Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]([S:18][C:19]([F:22])([F:21])[F:20])[C:15]([CH:23]([OH:25])[CH3:24])=[N:14]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[C:23]([C:15]1[C:16]([S:18][C:19]([F:20])([F:21])[F:22])=[CH:17][N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=1)(=[O:25])[CH3:24]
Reactant: CC(O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1SC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-(1-hydroxyethyl)-4-trifluoromethylthiopyrazole (1.1 g) in dichloromethane (40 ml) was added pyridinium chlorochromate (0.62 g), and the mixture stirred at room temperature overnight. Ether (50 ml) was added and the mixture filtered on diatomaceous earth. Evaporation of the filtrate in vacuo gave a brown solid, which was triturated with hexane and filtered. The filtrate was evaporated in vacuo to give a yellow solid, which recrystallised from cyclohexane to give 3-acetyl-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylthiopyrazole (0.4 g) in the form of a yellow solid, m.p. 89°-91° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([CH2:19]O)=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.CS([Cl:34])(=O)=O>ClCCl>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:13]2[S:14][C:15]([CH2:19][Cl:34])=[C:16]([CH3:18])[N:17]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)sc1CCl
Temperature: 0 °C

Procedure:
[2-(3,5-Bis-trifluoromethyl-phenyl)-4-methyl-thiazol-5-yl]-methanol (0.460 g, 1.35 mmol), is dissolved in anhydrous dichloromethane (6 mL) and cooled to 0° C. with stirring under nitrogen. Triethyl amine (0.350 mL, 2.60 mmol) and methane sulfonyl chloride (0.200 mL, 2.0 mmol) are added and the reaction is monitored by TLC. After the starting material is completely consumed, the reaction is diluted with dichloromethane and extracted against saturated sodium bicarbonate solution. The two phases are separated and the organic layer is washed with water and brine, dried over sodium sulfate, then concentrated. The residue is further purified using flash column chromatography. The 2-(3,5-Bis-trifluoromethyl-phenyl)-5-chloromethyl-4-methyl-thiazole is formed quantitatively and used without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6])[CH:2]=[CH2:3].Cl>C(#N)C>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCCn1ccnc1
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCCn1ccnc1
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-t-butyldimethylsilyloxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (19.0 g) in acetonitrile (94 ml) was added conc. hydrochloric acid (9.4 ml) dropwise at 0° C. The solution was stirred at the same temperature for 30 minutes and quenched by the addition of triethylamine (16.7 ml). To the mixture was added ethyl acetate (200 ml) and the insoluble solid was removed by filtration. The filtrate was concentrated and the residue was dissolved in ethyl acetate (100 ml). The insoluble solid was filtered off and the filtrate was concentrated to give a light brown paste. The paste was chromatographed on a 90 g of silica gel to give (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-[3-(imidazol-1-yl)propyl]pyrrolidine (12.5 g) as a pale yellow paste.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13])[NH2:2].O=[C:17]([CH:23]1[CH2:27][CH2:26][CH2:25][C:24]1=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)C>C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[C:23]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:1]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=2[C:12]([F:13])([F:14])[F:15])[N:2]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C(=O)C1CCCC1=O
Reactant: NNc1ccc(C(=O)O)cc1C(F)(F)F
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nn(-c2ccc(C(=O)O)cc2C(F)(F)F)c2c1CCC2

Procedure:
4.0 g (18.2 mmol) of 4-hydrazino-3-trifluoromethylbenzoic acid is dissolved in 20 mL of glacial acetic acid, combined with 3.3 g (18.2 mmol) of ethyl oxo-(2-oxocyclopentyl)acetate, and refluxed for 2 hours under a nitrogen atmosphere. After cooling, it is stirred with diethyl ether and the precipitate is suction filtered. Yield: 2.9 g (43%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)([O-])=O.N>>[C:4]1([NH2:1])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2ccccc12
Agent: N
Product: Nc1cccc2ccccc12

Procedure:
The procedure was as described in Example II-3 except that 100 g of 1-nitronaphthalene and 4 g of catalyst prepared according to Example I-1 were used as the educt. The hydrogenation was carried out without the addition of ammonia. The catalyst was recycled once (total of 2 runs). The purity of the 1-naphthylamine obtained was between 99.1 and 99.3%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[CH3:19][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])=[O:25])[C:21](O)=[O:22]>>[CH3:19][CH:20]([C:24]([NH:26][CH2:27][CH2:28][C:29]([F:34])([F:35])[C:30]([F:32])([F:31])[F:33])=[O:25])[C:21]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2)=[O:22]
Reactant: CC(C(=O)O)C(=O)NCCC(F)(F)C(F)(F)F
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CC(C(=O)NCCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(C)c2ccccc2-c2ccccc21

Procedure:
In an analogous manner to that described in Example 20 d), the condensation of (S)-7-amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one and (2RS)-2-methyl-N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid yielded the title compound as a white solid;
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Product: N#CSC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O
Reaction time: 15 h

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 0.12 moles of α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=O)CCC.[H-].[Na+].[CH2:17]([O:21][C:22]1[C:26](S(C)(=O)=O)=[N:25][S:24][N:23]=1)[CH2:18][CH2:19][CH3:20]>C1COCC1>[CH2:17]([O:21][C:22]1[C:26]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[N:25][S:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Reactant: CCCCOC(=O)N1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC[C@@H]1CCCN1
Reaction time: 1 h

Procedure:
A solution of (S)-1-butyloxycarbonyl-2-pyrrolidinemethanol (1.21, 0.006 mol) in THF (5 mL) was added to a suspension of 60% NaH in oil (0.24 g, 0.006 mol) in THF (30 mL). After 1 h, the mixture was heated to gentle reflux for 1 h. To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue treated with cold H2O, and the mixture extracted with EtOAc. The extracts were dried and treated with a stream of dry HCl for 3 min. After another hour, the solvent was evaporated, the residue treated with cold H2O, and the mixture extracted with ether. The aqueous fraction was made basic and extracted with EtOAc. The extracts were washed with water, dried, and the solvent evaporated to give a liquid. The HCl salt (0.72 g) crystallized from EtOAc, m.p. 99°-100° C. (Compound 32).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:17][C:15]2[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([NH:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[N:13]3[N:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(CCl)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 800 mg; 3.46 mmol; 1.0 eq.) and 4-(chloromethyl)benzoyl chloride (981 mg; 5.2 mmol; 1.5 eq.) as a brownish foam (1.32 g, 99%). LC/MS, M+(ESI): 384.0, M−(ESI): 382.0.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.[CH2:25]([Mg]Br)[CH3:26].[Cl-].[NH4+]>O1CCCC1.CCOCC>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C@:8]([CH2:25][CH3:26])([OH:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC[C@](C)(O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a solution of 100 mg (0.303 mmol) 7β-methyl-5α-4-azapregn-1-ene-3,20-dione in 10 ml dry tetrahydrofuran at -40° C. under N2 was added 15 eq ethylmagnesium bromide (4.5 mmol) in ether. The reaction was stirred and allowed to warm to RT over 18 hours. Aqueous ammonium chloride (5 ml) was added and the solvents were evaporated. The residue was partitioned between methylene chloride and water. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The product was purified via HPLC on a 19×300 mm 8 micron silica column using 5% isopropanol/hexane at 20 ml/min to yield 53 mg (0.147 mmol, 49% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH3:22])=[C:17]([F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[CH2:22][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:17]([F:24])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CCC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
In a 250 mL round bottom flask, 4-(4-acetyl-3-fluoro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 12 mmol) in tetrahydrofuran (00 mL) were cooled to −78° C. Lithium diisopropylamide (1.4 g, 13 mmol) was added and stirred 30 min. then warmed to 0° C. Re-cooled to −78° C. and ethyl bromoacetate (1.4 mL, 13 mmol) in tetrahydrofuran (25 mL) was added. The reaction warmed to ambient temperature over 14 h. The reaction was quenched with NH4Cl sol. and the solvents were concentrated under vacuum. The reaction was chromatographed through silica gel with hexanes/ethyl acetate (7:3) as eluent to produce 4.10 g (82%) of oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH3:9].C([N-]C(C)C)(C)C.[Li+].[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[C:29]([CH3:35])[CH:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:28][C:29]=1[CH3:35])[OH:32]
Reactant: CCCCOCC(=O)OC
Reactant: Cc1cc(OCc2ccccc2)ccc1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCOC(C(=O)OC)C(O)c1ccc(OCc2ccccc2)cc1C

Procedure:
In analogy to the procedure described in example 125 a], butoxy-acetic acid methyl ester (V. Franzen, L. Fikentscher, Ann. 1958, 617, 1-10) was deprotonated with lithium diisopropylamide and treated with 4-benzyloxy-2-methyl-benzaldehyde in tetrahydrofuran at −78° C. for 3 h to obtain 3-(4-benzyloxy-2-methyl-phenyl)-2-butoxy-3-hydroxy-propionic acid methyl ester as a mixture of two diastereomeric racemates as yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][CH:8]=[CH:7][N:6]=2.O.[Se](=O)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]=[O:15])=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: O=[Se]=O
Reactant: Cc1c(Cl)cnc2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1c(Cl)cnc2ncccc12
Temperature: 110 °C
Yield: 31.1 %

Procedure:
3-Chloro4-methyl-[1,8]naphthyridine (3.0 g, 16.7 mmol) from Step 3 was dissolved in 4:1 dioxane:water (30 mL) and selenium dioxide (5.9 g, 50.4 mmol) was added. The reaction mixture was heated (110° C.) for 2.5 h, cooled to RT, poured into satd. aq. NaHCO3 (30 mL) and water (10 mL). The mixture was subsequently treated with DCM (80 mL) and the solids filtered off through Celite and rinsing the filter cake with DCM. After separating the aqueous and organic layers, the aqueous phase was re-extracted with DCM (4×80 mL) and the combined organics were dried (Na2SO4) and concentrated. The crude product was chromatographed by SGC (MeCN eluant) to yield the title compound 3-chloro-[1,8]naphthyridine-4-carbaldehyde (1.0 g, 5.2 mmol). Note: owing to weak UV activity, it was found more efficacious to monitor column fractions with MS rather than UV, as in Step 3. MS (ESI+) for m/z 193 (M+H)+. 1H NMR(CDCl3)δ 10.79 (s, 1H), 9.28 (dd, 1H), 9.17 (s, 1H), 9.14 (dd, 1H), 7.63(dd. 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24](=O)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[N:11]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:10]=1.COC1C=CC=CC=1C1C2C(=NC=C(B3OC(C)(C)C(C)(C)O3)C=2)[N:51](S(C2C=CC(C)=CC=2)(=O)=O)[CH:50]=1.BrC1C=CN=C(C(C#N)C(N(C)C)=O)C=1.C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1>[C:50]([CH:24]([C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:32])=[O:33])[C:12]3=[N:13][CH:14]=2)[CH:23]=[CH:22][N:21]=1)[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])#[N:51]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccnc(C(=O)C(=O)N(C)C)c3)cc12
Agent: CN(C)C(=O)C(C#N)c1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccnc(C(C#N)C(=O)N(C)C)c3)cc12
Temperature: 80 °C

Procedure:
2-{4-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-2-oxo-acetamide was 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (493 mg, 0.977 mmol), 2-(4-bromo-pyridin-2-yl)-2-cyano-N,N-dimethyl-acetamide (80%, 391 mg, 1.46 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (39.8 mg, 0.048 mmol) were combined in a vial under nitrogen and dissolved in acetonitrile (2.5 mL) and toluene (2.5 mL). Saturated sodium bicarbonate (5 mL) was added and the system was purged with nitrogen gas. The reaction mixture was capped and heated for 15 h at 80° C. The cooled mixture was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 2-cyano-2-{4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-acetamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>O1CCOCC1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Reactant: C1CSCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCSCC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.30 g, 0.785 numol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).
Reaction SMILES: C(N1C[CH2:12][CH:11]([N:14]2[C:18]3=[N:19][C:20]([Cl:31])=[N:21][C:22]([N:23]4[CH2:29][CH:28]5[O:30][CH:25](CC5)[CH2:24]4)=[C:17]3[CH:16]=[N:15]2)CC1)C1C=CC=CC=1.[CH2:32](NN)[CH3:33].NN.C12OC(CC1)CNC2>>[Cl:31][C:20]1[N:19]=[C:18]2[N:14]([CH2:11][CH3:12])[N:15]=[CH:16][C:17]2=[C:22]([N:23]2[CH:29]3[CH2:32][CH2:33][CH:24]2[CH2:25][O:30][CH2:28]3)[N:21]=1
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCN(Cc4ccccc4)CC3)c2n1
Reactant: CCNN
Agent: C1CC2CNCC1O2
Agent: NN
Product: CCn1ncc2c(N3C4CCC3COC4)nc(Cl)nc21

Procedure:
A procedure similar to that used for the synthesis of 3-(1-(1-benzylpiperidin-4-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane is used, using ethyl hydrazine as the hydrazine component and substituting 3-oxa-8-azabicyclo[3.2.1]octane for 8-oxa-3-azabicyclo[3.2.1]octane. (65%, MS=294.3 (M+H))
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([Br:28])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:18])=[CH:11][C:10]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1>O=S(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:29][C:30]([OH:32])=[O:31])[CH:5]=[C:6]([Br:28])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:2][CH2:3][C:4]([CH3:29])=[CH2:5])=[CH:11][C:10]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1
Reactant: Cc1cccc(C(=O)c2cc(O)c(C(C)C)cc2Oc2c(Br)cc(CC(=O)O)cc2Br)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: C=C(C)CCOc1cc(C(=O)c2cccc(C)c2)c(Oc2c(Br)cc(CC(=O)O)cc2Br)cc1C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 109.8 %

Procedure:
Five drops of SOCl2 was added to a solution of 3,5-dibromo-4-[4-hydroxy-5-isopropyl-2 -(3-methylbenzoyl)phenoxy]phenylacetic acid (0.30 g, 0.52 mmol), in 20 mL MeOH. The mixture was stirred at room temperature for 12 h and concentrated leaving the title compound (0.18 g, 60%). 1H NMR (CDCl3): δ 7.9–7.7 (m, 2H), 7.5–7.1 (m, 4H), 6.9 (s, 1H), 6.2 (s, 1H), 4.7 (s, 3H), 4.5 (s, 2H), 3.1 (m, 1H), 2.4 (s, 3H), 1.1 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:13])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH:15]([CH3:19])[C:16](=O)[CH3:17]>COCCOC>[NH2:1][C:2]1[C:3]2[N:4]([C:15]([CH3:19])=[C:16]([CH3:17])[N:13]=2)[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:12]=1
Reactant: CCOC(=O)c1cnc(N)c(N)c1
Reactant: CC(=O)C(C)Br
Solvent: COCCOC
Product: CCOC(=O)c1cc(N)c2nc(C)c(C)n2c1
Yield: 17.9 %

Procedure:
Ethyl 5,6-diaminonicotinate (1.4 g, 7.7 mmol) and 3-bromo-2-butanon (1.16 g, 7.2 mmol) were added to 1,2-dimethoxyethan (50 ml) and refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride. The methylene chloride solution was washed with saturated sodium bicarbonate and dried (Na2SO4). The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride:methanol (10:1) as eluent to give 0.3 g (17%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:22])([F:21])[C:11]([CH:13]=[C:14]1[CH2:18][O:17]C(C)(C)O1)=[O:12]>>[OH:17][CH2:18][C:14]1[CH2:13][C:11]([C:10]([F:22])([F:21])[F:9])([OH:12])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CC1(C)OCC(=CC(=O)C(F)(F)F)O1
Reactant: NNc1ccccc1
Product: OCC1=NN(c2ccccc2)C(O)(C(F)(F)F)C1

Procedure:
The procedure is as described in example 1, but using phenylhydrazine and 1,1,1-trifluoro-3-(2,2-dimethyl-1,3-dioxolan-4-ylidene)acetone.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4].[N-]=[N+]=[N-]>>[NH2:1][CH2:2][C:5]([NH:7][CH2:8][C:13]([NH:1][C@H:2]([C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10](=[O:12])[NH2:11])=[O:6])[CH2:3][OH:4])=[O:14])=[O:6]
Reactant: NC(=O)C[C@H](NC(=O)[C@@H](N)CO)C(=O)O
Agent: [N-]=[N+]=[N-]
Product: NCC(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)O
Yield: 63 %

Procedure:
H-Ser-Asn-OH prepared in (1) and benzyloxycarbonyl-Gly-Gly-NHNH2 were condensed according to the azide method, and the reaction mixture was extracted with n-butanol to separate benzyloxycarbonyl-Gly-Gly-Ser-Asn-OH as a product. The product was subjected to catalytic hydrogenating decomposition in the presence of 5% palladium on carbon to obtain H-Gly-Gly-Ser-Asn-OH melting at 219° C. with decomposition in a yield of 63%.