Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])[CH2:27][CH2:26]1>CC(O)C.Cl>[CH3:1][NH:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:36][C:35]4[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=4[O:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)=O)sc3c2)ccn1
Reactant: CN1CCN(CCOc2ccccc2N)CC1
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccccc4OCCN4CCN(C)CC4)sc3c2)ccn1
Temperature: 80 °C

Procedure:
To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (25 mg, 0.072 mmol, 1.0 eq) in 1 mL of IPA and 1 mL conc. HCl was added 2-(2-(4-methylpiperazin-1-yl)ethoxy) aniline (25 mg, 0.108 mmol, 1.5 eq) and reaction mixture heated at 80° C. in oil bath for 2 hours. Thereafter, the product was purified via reverse phase HPLC. This procedure was generalized for other analogues for which progress of the reaction was monitored by LC-MS and amount of aniline and reaction time adjusted as needed. LC/MS (m/z) [519.1] (MH+)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[N:11]=1>[H-].[Na+].CN(C)C=O>[CH2:1]([O:8][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(Cl)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(OCc2ccccc2)n1
Yield: 60.4 %

Procedure:
Following the procedure of Example 4a) above, benzyl alcohol (5 g; 46 mmols) reacted with sodium hydride (1.19 g), was refluxed for 1 hour with 2,6-dichloropyridine (6.9 g; 46 mmols) using sodium hydride and dry dimethylformamide as solvent. 2-Benzyloxy-6-chloropyridine (6.1 g; 60%) was obtained as a colorless oil following solvent extraction with chloroform/water (500 ml; 50/50), purification and chromatographic separation of the product from the organic layer, identified by elemental analysis and mass spectrum.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18]Br.O>C(O)C>[O:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:14][CH2:15][C:16]#[C:17][CH2:18][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: BrCC#CCOC1CCCCO1
Solvent: O
Solvent: CCO
Product: C(#CCSc1ccccc1)COC1CCCCO1

Procedure:
A stirred solution of sodium ethoxide in ethanol, obtained from 1.3 g of sodium and 50 ml of absolute ethanol was treated dropwise with 5.5 g (0.05 mol) of thiophenol in 15 ml of absolute ethanol. The reaction mixture was refluxed for 1 hour and then treated with 5.84 g (0.025 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether, refluxing the mixture for 2 additional hours. It was then cooled, poured into water and extracted with methylene chloride. The organic extract was washed with water, dried and evaporated to dryness in vacuo. The residue was purified by silica gel column chromatography, to produce 4-phenylthiobut-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4](I)[CH:3]=1.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:21])=[C:16](B(O)O)[CH:17]=1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([C:14]2[CH:13]=[C:12]([F:11])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH:3]=1
Reactant: CNc1cnc(Cl)cc1I
Reactant: Cc1ccc(F)cc1B(O)O
Product: CNc1cnc(Cl)cc1-c1cc(F)ccc1C

Procedure:
The title compound was prepared in analogy to example 72, from 6-chloro-4-iodo-N-methylpyridin-3-amine (prepared according to WO2006013050) and 5-fluoro-2-methylphenylboronic acid after heating at reflux for 21 hours. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (85%). MS (ESI): m/z=251.08 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[N:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]([Br:16])[C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[N:8][C:7]([C:12]([F:15])([F:14])[F:13])=[C:6]([Br:16])[C:3]=1[CH2:4][OH:5]
Reactant: COc1nc(C(F)(F)F)c(Br)c(C=O)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1nc(C(F)(F)F)c(Br)c(CO)c1Br
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dibromo-2-methoxy-6-(trifluoromethyl)isonicotinaldehyde (980 mg, 2.7 mmol) in ethanol (10 mL) was added sodium borohydride (102 mg, 2.7 mmol). The reaction mixture was stirred for 20 min, concentrated, and the residue was purified by flash chromatography (silica gel; 50% ethyl acetate/hexanes as eluant) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 5.10 (s, 2H), 4.05 (s, 3H), 2.32 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([P:13]([OH:16])(=[O:15])[OH:14])[P:9]([OH:12])(=[O:11])[OH:10].[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>>[C:17]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([P:13]([OH:16])(=[O:14])[OH:15])[P:9]([OH:10])(=[O:12])[OH:11])(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: O=P(O)(O)C(CCCCCCO)P(=O)(O)O
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)OCCCCCCC(P(=O)(O)O)P(=O)(O)O

Procedure:
Following the General Synthetic Procedure B, methyl 6-chlorohexanoate is reacted with tetramethyl methanebisphosphonate to produce tetramethyl 5-methoxycarbonylpentyl-methanebisphosphonate that is then hydrolyzed to yield 5-carboxypentyl-methanebisphosphonic acid, and then hydrogenated to reduce the carboxy group to a hydroxymethylene group. The resulting 6-hydroxyhexyl-methanebisphosphonic acid is then methacrylated with methacryloyl chloride to afford 6-methacryloxyhexyl-methanebisphosphonic acid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N:17]=[CH:18]2>C(Cl)Cl.CO>[Cl:12][C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][N+:17]([O-:9])=[CH:18]2
Reactant: Clc1cccc2cnccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: [O-][n+]1ccc2c(Cl)cccc2c1
Yield: 79.5 %

Procedure:
According to Scheme 28 Step 1: A solution of MCPBA (1.9, 15.0 mmol, 3.6 g) and 5-chloroisoquinoline (1 eq, 7.80 mmol, 1.27 g) in CH2Cl2 (30 mL) was stirred for 2 hours at room temperature. The reaction mixture was diluted with CH2Cl2 (20 mL) and MeOH (10 mL) and the organic phase washed with 2M NaOH solution. The aqueous layer was extracted with CH2Cl2. The organic fractions were combined, dried over MgSO4, filtered and evaporated to yield the title compound (6.20 mmol, 1.12 g, 79%) as an orange solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][C:15](=[O:26])[CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)([CH3:13])([CH3:12])[CH3:11].Cl>C(N(CC)CC)C>[C:10]([O:14][C:15](=[O:26])[CH2:16][CH2:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCSc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCSc1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (3.3 ml) and benzoyl chloride (2.0 ml) were added to the compound prepared in Example 1 and the reaction solution was stirred for 30 minutes at room temperature. 1 N hydrochloric acid was added to the reaction solution. The reaction solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, water, a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The residue was washed with ether to give the title compound (5.17 g).
Reaction SMILES: [C:1]([C:3]([NH:6][S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])([CH3:5])[CH3:4])#[N:2].[CH3:12][SH:13].C(=O)([O-])[O-].[K+].[K+].CS.CO.Cl>CO>[C:1]([C:3]([NH:6][S:7]([CH2:10][CH2:11][S:13][CH3:12])(=[O:8])=[O:9])([CH3:5])[CH3:4])#[N:2]
Reactant: CS
Reactant: C=CS(=O)(=O)NC(C)(C)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CSCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8.2 g (0.0470 moles) N-(2-cyano-2-propyl)-vinylsulfonamide (the product of Example 26) in 30 ml methanol, 32 ml of a 1.5M solution of methanethiol was added over 5 minutes. A small amount (a few mg) of potassium carbonate was added to the mixture and it was stirred overnight at room temperature. The reaction mixture was warmed to about 30° C., more methanethiol/methanol solution (about 10 ml) was added, and the resulting mixture was stirred at 30° C. for four hours. The mixture was acidified with 10% hydrochloric acid and then evaporated to afford 10.0 g of a pale yellow oil. The oil was dissolved in methylene chloride, filtered and evaporated to dryness. The residue was purified by flash chromatography with 30% hexane in ethyl acetate to give 9.3 g of the above-identified product, as a colorless oil which crystallized upon standing.
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[Cl:5][C:6]1[C:11]2[CH2:12][NH:13][CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:11]2[CH2:12][N:13]([S:2]([CH3:1])=[O:3])[CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)Cl
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphinyl chloride (0.98 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (98:2) as eluent gave 6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethylacetate/hexane. Yield 2.1 g (m.p. 82°-84° C.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](=[O:10])(=[O:9])[NH2:8])=[C:4]([NH:11][C:12]([C:14]2[C:15](=[O:31])[N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:17]=[C:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[C:19]=2[OH:20])=O)[CH:3]=1.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]2[S:7](=[O:10])(=[O:9])[N:8]=[C:12]([C:14]3[C:15](=[O:31])[N:16]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:17]=[C:18]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[C:19]=3[OH:20])[NH:11][C:4]=2[CH:3]=1
Reactant: CC(C)CCn1nc(-c2cccs2)c(O)c(C(=O)Nc2cc(Cl)sc2S(N)(=O)=O)c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)CCn1nc(-c2cccs2)c(O)c(C2=NS(=O)(=O)c3sc(Cl)cc3N2)c1=O
Temperature: 140 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
To a solution of the amide intermediate (15a) (54 mg, 0.11 mmol) in anhydrous pyridine (1.5 mL) in a sealed tube, 1,8-Diazabicyclo[5,4,0] undec-7-ene (DBU) (20 μL) was added and then stirred at 140° C. (oil bath temperature) for 24 hrs. The reaction mixture was cooled to room temperature and solvent was removed in vacuo, and then the residue was further dried in high vacuum for 2 hrs. The crude material was purified by flash chromatography on silica gel using hexane and EtOAc to give the desired product (5m) (8.0 mg, 15%) as a yellow solid. LC-MS (ESI+): m/e=485.21 [M+1]+ (exact ms: 484.01); 1H NMR (400 MHz, DMSO-d6): δ 7.86 (dd, 1H, J=3.2, 1.2 Hz), 7.52 (dd, 1H, J=5.2, 0.8 Hz), 7.46 (s, 1H), 7.07 (dd, 1H, J=5.2, 3.2 Hz), 4.03 (m, 2H), 1.60 (m, 3H), 0.93 (d, 6H, J=6.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([NH:19][CH2:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(NCC(c2ccccc2)c2ccccc2)c2cccc(N)c2)cc1
Yield: 85.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of [(4-methoxyphenyl)-(3-nitrophenyl)methyl]-(2,2-diphenylethyl)amine (2.54 g) [prepared as described in step (a) above] in methanol (50 ml), nickel chloride hexahydrate (2.76 g) and sodium borohydride (878 mg) were reacted, to afford the title compound (2.02 g) as a clear colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].N1C=CC=CC=1.[Cl:36][C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:37]([Cl:36])=[O:39])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (19.9 mg, 0.05 mmol) and pyridine (20 μL, 0.15 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (22.7 mg, 0.08 mmol) in CH2Cl2 (0.5 mL). The resulting solution was warmed to rt, and stirred for 1 h. The completion of reaction was confirmed by LC-MS, and the product was used for next step without workup.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl>[C:25]([O:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[S:12][CH:13]=[C:14]([CH3:17])[C:15]=3[CH3:16])=[C:6]2[N:5]=[CH:4][N:3]=1)(=[O:27])[CH3:26]
Reactant: Cc1csc(-c2cnn3c(O)ncnc23)c1C
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ncnc2c(-c3scc(C)c3C)cnn12
Reaction time: 0.17 h

Procedure:
To a mixture of 4-hydroxy-8-(3-methyl-4-methylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazine (0.100 g), triethylamine (0.1 ml) and methylene chloride (10 ml) is added dropwise acetyl chloride (0.1 ml) at room temperature. After reacting for 10 minutes, to the reaction mixture is added methylene chloride (90 ml). The mixture is washed with water (20 ml×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (0.110 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:29]2([OH:36])[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:27]([CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:28]2=[O:37])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(Br)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
To a stirred solution of 3-bromophenol (11.9 g, 69.2 mmol) in dichloromethane (160.0 mL) at 0° C. was added isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 38.0 mL, 76.1 mmol). The solution was stirred at 0° C. for 30 min, then 1-benzhydrylindoline-2,3-dione (10.0 g, 34.6 mmol) was added. The reaction was stirred at ambient temperature for 16 h, then concentrated in vacuo to dryness. The residue obtained was dissolved in ethyl acetate (400.0 mL) and washed with saturated ammonium chloride solution (3×100.0 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. Purification by flash chromatography with 30% ethyl acetate in hexanes afforded 3-(4-bromo-2-hydroxyphenyl)-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (11.7 g, 70%) as a beige solid: 1H NMR (300 MHz, CDCl3) δ 9.09 (br s, 1H), 7.47-7.16 (m, 11H), 7.12-7.00 (m, 3H), 6.92-6.84 (m, 2H), 6.72-6.66 (m, 1H), 6.51-6.45 (m, 1H), 4.57 (br s, 1H); MS (ES+) m/z 484.2 (M+1), 486.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[S:18][CH:19]=[CH:20][C:11]2=3)=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:28](N(C)C)[N:29]([CH3:31])[CH3:30])(C)(C)C>>[CH3:28][N:29]([CH:31]=[C:14]1[CH2:15][CH2:16][N:10]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[C:13]1=[O:17])[CH3:30]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Product: CN(C)C=C1CCN(Cc2ccc([N+](=O)[O-])cc2)c2ccsc2C1=O
Reaction time: 48 h

Procedure:
A mixture of 3.2 g of 4,5,6,7-tetrahydro-4-(4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one and 32 ml of tert-butoxybis(dimethylamino)methane is heated on a steam bath for 3.5 hours. The reaction mixture is allowed to stand for 48 hours. The reaction mixture is evaporated in vacuo and the concentrate is dissolved in 150 ml of methylene chloride and filtered through hydrous magnesium silicate two times. The volatiles are evaporated in vacuo to a residue which is dissolved in 25 ml of ethyl acetate and filtered. The filtrate is cooled to give 3.2 g of the desired product as a light orange solid, m.p. 214°-216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:34]C)[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]4C=CC=CC=4)[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36].Br.C(O)(=[O:44])C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:34])[C:10](=[O:33])[N:11]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:22][CH2:23][O:24][C:25](=[O:44])[CH3:26])[C:16](=[O:32])[C:12]3=2)[C:7]1=[O:36]
Reactant: CC(=O)O
Reactant: COc1c2c(c3n(c1=O)CCCCN(CCOCc1ccccc1)C3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: Br
Solvent: C1COCCO1
Product: CC(=O)OCCN1CCCCn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 11-(3-chloro-4-fluorobenzyl)-9-methoxy-2-[2-(benzyl-oxy)ethyl]-3,4,5,6,12,13-hexahydro-2H[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (120 mg, 0.21 mmol) and 33% hydrogen bromide in acetic acid (1 mL) in dioxane (1 mL) was stirred at room temperature for 1 hour. The product mixture was concentrated under vacuum. The residue was subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound. 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J=6.7, 1.6 Hz, 1H), 7.18 (br signal, 1H), 7.12 (t, J=8.6 Hz, 1H), 4.79 (br signal), 4.76 (d, J=14.7 Hz, 1H), 4.54 (d, J=14.7 Hz, 1H), 4.46 (br signal), 4.18 (m, 2H), 3.48-3.25 (m), 3.00-2.93 (m), 2.61-2.57 (m), 2.03 (s, 3H), 2.09-1.75 (m). (ES MS M+1=506.2)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@@H:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[C:26]1([C@H:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]2[S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@@H]2c2ccccc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=S(=O)(c1ccc(O)cc1)N1c2ccccc2-c2ccccc2[C@@H]1c1ccccc1

Procedure:
The title compound was prepared from (S)-5-[(4-methoxyphenyl)sulfonyl]-6-phenyl-5,6-dihydrophenanthridine* (1.35 g, 3.16 mmol), cyclohexene (6.16 g, 75 mmol), and 1.0 M boron tribromide in dichloromethane (20 mL, 20 mmol) according to the procedure and in the same manner as described in Example 1, step b; and yielded, after chromatographic purification and crystallization from diethyl ether-hexane, 4-{[(S)-6-phenylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.627 g, 1.52 mmol, 48%) as a homogeneous, colorless, crystalline, single enantiomer*, m.p. 210-212° C.;
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:41]([NH:48][NH2:49])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:10]([NH:49][NH:48][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:12])[CH:7]([CH3:9])[CH3:8]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: NNCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)C
Yield: 65 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-valine (J. Med. Chem., 39, 3203-3216, 1996) (2.11 g, 12.0 mmol), EDAC (2.41 g, 12.6 mmol), HOBT (1.70 g, 12.6 mmol), NMM (1.38 mL, 12.6 mmol), benzylhydrazine×2HCl (2.45 g, 12.6 mmol) and Et3N (3.52 mL, 25.0 mmol), which gave the title compound (2.08 g, 65%) as a light yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:18]=2[N:19]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)(=O)C>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:22]=[CH:23][C:17]2[O:16][C:15]([C:14]3[CH:13]=[CH:12][N:11]=[CH:10][C:9]=3[OH:8])=[N:19][C:18]=2[CH:20]=1
Reactant: [H][H]
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3OCc3ccccc3)nc2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Oc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Yield: 96.9 %

Procedure:
A mixture of 4.69 g of 2-(3-benzyloxypyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.0 g of 5% palladium on carbon and 70 ml of acetic acid was stirred under about one atmosphere of hydrogen at room temperature for nine hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3.44 g of 4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-ol (hereinafter, referred to as “active compound 114”).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1)(=O)=O.[CH3:35][NH:36][CH3:37]>C1COCC1>[CH3:35][N:36]([CH3:37])[C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=2)[C:8]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:7]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[Cl:34])[N:6]=1
Reactant: CNC
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: CN(C)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
2-Methylsulfonyl-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (from Example 20) (100 mg, 0.19 mmol) was reacted with excess dimethylamine (0.14 mL, 0.28 mmol) in THF in a sealed tube at 60° C. overnight by general procedure described in Example 103 to afford the title compound: HPLC/MS: m/e=506 (M++1); Rt=4.99 min. 1H-NMR 400 MHz (CDCl3); δ 3.00-3.20 (s, 6H), 6.89-6.94 (m, 1H), 7.08-7.21 (m, 8H), 7.35 (d, J=2 Hz, 1H).