Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>ClC(Cl)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:25]3[CH2:26][CH2:27][N:22]([C:28]4[N:29]=[CH:30][CH:31]=[CH:32][N:33]=4)[CH2:23][CH2:24]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CC(Cl)Cl
Product: O[C@@H](COc1cccc(-c2noc3cc(F)ccc23)c1)CN1CCN(c2ncccn2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane and and 2-piperazin-1-yl-pyrimidine, essentially as described above in Example 57. Purity by LC/MS=100%, [M+H]+=450.
Reaction SMILES: [C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[K+].[O-:17][Mn](=O)(=O)=O.[K+]>O1CCOCC1.O>[C:1]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]([OH:17])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)C(=O)c1cccc(CO)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
3-Pivaloylbenzyl alcohol (0.80 g, 4.16 mmol) was dissolved in dioxane (20 ml). A solution of KOH (0.35 g, 6.30 mmol) in water (5 ml) was added followed by KMnO4 (1.45 g, 9.17 mmol). The mixture was stirred at room temperature over the weekend. The solution was filtered through Celite and extracted with ether. The aqueous phase was acidified with dil. HCl and extracted with ether (3×50 ml). The organic layer was dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a white solid (0.80 g).
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([CH2:14][CH3:15])[CH2:9][C:10]([F:13])([F:12])[F:11])[C:5](O)=[O:6])=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C@@H:4]([C@@H:8]([CH2:14][CH3:15])[CH2:9][C:10]([F:11])([F:12])[F:13])[CH2:5][OH:6]
Reactant: CC[C@@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](CC(F)(F)F)[C@H](N)CO
Temperature: 40 °C
Reaction time: 2 h

Procedure:
(2S,3S)-2-Azido-3-ethyl-5,5,5-trifluoro-pentanoic acid was dissolved in THF (5 mL) at 0° C. and lithium aluminum hydride (1 M solution in THF) (1 mL, 1 mmol) was added. The resulting solution was stirred at 40° C. for 2 h. The reaction was quenched by sequential addition of water (60 μL), 15% aqueous sodium hydroxide (60 μL), and water (150 μL) with vigorous stirring between each addition. The mixture was then filtered and concentrated to give (2S,3S)-2-amino-3-ethyl-5,5,5-trifluoro-pentan-1-ol.
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1)[C:3]1[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=1[CH3:12].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:19][C:17]1[CH:16]=[CH:15][N:14]=[C:13]([CH2:2][C:3]2[S:7][C:6]([NH:8][C:9]([NH2:11])=[NH:10])=[N:5][C:4]=2[CH3:12])[CH:18]=1
Reactant: Cc1ccnc(C(O)c2sc(NC(=N)N)nc2C)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccnc(Cc2sc(NC(=N)N)nc2C)c1
Yield: 44.1 %

Procedure:
A solution of N-(5-(hydroxy-(4-methylpyridin-2-yl)methyl)-4-methylthiazol-2-yl)guanidine (65 mg) and triethylsilane (300 mg) in trifluoroacetic acid (3 ml) was stirred for 48 hours and then evaporated under reduced pressure. Water was added, and the pH was adjusted to 12 with 4N aqueous sodium hydroxide. The resultant mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and-evaporated under reduced pressure. The residue was crystallized from dichloromethane to give N-(5-(4-methylpyridin-2-ylmethyl)-4-methylthiazol-2-yl)-guanidine (27 mg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[S:37][CH3:38]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[S:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CSc1cc(C(C)=O)ccc1OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.88 g, 8.5 mmol), K2CO3 (1.8 g) and 1-[4-(3-bromopropoxy)-3-methylmercaptophenyl]ethanone (2.3 g, 7.6 mmol) in acetonitrile (100 ml) was heated at reflux for 4 hours. At the end of the reaction, the solvent was concentrated, then diluted with dichloromethane (250 ml). The insolubles were filtered off. The dichloromethane solution was concentrated to dryness as an oil. Purification was effected by flash chromatography on a silica gel column (SiO2, 54 g, eluted with dichloromethane, 500 ml; 1% methanol-dichloromethane, 1.1 l). The purest fractions were combined to give a colorless oil which solidified to an off-white solid (2.4 g). Recrystallization from ethanol (100 ml) yielded 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazol-3-yl]-1-piperidinyl]propoxy]-3-methylmercaptophenyl]ethanone as off-white needle crystals, 2.15 g, m.p.=150-152° C.
Reaction SMILES: C(OC(=O)NCC#C)(C)(C)C.C(O[C:17](=O)[N:18]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:24]=[C:23]([CH:34]([CH3:36])[CH3:35])[N:22]=1)C)(C)(C)C>>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]2[N:24]=[C:23]([CH:34]([CH3:36])[CH3:35])[N:22]=[C:21]([CH2:20][NH:18][CH3:17])[CH:26]=2)=[CH:32][CH:31]=1
Reactant: CC(C)c1nc(CN(C)C(=O)OC(C)(C)C)cc(-c2ccc(F)cc2)n1
Agent: C#CCNC(=O)OC(C)(C)C
Product: CNCc1cc(-c2ccc(F)cc2)nc(C(C)C)n1

Procedure:
Prop-2-ynyl-carbamic acid tert-butyl ester was converted to [6-(4-fluoro-phenyl)-2-isopropyl-pyrimidin-4-ylmethyl]-methyl-carbamic acid tert-butyl ester using methods described in Example 112, Step A. This ester was deprotected according to the methods described in Example 1, Step D, to provide the title compound. MS (ESI): exact mass calcd. for C15H18FN3, 259.15; m/z found, 260.3 [M+H]+. 1H NMR (DMSO-d6): 9.45 (s, 2H); 8.31-8.28 (m, 2H), 8.10 (s, 1H), 7.45-7.41 (m, 2H), 4.35 (t, J=6.0, 2H), 3.26-3.18 (m, 1H), 2.69 (t, J=5.4, 3H), 1.37 (d, J=6.9, 6H).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([CH:7]=[C:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCC(=Cc2ccccc2)CC1

Procedure:
In an alternate method, when n is the bridging group --CH2 --, the 8-phenylmethylene-1,4-dioxaspiro[4.5]decane is treated with acetic acid and water as previously described, yielding the corresponding 4-phenylmethylenecyclohexanone. The cyclohexanone is then reduced with hydrogen gas in the presence of 10% palladium on charcoal (Degussa type), yielding the corresponding 4-phenylmethylcyclohexanol, which is in turn treated with sodium dichromate and sulfudc acid in water, affording the 4-phenylmethylcyclohexanone. The 4-phenylmethylcyclohexanone is then reacted with cyanoguanidine, as previously described, yielding the targeted 2,4-diamino-6-phenylmethyl-5,6,7,8-tetrahydroquinazoline. Example 3 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[C:14]=2[Cl:21])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.[OH-].[K+:23].O>CC(C)=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([CH3:20])[C:14]=2[Cl:21])=[C:6]([CH2:8][C:9]([O-:11])=[O:10])[CH:7]=1.[K+:23]
Reactant: Cc1ccc(Nc2ccc(Cl)c(C)c2Cl)c(CC(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(Nc2ccc(Cl)c(C)c2Cl)c(CC(=O)[O-])c1
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
A suspension of 5-Methyl-2-(2′,4′-dichloro-3′-methylanilino)phenylacetic acid (15.42 mmoles) in acetone is heated to reflux temperature and allow to stir for 10 min at ca. 55° C. The resulting solution is slightly cooled to 50° C. and filtered hot over Whatman glasfiber filter. The filter is washed with acetone at 50° C. The filtrate is heated to 50° C. and a mixture of potassium hydroxide 45% (14.65 mmoles) (0.95 eq.) and water is dropwise added over ca. 15 min. The dropping funnel is rinsed with water and acetone. The resulting suspension is stirred at 50° C. for 30 min. The slurry is then allowed to cool to 25° C. over ca. 2 hours. The suspension is stirred over night at room temperature and filtered. The filter cake is washed in three portions. The crystals are dried first for 3 h at 50° C./10 mbar and then further for 17 h at 80° C./10 mbar to yield a white powder, m.p. 315-317° C., 326.9° C., melting enthalpy 29 J/g.
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:35])[NH:11][C:12]2[C:13]([CH3:34])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4([C:32]#[N:33])[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCO.Cl.[N-:43]=[N+:44]=[N-:45].[Na+]>COCCOCCOC.C(Cl)Cl.O>[C:1]1([C@H:7]([O:9][C:10](=[O:35])[NH:11][C:12]2[C:13]([CH3:34])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]4([C:32]5[NH:45][N:44]=[N:43][N:33]=5)[CH2:30][CH2:31]4)=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C#N)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Agent: CN(C)CCO
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOCCOC
Solvent: O
Product: Cc1noc(-c2ccc(-c3ccc(C4(c5nnn[nH]5)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{5-[4′-(1-Cyano-cyclopropyl)-biphenyl-4-yl]-3-methyl-isoxazol-4-yl}-carbamic acid (R)-1-phenyl-ethyl ester (0.385 g, 0.83 mmol) and N,N-dimethylethanolamine (0.101 mL, 1.0 mmol) were combined in diglyme (diethylene glycol dimethyl ether; 2 mL). Hydrochloric acid (4M in 1,4-dioxane; 4.2 mL) was added, and the reaction was stirred for 15 minutes. Additional N,N-dimethylethanolamine (0.221 mL, 2.2 mmol) was added, followed by sodium azide (0.098 g, 1.5 mmol), and the reaction was stirred at 120° C. for 24 hours. After cooling to room temperature, the mixture was diluted with CH2Cl2 (20 mL) and H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([OH:25])=[C:5]([C:21]([O:23]C)=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[C:10]([OH:19])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)[CH3:2].[Li+].[I-].Cl>CCOC(C)=O>[CH2:1]([C:3]1[C:4]([OH:25])=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[C:10]([OH:19])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[CH:12]2)[CH3:2]
Reactant: CCc1c(-c2ccc3c(ccn3C)c2O)[nH]c(=O)c(C(=O)OC)c1O
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCc1c(-c2ccc3c(ccn3C)c2O)[nH]c(=O)c(C(=O)O)c1O
Temperature: 60 °C
Yield: 45.7 %

Procedure:
To a solution of methyl 5-ethyl-4-hydroxy-6-(4-hydroxy-1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.045 g, 0.12 mmol) in EtOAc (1.0 mL) was added LiI (0.050 g, 0.37 mmol). The reaction mixture was stirred and heated at 60° C. for 1 h until complete consumption of starting material was observed. The mixture was then cooled to room temperature and acidified with aqueous HCl (1M, 1.0 mL) to pH˜2. The product was extracted with EtOAc (3×5 mL). The organic phase was dried over Na2SO4. Upon removal of the solvent the residue was triturated with Et2O. The solid was collected by filtration affording product (0.018 g, 42%) as a solid.
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(CCSC)OC(C)=O
Reactant: CSCC=COC(C)=O
Agent: [C]=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 100 °C
Yield: 24.6 %

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene, (Z: E ratio 43:57), and 2.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. A catalyst comprising [Pd(CH3CN)4 ]+2 [BF4 ]2- plus Pφ3 was added. Toluene LPd(CH3CN)4][BF4]2 was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 100° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced in a yield of 8.5 percent, and that 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced in a yield of 24.6 percent, based on the 1-acetoxy-3-methylthiopropene reactant charged. Note that each of the products is hydrolyzable to methionine hydroxy analog.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[CH3:31][N:32]1[C:37](=[O:38])[CH:36]=[C:35]2[S:39][CH:40]=[C:41](B3OC(C)(C)C(C)(C)O3)[C:34]2=[CH:33]1>>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:13][CH2:14][C@H:9]([OH:8])[CH2:10][CH2:11]3)[CH:19]=2)=[C:21]2[CH:29]=[C:28]([C:41]3[C:34]4=[CH:33][N:32]([CH3:31])[C:37](=[O:38])[CH:36]=[C:35]4[S:39][CH:40]=3)[O:27][C:22]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: Cn1cc2c(B3OC(C)(C)C(C)(C)O3)csc2cc1=O
Product: Cn1cc2c(-c3cc4c(-c5cnn([C@H]6CC[C@H](O)CC6)c5)cnc(N)c4o3)csc2cc1=O

Procedure:
The title compound was prepared in 60% yield from 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-c]pyridin-6(5H)-one by a procedure analogous to Example 229. 1H NMR (400 MHz, CD3OD): δ 8.98 (s, 1 H), 8.11 (s, 1 H), 7.99-8.03 (m, 1 H), 7.87-7.95 (m, 2 H), 7.43-7.52 (m, 1 H), 6.96-7.10 (m, 1 H), 4.16-4.37 (m, 1 H), 3.88 (s, 3 H), 3.61-3.78 (m, 1 H), 1.85-2.31 (m, 6 H), 1.39-1.69 (m, 2 H); MS (ESI): 462.28 [M+H]+; HPLC tR=2.30 min (ZQ3, polar—4 min).
Reaction SMILES: B.[C:2]1([S:8]([N:11]2[CH2:16][CH:15]([C:17]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[N:14]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:13](=O)[CH2:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP([O-])(O)=O.[K+].C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[C:2]1([S:8]([N:11]2[CH2:12][CH2:13][N:14]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:15]([C:17]3[CH:18]=[C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:16]2)(=[O:9])=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)CC(=O)N3c3ccccc3)c2)c1
Agent: B
Agent: O=C([O-])O
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)CCN3c3ccccc3)c2)c1
Temperature: 85 °C
Yield: 28.7 %

Procedure:
A solution of borane in THF (1M, 274.4 μL) was added to a solution of 4-benzenesulfonyl-6-(3′-methanesulfonyl-biphenyl-3-yl)-1-phenyl-piperazin-2-one (50 mg) in THF (1.5 mL). The reaction mixture was heated to 85° C. for 3 hours. An aqueous solution of KH2PO4 (1M, 2 mL) was added slowly and the biphasic mixture was heated to 75° C. for 15 min, and then poured into a saturated solution of sodium bicarbonate. Ethyl acetate was added, the phases were separated, and the inorganic one was extracted with ethyl acetate (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. Column chromatography (SiO2, n-heptane/ethyl acetate 1:1) yielded 4-benzenesulfonyl-2-(3′-methanesulfonyl-biphenyl-3-yl)-1-phenyl-piperazine (14 mg, 29%) as a white foam, MS: 533.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[F:20][C:21]([F:35])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31].Cl>O1CCOCC1.O>[F:35][C:21]([F:20])([F:34])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH:33][C:11]([NH:10][C:5]1[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([CH3:9])[N:6]=1)=[O:13])(=[O:32])=[O:31]
Reactant: NS(=O)(=O)c1ccccc1C=CC(F)(F)F
Reactant: COc1nc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C=CC(F)(F)F)n1
Reaction time: 3 h

Procedure:
5.2 g of N-(4-methoxy-6-methyl-1,3,5-triazin-2-yl)-phenylcarbamate are added to a solution of 5 g of 2-(3,3,3-trifluoro-1-propen-1-yl)-phenylsulfonamide and 3.3 g of 1,5-diazabicyclo[5,4,0]undec-5-one in 80 ml of dioxan, and the mixture is stirred for 3 hours at 20°-25° C. The clear reaction solution is then taken up in 300 ml of water and the aqueous solution is acidified with 2N hydrochloric acid to pH 4-5. The resinous precipitate is extracted from the aqueous phase with ethyl acetate and the organic extract is dried and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:13]2[N:14]([CH3:24])[C:15](=[O:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:25][C:26]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:13]2[N:14]([CH3:24])[C:15](=[O:23])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][CH2:11][N:29]2[CH2:30][CH2:31][C:26]([OH:25])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:27][CH2:28]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1c(C(CC=O)c2ccc(Cl)c(Cl)c2)cc2ccccc2c1=O
Reactant: OC1(c2ccccc2)CCNCC1
Product: Cn1c(C(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)cc2ccccc2c1=O

Procedure:
3-[1-(3,4-Dichlorophenyl)-3-oxopropyl]-2-methyl-2H-isoquinolin-1-one (0.303 g) was coupled to 4-hydroxy-4-phenyl-piperidine (0.15 g) by method similar to that described in Example 1. After aqueous work up, the product was purified by column chromatography. Eluting with ethyl acetate, followed by dichloromethane:methanol, (9:1) afforded the title compound as a solid; mp 100°-102° C.; MS: m/z=521(M+1); NMR: 1.55 (t,2, J=12), 1.89 (m,2), 2.10 (m,1), 2.28 (m,5), 3.35 (s,3), 4.46 (broad,1), 6.90 (s,1), 7.17-7.71 (m,11), 8.18 (d,1, J=8). Analysis for C30H30Cl2N2O2.0.5 H2O Calculated: C, 67.92; H, 5.89; N, 5.28; Found: C, 68.22; H, 5.86; N, 5.16.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:44])[CH2:10][C:11]1[CH:43]=[CH:42][CH:41]=[CH:40][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]3)=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH:31]1[CH2:32][CH:29]([C:26]2[CH:25]=[CH:24][C:23]([NH:22][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:40]=[CH:41][CH:42]=[CH:43][C:11]=4[CH2:10][C:9]([NH2:8])=[O:44])[C:20]([CH3:21])=[CH:19][N:18]=3)=[CH:28][CH:27]=2)[CH2:30]1
Reactant: Cc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C3CNC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 11.1 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 3-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A123) (0.087 g, 0.17 mmol) in DCM (3 mL) and the resulting mixture stirred at room temperature for 3 hours. The volatiles were removed in vacuo then 2 M aqueous K2CO3 solution (5 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried. The resulting residue was purified by semi preparative HPLC to give the title compound 32 as a light tan solid (7.6 mg, 10%); 1H NMR (300 MHz, d4-MeOH) δ 8.12 (s, 1H), 7.74 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.18-7.28 (m, 4H), 4.31-4.39 (m, 2H), 4.19-4.27 (m, 3H), 3.66 (s, 2H), 3.13-3.18 (m, 2H), 2.96-3.01 (m, 2H), 2.12 (s, 3H). LCMS-B: rt 4.725 min; m/z 402 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12](O)=[O:13])=[O:4].C(Cl)(=O)C(Cl)=O.[NH3:26]>C1COCC1>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][C:7]1[C:8]([F:17])=[CH:9][C:10]([Cl:16])=[C:11]([CH:15]=1)[C:12]([NH2:26])=[O:13])=[O:4]
Reactant: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 5-((2,2,2-trifluoroacetamido)methyl)-2-chloro-4-fluorobenzoic acid (1.0 g), oxalyl chloride (1.0 mL), THF (50 mL) and ammonia gas to afford 0.800 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.53 (m, 2H), 7.43 (m, 1H) 7.44 (m, 2H), 7.48 (m, 1H), 10.0 (br s, 1H)); MS (m/z): 297.10 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:30](=[O:31])[N:12]3[CH:13]=[CH:14][C:15]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)=[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:11]3=[N:10]2)=[N:6][CH:7]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C(=O)([O-])[O-].[K+].[K+].CN(C)CCN>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[N:32]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[C:30](=[O:31])[N:12]4[CH:13]=[CH:14][C:15]([C:23]5[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=5)=[C:16]([C:17]5[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=5)[C:11]4=[N:10]3)=[N:6][CH:7]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: c1cn[nH]c1
Reactant: O=c1n(Cc2ccc(Br)cn2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1n(Cc2ccc(-n3cccn3)cn2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Temperature: 110 °C
Yield: 4.5 %

Procedure:
A mixture of 2-((5-bromopyridin-2-yl)methyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (29.6 mg, 0.06 mmol), pyrazole (22.5 mg, 0.33 mmol), copper (I) iodide (8 mg, 0.042 mmol), potassium carbonate (25 mg, 0.18 mmol) and N,N-dimethylethylenediamine (5.3 mg, 0.06 mmol) in 1 mL toluene was heated at 110° C. under argon for 20 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (Na2SO4) and concentrated. The crude product was purified by preparative reverse phase HPLC (with TFA) to isolate 1.3 mg of the title compound as a yellow solid. HPLC/MS: retention time=2.44 min, [M+H]+=480.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH2:11]([C:15]1[C:19]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=2[S:17][C:16]=1C(O)=O)[CH2:12][CH2:13][CH3:14].C(=O)=O>>[CH2:11]([C:15]1[C:19]2[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=2[S:17][CH:16]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1c(C(=O)O)sc2ccc([N+](=O)[O-])cc12
Agent: O=C=O
Solvent: c1ccc2ncccc2c1
Product: CCCCc1csc2ccc([N+](=O)[O-])cc12
Temperature: 180 °C

Procedure:
5.6 g of Cu are heated to 210° C. under N2 for 20 minutes and, after cooling, 110 g of quinoline and 27.9 g of 3-butyl-5-nitro-2-benzothiophenecarboxylic acid are added. The mixture is heated to 180° C., whilst stirring, until the evolution of CO2 has ended. After cooling, the reaction mass is decanted off with CH2Cl2, the quinoline is washed out by shaking with 20% strength HCl and the organic phase is washed, dried and purified on Al2O3. Melting point: 82°-83° C.