Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC([N:7]2C(N)=CC(C3C=CC(N)=CC=3)=N2)=CC=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:7])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1ccc(-n2nc(-c3ccc(N)cc3)cc2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-tolyl)-3-(4-aminophenyl)-5-aminopyrazole (0.6 g, 2.27 mmol) in THF (20 mL) and H2O (8 mL) at room temperature was added 4-methoxybenzenesulfonyl chloride (0.94 g, 4.55 mmol) and potassium carbonate (0.95 g, 6.88 mmol). The mixture was stirred at room temperature overnight and was then partitioned between H2O (20 mL) and EtOAc (100 mL). The layers were separated and the organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparatory TLC, eluting with 2:1 hexanes/EtOAc to yield N-[4-5-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]phenyl]-4-methoxy benzenesulfonamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:30])[CH3:29]>>[C:28]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:30])[CH3:29]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: CC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(C)=O)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea (example 14) and acetyl chloride as starting materials.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)[OH:2].[C:12]([N:15]([CH3:19])[C:16](Cl)=[O:17])(=[O:14])[CH3:13]>>[CH3:19][N:15]([C:12](=[O:14])[CH3:13])[C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:11])([CH2:9][CH3:10])[S:4]1)=[O:17]
Reactant: CC(=O)N(C)C(=O)Cl
Reactant: CCC1(C)SC(=NO)N=C1C
Product: CCC1(C)SC(=NOC(=O)N(C)C(C)=O)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-oxime was reacted with N-acetyl-N-methyl-carbamoyl chloride as described above to yield 2-oxo-4,5-dimethyl-5-ethyl-3-thiazoline-O-[methyl(acetyl)carbamoyl]oxime, m.p. 98°-101° C.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:32])[N:13]2[C:16](=[C:25](OS(C)(=O)=O)[CH3:26])[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>C1C=CC=CC=1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:32])[N:13]2[C:16](=[C:25]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH3:26])[C:17]([O:19][CH2:20][C:21]([Cl:23])([Cl:22])[Cl:24])=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(COc3ccccc3)SC21
Reactant: C1COCCN1
Solvent: c1ccccc1
Product: CC(=C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 2,2,2-trichloroethyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-methanesulfonyloxyethylidene)acetate (1.52 g) in benzene (30 ml) is added morpholine (0.48 ml) at beneath 10° C. After stirring for 1 hour, the mixture is washed with water, dried, and evaporated. Purification of the obtained residue by chromatography over silica gel gives 2,2,2-trichloroethyl α-[3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo[3,2,0]hept-2-en-6-yl]-α-(1-morpholinoethylidene)acetate (0.76 g). Yield: 50%.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of p-cresol (2 mL, 19.1 mmol) in anhydrous DMF (50 mL) were added Cs2CO3 (8.1 g, 24.9 mmol) and methyl bromoacetate (1.9 mL, 20.1 mmol). The suspension was stirred at room temperature for 3 h. After dilution with ethyl acetate, the reaction mixture was washed with a 0.5 N HCl solution, a saturated solution of NaHCO3, and brine, dried on MgSO4, and concentrated. The resulting oil was purified by chromatography on silica gel (Hexane/ethyl acetate 8/2) to afford the title compound as a colorless oil (3.10 g, 90%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:39][CH:38]=1.CO>N1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41]([NH:34][C:30]2[N:29]=[CH:28][N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:12]2[O:13][C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11]2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O1
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](OC(=O)c3ccccc3)[C@H](COC(=O)c3ccccc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of compound 4 (0.88 g, 1.92 mmol) in dry pyridine (40 mL) was added 4-monomethoxytrityl chloride (1.18 g, 3.84 mmol). The mixture was stirred at 60° C. for 24 h. After addition of methanol (5 mL), the solution was concentrated to dryness, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (30 mL), aqueous saturated NaHCO3 (30 mL) and water (30 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene to give pure 5 (1.01 g, 72%) as a foam: 1H NMR (CDCl3): δ 2.9-3.0 (m, 2H, H-2′ and H-2″), 3.62 (s, 3H, OCH3), 4.6-4.8 (m, 3H, H-4′, H-5′ and H-5″), 5.85 (pt, 1H, H-3′), 6.44 (dd, 1H, H-1′, J1′,2′=3.1 Hz, J1′,2″=7.3 Hz), 6.9 (br s, 1H, NH-6), 6.7-6.8 and 7.2-7.4 (2m, 24H, 2 benzoyls and MMTr), 7.97 and 8.13 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 732 [M+H]+, (FAB−) m/z 730 [M−H]−; UV (95% ethanol): λmax 274 nm (ε 12100), 225 nm (ε 24200), λmin 250 nm (ε 5900); [α]D20=−16 (c 1.12, DMSO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[CH:13](O)=[O:14]>>[CH:13]([NH:1][C:2]1[CH:3]=[C:4]([C:8]([Br:12])=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])=[O:14]
Reactant: O=CO
Reactant: Cc1cc(Br)c(C(=O)O)cc1N
Product: Cc1cc(Br)c(C(=O)O)cc1NC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-Amino-6-bromo-4-methylbenzoic Acid (19) (6.4145 g, 27.88 mmol) in 90% aqueous formic acid (36 mL) is heated to reflux for about 3 hours. The mixture is then cooled to ambient temperature, added to ice water (150 mL) and stirred for about 15 minutes. The solids that form are filtered and dried to provide 3-(Formylamino)-6-bromo-4-methylbenzoic Acid (20):, as a purple-pink solid (5.961 g, 82% Yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=3)=[CH:9][CH:8]=1>ClCCl>[OH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]2[O:12][C:13]3[C:18]([C:19](=[O:21])[CH:20]=2)=[CH:17][CH:16]=[C:15]([OH:22])[CH:14]=3)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2cc(=O)c3ccc(O)cc3o2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1cc(-c2ccc(O)cc2)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A boron tribromide solution (1.8 ml, 6 equivalents) is added to a well-stirred solution of 4′-methoxy-7-hydroxyflavone (3 mmol) in dichloromethane (50 ml) at −78° C. under an argon atmosphere. When the addition of the boron tribromide solution is complete, the reaction mixture is stirred at room temperature for 24 hours and introduced into an ice/water mixture (300 ml). The product is filtered off and recrystallised from ethanol/water to give 4′,7-dihydroxyflavone. 1H NMR (300 MHz, d6-DMSO): δ 10.78 (br s, OH), 10.28 (br s, OH), 7.91–6.93 (dm, 4H), 7.87 (d, 1H), 6.98 (d, 1H), 6.72 (s, 1H; 13C NMR (62.90 MHz, d6-DMSO): δ176.19 (s), 162.43 (s), 162.33 (s), 160.58 (s), 157.27 (s), 128.02 (s), 126.36 (s), 121.68 (s), 116.01 (s), 115.78 (s), 114.67 (s), 104.37(s), 102.48 (s); EI-MS (70 eV) m/e (rel. abund.)=254.24 (100). The product is yellowish and exhibits the UV absorption maximum at λ=329 nm with ε=27960 (in 2-propanol) (cf. FIG. 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>CCOC(C)=O>[F:1][C:2]1[C:3]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(CCN2CCOCC2)c(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: COc1cc(CCN2CCOCC2)c(F)cc1N
Reaction time: 8 h
Yield: 56.2 %

Procedure:
4-{2-[2-fluoro-5-(methyloxy)-4-nitrophenyl]ethyl}morpholine (0.4 g, 1.4 mmol) was placed in a 100 mL high pressure vessel and dissolved in 30 mL of EtOAc. 5 wt % Platinum(sulfided)/carbon (0.274 g, 0.07 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any hydrogen. The solution was filtered through celite and evaporated to give the title compound of step B (0.2 g, 0.79, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 6.69 (d, J=6.97 Hz, 1H), 6.40 (d, J=11.36 Hz, 1H), 4.97 (bs, 2H), 3.86-3.98 (m, 2H), 3.78-3.86 (m, 2H), 3.72 (s, 3H), 3.38-3.49 (m, 2H), 3.10-3.21 (m, 2H), 2.99-3.10 (m, 2H), 2.86-2.97 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[C:12]([O:16][C:17]([N@@:19]1[CH2:21][CH:20]1[CH3:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17]([NH:19][C@H:20]([CH3:22])[CH2:21][C:4]1[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=[C:2]([F:1])[CH:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: Fc1cc(Br)c2occc2c1
Reactant: CC1CN1C(=O)OC(C)(C)C
Product: C[C@H](Cc1cc(F)cc2ccoc12)NC(=O)OC(C)(C)C
Yield: 44.3 %

Procedure:
Beginning with 5.7 gm (26.6 mMol) 5-fluoro-7-bromobenzofuran and 3.9 gm (24.8 mMol) (R)-(−)-N-tert-butoxycarbonyl-2-methylaziridine, 3.22 gm (44%) of the desired compound were prepared essentially as described in Example 10.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]([O:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1)[C:10]([F:13])([F:12])[F:11].[CH2:23]1[C:27]2([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][C@@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:24]1[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:22][C:17]1[N:18]=[C:19]([N:30]2[CH2:29][CH2:28][C:27]3([CH2:23][N:24]([C:38]([O:40][CH2:41][C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[O:39])[C@H:25]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:26]3)[CH2:32][CH2:31]2)[CH:20]=[C:15]([O:14][C@H:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Br:1])[C:10]([F:13])([F:12])[F:11])[N:16]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Reactant: Nc1nc(Cl)cc(O[C@H](c2ccc(Cl)cc2Br)C(F)(F)F)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of (R)-4-(1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine (100 mg, 0.24 mmol, Step 1) in dioxane (5 mL) was added (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (100 mg, 0.29 mmol), and NaHCO3 (300 mg, 3.5 mmol). After 5 h, an additional amount of NaHCO3 (300 mg, 3.5 mmol) was added and the reaction mixture was heated to 90° C. for 36 h. The reaction was then cooled to RT and filtered. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-bromo-4-chlorophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:24])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH:13]([CH3:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:24]
Reactant: CCOC(C)=O
Reactant: COC(CC1CC(C)c2ccccc2C1=NN(C)C)OC
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(CC1CC(C)c2ccccc2C1=O)OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Dimethylhydrazono)-1,2,3,4-tetrahydro-4-methyl-2-naphthaleneacetaldehyde dimethyl acetal (23.1 g) was dissolved under argon in a mixture of 1000 ml of tetrahydrofuran and 350 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 13.6 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 500 ml of ethyl acetate were added to the reaction mixture and it was washed three times with a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) (1×800 ml, 2×500 ml). The aqueous wash phases were extracted twice with 500 ml of ethyl acetate each time, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 20.0 g of crude 1,2,3,4-tetrahydro-4-methyl-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.N1C2C(=CC=CC=2)C=CC=1.O=P(Cl)(Cl)[Cl:24]>O>[Br:1][C:2]1[C:3]([Cl:24])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Br)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a cooled (0-5° C.) mixture of 3-bromo-2-hydroxy-5-nitropyridine (47.0 g, 0.214 mol) and quinoline (13.7 g, 0.107 mol) was added POCl3 (26.0 mL, 0.278 mol) dropwise over ˜10 min (the mixture was difficult to stir initially but became less viscous as the reaction progressed and the mixture warmed). After stirring at 120° C. for 3.5 h, the mixture was cooled to 100° C. and water (90 mL) was added. The resulting mixture was stirred vigorously while cooling to 0-5° C. The product was collected by filtration, washed with water and dried in vacuo at 45° C. to give 3-bromo-2-chloro-5-nitropyridine (42.0 g, 82% yield). 1H NMR (CD3OD) δ 9.19 (d, J=2.4 Hz, 1H), 8.93 (d, J=2.4 Hz, 1H).
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18]([CH3:19])=[O:30])[O:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cncnc43)cc2o1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cncnc43)cc2o1
Temperature: 0 °C
Reaction time: 6 h
Yield: 33.8 %

Procedure:
A mixture of 6-((9H-purin-9-yl)methyl)-2-(methylthio)benzo[d]oxazole (400 mg, 1.35 mmol) and m-CPBA (289 mg, 1.69 mmol) in DCM (25 mL) was stirred at 0° C. for 6 h. The reaction mixture was washed with aq Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:5 petroleum ether/ethyl acetate to give 6-((9H-purin-9-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole as a light yellow solid (143 mg, 33.89%). 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 9.03 (s, 1H), 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.66 (s, 1H), 7.44 (d, J=9.9 Hz, 1H), 5.62 (s, 2H), 3.18 (s, 3H). LCMS (ESI) m/z 314 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C@H:10]([NH:20]C(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[F:37][CH:38]([F:56])[C:39]1[C:47]2[C:46]([F:49])([F:48])[CH2:45][CH2:44][C:43]([F:51])([F:50])[C:42]=2[N:41]([CH2:52][C:53](O)=[O:54])[N:40]=1.Cl.BrC1C([C@@H](N)CC2C=C(F)C=C(F)C=2)=NC(SC)=NC=1>>[Br:1][C:2]1[C:3]([C@@H:10]([NH:20][C:53](=[O:54])[CH2:52][N:41]2[C:42]3[C:43]([F:50])([F:51])[CH2:44][CH2:45][C:46]([F:49])([F:48])[C:47]=3[C:39]([CH:38]([F:56])[F:37])=[N:40]2)[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Reactant: O=C(O)Cn1nc(C(F)F)c2c1C(F)(F)CCC2(F)F
Agent: CSc1ncc(Br)c([C@@H](N)Cc2cc(F)cc(F)c2)n1
Agent: Cl
Product: CSc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (12B) was prepared according to the method presented for the synthesis of compound 11G of Example 11 utilizing 2-(3-(difluoromethyl)-4,4,7,7-tetrafluoro-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid and 12A. MS (m/z) 644.22 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:8][F:9])([OH:7])[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH2:15](O)[CH3:16]>>[CH2:15]([O:5][C:4](=[O:6])[C:3]([CH2:8][F:9])([OH:7])[CH2:2][F:1])[CH3:16]
Reactant: O=C(O)C(O)(CF)CF
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)(CF)CF
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude 3-fluoro-2-fluoromethyl-2-hydroxy-propionic acid (17 g) was dissolved in ethanol (400 ml) and H2SO4 (98%, 30 g) was added. The reaction mixture was refluxed for 16 h. The reaction mixture was cooled to ambient temperature and filtered. The solution was carefully treated with 30 g solid Na2CO3 and the resulting mixture was stirred for 30 min at room temperature. 400 ml DCM were added and the mixture was filtered. The solution was concentrated (50° C., 150 mbar) and further purified by distillation (82° C., 20 mbar) to give a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[NH2:8]
Reactant: Cc1cc([N+](=O)[O-])ccc1SCc1ccccn1
Solvent: CC(=O)O
Product: Cc1cc(N)ccc1SCc1ccccn1
Yield: 51 %

Procedure:
To 2-[[(2-methyl-4-nitrophenyl)sulfanyl]methyl]pyridine (3.1 g) were added acetic acid (24.4 ml) and then, reduced iron (9.15 g), and the mixture was stirred for 16 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 3-methyl-4-[(2-pyridinylmethyl)sulfanyl]aniline (1.4 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][N:9]1C(=O)C2C(=CC=CC=2)C1=O.NN.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][O:8][NH:9][S:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCO1
Agent: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOCC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6.9 %

Procedure:
2-(tetrahydro-2H-pyran-2-ylmethoxy)-1H-isoindole-1,3(2H)-dione (6.8 mmol, 1.77 g) was combined with hydrazine (6.8 mmol, 0.21 mL) in anhydrous THF (15 mL) under nitrogen. The reaction immediately formed a white suspension and was allowed to stir at room temperature for 2 hours. The suspension was filtered directly into a flask containing 4-methoxybenzenesulfonyl chloride (6.8 mmol, 1.40 g) and diisopropylethylamine (8.1 mmol, 1.42 mL) was added. After stirring at room temperature for 24 hours, the reaction was concentrated to a yellow solid. The resulting solid was partitioned between ethyl acetate and 1N HCl, and the organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine, and dried over magnesium sulfate. The crude product was concentrated to a yellow solid and purified by silica gel chromatography (2:1 hexanes/ethyl acetate). The purified product was combined with ether and filtered to remove the residual phthalimide-hydrazine biproduct. The final product was crystallized using hexanes and ethyl acetate to provide 141 mg (7%) of white crystals. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 7.83 (2H,d), 7.05 (1H,s), 6.97 (2H,d), 4.01-3.86 (3H,m), 3.86 (3H,s), 3.63-3.57 (1H,m), 3.42-3.36 (1H,m), 1.88-1.78 (1H,m), 1.59-1.43 (4H,m), 1.3-1.15 (1H,m).
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13]([O:25]C(=O)C)[C:14]2=O)[CH2:6]1)(=[O:3])[CH3:2].[CH3:29][NH2:30]>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C@@H:13]([OH:25])[C@@H:14]2[NH:30][CH3:29])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)[C@H](OC(C)=O)C[C@@H]32)C1
Reactant: CN
Product: CN[C@H]1[C@H](O)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
3β,16α-bis(Acetyloxy)-androst-5-en-17-one (2.04 g) was dissolved in methylamine solution (20.4 ml; 33% in methanol) and the solution was stirred at room temperature for 20 min. during which time the 17,17-methylimine crystallised out. Sodium borohydride (1.02 g) was added portionwise to the stirred suspension, keeping the temperature below 25° C. After 11/2 h., the excess methylamine was removed under reduced pressure, water (200 ml) was added, and the mixture was extracted with dichloromethane. The extracts were washed with water, dried (Na2SO4) and evaporated to give a white froth (2.07 g), crystallisation of which from dichloromethane-ether afforded pure 17β-methylamino-androst-5-ene-3β,16α-diol 3-acetate as needles, (1.74 g; 91.6%) m.p. 192°-194° C., [α]D -79.4° (c 0.75 in CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(F)c(F)c1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)c(F)c1
Yield: 21.3 %

Procedure:
Using 1.00 g of (3,4-difluorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.20 g of sodium hydride (60% in oil), and 1.38 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.32 g of 2-(3,4-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (19)).