Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH:45]=O)[N:44]=[C:38]12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].P([O-])([O-])([O-])=O>ClCCl>[S:37]1[CH2:41][CH2:40][N:39]2[CH:42]=[C:43]([CH2:45][NH:1][C:2]3[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:23][C@@H:22]([C:24]5[CH:35]=[CH:34][C:27]6[O:28][C:29]([CH3:32])([CH3:33])[O:30][CH2:31][C:26]=6[CH:25]=5)[O:21][C:20]4=[O:36])[CH:5]=[CH:6][CH:7]=3)[N:44]=[C:38]12
Reactant: O=Cc1cn2c(n1)SCC2
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NCc5cn6c(n5)SCC6)c4)C(=O)O3)ccc2O1
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (200 mg) and 2,3-dihydroimidazo[2,1-b][1,3]thiazole-6-carboxaldehyde (62 mg) (WO94/10178) in dichloromethane (10 ml) was treated under nitrogen with sodium triacetoxy borohydride (340 mg) and stirred at 20° for 1.5 h. The mixture was cooled to 0°, phosphate buffer solution (pH6.5, 20 ml) was added and the mixture was extracted with EtOAc (3×30 ml). The combined organic extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by SPE. Elution with dichloromethane, dichloromethane-EtOH-ammonia (400:8:1) then (225:8:1) gave the title compound (172 mg). LCMS RT=3.16 min, ES +ve 637 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].Cl.O1CCOCC1>CO.[Pt]=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccccn2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2)c1

Procedure:
A solution of 4-Methyl-2-(5-pyridin-2-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 10a (30 mg, 0.068 mmol) in MeOH (2.3 mL), platinum oxide (1.55 mg, 0.007 mmol) and 4N HCl/dioxane (19 μl) was hydrogenated at 30 psi for 3 hours. The reaction mixture was filtered through celite, washed with MeOH and concentrated in vacuo. The residue was partitioned between dichloromethane and Na2CO3 to give the free base; (30 mg, 99%). Calculated for C26H32F3NO2 (M+H) 447.53, Found 448.4
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: Fc1ccc(CBr)cc1
Product: Fc1ccc(Cn2cnc3c(N4CCOCC4)nc(Cl)nc32)cc1

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (75 mg) was reacted with 1-(bromomethyl)-4-fluorobenzene via General Procedure C to give 4-(2-chloro-9-(4-fluorobenzyl)-9H-purin-6-yl)morpholine which was reacted with 150 mg tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl carbonate via General Procedure A and purified via reverse phase HPLC to give 50 mg of 142 as a white solid. MS (Q1) 406.2 (M)+.
Reaction SMILES: CS(Cl)(=O)=O.[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([OH:26])=O)[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:58])([F:57])[F:56])[CH:48]=1>C(Cl)Cl>[CH:6]1([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@H:18]3[C@@H:23]([C:24]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([CH2:53][OH:54])=[C:49]([C:55]([F:56])([F:57])[F:58])[CH:48]=4)=[O:26])[CH2:22][CH2:21][CH2:20][N:19]3[C:27](=[O:36])[C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:29]=3[F:35])=[CH:14][CH:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)O)[C@@H]1c1ccc(NC2CCCC2)cc1
Reactant: Nc1ccc(CO)c(C(F)(F)F)c1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(F)c1C(=O)N1CCC[C@H](C(=O)Nc2ccc(CO)c(C(F)(F)F)c2)[C@@H]1c1ccc(NC2CCCC2)cc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
Step b) Methanesulfonyl chloride (378 mg, 3.3 mmol) was added to a solution of (2R,3S)-2-[4-(cyclopentylamino)phenyl]-1-(2-fluoro-6-methyl-benzoyl)piperidine-3-carboxylic acid prepared above (1.4 g, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) in dry CH2Cl2 (25 mL) at 0° C. under a nitrogen atmosphere. The solution was stirred for an additional 15 minutes, then [4-amino-2-(trifluoromethyl)phenyl]methanol (631 mg, 3.3 mmol) and Hunig's base (586 μL, 3.3 mmol) were added sequentially. The reaction mixture was allowed to attain room temperature over a period of 30 minutes. When TLC and LCMS indicated completion of the reaction, excess solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, 0-20% ethyl acetate in dichloromethane) to get the desired compound (1.2 g) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 9.50 (bs, 0.6H), 9.38 (bs, 0.4H), 7.75-7.70 (m, 1H), 7.50-7.33 (m, 3H), 7.24-7.19 (m, 2H), 7.06-6.90 (m, 2H), 6.67-6.55 (m, 3H), 4.77-4.76 (m, 2H), 3.78-3.66 (m, 1H), 3.32-3.00 (m, 3H), 2.44-1.45 (m, 17H). MS: (ES) m/z 598 (M+H+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[C:14]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:25]2[CH2:24][CH2:23][CH:22]([NH:21][C:14](=[O:15])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:27][CH2:26]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
Method 1 was followed using 4-chloro-3-nitroacetophenone (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (2.0 eq) at 55° C. overnight yielding tert-butyl 1-(4-acetyl-2-nitrophenyl)piperidin-4-ylcarbamate (95%). LCMS (m/z): 364.1 (MH+); LC Rt=2.99 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([O:14][CH2:15][CH2:16][CH3:17])[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:14][C@@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([NH:19][CH3:18])[CH:21]=2)=[CH:3][CH:4]=1)[C:10]([O:12][CH3:13])=[O:11])[CH2:16][CH3:17]
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CCCO[C@@H](Cc1ccc(Br)cc1)C(=O)OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCO[C@@H](Cc1ccc(-c2cccc(NC)c2)cc1)C(=O)OC
Temperature: 90 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
38 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 100 mg (0.33 mmol) of methyl (S)-3-(4-bromophenyl)-2-(propyloxy)propionate and 90 mg (0.39 mmol) of methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 1 ml of dimethylformamide. 0.2 ml of a 2M potassium phosphate solution is added and the reaction mixture is stirred at 90° C. for 2 hours. The reaction is halted by the addition of 10 ml of water and then extraction is carried out with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 80/20). 76 mg of methyl (S)-2-propyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtained in the form of an oil. Yield=70%.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C:11]1([CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([O:18]C)=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8]([NH:10][C:11]1([CH3:20])[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=[O:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCCC1(C)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(C)CCCC1C(=O)O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (23.50 g, 981 mmol) was added to a solution of methyl 2-{ [(tert-butoxy)carbonyl]amino}-2-methylcyclopentane-1-carboxylate (50.51 g, 196 mmol) in THF (300 ml) and water (150 ml). The reaction was heated at 50° C. for 18 hours and then to 60° C. for 18 hours. The reaction was concentrated in vacuo and then acidified to pH 7 with concentrated HCl and then to pH 3 with 2 M HCl (aq). The organics were extracted with ethyl acetate (3×300 ml) and the combined organics were washed with brine (50 ml), dried over magnesium sulfate and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.[H-].[Na+].Br[CH2:26][C:27]1[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:26][C:27]5[O:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=5)[C:14]4=[O:22])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
To a stirred solution of 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.29 g, 1.00 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.05 g, 1.25 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then 2-(bromomethyl)-5-(trifluoromethyl)furan (0.25 mL, 1.80 mmol) was added. The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuum. The residue was purified by column chromatography with ethyl acetate in hexanes (10% to 40% gradient) to afford 3-methyl-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one (0.35 g, 80%): mp 111-112° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.46 (d, J=9.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.15-7.12 (m, 1H), 7.06-7.01 (m, 3H), 6.77-6.76 (m, 1H), 6.55-6.52 (m, 1H), 5.20-4.85 (m, 4H), 2.44 (s, 3H); 13C NMR (75 MHz, CDCl3) δ175.7, 163.9, 158.1, 154.9, 151.6, 141.4, 130.2, 129.5, 123.9, 123.1, 120.7, 117.9, 117.1, 112.9, 109.3, 108.9, 108.8, 107.9, 81.2, 56.2, 37.5, 9.8; MS (ES+) m/z 462.9 (M+23).
Reaction SMILES: [O:1]=[C:2]1[CH:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[OH:1][C@H:2]1[C@@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN2CCC(=O)C2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of Example 35C (46 g, 0.192 mol) in methanol (460 mL) was added NaBH4 (13 g, 0.345 mol) at approximately 0° C., and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution (100 mL), and the volatiles were removed under reduced pressure. The residue obtained was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated. The material obtained was purified by column chromatography over silica gel using 5-6% methanol in chloroform to get the first eluting product (Example 36A, 5.3 g) and second eluting product (Example 35D, 5.1 g) together with 20 g of a mixture of both diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[H-].[Na+].[F:16][C:17]([F:26])([F:25])[CH2:18][CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22]>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH2:4][C:20]([CH2:19][CH2:18][C:17]([F:16])([F:25])[F:26])([C:21]#[N:22])[C:23]#[N:24]
Reactant: FC(F)(F)c1ccc(CBr)c(Cl)c1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(C(F)(F)F)cc1Cl
Yield: 38.6 %

Procedure:
Using 0.10 g of 2-chloro-4-(trifluoromethyl)benzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and. 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.05 g of 2-(2-chloro-4-(trifluoromethyl)benzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (41)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:14])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Product: O=C(Nc1ccc2c(c1)OCCO2)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 10(c). 6-Bromo-naphthalene-2-carboxylic acid (0.5 g, 2 mmol, Lancaster) reacted with 1,4-benzodioxan-6-amine (0.332 g, 2.2 mmol, Aldrich) to give the title compound as a light-yellow solid. Mp 222.7° C. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([CH3:36])[N:29]=1>C1C=CC=CC=1>[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([CH2:36][Cl:8])[N:29]=1
Reactant: Cc1ccc(C#N)c(Cl)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccc(CCl)nc1Cl
Reaction time: 4 h

Procedure:
NCS (1.44 g, 10.8 mmol) and benzoyl peroxide (238 mg, 0.98 mmol) were added to a stirred solution of 2-chloro-3-cyano-6-methyl-pyridine (750 mg, 4.92 mmol) in benzene (35 mL) and the mixture was heated to reflux. After 4 h, the mixture was cooled and filtered. The filtrate was diluted with ethyl acetate and was washed with sodium metabisulfite solution, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (chloroform) to give the title compound:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17](F)[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH2:9][CH2:8]1>CS(C)=O>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:23])=[C:17]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:18]=3[O:20][CH3:21])[C:13](=[O:24])[C:12]([C:25]([OH:27])=[O:26])=[CH:11]2)[CH2:8][CH2:9]1
Reactant: C1COCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CS(C)=O
Product: COc1c(N2CCOCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 70 °C
Reaction time: 6 h
Yield: 59.8 %

Procedure:
1.2 g (0.012 mole) of morpholine was added to a solution of 0.9 g (0.003 mole) of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (IIc) (prepared as described in Preparation 6) in 5 ml of dimethyl sulfoxide, and the mixture was stirred at 70° C. for 6 hours. At the end of this time, the solvent and the excess morpholine were removed at the same temperature by evaporation under reduced pressure. The residue was washed with ethyl acetate and then subjected to silica gel column chromatography eluted with methanol, to afford 0.65 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-morpholino-1,4-dihydro-4-oxoquinoline-3-carboxylic acid as a pale brown powder melting at 235°-237° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][NH:18][C:17]([CH3:21])([CH3:20])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3].C(N(C(C)C)CC)(C)C.[Cl:31][C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[C:13]3[CH2:19][N:18]([C:32]([Cl:31])=[O:34])[C:17]([CH3:20])([CH3:21])[C:14]=3[NH:15][N:16]=2)[N:6]=1)[CH3:3]
Reactant: CCOc1ccnc(Nc2n[nH]c3c2CNC3(C)C)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccnc(Nc2n[nH]c3c2CN(C(=O)Cl)C3(C)C)n1
Temperature: 22 °C

Procedure:
To a −78° C. solution of N-(4-ethoxypyrimidin-2-yl)-6,6-dimethyl-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-amine hydrochloride (0.300 g, 1.09 mmol) in CH2Cl2 (15 mL) and diisopropylethylamine (0.952 mL, 5.47 mmol) was added triphosgene (0.227 g, 0.766 mmol) in CH2Cl2 (5 mL) dropwise over 10 min. The reaction was quenched with H2O (10 mL), warmed to 22° C., and made pH 8-9 with NaHCO3. The aqueous layer was extracted with CH2Cl2 (2×30 mL) and the combined organic layers washed with brine (1×30 mL), dried over MgSO4, and concentrated to give the desired product M1(i) as a brown solid (0.35 g, 95%). Mass Spectrum: Calcd for C14H18ClN6O2 (M+H): 337. Found: 337.
Reaction SMILES: [CH:1]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:7]=1[NH2:13])([CH3:3])[CH3:2].[C:20](OCC)(=O)[CH:21]=[O:22].C1(C)C=CC=CC=1>C(O)C>[CH:17]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[N:13]=[CH:20][C:21](=[O:22])[NH:12]2)([CH3:19])[CH3:18]
Reactant: CCOC(=O)C=O
Reactant: CC(C)[Si](Oc1cccc(N)c1N)(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)[Si](Oc1cccc2[nH]c(=O)cnc12)(C(C)C)C(C)C
Reaction time: 8 h

Procedure:
A solution of (b) (80.7 g) in ethanol (1 liter) was treated with a 50% solution of ethyl glyoxalate in toluene (60 ml, 294 mmol) and heated to reflux for 2 hours. The mixture was left at room temperature overnight and filtered affording 5-triisopropylsilanyloxy-1H-quinoxalin-2-one. The filtrate was evaporated and the residue chromatographed eluting with a 0-3% gradient of methanol in dichloromethane affording 8-triisopropylsilanyloxy-1H-quinoxalin-2-one as a white solid (14.9 g).
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])=[CH:42][CH:41]=1>CC#N>[NH2:53][CH2:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccccc1-c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 32.7 %

Procedure:
Using the general alkylation procedure: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.194 g, 0.51 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.72 mmol) followed by 4′-bromomethyl-2-cyanobiphenyl (0.303 g, 1.11 mmol) and the resultant mixture heated to 60° C. for 25 h. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided a tan foam (79 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>CN(C=O)C>[N+:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cn2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.4 %

Procedure:
A solution of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (380 mg, 2 mmol) in anhydrous DMF (10 ml) was treated with potassium carbonate (552 mg, 4 mmol) followed by 4-nitrobenzyl chloride (343 mg, 2 mmol) and the whole mix stirred under argon for 16 h at room temperature. The reaction mixture was separated between water (20 ml) and ethyl acetate (20 ml). The organic layer was washed again with a water/brine mix (1:1) (10 ml) then dried over sodium sulphate and the solvent removed under reduced pressure to give a yellow oil (751 mg) which was chromatographed on a 5 g pre-packed silica column eluting from 0-20% ethyl acetate in petroleum ether to give the title compound as a yellow oil (416 mg, 64%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>ClCCl>[Br:21][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[N:12]([C:13]([CH3:15])=[CH2:14])[C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=2[N:9]=1
Reactant: C=C(C)n1c(OCCCCCO)nc2ccccc21
Reactant: BrC(Br)(Br)Br
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(C)n1c(OCCCCCBr)nc2ccccc21
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A solution of 1.06 g of the compound obtained in Example 13a in 20 ml of dichloromethane was added with 1.8 g of carbon tetrabromide and 1.4 g of triphenylphosphine and stirred for 1 hour. The reaction mixture was added with saturated aqueous NaOH for washing. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.2 g of the title compound (yield: 91%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:12]([OH:14])=O)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([N:23]2[C:12](=[O:14])[CH:10]([CH2:9][S:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:11][C:24]2=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: S=C=Nc1ccccc1
Reactant: N[C@@H](CSCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1C(CSCc2ccccc2)NC(=S)N1c1ccccc1

Procedure:
When approximately equimolar amounts of S-benzylcysteine, sodium hydroxide, and phenylisothiocyanate was reacted according to the procedure described for the preparation of the compound of Example 2, the title compound herein was obtained.