Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=C)[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1.I([O-])(=O)(=O)=[O:18].[Na+]>C(#N)C.O.C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[CH3:1][CH:2]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][C:13](=[O:18])[CH2:14][O:15][C:7]3=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: C=C1COc2cc3c(cc2OC1)C(C)CC3
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC1CCc2cc3c(cc21)OCC(=O)CO3
Temperature: 30 °C
Yield: 49.6 %

Procedure:
6.6 g (30.5 mmol) of 1-methyl-7-methylene-2,3,7,8-tetrahydro-1H,6H-5,9-dioxacyclohepta[f]indene were dissolved in a mixture of 140 ml of acetonitrile, 140 ml of water and 90 ml of carbon tetrachloride. 6.50 g (30.5 mmol) of sodium periodate were added at room temperature with stirring, with the temperature falling to 15° C. After stirring for 30 min, 0.3 g (1.5 mmol, 5 mol %) of ruthenium (III) chloride hydrate were then added, with the temperature increasing back to 30° C. The mixture was stirred for 48 h at room temperature, in the course of which, after 6 h, a further 6.50 g (30.5 mmol) of sodium periodate and 0.3 g (1.5 mmol, 5 mol %) of ruthenium (III) chloride hydrate were added. The reaction mixture was then poured into 500 ml of water and the product was extracted three times, each time with 200 ml of dichloromethane. The combined organic extracts were washed with 200 ml of 20% sodium hydrogen sulfite solution and 200 ml of water and dried over sodium sulfate. After removing the solvent on a rotary evaporator and flash chromatography (pentane/ether, 4:1, Rf=0.32) on silica gel, 3.3 g (50%) of 1-methyl-2,3-dihydro-1H-5,9-dioxacyclohepta[f]inden-7-one (2) were obtained as colorless crystals of m.p. 79-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:18]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([Cl:18])[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccco1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccco1

Procedure:
Following the procedure described in Example 42(b), 14 g of 2-t-butoxycarbonylamino-1-(2-furyl)ethanol [prepared as described in step (a) above] was treated with phosphorus pentachloride to afford 15 g of the title compound as crystals, melting at 75°-77° C. This substance was used for the next step without purification because it was decomposed by silica gel column chromatography.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:32][CH:31]=1>C1COCC1>[O:28]=[C:4]1[C:3](=[CH:2][NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:34][CH:35]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:13])[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])[CH:15]=3)=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NC(=O)c4cccs4)c3)ccc2C1=CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4cccc(NC(=O)c5cccs5)c4)ccc32)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 45, 80 mg, 0.2049 mmol) and THF (2 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (41 mg, 0.2482 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The room temperature reaction mixture was concentrated in vacuo. The solid residue was recrystallized from EtOAc (5 mL) and Hexanes (2 mL) yielding the title compound in 74% yield (0.082 g, 0.1525 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[O:9]1[CH:11]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:9][CH:11]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH2:10][N:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[N:6][C:5]1=[O:8]
Reactant: O=c1ncc(Br)c[nH]1
Reactant: ClC(Cl)(Cl)C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ncc(Br)cn1CC(O)C(Cl)(Cl)Cl
Temperature: 80 °C
Yield: 52 %

Procedure:
A stirred mixture of 5-bromopyrimid-2-one (0.009 mol), 1,2-epoxy-3,3,3-trichloropropane (0.009 mol) and K2CO3 (33 mg) in dimethylformamide (40 ml ) was heated at 80° C. for 4 h. The reaction mixture was then evaporated to dryness at reduced pressure (1 mm Hg). The crystalline residue was triturated with a little ether and dissolved in ethyl acetate. The filtered ethyl acetate solution was concentrated to about 50 ml and left in the cold when the product crystallized out in 52% yield. m.p. 210°-212° C. (ethyl acetate).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[C:25]1([CH2:31][C:32]#[CH:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:33]#[C:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Reactant: C#CCc1ccccc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-1-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. Further 3-phenyl-1-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100° C. for further 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+1); Rt: 2.43 min.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24](=[O:40])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][Si](C)(C)C)=[C:28]([N+:37]([O-:39])=[O:38])[CH:27]=1)([CH3:22])([CH3:21])[CH3:20].[I:41][C:42]1[C:47]([CH:48]=[O:49])=[C:46]([O:50][CH3:51])[N:45]=[CH:44][CH:43]=1>C1COCC1>[C:19]([O:23][C:24](=[O:40])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:48]([OH:49])[C:47]2[C:46]([O:50][CH3:51])=[N:45][CH:44]=[CH:43][C:42]=2[I:41])=[C:28]([N+:37]([O-:39])=[O:38])[CH:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Reactant: COc1nccc(I)c1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1nccc(I)c1C(O)Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The resultant (3-nitro-phenyl)-carbamic acid tert-butyl ester 2 can then be placed into solution with THF and reacted with ((trimethylsilyl)methyl)magnesiumchloride. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF can then be added and allowed to react under conditions known to a skilled artisan to afford (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester 3. Tetra-butylammonium fluoride can then be added to a solution of ester 3 and 4-iodo-2-methoxynicotinaldehyde in THF to afford {4-[2-hydroxy-2-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester 4. A solution of compound 4, in turn, can be added to 2,2,2-trifluoroacetic anhydride and allowed to react to afford trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester 5.
Reaction SMILES: [Li+].[OH-].[F:3][CH:4]([F:34])[O:5][CH2:6][C@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11].Cl.C([O-])(O)=O.[Na+]>O.C1COCC1>[F:34][CH:4]([F:3])[O:5][CH2:6][C@H:7]([N:13]1[CH2:18][CH2:17][C@@H:16]([CH2:19][C:20]([OH:22])=[O:21])[CH2:15][C@H:14]1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)C[C@@H]1CCN([C@H](CCC(C)C)COC(F)F)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC[C@H](COC(F)F)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.9 %

Procedure:
A solution of LiOH (5 mg, 0.209 mmol) in H2O (0.5 ml) was added to a stirred solution of the ester (Step 1, 13 mg, 0.028 mmol) in THF (1 ml) at RT. The mixture was stirred at RT for 3 days. 2N HCl (0.5 ml) was added. The pH of the aqueous layer was adjusted to ˜7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated to give the title compound (12 mg) as a colourless solid after evaporation from pentane. M/Z 452 (MH+).
Reaction SMILES: C[Si](C)(C)[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.C(OC(C)C)(=O)C.O>CO>[NH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:3]1
Reactant: C[Si](C)(C)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CO
Product: c1ccc2[nH]ccc2c1
Reaction time: 2 h

Procedure:
A mixture of the 2-trimethylsilyl indole product of Example 1 (0.50 g, 2.6 mmol) in 5 mL methanol was treated with 2.5N HCl (2.11 mL, 5.2 mmol) and the reaction mixture was aged at room temperature for 2 h. Isopropyl acetate (50 mL) and water (10 mL). were then added. The layers were separated and the organic layer was concentrated under vacuum. The residual oil was chromatographed over silica gel to afford the indole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][C:24]3[N:25]=[N:26][NH:27][CH:28]=3)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1>CCO.[Pt]>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:29])[CH2:21][CH2:22][CH2:23][C:24]3[N:25]=[N:26][NH:27][CH:28]=3)[CH2:17][CH2:18]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)/C=C/c2cc(Cl)cc(Cl)c2)CC1
Agent: [Pt]
Solvent: CCO
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)CCc2cc(Cl)cc(Cl)c2)CC1

Procedure:
A solution of (E)-N-(1-(3-(3,5-dichlorophenyl)acryloyl)piperidin-4-yl)-4-(1H-1,2,3-triazol-4-yl)butanamide (Example 38) (70 mg, 0.160 mmol) in EtOH (6 ml) was allowed to pass through the H cube fitted with a 10% Pt/C catalytic cartridge for 3 hours. The reaction mixture was concentrated under reduced pressure to afford the title product;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=O)[C:2]1=2.S(Cl)(Cl)=O.[NH3:17].C([O-])(O)=O.[Na+]>ClCCl.O.CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([NH2:17])=[O:12])[C:2]1=2
Reactant: N
Reactant: O=C(O)c1cccc2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2ccsc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzo[b]thiophene-7-carboxylic acid (505 mg, 2.84 mmol) in dichloromethane (10 mL) is stirred at rt and thionyl chloride (669 mg, 5.68 mmol, 2.0 equiv.) is added, followed by DMF (0.06 mL), causing gas evolution. The resulting solution is stirred at rt for 1 hour. Aqueous ammonia (10 mL) is then added cautiously to the mixture causing vigorous gas evolution. The resulting mixture is then diluted with water (50 mL), and pH is brought to neutral by adding saturated NaHCO3 (aq.). The aqueous layer is extracted with DCM, and the organic layers are combined and dried over Na2SO4. Evaporation of the solvent under reduced pressure affords the title compound (81% pure) as a yellow solid (500 mg, 98%) which is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][C:8]([O:9]CC2C=CC=CC=2)=[CH:7][CH:6]=1.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([OH:9])=[CH:17][CH:18]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(OCc4ccccc4)cc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccc(O)cc3)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.6 %

Procedure:
To 0.72 g of ([4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene, were added 2 ml of ethyl acetate, 0.7 ml of ethanol and 36 mg of 10% palladium/carbon, and the mixture was stirred for 5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, the filtrate was concentrated to obtain 0.48 g of 4-{2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:3]1=[O:23].Br[CH:25]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27].C(OCC)(=O)C>C(Cl)Cl>[CH2:29]([O:28][C:26]([CH:25]([NH:1][CH:2]1[CH2:8][S:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][N:4]([CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:3]1=[O:23])[CH2:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:27])[CH2:30][CH2:31][CH3:32]
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccccc2)SCC(N)C1=O
Reactant: CCCCOC(=O)C(Br)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O

Procedure:
0.34 g of t-butyl α-(6-amino-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl)acetate [prepared as described in Example 7(g) above] was N-alkylated with 0.45 g of butyl 2-bromo-4-phenylbutyrate in the manner described in Example 1(h). The resulting product was subjected to silica gel column chromatography using a 1:40 by volume mixture of ethyl acetate and methylene chloride as the eluent. As a result, the title compound was separated into isomers A and B (resulting from the asymmetric carbon atom to which the phenethyl group is attached).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 461 [M+1]+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=O.O.[NH2:25][NH2:26]>C(O)C>[N:25](=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:23])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[NH2:26]
Reactant: CN(c1ccccc1C=O)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(c1ccccc1C=NN)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of N-(2-formylphenyl)-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.40 g, 1.2 mmol) in ethanol (13 mL) is treated with hydrazine monohydrate (69 □L, 1.6 mmol). The reaction is stirred at rt overnight. The reaction is concentrated, taken up in ether-hexane, filtered and evaporated. An 87% yield (0.37 g) of N{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11].[CH3:14][N:15](C)C=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]#[N:15])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)Nc1ccc(I)cc1Cl
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)Nc1ccc(C#N)cc1Cl
Temperature: 90 °C
Yield: 88 %

Procedure:
A mixture of N-(2-chloro-4-iodophenyl)methanesulfonamide (4.4 g, 13.3 mmol, Industrie Chimique Belge 1974, 39, 490–500), zinc(II)cyanide (1.95 g, 16.6 mmol) and palladium(0) tetrakis(triphenyl phosphine) (1.53 g, 1.33 mmol) in N,N-dimethyl formamide (DMF) (30 ml) was heated at 90° C. for 1.5 hours. Then, the mixture was diluted with ethyl acetate and toluene (8:1) solution (250 ml) and washed with water, brine, dried over sodium sulfate. Then, filtration, evaporation to remove solvent gave the crude residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of methylene dichloride/hexane(2/1 to 4/2) to furnish 2.69 g (88% yield) of title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[CH2:10][OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)Cc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid [Aldrich] (3.00 g, 9.96 mmol) in tetrahydrofuran (30 mL) at 0° C. was added 1.0 M borane-THF complex in tetrahydrofuran (32 mL, 32 mmol). The reaction mixture was stirred at room temperature for 3 hrs, and then cooled with an ice bath, quenched with AcOH:MeOH (1:5, 10 mL), and partitioned between saturated aqueous NaHCO3 solution and dichloromethane (DCM). The aqueous phase was then extracted several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated under reduced pressure. The residue was used directly for the next reaction. LCMS (ES) m/e 288.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][NH:62]3)[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]>CN(C=O)C>[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][N:62]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(F)c(F)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 4.2 mmol), HATU (1.60 g, 4.2 mmol) and N,N-diisopropylethylamine (2.00 ml, 11.6 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-4,5-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole, D21 (1.06 g, 4.2 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue was washed with water then was triturated with ethyl acetate to afford the title compound as an off-white solid (1.68 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(c1ccc(Br)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A cooled (0° C.) solution of 4-bromobenzoyl chloride (250 mg; 1.14 mmol) in THF (5 ml) was treated with a 2 M solution of morpholine in THF (219 μl; 2.51 mmol). The reaction mixture was allowed to warm to RT and stirred for 2 days, diluted with EtOAc and washed with a saturated NH4Cl solution in water. The organic phase was dried over MgSO4, filtered and concentrated to dryness affording the title compound as a pink solid (307 mg, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.I[C:45]1[CH:50]=[N:49][CH:48]=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[N:14]=[CH:13][N:12]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:30]=[CH:31][C:32]([C:45]3[CH:50]=[N:49][CH:48]=[CH:47][N:46]=3)=[CH:33][CH:34]=2)=[CH:4][CH:3]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(ncn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5cnccn5)cc4)nc32)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of N-(3-{1-(4-chloro-phenyl)-6-oxo-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,6-dihydro-purin-9-yl}-phenyl)-methane sulfonamide (prepared as described in example 26, 0.5 g, 0.809 mmol) in N,N-dimethylformamide (20 mL) is degassed with argon for 0.5 h. Then 2-iodopyrazine (0.25 g, 1.21 mmol), cesium carbonate (0.527 g, 1.61 mmol), Pd(dppf)2Cl2 (0.059 g, 0.08 mmol) is added and the resulted mixture is degassed with argon for 0.5 h. The reaction mixture is stirred at rt for 18 h. The reaction mixture is poured into water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to afford N-{3-[1-(4-chloro-phenyl)-6-oxo-2-(4-pyrazin-2-yl-phenyl)-1,6-dihydro-purin-9-yl]-phenyl}-methane sulfonamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.25 (s, 1H), 8.69 (m, 1H), 8.62 (m, 2H), 8.03 (m, 2H), 7.74 (s, 1H), 7.46-7.56 (m, 9H), 7.25 (m, 1H), 3.05 (s, 3H); LC-MS calculated for C28H20ClN7O3S (M+H+) 570.1, found 569.9.