Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)=O.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:19]2[CH2:2][CH2:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([N:16]4[CH:17]=[CH:18][N:19]=[C:15]4[CH3:14])=[CH:9][CH:8]=3)[C:18]2=[CH:17][N:16]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: Cc1nccn1-c1ccc(C2=CCCn3c2cnc3C)cc1
Temperature: 200 °C

Procedure:
50 g (0.25 mol) of 4-chloro-4'-fluorobutyrophenone are combined with 130 g (1.58 mol) of 2-methylimidazole and heated to 200° C. under nitrogen for 18 hr. Crystallization from ethyl acetate provides the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#N)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15](C)C=O.[BH4-].[Na+].ClCC#N>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:14]#[N:15])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: N#CCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: N#CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
4.4 G. of 1-amino-2-nitro-4-thiocyanatobenzene in 10 ml. of dimethylformamide is treated under nitrogen with 0.85 g. of sodium borohydride in 10 ml. of DMF at not greater than 30° C. The mixture is stirred at 15° to 20° C. for 1 hour, then treated with 5 g. of chloroacetonitrile at 20° to 25° C. The mixture is treated overnight at room temperature and poured into water. Filtration and recrystallization from methanol affords 1 -amino-2-nitro-4-cyanomethylthiobenzene.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([NH:29][C:30]([C:32]3[CH:41]=[CH:40][C:35]4[N:36]=[N:37][N:38]([OH:39])[C:34]=4[CH:33]=3)=[O:31])[CH2:23][C@@H:24]([OH:28])[C:25]([OH:27])=[O:26])=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[CH2:42](O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[CH2:42]([O:26][C:25](=[O:27])[C@H:24]([OH:28])[CH2:23][C@H:22]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)=[CH:20][CH:19]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: OCc1ccccc1
Reactant: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)O)c1ccc2nnn(O)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCc1ccccc1)c1ccc2nnn(O)c2c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
4.0 M HCl in 1,4-dioxane (270 μL, 1.0 mmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid (130 mg, 270 μmol) in benzyl alcohol (559 μL, 5.4 mmol), and the resulting mixture was stirred at 60° C. for 15 minutes. The mixture was purified by preparative HPLC (C18 column chromatography using 30-90% MeCN in water with 0.05% TFA) to yield the title compound as an off-white solid (16.0 mg, purity 99.2%). MS m/z [M+H]+ calc'd for C31H27ClN4O5, 571.17. found 571.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.C(=O)([O-])[O-].[Na+].[Na+].[Br-].[Li+].[C:25]([O:28][CH2:29][CH3:30])(=O)C>COCCOC.O.[Pd].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>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:1]3[CH:2]=[C:7]([CH:8]=[C:29]([O:28][CH3:25])[CH:30]=3)[C:6]#[N:5])=[CH:8][C:7]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: COCCOC
Solvent: O
Product: COc1cc(C#N)cc(-c2ccc3c(c2)C(C)(C)OC(=O)N3)c1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 53 %

Procedure:
A mixture of (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid (4.2 g, 19.0 mmol), 3-cyano-5-methoxyphenyltriflate (5.1 g, 19.0 mmol), tetrakis(triphenylphosphine)-palladium (0) (1.1 g, 0.95 mmol), sodium carbonate (4.0 g, 38.0 mmol), and lithium bromide (5 g, 57 mmol) in DME (50 mL) and water (25 mL) was subject to a blanket of nitrogen for 15 minutes at 50° C. and then was heated at 85° C. for 1 hour. The reaction was cooled to room temperature and ethyl acetate (100 mL) was added. The organic layers were washed twice with aqueous ammonium chloride (100 mL) and once with brine (100 mL), dried over magnesium sulfate and concentrated. Purification via chromatography (silica gel, 40% ethyl acetate/hexane) gave 3-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-methoxy-benzonitrile as a white solid (0.69 g, 53%): mp 254-255° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.84 (s, 1H), 7.67-7.61 (m, 2H), 7.55 (bs, 1H), 7.4 (bs 1H) 6.99 (d, 1H, J=7.94 Hz), 3.88 (s, 3H), 1.67 (s, 6H); MS (EI) m/z 308 ([M+H]+, 30%); Anal. Calc. For C18H16N2O3: C, 68.13; H, 5.40; N, 8.83. Found: C, 68.03; H, 5.22; N, 8.46.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46](O)=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])C(C)C)[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24](C(C)C)[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH2:67]([N:73]=[C:74]=[O:75])[CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]>CO.N1C=CC=CC=1.CC(=O)CC(=O)C>[NH2:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]2[N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:9]([CH3:49])[CH3:10])[NH:18][C:19](=[O:39])[CH:20]([CH:32]3[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]3)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:3]([CH3:4])[CH3:2])[C:25]([OH:27])=[O:26])[C:74](=[O:75])[N:73]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:46]2=[O:47])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66]
Reactant: CCCCCCN=C=O
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Solvent: c1ccncc1
Solvent: CO
Solvent: CC(=O)CC(C)=O
Product: CCCCCCN1C(=O)C([C@@H](OC2O[C@H](CN)[C@H](O)[C@H]2OC)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)N(CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C1=O
Yield: 56.9 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 47.3 mg (50 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 3.0 ml of methanol, 200 μl of pyridine, 200 μl of 2,4-pentanedione and 50 μmol of hexylisocyanate to give 15 mg of the desired product.
Reaction SMILES: [Li+].[OH-].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]([CH3:19])([C:15]([O:17]C)=[O:16])[C:11]2=[O:20])=[CH:6][CH:5]=1.Cl>C1COCC1.CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C:12]([CH3:19])([C:15]([OH:17])=[O:16])[C:11]2=[O:20])=[CH:8][CH:9]=1
Reactant: COC(=O)C1(C)CCN(c2ccc(F)cc2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCN(c2ccc(F)cc2)C1=O
Yield: 92.4 %

Procedure:
LiOH (1.2 mL, 1.19 mmol, 1.0 M in H2O) was added to a solution of methyl 1-(4-fluorophenyl)-3-methyl-2-oxopyrrolidine-3-carboxylate (0.149 g, 0.593 mmol) in a mixture of THF (4.5 mL) and MeOH (1.5 mL) at room temperature for 1 hour. The reaction mixture was acidified with aq. 1 N HCl solution (1.4 mL), extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated to afford the desired product (0.13 g, 92%). 1H-NMR (400 MHz, CD3OD) δ 7.62 (m, 2H), 7.13 (t, 2H), 3.97 (m, 1H), 3.86 (m, 1H), 2.63 (m, 1H), 2.13 (m, 1H), 1.47 (s, 3H); 19F NMR (376 MHz, CD3OD) δ −119.3.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([S:13](/[CH:16]=[CH:17]/[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[C:7]1([S:13]([CH:16]2[CH:17]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[CH:3]3[CH2:4][CH2:5][CH:6]2[CH:1]=[CH:2]3)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=CCCC=C1
Reactant: O=S(=O)(/C=C/S(=O)(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)C1C2C=CC(CC2)C1S(=O)(=O)c1ccccc1
Yield: 104.4 %

Procedure:
A mixed solution of 3.16 g (39.5 mmol) of 1,3-cyclohexadiene, 10.5 g (34.1 mmol) of trans-1,2-bis(phenylsulfonyl)ethylene, and 200 ml of toluene was refluxed for 7 hours. Then, the mixed solution was cooled and concentrated under reduced pressure to yield a reaction mixture. The reaction crude product was recrystallized (chloroform/hexane) to yield 5,6-bis(phenylsulfonyl)-bicyclo[2,2,2]octa-2-ene (13.8 g, 35.6 mmol, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=O)([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][O:71][NH3+:72].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:39])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](=[O:29])[NH:72][O:71][CH3:70])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])[C:5]2=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CONC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (30 mg, 0.05 mmol), EDCI (20 mg, 0.1 mmol), HOBt (16 mg, 0.1 mmol) and DIPEA (40 mg, 0.3 mmol) in THF (1 mL) was added o-methylhydroxylamine hydrochloride (22 mg, 0.25 mmol). The mixture was stirred at room temperature overnight and purified by prep-HPLC to give the title compound as a white solid (11 mg).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C>[NH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCN(C(=O)OCc3ccccc3)CC2)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of benzyl 4-formylpiperidine-1-carboxylate (3 g) and tert-butyl piperazine-1-carboxylate (2.2 g) in dichloromethane (100 ml) was added sodium triacetoxyborohydride ((2.6 g). The resulting solution was stirred at room temperature for 18 hours and then washed with 2M sodium hydroxide (2×50 ml) and 2M hydrochloric acid (2×50 ml), dried over Magnesium sulphate, filtered and evaporated to afford tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) as an oil. Tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (4.9 g) was dissolved in ethanol and purged with argon. 20% Palladium hydroxide on carbon (500 mg) was added. The reaction mixture was purged with argon, evacuated and filled with hydrogen from a balloon. The reaction mixture was stirred at room temperature for 2 hours. A white solid precipitate formed. The reaction mixture was warmed to 40° C. and stirred at this temperature for a further 1 hour until the precipitate dissolved. The reaction mixture was allowed to cool to room temperature and stirred for a further 18 hours. The reaction mixture was purged with argon, filtered through celite and evaporated to afford tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (3.2 g) as a solid. Mass spectrum: M+H+ 284
Reaction SMILES: [OH-].[Na+].O.[NH2:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH:12]1([CH2:18]Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CO>[CH:12]1([CH2:18][O:11][C:10]2[C:5]([NH2:4])=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCCC1
Reactant: Nc1ncccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ncccc1OCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At RT, 96 g of sodium hydroxide 45% strength in water (1081 mmol, 1 equivalent) were initially charged in 1170 ml of methanol, 119 g of 2-amino-3-hydroxypyridine (1080 mmol, 1 equivalent) were added and the mixture was stirred at RT for 10 min. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 2900 ml of DMSO and 101 g of cyclohexylmethyl bromide (1135 mmol, 1.05 equivalents) were added. After 16 h at RT, the reaction mixture was added slowly to 6 l of water and the aqueous solution was extracted twice with in each case 21 of ethyl acetate. The combined organic phases were washed with in each case 1 l of saturated aqueous sodium bicarbonate solution and water, dried, filtered and concentrated. The residue was triturated with 500 ml of n-pentane, filtered and dried under reduced pressure. This gave 130 g (58% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[C:21]([Cu])#[N:22].Cl>CN(C=O)C.O>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[C:3]([O:16][C:17]([F:18])([F:19])[F:20])[CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c(OC(F)(F)F)c1
Reactant: N#C[Cu]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(N)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 45.9 %

Procedure:
1,1-Dimethylethyl {4-bromo-3-[(trifluoromethyl)oxy]phenyl}carbamate (Intermediate 50, 1.0 g, 2.8 mmol) was dissolved in dry DMF (25 mL). To this solution was added CuCN (1.0 g, 11.1 mmol), and the reaction mixture was heated to reflux for 5 h. A second portion of CuCN (500 mg, 5.6 mmol) was added and heating at reflux was continued for 10 h. The reaction mixture was cooled to room temperature, and FeCl3 was added. This was followed by 1N HCl at 0° C. and the mixture was stirred for 2 hr at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 silica gel), eluting with 30% ethyl acetate/pet ether to give the title compound (260 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[CH:17]1([C:20](=O)[CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:19][CH2:18]1.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[CH:17]1([C:20]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)[C:3]3[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:1]=2)[CH2:19][CH2:18]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the solution of 2-amino-4′-fluorobenzophenone (100 g) in acetic acid (500 ml) added methyl 3-cyclopropyl-3-oxopropanoate (132 g), sulfuric acid (5 ml) and stirred for 15 minutes at 25° C. Heated the reaction mixture to 100° C. for 10 hrs. Cooled the reaction mixture to 0-5° C. and pH adjusted to neutral conditions with 40% sodium hydroxide solution. Filtered the solid formed and washed with water. The wet solid was dissolved in methylene chloride and separated the water from it. Silica slurry was given to the reaction mixture and filtered it. Methylene chloride was distilled off and the compound was co-distilled with methanol. To the compound added methanol (150 ml) and stirred for 1 hr at 25° C. Filtered the solid and washed with methanol (50 ml). Dried the obtained solid to get the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[S:19])[C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[C:7]([N+:14]([O-])=O)[C:6]=1[CH2:17][CH3:18])[CH3:2]>O1CCCC1.[Ni].C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[S:19])[C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([NH2:14])[C:6]=1[CH2:17][CH3:18])[CH3:2]
Reactant: CCOC(=S)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1CC
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=S)c1cc(N)cc(N)c1CC

Procedure:
25.9 g (0.0862 mol) of 3,5-dinitro-2-ethylthiobenzoic acid ethyl ester are dissolved in 260 ml of tetrahydrofuran and hydrogenated at 30°-35° C. in the presence of 10 g of Raney nickel. The catalyst is then isolated by filtration, and the residue is taken up in ethyl acetate, dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:20])=[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=1)[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8][CH:7]2[CH2:17][O:18][CH3:19])(=[O:3])C.Cl[O-].[Na+].S([O-])([O-])=[O:25].[Na+].[Na+]>O1CCOCC1>[CH3:19][O:18][CH2:17][CH:7]1[C:6]2[C:11](=[C:12]([CH3:14])[CH:13]=[C:4]([C:1]([OH:25])=[O:3])[C:5]=2[CH3:20])[S:10](=[O:16])(=[O:15])[CH2:9][CH2:8]1
Reactant: O=S([O-])[O-]
Reactant: COCC1CCS(=O)(=O)c2c(C)cc(C(C)=O)c(C)c21
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: COCC1CCS(=O)(=O)c2c(C)cc(C(=O)O)c(C)c21
Yield: 75 %

Procedure:
To a solution of 0.32 g (1.1 mmol) of 6-acetyl-4-methoxymethyl-5,8-dimethylthiochroman-1,1-dioxide in 1 ml of dioxane was added 3.8 ml of a sodium hypochlorite aqueous solution, and the mixture was allowed to react at 0° C. for 1 hour and further allowed to react at room temperature overnight. A 20 wt % sodium sulfite aqueous solution was added to the reaction mixture, and the mixture was washed with ethyl acetate. An aqueous layer was acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride aqueous solution, and an organic layer was dried over anhydrous sodium sulfate and filtered. Then, the solvent was distilled off under reduced pressure to give 0.24 g (yield 75%) of the titled compound as a crude product.
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].C(O)(=O)C.O>[Zn].C(Cl)(Cl)Cl>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH2:9][CH2:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Agent: [Zn]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C1CCC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared as in Example 1, were suspended in 150 ml. of glacial acetic acid and then this mixture was poured into 20 g. of zinc dust suspended in 150 ml. of distilled water. A slight exotherm occurred during stirring and the temperature was maintained at 50° C. for 3 hours by external heating. Then 200 ml. of chloroform were added and stirring was continued for 30 minutes more. The chloroform layer was separated and washed with a saturated sodium carbonate solution and dried over anhydrous magnesium sulfate. Evaporation of the chloroform left a white solid. One recrystallization from methanol gave white crystals, m.p. 169°-170° C. Infrared spectrum showed carbonyl at 1740 cm-1. The nmr indicated two bridgehead protons at 431 Hz (singlet) and four α- protons at 303 Hz and 245 Hz (as a multiplet).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH:24]([NH:26][C:27]1[N:32]=[C:31]([N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[CH:34]2)[C:30](Br)=[CH:29][N:28]=1)[CH3:25])=O)C1C=CC=CC=1>CC(O)C.[OH-].[OH-].[Pd+2]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH:12]([CH:24]([NH:26][C:27]2[N:32]=[C:31]([N:33]3[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[N:35]=[CH:34]3)[CH:30]=[CH:29][N:28]=2)[CH3:25])[CH2:13]1)=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(Nc1ncc(Br)c(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1
Yield: 30.8 %

Procedure:
A solution of 2-[1-(1-(benzyloxycarbonyl)-4-(tert-butyloxycarbonyl)-piperazin-2-yl)-ethylamino]-4-(benzimidazol-1-yl)-5-bromopyrimidine (83 mg) in 1 mL of iPrOH was stirred over Pd(OH)2/C (75 mg) under an H2 atmosphere (balloon) for 2 days, then filtered through Celite®, washing liberally with MeOH, and concentrated. The residue was dissolved in 10 mL of 0.2 N HCl and washed with 2×5 mL of CH2Cl2. The aqueous phase was basified (pH>1 1) with 1N NaOH and extracted with 4×10 mL of EtOAc. The combined organics were dried over Na2SO4 and concentrated, and the residue was purified by preparative thin-layer chromatography, eluting with 9:1 CH2Cl2—MeOH to provide 17 mg of the title compound. Mass spectrum (ESI) 368.3 (M−tBu).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=O)[O:33]C(C)(C)C)[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17](COCC[Si](C)(C)C)[N:18]=2)[CH:14]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.[NH:62]1[CH2:67][CH2:66][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:64][CH2:63]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32]([N:62]1[CH2:63][CH2:64][CH:65]([N:68]2[CH2:77][C:76]3[C:71](=[CH:72][CH:73]=[CH:74][CH:75]=3)[NH:70][C:69]2=[O:78])[CH2:66][CH2:67]1)=[O:33])[CH2:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH3:22])[CH:21]=1)[NH:18][N:17]=[CH:16]2
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nccn2Cc2cccc(F)c2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(1-(3-fluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (14.4 mg, 0.025 mmol) was dissolved in a minimum amount of ethyl acetate, followed by addition of hydrochloric acid (4 N in dioxane, 1.0 mL). The mixture was stirred under nitrogen for 3 days. After removing the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was collected by filtration. The resulting solid was dissolved in dimethylformamide (1.0 mL). The mixture was cooled to 0° C. and treated with carbonyl diimidazole (4.7 mg, 1.1 equiv) and triethylamine (7.5 μL, 0.054 mmol). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (6.7 mg, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was removed and the residue purified by column chromatography to afford 7.2 mg (47%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.49-1.68 (m, 4H), 2.44 (s, 3H), 2.71-2.84 (m, 2H), 3.20-3.27 (m, 4H), 4.01-4.15 (m, 2H), 4.19 (s, 2H), 4.35 (m, 1H), 5.12 (d, J=16.2, 1H), 5.21-5.30 (m, 2H), 6.57-6.69 (m, 2H), 6.80 (d, J=7.9, 1H), 6.82 (s, 1H), 6.88-7.20 (m, 8H), 7.91 (s, 1H). Mass spec.: 607.71 (MH)+.