Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10](=[CH:11][C:12]3[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])[C:9](=[O:19])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([NH2:28])[CH:24]=[CH:25][C:26]=1[F:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([NH:28][C:2]2[C:3]3[C:10](=[CH:11][C:12]4[NH:13][C:14]([CH3:18])=[CH:15][C:16]=4[CH3:17])[C:9](=[O:19])[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[F:27]
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Cl)c32)[nH]1
Reactant: Nc1ccc(F)c(Cl)c1
Product: Cc1cc(C)c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Yield: 57 %

Procedure:
The title compound (57% yield) was prepared from 4-chloro-5-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one and 3-chloro-4-fluoro-phenylamine according to the procedure described for Example 12 without the conversion to the HCl salt. 1H NMR (360 MHz, DMSO-d6) δ 13.10 (br s, 1H, NH), 11.60 (br s, 1H, NH), 9.10 (s, 1H), 8.27 (s, 1H, H-vinyl), 7.70 (m, 1H), 7.3-7.4 (m, 3H), 6.04 (br s, 1H), 2.33 (s, 3H, CH3), 2.16 (s, 3H, CH3). MS 384.3 [M++1].
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:22][C:16]2[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:31]1([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH2:33][O:32]1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:22][C:16]2[N:17]=[CH:18][N:19]([CH2:33][C:31]([C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[F:23])([OH:32])[CH2:34][N:35]3[CH:39]=[N:38][CH:37]=[N:36]3)[C:20](=[O:21])[C:15]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Reactant: O=c1[nH]cnc2sc(CCCCOCc3ccccc3)cc12
Product: O=c1c2cc(CCCCOCc3ccccc3)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
This compound was prepared by procedure B using 6-(4-benzyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one and 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5). 1HNMR (CDCl3, 200 MHz): 1.61-1.86 (m, 4H), 2.84 (t, J=6 Hz, 2H), 3.49 (t, J=6 Hz, 2H), 4.23 (d, J=16 Hz, 1H), 4.49 (s, 2H), 4.53 (d, J=16 Hz, 1H), 4.72 (d, J=16 Hz, 1H), 4.80 (d, J=16 Hz, 1H), 6.22 (s, 1H), 6.72-6.90 (m, 2H), 7.08 (s, 1H), 7.32 (bs, 5H), 7.50-7.62 (m, 1H), 7.84 (s, 1H), 7.92 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH3:17])[CH2:11]2)[S:7][N:6]=1)(=O)=O.[CH2:18]([OH:22])[C:19]#[C:20][CH3:21].[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH2:16]([CH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([C:8]2[S:7][N:6]=[C:5]([O:22][CH2:18][C:19]#[C:20][CH3:21])[N:9]=2)[CH2:11]1)[CH3:17]
Reactant: CCC1CCCC(c2nc(S(C)(=O)=O)ns2)C1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1nsc(C2CCCC(CC)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
170 mg of 3-methylsulfonyl-5-(3-ethylcyclohexyl)-1,2,4-thiadiazole and 52 mg of 2-butyn-1-ol were dissolved in 1.5 ml of N,N-dimethylformamide, 32 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 12 hours under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 80 mg of 5-(3-ethylcyclohexyl)-3-(2-butynyloxy)-1,2,4-thiadiazole (hereinafter referred to as the present invention compound (14)).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[CH:4]=1.Br[CH:12](C)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].O>C1COCC1>[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][O:10][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:4]=1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)COCc1cccnc1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a suspension of 1.24 g of sodium hydride (60% oil dispersion; 31 mmol) in 90 mL of THF were added dropwise 3.27 g of 3-pyridinemethanol (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The resulting white suspension was stirred at room temperature for an hour, to which was then added dropwise 6.27 g of tert-butyl 2-bromopropionate (30 mmol) in 10 mL of dry THF at room temperature over 5 min. The mixture was stirred at room temperature for 11.5 hours. After adding water, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated. The residue was purified by column chromatography on silica gel (eluent: n-hexane:ethyl acetate=1:1) to give 4.01 g of tert-butyl (pyridin-3-yl)methoxyacetate (Yield: 56.3%) as a dark brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[OH2:22]>C(#N)C.CCOC(C)=O.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][O:12][S:11](=[O:22])(=[O:14])[N:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1=O
Reactant: O
Agent: Cl[Ru](Cl)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2cc(F)cc(Br)c2)COS1(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice water cooled solution of (4S)-tert-butyl 4-(3-bromo-5-fluorophenyl)-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (34.6 g, 91 mmol) in acetonitrile (420 mL) under stirring was added NalO4 (29.2 g, 137 mmol), and ruthenium trichloride hydrate (0.359 g, 1.729 mmol), followed by water (320 ml). The reaction mixture was stirred at 0° C. for 2 hours. The mixture was diluted with EtOAc (500 ml), washed with brine (200 ml) twice, dried over Na2SO4, filtered and concentrated to afford the crude product, which was used directly at the next step. 40.3 grams of the crude product was obtained. LC-MS: (MW+Na): 419.9 m/z at 1.01 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].[C:12]([N:19]1[CH2:23][CH2:22][C@H:21](O)[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:22]1[CH2:21][CH2:20][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:23]1)[N:6]=[C:5]2[I:11]
Reactant: Fc1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(I)c3cc(F)ccc32)C1
Yield: 32 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and BOC—(S)-3-pyrrolidinol in 32% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.43 (9H, s), 2.38-2.40 (1H, m), 2.56-2.66 (1H, m), 3.51-3.57 (1H, m), 3.74-3.78 (2H, m), 3.85-3.94 (1H, m), 5.12-5.15 (1H, m), 7.13 (1H, d, J=8.0 Hz), 7.23-7.27 (1H, m), 7.35-7.37 (1H, m).
Reaction SMILES: Cl[C:2]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].ClC(Cl)Cl.[C-:23]#[N:24].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:2](=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])[C:23]#[N:24]
Reactant: Cc1ccccc1N=C(Cl)c1c(Cl)cccc1Cl
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccccc1N=C(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.45 parts of N-[chloro(2,6-dichlorophenyl)methylene]-2-methylbenzenamine in 150 parts of trichloromethane is added a solution of 4.88 parts of potassium cyanide and 8.5 parts of N,N,N-triethylbenzenemethanaminium chloride in 8 parts of water while stirring vigorously. Stirring is continued for 30 minutes at room temperature. The organic phase is separated, washed twice with water, dried, filtered and evaporated. The residue is dissolved in petroleumether and the solution is decanted from some insoluble tar. The petroleumether is evaporated in vacuo. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 17.5 parts of petroleumether, yielding 2.8 parts of 2,6-dichloro-α-[(2-methylphenyl)imino]benzeneacetonitrile; mp. 55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[N:13]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH2:23])[N:15]=[CH:16][CH:17]=1.N1C=CNN1S1C=CC(N)=C1>>[N:15]1[N:14]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[N:13]=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Nc1ccsc1-n1nccn1
Agent: NC1=C[SH](N2NC=CN2)C=C1
Product: COc1ccc(CC(=O)Nc2ccsc2-n2nccn2)cc1

Procedure:
The title compound was prepared from (2-(4-methoxyphenyl)acetic acid (1.21 g, 7.22 mmol) and a 1:1 mixture of 2-(2H-1,2,3-triazol-2-yl)thiophen-3-amine and 1-(1H-1,2,3-triazol-2-yl)thiophen-3-amine (431 mg, 2.61 mmol) according to protocol B to give N-(2-(2H-1,2,3-triazol-2-yl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide. Retention time (min)=5.712, method [7], MS (ESI) 315.0 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.99 (s, 1H), 8.06 (d, J=6.4 Hz, 1H), 7.67 (s, 2H), 7.28-7.31 (m, 2H), 7.02 (d, J=5.7 Hz, 1H), 6.98 (d, J=9.1 Hz, 2H), 3.88 (s, 3H), 3.76 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: NCCON
Reactant: N#CCCCCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: N#CCCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 7.2 mmol (1.85 g) of 3', 4'-dichloro-5-cyanovalerophenone (melting point 49°-51° C), 7.2 mmol (1.08 g) of 2-aminooxyethylamine dihydrochloride, 1.0 ml of pyridine and 7 ml of absolute ethanol was refluxed for 3 hours. The reaction mixture was then further processed in a manner identical to that described in Example 1. After crystallization from an ethanol-ether mixture the above entitled compound was obtained with a melting point of 134°-135° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]([N:13]1[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:15][CH2:14]1)=[O:12])[CH3:10])=O)(C)(C)C.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:8][C@H:9]([C:11]([N:13]1[CH2:14][CH2:15][CH:16]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:18]1)=[O:12])[CH3:10]
Reactant: COC(=O)COC1CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)COC1CCN(C(=O)[C@H](C)N)CC1

Procedure:
Prepared from methyl N-(tert-butyloxycarbonyl-L-alanyl)-4-piperidinyloxyacetate and trifluoroacetic acid in methylene chloride analogously to Example 2.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[Br:21].[H-].C([Al+]CC(C)C)C(C)C.CO.Cl>C(Cl)Cl>[C:15]1([S:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH:3]=[O:2])=[C:7]([Br:21])[CH:8]=2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: O=CCCc1ccc(S(=O)(=O)c2ccccc2)cc1Br
Temperature: -78 °C
Yield: 73.5 %

Procedure:
To a solution of 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionic acid methyl ester (6.73 g, 17.6 mmol) in DCM (100 mL) was added diisobutyl aluminum hydride (1.0M in toluene, 17.6 mL) at −78° C. under Argon. The reaction was maintained at −78° C. for 90 minutes, and MeOH (7 mL ca.) was then added at −78° C. The mixture was allowed to warm to room temperature. HCl (2M) was added and the mixture was extracted twice with DCM. The combined organic extracts were washed with water, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified via flash chromatography (hexane/EtOAc, 8/2) affording 3-(4-benzenesulfonyl-2-bromo-phenyl)-propionaldehyde (4.57 g, 74% yield).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)(=O)=O.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K].O>CN(C)C=O>[O:10]1[CH:11]=[CH:12][C:8]([CH2:7][CH2:6][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])=[CH:9]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCCc1ccoc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCc1ccoc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the 2-(3-furyl)ethyl methanesulfonate in 500 ml of N,N-dimethylformamide, 14.2 g (76.8 mmol) of potassium phthalimide was added, followed by overnight stirring at 100° C. After cooling to room temperature, the reaction mixture was added to water while being stirred vigorously. The resulting precipitate was filtered, washed with water and dried to yield N-[2-(3-furyl)ethyl]phthalimide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCC(N)CC
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCC(CC)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and pentan-3-amine. MS (M+H, 236).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=S)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 76.9 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.037 g, 0.13 mmol) was treated with 4-chlorophenyl isothiocyanate (0.024 g, 0.14 mmol, 1.05 equiv.) in CH2Cl2 (1 mL), in a similar manner as described in Example 1.10 to afford Compound 71 (0.048 g, 0.10 mmol, 80%) as a solid film. LCMS m/z (%)=451 (M+H79Br35Cl, 85), 453 (M+H81Br35Cl, 100), 455 (M+H81Br37Cl, 35). 1H NMR (400 MHz, CDCl3) δ: 8.00 (s, 1H), 7.85 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J=2.7, 8.8 Hz, 1H), 7.37 (s, 4H), 7.30 (d, J=2.7 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3].CN1CCOCC1.[C:32]([OH:37])(=[O:36])[CH:33]([CH3:35])[CH3:34]>ClCCl>[C:32]([O:37][CH:2]([O:4][C:5]([NH:7][CH2:8][CH:9]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:6])[CH3:3])(=[O:36])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C(=O)O
Reactant: CC(C)CC(CNC(=O)OC(C)Cl)CC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(C)OC(=O)C(C)C)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of (40) (0.53 g, 1.50 mmol) in isobutyric acid (1 mL) was added to a mixture of isobutyric acid (0.96 mL, 10.8 mmol) and N-methylmorpholine (1.14 mL, 10.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with dichloromethane, washed successively with water, 10% aqueous NaHCO3 solution and brine, then dried over anhydrous Na2SO4. After filtration and removal of the solvent in vacuo, the residue was purified by flash chromatography on silica gel, eluting with 5% ethyl acetate in hexane to afford the title compound (41) as a mixture of two diastereomers (400 mg, 66%). 1H—NMR (CDCl3, 400 MHz): δ 0.85 (m, 6H), 1.14 (m, 8H), 1.44 (m, 3H), 1.62 (m, 1H), 2.13 (m, 1H), 2.32 (m, 2H), 2.51 (m, 1H), 3.06 (m, 1H), 3.24 (m, 1H) 4.95 (m, 1H), 5.10 (s, 2H), 6.76 (q, 1H).
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[C:33]([Cu])#[N:34]>CC(N(C)C)=O.C(OCC)(=O)C>[C:33]([C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:21][CH:22]([CH3:23])[CH3:24])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3)#[N:34]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Temperature: 150 °C

Procedure:
In a 25 mL sealed tube, (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (150 mg, 0.297 mmol) (as prepared in Ex. 3, Part A) was taken up in DMA (4 mL). To this mixture was added CuCN (53.3 mg, 0.595 mmol) and the mixture heated at 150° C. for 24 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL) and filtered through diatomaceous earth (Celite®). The ethyl acetate solution was washed with brine (10 mL) and water (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product as gummy solid which was carried forward without further purification. LC/MS (ESI) m/e 451.2 [(M+H)+, calcd for C25H31N4O4, 451.5]; LC/MS retention time (method B): tR=2.02 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:16])=[C:8]2[CH:14]=[C:13]([CH3:15])[S:12][C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[K+].[CH2:19](I)[CH3:20].Cl>O.C(O)C>[CH2:19]([N:10]1[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7](=[O:16])[C:8]2[CH:14]=[C:13]([CH3:15])[S:12][C:9]1=2)[CH3:20]
Reactant: CCOC(=O)c1cnc2sc(C)cc2c1O
Reactant: CCI
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1cc(C(=O)O)c(=O)c2cc(C)sc21

Procedure:
A mixture of 1.4 parts of ethyl-4-hydroxy-2-methylthieno-[2,3-b]pyridine-5-carboxylate, 12 parts by volume of 10 percent aqueous potassium hydroxide, 48 parts by volume of ethanol, 60 parts by volume of water and 1.8 parts by volume of ethyl iodide is refluxed for about 3 hours. After cooling, the reaction mixture is added to 60 parts by volume of water containing 3 parts by volume of concentrated hydrochloric acid and the resulting crystals are collected by filtration to give 7-ethyl-4,7-dihydro-2-methyl-4-oxothieno[2,3-b]pyridine-5-carboxylic acid as colorless crystals. Recrystallization from chloroform-ethanol yields colorless prisms melting at 229°-230° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[O:25])[CH2:18]2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:24]2[CH:17]3[CH2:23][CH2:22][CH:21]2[CH2:20][C:19](=[O:25])[CH2:18]3)=[CH:4][CH:3]=1
Reactant: O=C1CC2CCC(C1)N2
Reactant: BrCc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC2CCC(C1)N2Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred solution of 1-bromo-4-bromomethylbenzene (0.39 g, 1.56 mmol), triethylamine (0.45 mL, 3.20 mmol) and 8-azabicyclo[3.2.1]octan-3-one (0.33 mL, 2.32 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to ambient temperature and the solid removed by filtration. The filtrate was concentrated under reduced pressure to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-100% DCM in ethyl acetate) to afford the title compound as an off-white solid (400 mg, 90%). 1H NMR (CDCl3, 300 MHz): 7.48-7.43 (m, 2H), 7.32-7.28 (m, 2H), 3.69 (s, 2H), 3.49-3.43 (m, 2H), 2.66 (dd, J=16.0, 4.3 Hz, 2H), 2.26-2.17 (m, 2H), 2.14-2.06 (m, 2H), 1.66-1.56 (s, 2H). LCMS (Method B): RT=1.86 min, M+H+=294/296.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][O:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[C:22]([CH3:27])([CH3:21])[CH2:26][O:25][CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: CC1(C)COCN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.C([O:19][B:20](OC(C)C)[O:21]C(C)C)(C)C.Cl>C1COCC1>[Cl:15][C:9]1[CH:8]=[C:7]([B:20]([OH:21])[OH:19])[CH:12]=[CH:11][C:10]=1[S:13][CH3:14]
Reactant: CSc1ccc(Br)cc1Cl
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Butyl lithium (15 ml, 1.9M in hexanes) was added over 40 min to a solution of the product from step b) (6.82 g) and triisopropylborate (8.0 ml) in THF (30 ml) at −78° C. and stirred for a further 1 h. 2M HCl (20 ml) was added, the mixture was warmed to 20° C. and extracted with ether (three times). The organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol—ether as eluent) to give the sub-title compound (1.82 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([C@@:10]1([OH:32])[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1)#[CH:9]>>[OH:32][C@:10]1([C:8]#[C:9][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:26]2[CH2:25][CH2:24][C@@:23]2([CH3:31])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C:20](=[O:22])[CH3:21])[CH2:11]1
Reactant: Brc1cccnc1
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@](O)(C#Cc5cccnc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 23 °C
Reaction time: 0.75 h
Yield: 16.2 %

Procedure:
A solution of 3-bromopyridine (70 mg, 0.44 mmol), 3β-ethynyl-3α-hydroxy-5α-pregnan-20-one (150 mg, 0.44 mmol) in dry degassed diethylamine (1 mL) was stirred under argon at 23° C. Bis(triphenylphosphine)palladium chloride (10 mg) and CuI (5 mg) were added and the mixture was stirred at this temp. for 45 min. CH2Cl2 (4 mL) was added and the mixture was stirred at 23° C. for 1.5 hr. TLC showed 100% conversion of the starting material, hence, the solvent was removed and the residue was purified by chromatography on silica gel. Elution with hexane:acetone (3:1) gave 3α-hydroxy-3β-(3-pyridyl)ethynyl-5β-pregnan-20-one (30 mg) as a colorless solid; mp 230--35° C., TLC Rf (hexane:acetone 7:3)=0.24.