCl3 as the eluent) provided the (S)-5-(azidomethyl) pyrrolidin-2-one (8.45 g, 60.36 mmol, 88%) as a yellow oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].Cl[CH2:19][CH:20]=[N:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][N:21]=[CH:20][CH2:19][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: CON=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CON=CCOc1ccccc1S(N)(=O)=O
Yield: 57.3 %

Procedure:
30 g (0.2 mol) of potassium carbonate are introduced into a stirred solution of 18 g (0.1 mol) of 2-hydroxybenzenesulphonamide in 20 ml of acetonitrile. 11 g (0.1 mol) of 1-chloro-2-methoxyiminoethane are then rapidly added dropwise, and the mixture is heated at the boiling point for a further 3 hours. The precipitate which separates out is filtered off under suction, in filtrate is evaporated down, the oily residue is triturated with water, and the product is filtered off under suction and dried on clay. 14 g (57% of theory) of 2-(2-methoxyiminoethoxy)phenylsulphonamide of melting point 103° to 105° C. are obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]([N+:18]([O-])=O)[CH:12]=1)[CH2:2]2.O.O.[Sn](Cl)Cl>CN(C=O)C>[NH2:18][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[I:17])[C:10]([NH:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[O:21]
Reactant: O=C(NC1CN2CCC1CC2)c1ccc(I)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(C(=O)NC2CN3CCC2CC3)ccc1I
Yield: 98.1 %

Procedure:
A solution of 100 mg (0.25 mmol) of N-(1-azabicyclo[2.2.2]oct-3-yl)-4-iodo-3-nitrobenzamide and 281 mg (1.25 mmol) of tin(II) chloride dihydrate in 5 ml of DMF was stirred at room temperature for 6 h. The solvent was distilled off in a rotary evaporator, the residue was taken up in 10 ml of dichloromethane, and 10 ml of aqueous 1 M sodium hydroxide solution were added. The organic phase was dried over sodium sulfate, and the solvent was distilled off in a rotary evaporator. 91 mg (98%) of the desired title compound were obtained.
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16]>C1(C)C(C)=CC=CC=1>[C:7]1(=[O:8])[N:3]([CH2:2][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: COP(OC)OC
Reactant: O=C1c2ccccc2C(=O)N1CBr
Solvent: Cc1ccccc1C
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3-hexane gave (ii) (7.60 g, 65%) as a white solid: 1H NMR (300 MHz, CDCl3) δH 3.84 (d, JH,P=10.8 Hz, 6 H), 4.12 (d, J=11.4 Hz, 2 H), 7.76 (m, 2 H), 7.87 (m, 2 H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[CH:22]([C:28]([O:30]CC)=[O:29])[C:23]([O:25]CC)=[O:24]>C(O)C>[CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[O:17][CH:22]([C:28]([OH:30])=[O:29])[C:23]([OH:25])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)OCC
Reactant: Oc1cccc(CCNCc2ccccc2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(Oc1cccc(CCNCc2ccccc2)c1)C(=O)O
Reaction time: 4 h

Procedure:
To a solution of 8.0 g. (35.2 mMol) 3-(2-benzylaminoethyl)-phenol and 100 ml. ethanol there are added 35.2 mMol sodium methylate in the form of a methanolic solution and thereafter 6.8 g. (35.2 mMol) diethyl chloromalonate. After stirring for 4 hours, the reaction mixture is evaporated. 50 ml. Diethyl ether are added to the residue, as well as ice-cold 1N aqueous sodium hydroxide solution, shaken up and the ethereal phase is separated off. After drying over anhydrous sodium sulphate, the sulphate is precipitated from it by the dropwise addition of concentrated sulphuric acid, which is filtered off with suction and washed with diethyl ether. The product is very hygroscopic and is obtained in the form of a somewhat greasy mass. Yield 11.7 g. (74% of theory).
Reaction SMILES: Cl[C:2]1[C:3]2[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:4]=2[N:5]=[C:6]([NH:8]C(=O)C)[N:7]=1.[CH2:17]([OH:19])[CH3:18]>C(OCC)(=O)C>[Cl:16][C:14]1[CH:13]=[CH:12][C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([O:19][CH2:17][CH3:18])[C:3]=2[N:15]=1
Reactant: CCO
Reactant: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Solvent: CCOC(C)=O
Product: CCOc1nc(N)nc2ccc(Cl)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a suspension of N-(4,6-dichloro-pyrido[3,2-d]pyrimidin-2-yl)-acetamide (0.98 g, 3.8 mmol) in ethanol (35 mL) was added a solution of 21% Na ethanolate in ethanol (2.8 mL, 7.6 mmol). After stirring at room temperature for one hour, the solution was diluted with ethyl acetate then washed with brine. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated to yield the pure title compound as a beige solid (0.6 g, yield 70%) which was characterised as follows: MS (m/z) 225.6 [M+H]+.
Reaction SMILES: [F:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([F:35])[C:28]=1[C:36]1[N:41]=[C:40]([C:42](O)=[O:43])[CH:39]=[CH:38][C:37]=1[F:45]>>[NH2:9][C@H:8]1[C@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:42](=[O:43])[C:40]2[CH:39]=[CH:38][C:37]([F:45])=[C:36]([C:28]3[C:29]([F:35])=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:27]=3[F:26])[N:41]=2)[CH2:6][CH2:7]1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Product: COc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)ccc2F)c(F)c1

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 80), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinic acid (see US2012/225062) gave 201. 1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.26 (dd, J=8.7, 4.0 Hz, 1H), 8.11 (t, J=8.9 Hz, 1H), 7.90 (s, 1H), 6.94 (d, J=10.2 Hz, 2H), 4.82 (dd, J=10.4, 3.7 Hz, 1H), 4.40-4.14 (m, 1H), 4.08-3.91 (m, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.18-3.04 (m, 1H), 2.12-2.02 (m, 1H), 1.83-1.60 (m, 3H). LCMS (ES+) m/z 494 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH2:25])[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:6])=[O:5].[Cl:30][C:31]1[N:32]=[N:33][CH:34]=[C:35](Cl)[C:36]=1[Cl:37].C(N(CC)CC)C>O1CCCC1>[CH3:1][C:2]([CH3:29])([P:26](=[O:28])=[O:27])[N:3]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([O:22][CH2:23][CH2:24][NH:25][C:35]2[C:36]([Cl:37])=[C:31]([Cl:30])[N:32]=[N:33][CH:34]=2)[CH:16]=1)[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=[O:5])=[O:6]
Reactant: Clc1cnnc(Cl)c1Cl
Reactant: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCN)c1)C(C)(C)P(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCNc2cnnc(Cl)c2Cl)c1)C(C)(C)P(=O)=O

Procedure:
940 mg N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-methoxy-benzene sulfonamide, 400 mg (2.2 mmol) 3,4,5-trichloropyridazine and 0.31 ml (2.2 mmol) triethylamine in 20 ml dry tetrahydrofuran were stirred for 2 h at 80° C., the solvent was removed in a vacuum, the residue was stirred with water, extracted three times with ethyl acetate, dried over sodium sulfate, filtered, the solvent was removed in a vacuum and 1.26 g (quant.) of a mixture of N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,5-dichloropyridazin-4-ylamino)-ethoxy]-5-methylphenyl-}-2-methoxy-benzenesulfonamide and N-(dimethyloxophosphinyl-methyl)-N-{3-[2-(3,4-dichloropyridazin-5-ylamino)-ethoxy]-5-methylphenyl}-2-methoxy-benzenesulfonamide was obtained as an oil. MS (m/e)=573.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:3]1[C:4]([C:16]([F:17])([F:19])[F:18])=[N:5][N:6]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][OH:15])=[CH:11][CH:12]=2)[C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(CCO)cc1
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c(C(F)(F)F)nn1-c1ccc(CCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
A mixture of 2-{4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl} ethanol (step 450 mg, 1.67 mmol) and bromine (293 mg, 1.83 mmol) in chloroform (10 mL) was stirred at room temperature overnight. The organic solution was washed with 5% aqueous solution sodium thiosulfate, then with brine, and finally dried (Na2SO4) and evaporated. The crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 451 mg (77%) of the title compound as yellow solids: MS (EI) m/z 348 [M]+, 1H-NMR (CDCl3) δ 7.37 (4H, s), 3.89 (2H, br.s), 2.94 (2H, t, J=6.4 Hz), 2.33 (3H, s).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@@H:28]1[C@@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29]1>>[CH2:34]([C@H:33]1[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][C@@H:28]1[NH:27][C:21]([C:14]1[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Cc2ccccc2)[C@@H](N)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@@H]3Cc3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid, tert-butyl (rac.)-(3R,4S)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([N:10]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:11][CH2:12][C:13](OCC)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(OCC)C>[OH:2][NH:1][C:13](=[O:14])[CH2:12][CH2:11][N:10]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]
Reactant: CCOC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: NO
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N(CCC(=O)NO)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
Freshly prepared hydroxylamine reagent (20 mL; 20 mmol) was added to ethyl 3-[(benzyl)-(4-methoxybenzenesulfonyl)-amino]-propionate (3.30 g; 8.8 mmol) and the resulting mixture stirred for 18 h at room temperature. The mixture was poured into 1 N HCl (100 mL) and extracted with CH2Cl2 (2×10 mL). The combined extracts were washed with saturated aqueous NaCl (1×10 mL), dried over MgSO4, and evaporated under reduced pressure to give a crude gum. Trituration with diethyl ether afforded 2.33 g (68%) of the title compound as an off-white solid. 300 MHz 1H-NMR (DMSO-d6): δ 2.06 (m, 2H), 3.25 (m, 2H), 3.87 (s, 3H), 4.33 (s, 2H), 7.16 (d, 2H), 7.20-7.42 (m, 5H), 7.80 (d, 2H), 8.70 (bs, 1H), 10.38 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:23][CH2:24][CH2:25][CH2:26]I>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][CH:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: ClCCCI
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(CCCCl)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 28 %

Procedure:
To a solution of 3,4-difluorophenylacetic acid (5.00 g, 29.0 mmol) in THF (58 mL) was added NaHMDS (1 M in THF, 58.1 mL, 58.1 mmol) dropwise at 0° C. The reaction mixture was then stirred at 0° C. for 20 min, then 1-chloro-3-iodopropane (3.12 mL, 29.0 mmol) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then quenched under ice bath cooling with water (3 mL) and evaporated. To the residue was added NaOH (1 N, 150 mL) and the resulting solution was extracted with diethylether (2×100 mL). The aqueous layer was acidified with HCl (1 N, 200 mL) and extracted with diethylether (2×100 mL). The combined organic layers were then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 2×50 g, 0 to 50% ethyl acetate in heptane) afforded the title compound (2.02 g, 28%) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[C:10]([C:13]([OH:15])=[O:14])[CH:9]=1.[CH:16](O)=O>O>[CH:9]1[C:10]([C:13]([OH:15])=[O:14])=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[CH:16]2
Reactant: Nc1ccccc1-c1cc(C(=O)O)n[nH]1
Reactant: O=CO
Solvent: O
Product: O=C(O)c1cc2c3ccccc3ncn2n1
Reaction time: 0.5 h

Procedure:
3.0 g (0.0148 mole) of 5-(2-aminophenyl)-1H-pyrazole-3-carboxylic acid is suspended in 21 ml of 97+% HCOOH, and the reaction mixture heated in an oil bath at 100° for 2 hours. The reaction mixture is cooled, diluted with water (75 ml), stirred for 30 minutes and filtered, washing the precipitates well with water. The crude product is dried overnight in vacuo at 90°. Yield: 2.9 g. Percent crude yield: 91.8%.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6](=[O:23])[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])=[C:12]([CH3:22])[CH:11]=1)=[O:8].C(O)(C(F)(F)F)=O>CC(O)=O>[OH:23][C:6]1[C:7](=[O:8])[N:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])=[C:12]([CH3:22])[CH:11]=2)[CH:3]=[CH:4][N:5]=1
Reactant: COC(CNC(=O)C(=O)Nc1ccc(OCC(C)(C)O)c(C)c1)OC
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-n2ccnc(O)c2=O)ccc1OCC(C)(C)O
Yield: 73.1 %

Procedure:
A solution of N1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)oxalamide (11.4 g, 32.2 mmol) and TFA (2.97 mL, 38.6 mmol) in AcOH (120 mL) was stirred at 135° C. in a seal tube for 60 min. After cooling and concentration under vacuum, addition of CH2Cl2 (300 ml) produced a precipitate which was collected by filtration and was washed with CH2Cl2 (150 ml) to yield 3-hydroxy-1-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)pyrazin-2(1H)-one (7.19 g, 23.53 mmol, 73.1% yield) as brown solid. MS (M+1=226). 1H NMR (500 MHz, methanol-d3) δ ppm 7.13-7.26 (2H, m), 6.98 (1H, d, J=8.52 Hz), 6.50 (1 H, d, J=5.77 Hz), 6.41 (1H, d, J=6.05 Hz), 3.82 (2H, s), 2.29 (3H, s), 1.35 (6H, s).
Reaction SMILES: [C:1]([NH:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]=[N+:17]=[N-:18])=[C:12]([F:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[C:20]([O:24][CH3:25])(=[O:23])[C:21]#[CH:22]>C1C=CC=CC=1>[C:1]([NH:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:22]=[C:21]([C:20]([O:24][CH3:25])=[O:23])[N:18]=[N:17]3)=[C:12]([F:19])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C#CC(=O)OC
Reactant: CC(=O)NC1CC(c2ccc(N=[N+]=[N-])c(F)c2)=NO1
Solvent: c1ccccc1
Product: COC(=O)c1cn(-c2ccc(C3=NOC(NC(C)=O)C3)cc2F)nn1
Temperature: 105 °C
Yield: 70 %

Procedure:
5-Acetamido-3-(4-azido-3-fluorophenyl)isoxazoline (277 mg) is combined with methyl propiolate (0.356 ml) in 3 ml benzene in a screw cap pressure tube under nitrogen. The reaction is warmed to 105° C. for 1 hour, is cooled to room temperature, and is washed into a recovery flask with ethyl acetate. The volatiles are removed in vucuo. The crude material is recrystallized from ethyl acetate to provide 252 mg (70%/) of 5-acetamido-3-(4-(4-carbomethoxy-1,2,3-triazol-1-yl)-3-fluorophenyl)isoxazoline as an off-white solid, mp 221° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH:24]1([N:30]2[CH2:33][CH2:32][CH:31]2[C:34]([O-])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:34]([CH:31]2[CH2:32][CH2:33][N:30]2[CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:35])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: O=C([O-])C1CCN1C1CCCCC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2CCN2C2CCCCC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-cyclohexylazetidine-2-carboxylate 20A carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-cyclohexylazetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as an off-white solid (69%). MS ISP (m/e): 519.2 (100) [(M+H)]]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:13]([O-])([O-])=[O:14].[K+].[K+]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[C:4]([O:14][CH3:13])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cc(OC)nc(Cl)n1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
A 30 mL round-bottomed vial was charged with methyl 2,6-dichloropyrimidine-4-carboxylate (0.6 g, 2.9 mmol, 1 equiv.), methanol (6 mL, 0.97 M), K2CO3 (0.401 g, 2.9 mmol, 1 equiv.), and the reaction mixture was shaken at 65° C. for 1.5 h. The solvent was concentrated under reduced pressure and the residue was partitioned between EtOAc (25 mL) and H2O (25 mL) and the water layer was extracted with EtOAc (2×20 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide the crude chloropyrimidine (441 mg, 588 mg theoretical, 75%), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:22]2=[CH:23][C:24]([CH2:26][CH2:27][C@:21]2(C)[C@H:5]2[CH2:6][CH2:7][C@:8]3([CH3:20])[C@@:12]([O:16]C(C)=O)([C:13]([CH3:15])=[O:14])[CH2:11][CH2:10][C@H:9]3[C@@H:4]2[CH:3]=1)=[O:25].CN(C)[CH:31]=[O:32]>>[OH:16][C@:12]1([C@:8]2([CH3:20])[C@H:9]([C@H:4]3[C@H:5]([CH2:6][CH2:7]2)[C@:21]2([CH2:31][OH:32])[C:22](=[CH:23][C:24](=[O:25])[CH2:26][CH2:27]2)[C:2]([CH3:1])=[CH:3]3)[CH2:10][CH2:11]1)[C:13](=[O:14])[CH3:15]
Reactant: CN(C)C=O
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Product: CC(=O)[C@@]1(O)CC[C@H]2[C@@H]3C=C(C)C4=CC(=O)CC[C@]4(CO)[C@H]3CC[C@@]21C

Procedure:
Under the conditions of Example 1, 10 g. of megestrol (17α-hydroxy-6-methyl-4,6-pregnadiene-3,20-dione), dissolved in 400 ml. of dimethylformamide, is fermented for 48 hours with a Nigrospora sphaerica culture. After the batch has been worked up and the crude product crystallized from acetone/diisopropyl ether, 6.5 g. of 17α,19-dihydroxy-6-methyl-4,6-pregnadiene-3,20-dione is obtained, m.p. 184°-186° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15].C(N(CC)CC)C>C(OCC)C>[O:15]([CH:3]=[CH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:9]=1
Reactant: C#CC(=O)OCC
Reactant: Oc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C=COc1ccccc1

Procedure:
A solution of 5.77 mmol of ethyl propiolate in 20 ml ethyl ether is treated with 5.77 mmol 2-chlorophenol and 0.4 ml triethylamine (added slowly and with stirring). The reaction mixture is stirred overnight at RT, after which the solvent is removed under vacuum to yield ethyl 3-phenoxy-2-propenoate.