Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:13])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH:14](OCC)(OCC)OCC>C1COCC1>[N+:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]2[N:13]=[CH:14][O:1][N:2]=2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: CCOC(OCC)OCC
Reactant: N=C(NO)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ncon2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.5 %

Procedure:
To a stirred solution of 4-nitrobenzonitrile (1 g, 0.0068 mol) in ethanol (20 mL) and water (8 mL) was added hydroxylamine hydrochloride (1.9 g, 0.0272 mol) followed by sodium carbonate (2.2 g, 0.0204 mol). The resulting mixture was heated to reflux at 85° C. under an atmosphere of nitrogen for 2 hours The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The volatiles were evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H). To a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 0.0066 mol) in THF (15 mL) was added triethyl orthoformate (2.93 g, 0.0198 mol). The resulting mixture was cooled to between 0 and 5° C. Boron trifluoride dimethyl ether (0.9 g, 0.0079 mol) was then added dropwise and the resulting mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.65 g (55%) of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole. To a stirred solution of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole (0.2 g, 0.001 mol) in THF (15 mL) was added ammonium chloride (0.214 g, 0.004 mol) in water (5 mL) followed by zinc powder (0.262 g, 0.004 mol) portionwise. The resulting mixture was stirred at ambient temperature for 1 hr and then heated to 65° C. for 5 hours. The mixture was then filtered through celite and the organic layers were concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were washed with brine solution, dried over Na2SO4 and evaporated under reduced pressure to afford 0.155 g (92%) of 4-[1, 2, 4]oxadiazol-3-yl-phenylamine. 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.C([Zn]CC)C.ICI.[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]>ClCCl>[C:16]([NH:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24]2([CH2:2][CH2:26]2)[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])(=[O:18])[CH3:17]
Reactant: C=C1C[C@@](NC(C)=O)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Reactant: O=C(O)C(F)(F)F
Agent: CC[Zn]CC
Solvent: ICI
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(C)=O)(C(=O)OCC)CC21CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen, add a solution of trifluoroacetic acid (1.9 mL, 25 mmol) in dichloromethane (12.5 mL) dropwise very slowly to a cooled (ice bath) stirred solution of diethylzinc (1M in heptanes) (25 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diiodomethane (2.01 mL, 25 mmol) in dichloromethane (12.5 mL). After 10 minutes, add a solution of diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.46 g, 8.3 mmol) in dichloromethane (12.5 mL). After 60 minutes remove the ice bath and leave the reaction mixture to stir overnight at room temperature. Quench the clear reaction solution by dropwise addition of the reaction mixture to 0.2M aqueous hydrochloric acid (200 mL) under vigorous stirring. After 1 hour separate the dichloromethane layer, wash with brine, dry over magnesium sulfate, filter and concentrate in vacuum to yield the required product contaminated with unreacted starting material (4.4 g). Purify by flash chromatography eluting with ethyl acetate:cyclohexane (50:50 to 100:0) to give a colorless oil (3.1 g). Purify by SFC(RT=2.48 minutes (UV, 200 nm); HPLC Column: AD-H 30 mm×250 mm 5 μm; CO2 gradient: 5% iso-propyl alcohol w/0.2% dimethylethylamine for 0.5 minutes, then 5%-27% in 2.2 minutes. Column temperature: 35° C.; pressure: 100000 kPa; flow rate: 210 mL/minute) to yield unreacted diethyl (1S,2S,5R,6S)-2-acetamido-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate. (580 mg, 2.0 mmol) and title compound (1.82 g, 5.9 mmol). MS (m/z): 310 (M+1), 332 (M+23).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: NC(=O)c1cc([N+](=O)[O-])ccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1cc([N+](=O)[O-])ccc1-c1cc2ccccc2s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
2-Iodo-5-nitrobenzamide (Example 3A; 6.56 g) is introduced into dioxane (130 ml) and sat. sodium carbonate solution (65 ml) and, after addition of benzothiophene-2-boronic acid (6.00 g) and dichlorobis(triphenylphosphine)palladium (1.58 g), stirred at 80° C. overnight. The reaction mixture is filtered through kieselguhr and washed with ethyl acetate (250 ml) and water (100 ml). The organic phase is extracted with water (three times 100 ml) and sat. sodium chloride solution (100 ml) and then dried over sodium sulfate and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (cyclohexane:ethyl acetate 10:1--->pure ethyl acetate). After the product fractions have been concentrated in a rotary evaporator, the target compound is suspended in diethyl ether, filtered off with suction and dried. 4.75 g of product (64% of theory) are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:9]
Reactant: Nc1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(C(=O)O)cc(OCCO)c2Oc2cccc(OC)c2)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(C(=O)Nc3ccccc3)cc(OCCO)c2Oc2cccc(OC)c2)cc1

Procedure:
Analogously to Example 74, condensing 3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-benzoic acid with aniline there was obtained 3-(2-hydroxy-ethoxy)-5-(4-methoxy-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-N-phenyl-benzamide.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([OH:18])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:5]2=[O:27])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl.CN(C)C.[S:40](Cl)([C:43]1[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=1)(=[O:42])=[O:41]>C(#N)C.CO>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([O:18][S:40]([C:43]4[CH:49]=[CH:48][C:46]([CH3:47])=[CH:45][CH:44]=4)(=[O:42])=[O:41])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:19]3[CH:24]=[CH:23][C:22]([I:25])=[CH:21][C:20]=3[F:26])[C:5]2=[O:27])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Agent: CN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)cc1
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (23.9 g) was added acetonitrile (167 ml), and the mixture was stirred under ice-cooling. Triethylamine (11.0 ml) and trimethylamine hydrochloride (2.37 g) were added, and a solution of p-toluenesulfonyl chloride 11 (12.3 g) in acetonitrile (72.0 ml) was added dropwise. The mixture was stirred under ice-cooling for 1 hr, and stirred at room temperature for 3 hrs. Methanol (239 ml) was added, and the mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration and dried to give p-toluenesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 77 (28.7 g, yield 91%) as colorless crystals.
Reaction SMILES: C(O)(=O)C.[CH:5]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])[CH:11]=2)[CH2:7][CH2:6]1.[BH4-].[Na+]>CS(C)=O>[CH:5]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])[CH:11]=2)[CH2:7][CH2:6]1
Reactant: O=[N+]([O-])/C=C/c1cccc(OCC2CC2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])CCc1cccc(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
To an acetic acid (3.7 mL) and dimethyl sulfoxide (63 mL) solution of 1-cyclopropylmethoxy-3-((E)-2-nitro-vinyl)-benzene (3.73 g, 17 mmol) described in Manufacturing Example 66-1-2 was added sodium borohydride (1.03 g, 27.2 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. That mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (2.21 g, 59%).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=[N:13][C:14]=1[OH:15]>N1C=CC=CC=1>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1]([O:8][C:9]1[C:10]([C:16]([O:18][CH3:19])=[O:17])=[N:11][CH:12]=[N:13][C:14]=1[OH:15])=[O:6]
Reactant: COC(=O)c1ncnc(O)c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ncnc(O)c1OC(=O)C(C)(C)C
Temperature: 40 °C

Procedure:
Pivaloyl chloride 1.1 eq. was added to a solution of the product of Step 2 in pyridine, and the mixture was heated to 40° C. for 10 minutes. HPLC showed the complete conversion of starting material. The reaction mixture was concentrated, the resulting oil was diluted with ethyl acetate and washed with 1 N HCl solution. The title product was obtained as a brown solid after evaporation of the organic phase and trituration with diethyl ether.
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH:13]([CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[OH:14]>>[CH3:12][C:11]1[N:7]2[C:8]([CH:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[O:14][C:4]3[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=3[CH2:6]2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(O)C2CCN(C)CC2)n1Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc2n1Cc1ccccc1OC2C1CCN(C)CC1
Temperature: 70 °C

Procedure:
To a suspension of sodium hydride (3.20 g, 60% dispersion in oil, washed twice with hexane) in 20 ml dimethylformamide/benzene (20:80) was added a solution of [1-(2-fluorobenzyl)-5-methylpyrrol-2-yl][(1-methyl)piperidin-4-yl]methanol (15.45 g, 0.088 mole) in 80 ml of the same solvent. This was heated at 70° C. for 5 hours.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]([N:21]=[C:22]=[O:23])[CH2:18][CH2:19][CH2:20][C:13]1=2>C(Cl)Cl>[CH3:2][O:3][NH:4][C:22]([NH:21][CH:17]1[C:14]2[CH:15]=[CH:16][S:12][C:13]=2[CH2:20][CH2:19][CH2:18]1)=[O:23]
Reactant: O=C=NC1CCCc2sccc21
Reactant: CON
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CONC(=O)NC1CCCc2sccc21
Temperature: 15 °C
Reaction time: 0.33 h

Procedure:
A mixture of 5 grams of methoxyamine hydrochloride in 60 ml. of methylene chloride is stirred and cooled to 15°C., and 6 grams of triethylamine in 15 ml. of methylene chloride is added. After 20 minutes of stirring, 5.38 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate is added dropwise. After stirring an additional 0.5 hour at 15°C. to 20°C., the mixture is stirred at room temperature for 0.5 hour. The mix is then filtered, and the filtrate is washed with water and saturated sodium bicarbonate solution. The filtrate is dried (magnesium sulfate) and evaporated to dryness to afford the title compound which is recrystallized from acetone/hexane to give the product with melting point 138.5°C. to 141°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1>C(OCC)(=O)C>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH2:27][CH2:28][C:29](=[O:32])[NH:30][N:31]=2)=[CH:22][CH:21]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=C(CCc1ccccc1)c1ccc(O)cc1O
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(N=C(CCc3ccccc3)c3ccc(O)cc3O)cc2)=NN1
Temperature: 190 °C

Procedure:
A mixture containing 1.45 g of 1-(2,4-dihydroxyphenyl)3-phenyl-propan-1-one and 6-(4-aminophenyl)-4,5-dihydropyridazin-3(2H)one was heated for 72 h at 190° C. The product was treated with ethyl acetate, yield 0.37 g (16%), m.p. 208°-210° C.
Reaction SMILES: [NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([OH:10])=O)(=[O:4])=[O:3].CCN(C(C)C)C(C)C.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:39]1([C:45]2[C:46]3[CH:47]=[CH:48][C:49]([C:70]([O:72][CH3:73])=[O:71])=[CH:50][C:51]=3[N:52]3[C:59]=2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55][C@H:54]([N:64]([CH3:69])[CH2:65][CH2:66][NH:67][CH3:68])[CH2:53]3)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>CN(C=O)C>[NH2:1][S:2]([CH2:5][CH2:6][CH2:7][C:8]([N:67]([CH3:68])[CH2:66][CH2:65][N:64]([CH3:69])[C@@H:54]1[CH2:53][N:52]2[C:51]3[CH:50]=[C:49]([C:70]([O:72][CH3:73])=[O:71])[CH:48]=[CH:47][C:46]=3[C:45]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]3)=[C:59]2[C:58]2[CH:60]=[CH:61][CH:62]=[CH:63][C:57]=2[O:56][CH2:55]1)=[O:10])(=[O:4])=[O:3]
Reactant: NS(=O)(=O)CCCC(=O)O
Reactant: CNCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCN(C)C(=O)CCCS(N)(=O)=O)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(aminosulfonyl)butanoic acid (1.2 eq.), DIPEA (2 eq.), DIC (1.1 eq.) and HOBT (1.1 eq.) were added to a solution of methyl(7R)-14-cyclohexyl-7-{methyl[2-(methylamino)ethyl]amino}-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.07 M) in DMF. The reaction was stirred under N2 at RT overnight. The mixture was then partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with 1N HCl followed by brine, dried (Na2SO4), filtered and concentrated in vacuo. The product was used in the next step without further purification. (ES+) m/z 625 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[C:6]([O:14]C)[CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:11])([CH3:12])[CH3:13])=[C:6]([OH:14])[CH:5]=1
Reactant: COC(=O)c1ccc(C(C)(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)(C)C)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of borontribromide (3.38 mL, 35.1 mmol) in CH2Cl2 (35 mL), cooled to −60° C., is added under an argon atmosphere a solution of 4-tert-butyl-3-methoxy-benzoic acid methyl ester (2.60 g, 11.7 mmol) in CH2Cl2 (65 mL). The reaction is warmed to room temperature and stirring is continued overnight. Another aliquot of BBr3 (1.13 mL, 11.7 mmol) is added, and the mixture is stirred for 6 hrs at ambient temperature before quenching by careful addition of water. The aqueous layer is extracted with CH2Cl2, the combined organics are washed with 1N aqueous NaOH, dried (Na2SO4) and concentrated. Purification by flash chromatography on silica gel (eluents: CH2Cl2 100%, then CH2Cl2/acetone 97:3) gives the title compound as yellowish solid. MS: 209.0 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.37 min. 1H-NMR (CDCl3): δ 1.46 (s, 9H), 3.94 (s, 3H), 5.60 (s, 1H), 7.36 (dd, 1H), 7.50 (d,1H), 7.57 (dd,1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]([CH2:11][CH3:12])=[N:10][C:4]=2[CH:3]=1.[BH3-]C#N.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[CH:9]([CH2:11][CH3:12])[NH:10][C:4]=2[CH:3]=1
Reactant: CCC1=Nc2cc(Cl)ccc2Oc2ccccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1Nc2cc(Cl)ccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring solution of the title compound of Example 15 in THF was added NaCNBH3. The reaction was stirred for 24 hours at room temperature. The solvent was removed under reduced pressure, and the residue was taken up in CHCl3 with HCl (1M, 25 mL). The resulting mixtures were stirred for 1 hour at room temperature. The CHCl3 was separated, extracted with NaHCO3 (saturated) and brine. The solvent was removed to yield a yellow oil (2.06 g). The material was purified by column chromatography on silicagel 15/85 EtOAc/hexane to yield 1.06 g of the title compound. This material was employed in Example 17 without further purification.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2CC(F)(F)F)N1CCN(C2CCCC2)CC1
Yield: 60 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a light yellow solid (60%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[F:22][C:23]([F:33])([F:34])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3cccc(C(F)(F)F)c3)CC1)O2

Procedure:
Compound 54 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(trifluoromethyl)benzoyl chloride and conditions outlined in procedure N. M.p.=165-166° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.70-7.98 (m, 7H), 7.57 (m, 1H), 4.40 (m, 1H), 3.55 (brm, 2H), 3.30 (m, 1H), 3.11 (s, 2H), 2.10 (m, 1H), 1.85 (m, 3H); LCMS: 474 [M+H].
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([OH:21])([CH2:16][CH2:17][C:18]([CH3:20])=[CH2:19])[C:14]#[N:15].Cl>C(Cl)Cl>[OH:9][CH2:19][C:18]1([CH3:20])[O:21][C:13]([CH3:12])([C:14]#[N:15])[CH2:16][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)CCC(C)(O)C#N
Agent: Cl
Solvent: ClCCl
Product: CC1(C#N)CCC(C)(CO)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
To a cooled (ice bath) and stirred mixture of 139.52 g 86% m-chloroperbenzoic acid in 2 liters methylene chloride was added 87.98 g of crude 2,5-dimethyl-2-hydroxy-5-hexenenitrile. After 30 minutes at 3° C., the mixture was allowed to warm to room temperature (ca 25° C.). The resulting mixture, which contained the intermediate epoxy cyanohydrin, was then treated with 790 ml of 0.12 N hydrochloric acid to effect cyclization. After stirring vigorously for an additional 2 hours at ca 25° C., the organic phase was separated, washed with 10% aqueous sodium carbonate and dried (MgSO4). Evaporation of solvent and distillation of the residue afforded 62.87 g product with bp 100°-105° C. (0.3 torr).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(OP(OC2C=CC=CC=2)([N:28]=[N+:29]=[N-:30])=O)=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([C@@H:10]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][CH:13]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1ccc([C@@H](O)CO[Si](C)(C)C(C)(C)C)cn1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)N=[N+]=[N-])cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (R)-2-(tert-butyldimethylsilyloxy)-1-(6-methylpyridin-3-yl)ethanol (15.6 g, 0.055 mol) and diphenylphosphonic azide (62.8 mL, 0.292 mol) in toluene (200 mL) at 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (44.5 mL, 0.292 mol). The mixture was stirred at 0° C. for 30 minutes and then heated at 60° C. overnight. After cooling, the mixture was washed with water. The organic layer was dried and concentrated in vacuo. The residue was purified by flash chromatography (0-15% EtOAc/hexane) to afford a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-])=O>CCOC(C)=O.[Pd]>[NH2:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9](=[O:12])[CH2:10][CH3:11])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(=O)Cc1ccc(F)c(N)c1
Yield: 75.3 %

Procedure:
Treat a solution of 1-(4-fluoro-3-nitrophenyl)butan-2-one (0.83 g, 3.93 mmol) in EtOAc (30 mL) with 10% Pd/C (0.209 g, 0.197 mmol) and hydrogenate at atmospheric pressure (balloon) overnight. Remove the solids via filtration through diatomaceous earth, rinse well with EtOAc, concentrate the filtrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (536 mg, 75%). 1H NMR (400 MHz, DMSO-d6): δ 6.88 (dd, J=11.6, 8.2 Hz, 1H), 6.57 (dd, J=8.9, 2.1 Hz, 1H), 6.32 (m, 1H), 5.07 (s, 2H), 3.55 (s, 2H), 2.46 (q, J=7.3 Hz, 2H), 0.89 (t, J=7.3 Hz, 3H); MS (ESI) m/z: 182.1 (M+H+).