Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:21][C:18]4=[N:19][CH:20]=3)[CH:7]=2)[CH2:3][CH2:2]1.NC1C(F)=CC([F:44])=C(C=1)C(NC1CC1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(O)(=O)C.ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:7]=[C:8]([NH:13][CH2:14][C:15]3[CH:16]=[C:17]4[CH:23]=[C:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[NH:21][C:18]4=[N:19][CH:20]=3)[C:9]([F:12])=[CH:10][C:11]=2[F:44])[CH2:3][CH2:2]1
Reactant: Nc1cc(C(=O)NC2CC2)c(F)cc1F
Reactant: O=C(NC1CC1)c1ccc(F)c(NCc2cnc3[nH]c(-c4ccccc4)cc3c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NC1CC1)c1cc(NCc2cnc3[nH]c(-c4ccccc4)cc3c2)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.5 %

Procedure:
To a solution of compound D of Example 1 (22 mg, 0.1 mmol), in a mixture of acetic acid and dichloromethane (1:1, 1 mL) were added 5-amino-N-cyclopropyl-2,4-difluorobenzamide (30 mg, 0.15 mmol) and NaBH(OAc)3 (30 mg, 0.2 mmol). The mixture was stirred at RT for 1 h. The reaction mixture was concentrated and the residue was purified by preparative RP HPLC. The appropriate fractions were collected and concentrated to remove methanol and saturated solution of NaHCO3 was added to precipitate out the desired product. The solid was filtered and dried in vacuo to give the title compound (6.5 mg) as a solid. LC/MS; (M+H)+=419.2
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:10][N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[N:5]=[C:4]([NH:17][C:18]2[CH:26]=[C:25]3[C:21]([C:22](=[O:27])[NH:23][NH:24]3)=[CH:20][CH:19]=2)[N:3]=1.[CH3:28][NH:29][CH3:30]>C1COCC1>[CH:14]1([C:12]2[CH:13]=[C:9]([NH:8][C:6]3[N:7]=[C:2]([N:29]([CH3:30])[CH3:28])[N:3]=[C:4]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([C:22](=[O:27])[NH:23][NH:24]5)=[CH:20][CH:19]=4)[N:5]=3)[NH:10][N:11]=2)[CH2:16][CH2:15]1
Reactant: CNC
Reactant: O=c1[nH][nH]c2cc(Nc3nc(Cl)nc(Nc4cc(C5CC5)n[nH]4)n3)ccc12
Solvent: C1CCOC1
Product: CN(C)c1nc(Nc2ccc3c(=O)[nH][nH]c3c2)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
6-[4-Chloro-6-(5-cyclopropyl-2H-pyrazol-3-ylamino)-[1,3,5]triazin-2-ylamino]-1,2-dihydro-indazol-3-one (60 mg, 0.121 mmol) was dissolved in 5 ml of a 2 M solution of dimethylamine in THF and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and purified on prep HPLC to afford 38 mg (62% yield) of the desired product as a white solid (62.2% yield). H-NMR(DMSO-d6, 500 mHz) δ 11.20(s, 1H), 10.48(s br, 1H), 10.08(s, 1H), 7.92(s, 1H), 7.55(d, 1H), 7.13(s, 1H), 5.93(s, 1H), 3.20(d, 6H), 1.92(m, 1H), 0.96(m, 2H), 0.72(m, 2H). MS (ES+): m/e=393.2 (M+H), 391.2 (M−H); LC/Method A/3.835 min, 98.0% purity by area %.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[OH:12].C(=O)([O-])O.[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C(OCC)(=O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4][N:3]1[O:12][S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25]
Reactant: O=c1c2ccccc2nnn1O
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=c1c2ccccc2nnn1OS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 89.6 %

Procedure:
In water (20 ml) are dissolved 4-oxo-3,4-dihydro-3-hydroxy-1,2,3-benzotriazine (2.4 g) and sodium hydrogen carbonate (1.3 g), and thereto is added a solution of benzenesulfonyl chloride (2.65 g) in ethyl acetate (20 ml) under ice-cooling and the mixture is stirred for 2 hours. The precipitated crystals are separated by filtration. The ethyl acetate layer is separated from the filtrate and concentrated. The resulting crystals are separated by filtration and combined with the crystals obtained above. The crystals are washed with ether, dried and then recrystallized from benzene to give 4-oxo-3,4-dihydro-3-benzene-sulfonyloxy-1,2,3-benzotriazine (4.0 g), melting point: 132°-134° C. Infrared spectrum: 1705, 1390, 1195 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:29])[NH:5][NH:6][C:7](=O)[CH:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH3:9])[CH3:2]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]1[S:29][C:7]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH3:9])=[N:6][N:5]=1)[CH3:2]
Reactant: CCOC(=S)NNC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=S(=O)(O)O
Product: CCOc1nnc(C(C)Oc2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)s1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To 10 ml of concentrated sulfuric acid cooled to -5° C. was added, with stirring, 2.0 g of 3-[2-[4-(4-trifluoromethylphenoxy)phenoxy]-propionyl]-thiocarbazic acid-O-ethyl ester gradually. After stirring at the same temperature for 10 minutes, the reaction mixture was poured over 100 g of ice followed by extracting with ethyl acetate. The resulting ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography on silica gel to obtain 1.1 g of the compound No. 5 described in Table 1.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][S:3]1.Cl.[O:11]([CH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1)[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1>O1CCCC1>[O:11]([CH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24][C:7]([C@@H:5]2[CH2:4][S:3][C:2](=[O:1])[NH:6]2)=[O:9])[CH2:19][CH2:18]1)[N+:12]([O-:14])=[O:13]
Reactant: O=C1N[C@H](C(=O)O)CS1
Reactant: NC[C@H]1CC[C@H](CCO[N+](=O)[O-])CC1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1N[C@H](C(=O)NC[C@H]2CC[C@H](CCO[N+](=O)[O-])CC2)CS1

Procedure:
In 20 ml of anhydrous tetrahydrofuran was suspended 191 mg of (4R)-2-oxo-4-thiazolidinecarboxylic acid and 294 mg of trans-4-(2-nitroxyethyl)cyclohexylmethylamine hydrochloride, and 0.54 ml of triethylamine and 0.28 ml of diphenylphosphoric azide were added thereto with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluting solvent: cyclohexane/ethyl acetate=1/3) and recrystallizated from dichloromethane-diisopropyl ether to obtain 200 mg of the desired compound as a colorless crystalline solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.C([Li])CCC.CN(C)[CH:18]=[O:19]>O1CCCC1>[CH3:1][O:2][CH:3]([O:9][CH3:10])[C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: COC(OC)c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(OC)c1ccsc1C=O
Temperature: 25 °C
Yield: 78.9 %

Procedure:
To a solution of 3-dimethoxymethylthiophene (14 g) in tetrahydrofuran (80 ml) was slowly added n-butyllithium (1.6M in n-hexane, 47.8 ml) at -10° C. with stirring. The reaction mixture was further stirred at same temperature for 1 hour. N,N-Dimethyl-formamide (11.9 g) in tetrahydrofuran (40 ml) was then added. The reaction mixture was warmed to room temperature and stirred for overnight. Ice water was added and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to give brownish oily product (13 g, 80%).
Reaction SMILES: [C:1]([C@:3]1([CH2:18][O:19]C(=O)C)[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])#[N:2].[NH4+].[OH-]>CO>[C:1]([C@:3]1([CH2:18][OH:19])[O:7][C@@H:6]([N:8]2[CH:16]=[C:14]([CH3:15])[C:12](=[O:13])[NH:11][C:9]2=[O:10])[CH2:5][C@@H:4]1[OH:17])#[N:2]
Reactant: CC(=O)OC[C@@]1(C#N)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](O)[C@@](C#N)(CO)O2)c(=O)[nH]c1=O
Yield: 40.8 %

Procedure:
A solution of 4'-cyano-5'-O-acetylthymidine (0.85 g, 2.76 mM) and NH4OH (15 ml) in CH3OH (15 ml) was stirred at 24° C. for 2 hours. The solvent was removed by evaporation under pump vacuum. The residue was purified by flash chromatography on silica gel eluting with (7% CH3OH/CH2Cl2) and by preparative chromatography TLC affording 4'-cyanothymidine (300 mg, 1.12 mM). mp 238.5° C. to 242.5° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:19][NH:20][C:21]([NH2:23])=[O:22]>C(O)C>[C:1]1([C:7]2[C:15]([CH:16]=[N:19][NH:20][C:21]([NH2:23])=[O:22])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Product: NC(=O)NN=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 41.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and semicarbazide hydrochloride (0.25 g) in ethanol (7 ml) was refluxed for 1 hour and then cooled. The resulting precipitates were filtered and recrystallized from a mixture of water and ethanol to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde semicarbazone (0.26 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([OH:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[C@@H:10]([OH:14])[C@H:9]1[C:15](=[O:17])[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O)[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](F)[C@@H](O)[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,3S,4S)-4-fluoro-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (195 g, 0.782 mmol) in CH2Cl2 (10 mL) were added 3-chloro-2-fluoro-benzylamine (150 mg, 0.94 mmol), propylphosphonic anhydride (50% in EtOAc, 0.346 mL, 1.17 mmol) and DIPEA (0.41 mL, 2.35 mmol). The reaction mixture was stirred 1 h at RT, then quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:1). MS (UPLC): 391.3/393.1 [M+H]+, 435.4/437.4 [M+HCOO]−; tR (HPLC conditions f): 1.95 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[NH:8][C:7](=O)[C:6]=2[CH:13]=1.O.[NH2:16][NH2:17]>C(O)COCCO>[Cl:1][C:2]1[C:3]([Cl:14])=[CH:4][C:5]2[S:9](=[O:11])(=[O:10])[N:8]=[C:7]([NH:16][NH2:17])[C:6]=2[CH:13]=1
Reactant: NN
Reactant: O=C1NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Solvent: O
Solvent: OCCOCCO
Product: NNC1=NS(=O)(=O)c2cc(Cl)c(Cl)cc21
Yield: 59.6 %

Procedure:
50.2 g (0.2 mol) of 5,6-dichloro-3-keto-2H,3H-1,2-benzisothiazole 1,1-dioxide in 200 ml of diethylene glycol are stirred with 35 g of hydrazine hydrate for 30 hours at 160° C. to 165° C. Working up analogously to Example 1 gives 31.7 g (63% of theory) of 5,6-dichloro-3-hydrazino-1,2-benzisothiazole 1,1-dioxide which decomposes at 276° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CN1[C@@H]2CC3C=CC(OC)=C4O[C@H]5C(OC)=CC=C2[C@]5(C=34)CC1.OO.C(O)(=O)C(O)=O>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=C(O)C(=O)O
Agent: OO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314

Procedure:
EP 1 658 293 B (Zentiva, A.S.) discloses a method of preparation of oxycodone by reaction of thebaine with hydrogen peroxide or peroxoacids in the presence of oxalic acid and of another organic acid. To the resulting crystalline precipitate of 14-hydroxy-codeinone oxalate is added a base to form 14-hydroxycodeinone, which is hydrogenated with hydrogen in the presence of a catalyst to yield oxycodone.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH3:34]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: N
Product: C[C@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(N)=O
Yield: 89 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with ammonia to give the title compound as a white solid (216 mg, 89%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum 446.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24](F)=[C:23]([Cl:28])[CH:22]=1)(=[O:20])=[O:19])[CH3:17]>>[Cl:28][C:23]1[CH:22]=[C:21]([S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:26]=[CH:25][C:24]=1[S:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=C(O)Cc1cc(S)cc(C(F)(F)F)c1
Product: CCS(=O)(=O)c1ccc(Sc2cc(CC(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from step (iii) and the product from example 3 step (i).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[CH2:19][CH2:20][NH2:21])[CH3:14].[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH2:13][CH3:14])[CH:17]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cccc(CCN)c1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1cccc(CCNCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.245 ml of 3-ethoxyphenethyl-amine (1.5 mmol) were dissolved in 5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2 h. After cooling down to rt, 85 mg (2.25 mmol) of sodium borohydride were added and after 10 min stirring at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 0.15 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue, 461 mg of a light yellow oil, was not further purified and used directly in the next step.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C(N1C(O[C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=CC(C2C=CC=C(C(NS(CC(F)(F)F)(=O)=O)(C)C)C=2)=N1)C.[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH2:51]>CN(C=O)C>[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][NH:51][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][CH:18]=[CH:19][CH:20]=1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Reactant: NCC1CCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CCCO1)c1ccccc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 38 %

Procedure:
(1-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (52 mg, 0.12 mmol, 1.2 equiv) and diisopropylethylamine (38 mg, 0.29 mmol, 3 equiv) were added to a stirring solution of 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid (50 mg, 0.10 mmol, 1 equiv) in DMF (1 mL). 1-(tetrahydrofuran-2-yl)methanamine (20 mg, 0.20 mmol, 2 equiv) was then added and the mixture was stirred at 22° C. for 16 hours. The mixture was purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H phenyl]-1H-pyrazol-5-yl}oxy)-N-(tetrahydrofuran-2-ylmethyl)benzamide (38% yield). Calc'd (M+1)+: 595.2. Found: 595.1
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>C1COCC1>[N+:21]([C:18]1[CH:19]=[CH:20][C:13]([O:1][CH:2]2[CH2:5][O:4][CH2:3]2)=[C:14]([CH:17]=1)[C:15]#[N:16])([O-:23])=[O:22]
Reactant: OC1COC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1cc([N+](=O)[O-])ccc1OC1COC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
3-Hydroxy oxetane (370 mg, 5 mmol, 2 equiv) in THF (15 ml) under argon gas, was cooled to 0° C. Potassium tert-butoxide (617 mg, 5.5 mmol, 2.2 equiv) was added in one portion, and the reaction mixture was stirred for 20 minutes at 0° C. Then 2-fluoro-5-nitrobenzonitrile (415 mg, 2.5 mmol, 1 equiv) was added in one portion, and the reaction mixture was stirred for 10 minutes at 0° C. and allowed to warm up to ambient temperature over 1 hour. The reaction mixture was concentrated, and the residue was taken in DCM and water. The layers were separated, and the organic layer was washed with water (×2), dried over Na2SO4, filtered, and concentrated to provide 5-nitro-2-(oxetan-3-yloxy)benzonitrile (495 mg, 90%) as a brown-yellow solid that was used without further purification.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C-:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].CN([S+](N(C)C)N(C)C)C.FC(F)(F)C(=C(F)F)C(F)(F)F.F[Si](C)(C)C>C(#N)C1C=CC=CC=1>[Br:1][C:5]([C:6]([F:9])([F:8])[F:7])([C:10]([F:11])([F:12])[F:13])[C:4]([F:14])([F:15])[F:3]
Reactant: BrBr
Reactant: FC(F)(F)[C-](C(F)(F)F)C(F)(F)F
Agent: CN(C)[S+](N(C)C)N(C)C
Agent: C[Si](C)(C)F
Agent: FC(F)=C(C(F)(F)F)C(F)(F)F
Solvent: N#Cc1ccccc1
Product: FC(F)(F)C(Br)(C(F)(F)F)C(F)(F)F
Yield: 81 %

Procedure:
Bromine, 17.25 g (0.108 mol), was added dropwise at 0° to a solution of tris(dimethylamino)sulfonium 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)-2-propanide, prepared by dissolving 33.4 g (0.12 mol) of tri(dimethylamino)sulfonium difluorotrimethylsilicate and 24.0 g (0.12 mol) of perfluoroisobutylene in 75 mL of benzonitrile, then pumping out the by-product fluorotrimethylsilane at reduced pressure. The reaction mixture was evacuated to transfer the volatile reaction product into a cold trap (-78°). Sublimation of the contents of the trap at atmospheric pressure gave 26.11 g (81%) of 2-bromo-1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propane as a very volatile solid: m.p. (sublimation) 49°-51°; 19F NMR (CDCl3) δ -67.6 ppm (s).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([O:25]C)[CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6]1>C(Cl)Cl>[CH:5]1([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([OH:25])[CH:23]=4)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: COc1ccc2c(c1)C(C1CCN(C(=O)C3CC3)CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC(C2CCc3ccc(O)cc32)CC1
Reaction time: 18 h
Yield: 35 %

Procedure:
A 1M boron tribromide solution (3 mL, 3 mmol) was added at -78 ° C. to a solution of N-cyclopropylcarbonyl-4-(6-methoxy-indan-1-yl)piperidine (0.45 g, 1.5 mmol) in methylene chloride. After stirring for 18 h the reaction was quenched with water. The organic layer was separated and washed with 1N NaOH solution and concentrated in vacuo. The residue was stirred for 18 h with a mixture of methanol and 1N NaOH. The methanol was removed in vacuo and the solution was made acid with 1N HCl. The insolubles were collected by filtration to give 0.15 g product, mp 75°-82° C. Anal. Calc'd for C18H23NO2 ·0.3H2O: C, 74.35%; H, 8.18%; N, 4.82%. Found: C, 74.4%; H, 8.08%; N, 4.74%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][CH:19]([C:21](O)=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C@H:19]([C:21]([NH:9][C:7](=[O:8])[C@@H:2]([NH2:1])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:22])[CH3:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: CCCC[C@H](N)C(N)=O
Product: CCCC[C@H](N)C(=O)NC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using L-norleucine amide (prepared from BOC-L-norleucine amide (from Example F above) using General Procedure F) and N-(3,4-dichlorophenyl)-D,L-alanine, the title compound was prepared as a solid (mp=156-161° C.).
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:25])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:28][C:29]([F:42])([F:41])[C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[CH:37]C(Cl)=O)=[CH:32][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:25])[N:9]([C:10]1[N:11]=[C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22](=[O:24])[CH3:23])[CH:17]=2)[O:13][CH:14]=1)[CH:37]=[CH:36][C:33]1[CH:32]=[CH:31][C:30]([C:29]([F:28])([F:41])[F:42])=[CH:35][CH:34]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)c1cccc(Cc2nc(NC(=O)OC(C)(C)C)co2)c1
Reactant: O=C(Cl)C=Cc1ccc(C(F)(F)F)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cccc(Cc2nc(N(C=Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)co2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-benzyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (15 mg, 0.05 mmol) in THF (1.0 mL) was added to a suspension of NaH (5 mg, 0.12 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 3-(4-trifluoromethyl-phenyl)-acryloyl chloride in THF (1.0 mL). The resulting suspension was stirred for 5 min at 0° C. followed by 30 min at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.17 min, [M+H]+=515.82.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH2:33]([C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([CH:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1)[CH3:34]
Reactant: CS(=O)(=O)c1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)cc1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(C3Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from 5-(4-methanesulfonyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 1. LC (method 5): tR=1.14 min; Mass spectrum (ESI+): m/z=465 [M+H]+.