Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].S(O)(O)(=O)=O.[NH2:8][C:9]1[N:14]=[C:13]([NH2:15])[CH:12]=[C:11]([SH:16])[N:10]=1.N[C:18]1N=C(N)C=C(S)N=1.CI>O>[CH3:18][S:16][C:11]1[N:10]=[C:9]([NH2:8])[N:14]=[C:13]([NH2:15])[CH:12]=1
Reactant: Nc1cc(S)nc(N)n1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1cc(N)nc(N)n1
Reaction time: 4 h
Yield: 188.9 %

Procedure:
To a stirred solution of 105 g KOH in 1 L of water was added 2,4-diamino-6-mercaptopyrimidine hemisulfate 1 (70.0 g) followed by methyl iodide (91 mL). The resulting mixture was vigorously stirred for 4 h and then the solid precipitate was filtered off, washed with water and air dried overnight to give 54.0 g of 6-Methylthio-pyrimidine-2,4-diamine as a tan colored solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2([CH2:15][OH:16])[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2=N[CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8].[C:36](C1C2C(=CC=CC=2)N(CC(O)=O)C=1)(=O)C>CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2([CH2:15][OH:16])[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2[C:22](=[CH:27][CH:26]=[CH:25][CH:36]=2)[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)O)c2ccccc12
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ccccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide using (3-acetyl-indol-1-yl)-acetic acid instead of (3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetic acid. White powder. TLC, Rf (EtOAc)=0.05; MS (LC/MS): 498/500 [M+H]+, 520/522 [M+Na]+; tR (HPLC conditions f): 1.84 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:13][C:12]2[CH:14]=[C:15]([F:26])[C:16]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=O)=[CH:17][C:11]=2[O:10]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:43])=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:13][C:12]2[CH:14]=[C:15]([F:26])[C:16]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[S:43])=[CH:17][C:11]=2[O:10]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2)N1CCOCC1
Solvent: c1ccccc1
Product: Fc1ccc(C2(c3ccc(Cl)cc3Cl)Oc3cc(F)c(C(=S)N4CCOCC4)cc3O2)cc1
Yield: 184.4 %

Procedure:
[2-(2,4-Dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxol-5-yl]-morpholin-4-yl-methanone (Example 108e, 79 mg, 0.16 mmol) and Lawesson's reagent (33 mg, 0.08 mmol) were heated in benzene (1 mL) under reflux for 4 h. The reaction mixture was evaporated in vacuo. Purification by flash chromatography afforded the title compound (75 mg, 92%) as a yellow oil.
Reaction SMILES: [O:1]=[C:2]([CH3:11])[CH:3]=[CH:4][C:5]1([CH2:8][C:9]#[N:10])[CH2:7][CH2:6]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]([CH3:11])[CH2:3][CH2:4][C:5]1([CH2:8][C:9]#[N:10])[CH2:7][CH2:6]1
Reactant: CC(=O)C=CC1(CC#N)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CCC1(CC#N)CC1
Yield: 101.2 %

Procedure:
A solution of the olefin from Step 1 (4.08 g, 26.8 mmol) in 85 mL ethyl acetate was treated with 30 psi hydrogen over 5% palladium on carbon (300 rag) in a Parr shaker for 1.5 h. The mixture was filtered through celite and evaporated to give 4.1 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([S:12](=[O:34])(=[O:33])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:21]([C:24]2[S:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[CH:25]=2)(=[O:23])=[O:22])[CH:5]=1>C1COCC1.CO.[OH-].[Na+]>[S:28]1[C:24]([S:21]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:13][S:12]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[O:10][CH3:11])[C:3]([OH:35])=[O:2])(=[O:33])=[O:34])(=[O:23])=[O:22])=[CH:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]1=2
Reactant: COC(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
To a solution of 3-[2-(Benzo[b]thiophene-2-sulfonylamino) -phenyl sulfamoyl]-4-methoxy-benzoic acid methyl ester (5 mmol, obtained as in Example 3) in THF (10 mL) and methanol (10 mL), 4 M aq. NaOH (5 mL) was added at RT. The reaction mixture was stirred at room temperature till the reaction was complete. The reaction mixture was then concentrated in vacuo and acidified with 10% aq. HCl to pH ˜3. A white precipitate was formed which was filtered, washed with ether and dried, affording 2.5 g of 3-[2-(benzo[b]thiophene-2-sulfonylamino) -phenylsulfamoyl]-4-methoxybenzoic acid. MS: 519.8 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 4.05 (s, 3H), 6.89 (d, 1H), 6.99 (dd, 1H), 7.11 (dd, 1H), 7.25 (d, 1H), 7.38 (d, 1H), 7.48 (dd, 1H), 7.53 (dd, 1H), 7.91 (s, 1H), 7.98 (d, 1H), 8.65 (d, 1H), 8.13 (dd, 1H), 8.16 (dd, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:27]2[C@H:31]([CH2:32][OH:33])[CH2:30][O:29][C:28]2=[O:34])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])#[N:2].[CH3:35]I>>[C:1]([C:3]1[CH:4]=[C:5]([N:27]2[C@H:31]([CH2:32][O:33][CH3:35])[CH2:30][O:29][C:28]2=[O:34])[CH:6]=[CH:7][C:8]=1[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH:24]3[CH2:26][CH2:25]3)=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])#[N:2]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)cc2C#N)CC1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C)CC2)c(C#N)c1
Yield: 54.8 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 93 and using (R)-3-{3-cyano-4-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (600 mg) described in Example 357 and methyl iodide (221 mg), the title compound (339 mg) was obtained.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH2:55]([O:62][NH2:63])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([O:62][NH:63][C:12](=[O:14])[CH2:11][C@H:10]([C:15]1[O:16][C:17]([CH3:24])=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:19]=1)[CH2:9][CH2:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)O)oc1C
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)c1nc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(methoxycarbonyl)-5-methyl-1,3-oxazol-2-yl]hexanoic acid (Preparation 70) (2.48 g, 7.36 mmol) was cooled to 0° and treated with 1-hydroxybenzotriazole hydrate (994 mg, 7.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.12 g, 11.06 mmol) and N-methylmorpholine (1.21 ml, 11.04 mmol). The mixture was stirred for 15 minutes then treated with O-benzylhydroxyamine (1.17 g, 7.36 mmol) and further N-methylmorpholine (0.81 ml, 7.36 mmol). The mixture was stirred for 1 hour being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate, washed sequentially with water, a saturated solution of sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (3.22 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCCCOc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.50 g, 1.9 mmol), tert-butyl 6-bromohexanoate (1.25 g, 4.9 mmol) and potassium carbonate (0.54 g, 3.9 mmol) and DMF (10 ml) was stirred at room temperature for 24 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.75 g, 90%).
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[F:11][C:12]1[CH:17]=[C:16](I)[CH:15]=[C:14]([F:19])[CH:13]=1>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:11][C:12]1[CH:17]=[C:16]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: Fc1cc(F)cc(I)c1
Reactant: C#Cc1nc(C)ccc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.8 %

Procedure:
To a solution of Cul (4.3 mg, 23 μmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (60 mg, 0.45 mmol), (PPh3)2PdCl2 (16 mg, 23 μmol), and 1,3-difluoro-5-iodobenzene (109 mg, 0.45 mmol). The reaction mixture was stirred at room temperature for 20 h. The solvent was evaporated to afford a brown oil which was taken up in DCM and the solution was washed with water. The aqueous phase was extracted twice with DCM. The organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 64 mg (0.26 mmol, 58%) of (2-(3,5-difluoro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1S(C)(=O)=O)=[O:4].C[N:19](C=O)C.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([S:14]([CH3:17])(=[O:16])=[O:15])=[N:7][S:8][C:9]=1[NH2:19])=[O:4]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(S(C)(=O)=O)nsc1S(C)(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(S(C)(=O)=O)nsc1N
Yield: 75 %

Procedure:
In a 3 neck flask fitted with a condenser, compound 16 (1 g, 3.33 mmol) is dissolved in THF (20 mL) and DMF (2 mL) and warmed to 50° C. Ammonia gas is then bubbled into the reaction mixture for 16 hrs. The solvent is then removed in vacuo to provide a crude solid. Water is added to the solid and the mixture is then filtered and washed with water (2×) followed by methylene chloride (5 mL×2) to provide 17 (588 mg, 75%) as a yellow powder. 1H NMR (d6 DMSO): δ 8.11 (2H, br. s), 3.74 (3H, s), 3.30 (3H, s). LRMS (M+): 237.1, (M−): 235.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28]C)=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:28])=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)ccc3OC)n2)c1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(F)ccc3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 2 Step A (2.89 g, 7.06 mmol) in DCM (30 mL) was added dropwise BBr3 (21.2 mL, 1.0 M in DCM, 21.2 mmol). After addition was complete, the cooling bath was removed, and the reaction mixture was allowed to stir at room temperature. After 1.5 h, the mixture was cooled to 0° C., then was quenched by careful addition (exothermic, gas evolution) of sat aq NaHCO3 (100 mL). The resulting mixture was diluted with DCM, the phases were separated, and the organic phase was concentrated in vacuo. Purification by chromatography on silica gel (0 to 35% EtOAc in hexanes, then 35 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 395.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.79 (s, 1H), 8.18 (s, 1H), 8.10 (t, J=8.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 7.49 (dd, J=10.0, 3.0 Hz, 1H), 7.09-7.06 (m, 1H), 6.98 (dd, J=9.0, 5.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[C:10](=[CH:21][N:22]([CH3:25])[CH3:23])[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)CC(=O)Nc1ccccc1Cl
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(2-chlorophenyl)-3-oxobutanamide (2.63 g), potassium carbonate (1.72 g) and N,N-dimethylformamide (31.0 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (3.30 mL) over 30 min at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was slowly poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.30 g).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH:16][C:29](=[O:30])/[CH:28]=[CH:27]/[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=3[O:18][CH3:17])=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: COc1cccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)(F)F)o3)n2)c1OC

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.09 min; [M+H]+=418.09.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[N:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[N:25]=[CH:24][C:23]([C:22]([F:32])([F:21])[F:33])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(C(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-trifluoromethyl-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=462.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1>C(OCC)(=O)C.CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(C(=O)OC)cc1N
Reaction time: 4 h

Procedure:
After dissolving 4-methylamino-3-nitrobenzoic acid methyl ester (540 mg, 2.5 mmol) in ethyl acetate-methanol (2:1) (20 ml), 10% palladium-carbon powder (5 mol %) was added thereto under a nitrogen atmosphere. The mixture was stirred for 4 hours under a hydrogen atmosphere, and then the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain 3-amino-4-methylaminobenzoic acid methyl ester. The compound was identified by LC-MS.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:22])=[O:21])=[C:5]([NH:10][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:4]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Product: COc1ccc(NS(=O)(=O)c2cc3ccccc3s2)c(NS(=O)(=O)c2cc3ccccc3s2)c1

Procedure:
N,N′-(4-methoxy-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) (472 mg) was prepared as in Example 31 using 4-methoxybenzene-1,2-diamine and benzothiophene-2-sulfonyl chloride as requisite starting materials.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:88]=[CH:87][C:72]([CH2:73][N:74]2[CH2:79][CH2:78][N:77]([C:80]([O:82][C:83]([CH3:86])([CH3:85])[CH3:84])=[O:81])[CH2:76][CH2:75]2)=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:70]=[CH:71][C:72]([CH2:73][N:74]4[CH2:75][CH2:76][N:77]([C:80]([O:82][C:83]([CH3:84])([CH3:86])[CH3:85])=[O:81])[CH2:78][CH2:79]4)=[CH:87][CH:88]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3nc4c(N5CCN(Cc6cccnc6)CC5)c(Br)cnc4[nH]3)cc2)CC1
Reaction time: 6 h
Yield: 26.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (50 mg, 0.13 mmol), DMF (0.3 mL), ethanol (1.2 mL), 1M Na2S2O4 (3 eq, 0.38 mmol, 0.38 mL) and tert-butyl 4-(4-formylbenzyl)piperazine-1-carboxylate (1.1 eq, 0.14 mmol, 45 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (22 mg, 27%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H, piperazine N(CH2)2), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.32 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, CH2), 3.62 (s, 2H, CH2), 3.67 (t, J=4.8 Hz, 4H, piperazine N(CH2)2), 7.39 (dd, J=7.8, 4.8 Hz, 1H, pyridine H-5), 7.46 (d, J=8.1 Hz, 2H, phenyl H-3 & H-5), 7.78 (d, br, J=8.0 Hz, 1H, pyridine H-4), 8.14 (d, J=8.1 Hz, 2H, phenyl H-2 & H-6), 8.23 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.50 (dd, J=4.8, 1.6 Hz, 1H, pyridine H-6), 8.56 (d, J=1.7 Hz, 1H, pyridine H-2), 13.46 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:13]=[O:14])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[K+]>CC(C)=O>[CH2:15]([O:12][C:11]1[C:10]([CH:13]=[O:14])=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(Br)c(O)c(C=O)c1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)c(OCc2ccccc2)c(C=O)c1
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Methyl 3-bromo-5-formyl-4-hydroxybenzoate (11.5 g, 44.39 mmol) was dissolved in acetone (100 mL) and then benzylbromide (8.35 g, 48.83 mmol) and potassium bicarbonate (6.74 g, 48.83 mmol) were added. The mixture was stirred overnight and the organic layer was washed with water. The organic layer was separated, dried over MgSO4 and concentrated. Product was purified from the residue by flash silica gel chromatography to give methyl 4-benzyloxy-3-bromo-5-formyl-benzoate (10.0 g).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:7]=1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>C1COCC1>[CH3:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH:9]=[CH:8][C:7]=1[CH:21]=[CH:22][CH:23]([OH:25])[CH3:24]
Reactant: CC(=O)C=Cc1ccc(OCc2ccccc2C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccccc2C)ccc1C=CC(C)O
Yield: 94 %

Procedure:
NaBH4 (20 mg, 0.51 mmol) was added to a 0.4 M solution of CeCl3 in MeOH (0.65 mL, 0.26 mmol), 31.4 (74 mg, 0.26 mmol), and THF (1 mL). The reaction was stirred, uncapped, until gas evolution ceased. The reaction was quenched with water (1.5 mL) and partitioned between water and diethyl ether. The aqueous layer was extracted 2 times with diethyl ether and the combined organic layers were washed with brine and concentrated in vacuo to yield 69 mg (93%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-ol (31.5). LC/MSD m/e: 266.3 (M—OH); 1H NMR (400 MHz) (DMSO-d6) δ 7.44 (2H, m), 7.25 (3H, m0, 6.86 (2H, m), 6.75 (1H, m), 6.08 (1H, m), 5.11 (2H, s), 4.40, (1H, m), 2.38 (3H, s), 2.32 (3H, s), 1.29 (3H, m).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](Cl)=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH3:32])=[O:38])=[O:19])[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: COC(=O)CCN
Reactant: COCc1cc(-c2nc(-c3cccc(C(=O)Cl)c3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: COCc1cc(-c2nc(-c3cccc(C(=O)NCCC(=O)OC)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in example 121 starting from 3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 130, and beta-alanine methyl ester hydrochloride. The title compound was obtained as a white foam. 1H NMR: (DMSO-d6, 300 MHz) δ 8.87 (m, 1H), 8.58 (m, 1H), 8.35 (m, 1H), 8.27 (m, 1H), 8.19 (dd, J=1.9 Hz, 7.9 Hz, 1H), 8.07 (m, 1H), 7.72 (t, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.38-7.25 (m, 3H), 7.15 (m, 1H), 4.23 (d, J=12.9 Hz, 1H), 4.17 (d, J=12.9 Hz, 1H), 3.63 (s, 3H), 3.54 (m, 1H), 3.25 (s, 3H), 3.64 (t, J=6.9 Hz, 2H), 2.04 (s, 3H). LC/MS (Method B): 486.2 (M+H)+ 484.2 (M−H)−. HPLC (Method A) Rt: 5 min (purity: 99.3%).