Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C1C=C(C2N=[C:15]([O:17]C)N=C(NCCC3C=CC(OC)=CC=3)C=2)C=CC=1)(=O)=O.[Cl:30]C1C=C(Cl)C=CC=1CCNC1N=C(OC)N=C(C2C=C(C=CC=2)OCC#N)C=1.[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=1[CH2:67][CH2:68][NH:69][C:70]1[N:75]=[C:74]([O:76][CH3:77])[N:73]=[C:72]([C:78]2[CH:79]=[C:80]([CH:87]=[CH:88][CH:89]=2)[O:81][CH2:82][C:83]([NH:85][OH:86])=[NH:84])[CH:71]=1>>[ClH:30].[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([F:66])[C:61]=1[CH2:67][CH2:68][NH:69][C:70]1[N:75]=[C:74]([O:76][CH3:77])[N:73]=[C:72]([C:78]2[CH:79]=[C:80]([CH:87]=[CH:88][CH:89]=2)[O:81][CH2:82][C:83]2[NH:84][C:15](=[O:17])[O:86][N:85]=2)[CH:71]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(S(C)(=O)=O)c3)nc(OC)n2)cc1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(OCC#N)c2)n1
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(OCC(=N)NO)c2)n1
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(OCc3noc(=O)[nH]3)c2)n1
Product: Cl

Procedure:
By proceeding in a similar manner to Example 34(a) above but: (i) substituting (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-acetonitrile [164 mg, Example 22(f)] for (3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-acetonitrile there is prepared 2-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-N-hydroxy-acetamidine (166 mg, 94%), (ii) substituting 2-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxy)-N-hydroxy-acetamidine for 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl-phenoxy)-N-hydroxy-acetamidine, and (iii) subjecting the product to silica gel chromatography eluting with 0 to 7% MeOH in DCM there is prepared 3-(3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenoxymethyl)-4H-[1,2,4]oxadiazol-5-one hydrochloride [Example 34(c)] as a solid. LC/MS: RT=2.4 minutes, MS: 472 (M+H). 1H NMR (300 MHz, (CD3)2SO): □12.82 (1H, br s), 7.18-7.55 (7H, m), 6.6 (1H, s), 5.18 (2H, s), 4 (3H, s), 3.68 (2H, m), 3.08 (2H, m). IC50=0.3 nM
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=O)(C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][NH:8][C@H:9]([C:24]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: COCCN
Product: COCCNC(=O)[C@@H]1CC(=NOCc2ccc(OC)cc2)CN1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, and 2-methoxyethylamine the title compound was obtained in 52% purity by LC/MS. MS(ESI+): m/z=322.2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8](Cl)(Cl)=[O:9].C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.Cl.[F:29][C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1>ClCCl>[F:29][C@@H:30]1[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:5]2[S:6][C:2]([CH3:1])=[CH:3][N:4]=2)=[O:9])[CH2:31]1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(Cl)Cl
Reactant: Cc1cnc(N)s1
Agent: Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NC(=O)N2CC[C@@H](F)C2)s1
Temperature: -45 °C
Reaction time: 0.5 h

Procedure:
5-Methylthiazol-2-amine (2.28 g, 20.0 mmol) was dissolved into dichloromethane (200 mL) and cooled to near −50° C. 20% Phosgene in toluene (12.6 mL, 24 mmol) was added rapidly over less than 30 seconds and stirred for 10 minutes more at −45° C. before the addition of diisopropylethylamine (17.4 mL, 100 mmol). The mixture was stirred for another 30 minutes near −45° C., (R)-3-fluoropyrrolidine hydrochloride (5.02 g, 40 mmol) was added, and after five minutes the cold bath was removed and the reaction warmed slowly to room temperature. The solution was quenched and stirred thoroughly with concentrated aqueous ammonium hydroxide (25 mL). The aqueous phase was separated and extracted with dichloromethane, and the combined organic phases were washed twice with water; each aqueous phase was back-extracted with dichloromethane. The combined organic phases were concentrated and then slurried in 3:1 hexanes/ethyl acetate. The solids were collected by filtration, rinsed with more 3:1 hexanes/ethyl acetate, and then slurried and rinsed first with 3:1 hexanes/dichloromethane, and then with 1:1 hexanes/dichloromethane to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17](O)=[O:18])[C:5]=3[C:4]=2[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:26])[N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:14]=[C:15]([CH2:16][C:17]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:18])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cn1c2ccc(Cl)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Reactant: C1CCNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cn1c2ccc(Cl)cc2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21
Reaction time: 15 h

Procedure:
A solution of 1.5 g (4 mmol) of 8-chloro-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 1.2 g (7.4 mmol) of 1,1′-carbonylbis-1H-imidazole in tetrahydrofuran is stirred for 1 h at 50° C. The mixture is cooled and an excess of pyrrolidine is added. After stirring for 15 h, the precipitate is collected by filtration, washed with water and with ether and recrystallized from propan-2-ol. 0.65 g (1.5 mmol) of solid is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]#N)[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.S(=O)(=O)(O)[OH:19].N([O-])=O.[Na+].[OH2:27]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([OH:19])=[O:27])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O
Reactant: N#Cc1c2ccccc2nc2ccc(Cl)cc12
Agent: O=N[O-]
Agent: [Na+]
Product: O=C(O)c1c2ccccc2nc2ccc(Cl)cc12
Temperature: 100 °C

Procedure:
A mixture of 19.8 gm of 2-chloro-9-cyano-acridine and 120 cc of 90% sulfuric acid was heated for 3 hours at 100°C and then cooled to 15°-20°C. A solution of 15 gm of sodium nitrite in 30 cc of water was added to the reaction mixture and the mixture was heated at 100°C for 2 hours. After cooling, the reaction mixture was added to a mixture of ice and water and then filtered. The precipitate was washed with water and extracted with a 10% aqueous sodium carbonate solution. The solution was made acidic by the addition of 6N hydrochloric acid, was filtered and the precipitate was washed with water and dried to obtain 10.6 gm of 2-chloro-9-carboxy-acridine melting at a temperature above 300°C. The product was used as such for the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[C:7]([C:9](F)(F)F)[CH:6]=[CH:5][N:4]=1.[OH-:14].[Na+].[C:16](=O)([O-])[OH:17].[Na+].[I-]>C(OCC)(=O)C.O.CO>[CH3:1][N:2]([CH3:13])[C:3]1[N:8]=[C:7]([C:9]([O:17][CH3:16])=[O:14])[CH:6]=[CH:5][N:4]=1
Reactant: [OH-]
Reactant: O=C([O-])O
Reactant: CN(C)c1nccc(C(F)(F)F)n1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccnc(N(C)C)n1
Temperature: 160 °C
Yield: 9.3 %

Procedure:
2-Dimethylamino-4-trifluoromethylpyrimidine (320 mg, 1.7 mmol, Reference Compound No. 1-1) and sodium hydroxide (670 mg, 17 mmol) were suspended in a mixed solvent of methanol (5.0 mL) and water (5.0 mL), and then the mixture was stirred while radiated with microwave for 2 and a half hours at 160° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate (30 mL), and extracted with water (30 mL), and then extracted with saturated aqueous sodium hydrogencarbonate solution (30 mL). The extracted aqueous layer was adjusted to pH7 with 6M hydrochloric acid, and was concentrated under reduced pressure. The remaining residue was suspended in N,N-dimethylformamide (5.0 mL), then sodium hydrogencarbonate solution (1.3 g, 14 mmol) and methyl, iodide (0.87 mL, 17 mmol) were added thereto, and the whole was stirred for 23 hours at room temperature. The reaction mixture was diluted with ethyl acetate (100 mL), washed twice with saturated aqueous sodium hydrogencarbonate solution (100 mL), and then washed twice with brine (100 mL), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography to give 28 mg of the title Reference Compound as a colorless needle (Yield: 9.3%)
Reaction SMILES: C([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5](F)[CH:4]=1)#N.[CH3:12][O-:13].[Na+].[CH3:15][N:16](C)C=O>CO.O>[C:15]([C:5]1[CH:4]=[C:3]([O:13][CH3:12])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])#[N:16]
Reactant: C[O-]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C=O)c(C#N)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a stirred solution of 4-cyano-2-fluorobenzaldehyde (0.5 g, 3.4 mmol) in dry dimethylformamide (3 ml) cooled to 5° C. under a nitrogen atmosphere, a solution of freshly prepared sodium methoxide in methanol (1.41M, 2.62 ml) was added slowly, dropwise. After addition, the reaction mixture was stirred at room temperature for 22 hours. A few drops of water were then added and the turbid solution filtered through celite. The filtrate was further diluted with water until crystallisation commenced to give 2-cyano-4-methoxybenzaldeyde as a pale yellow solid. A second crop was recovered from the filtrate.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CN(C)C=O>[F:16][C:2]([F:1])([F:15])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[N:7]([CH:24]([CH3:26])[CH3:25])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2cc(F)ccc12)C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C(=O)C(F)(F)F)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
A solution of 2,2,2-trifluoro-1-(6-fluoro-1H-indol-3-yl)-ethanone (1.63 g, 7.05 mmol) in N,N-dimethylformamide (15 mL) at 25° C. was treated with potassium carbonate (2.44 g, 17.63 mmol). The resulting mixture was stirred at 25° C. for 15 min. At this time, the reaction was treated with 2-iodopropane (1.06 mL, 10.58 mmol). The reaction was heated at 65° C. for 18 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (1×25 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 2,2,2-trifluoro-1-(6-fluoro-1-isopropyl-1H-indol-3-yl)-ethanone (1.74 g, 90%) as a yellow solid: mp 67-69° C.; EI-HRMS m/e calcd for C13H11F4NO (M+) 273.0776, found 273.0780.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[NH:16][C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH3:28]>CN(C=O)C.O>[C:1]([O:5][C:6]([C:8]1[CH:19]=[CH:18][C:11]2[CH2:12][CH2:13][O:14][C:15](=[O:17])[N:16]([CH2:27][CH3:28])[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc2c(c1)NC(=O)OCC2
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)OCCc2ccc(C(=O)OC(C)(C)C)cc21

Procedure:
A mixture of 6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester (1.1 g, 4.18 mmol), potassium carbonate (2.5 g, 18.1 mmol, 4.3 eq.) and iodoethane (1.67 mL, 20.87 mmol, 5 eq.) was stirred in DMF (20 mL) for 16 hours at 60° C. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated. Silica gel chromatography (0→20% ethyl acetate in hexanes) provided 5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocycloheptene-3-carboxylic acid tert-butyl ester as pale solid in quantitative yield: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.80 (dd, 1H), 7.28 (d, 1H), 4.48 (t, 2H), 3.91 (q, 2H), 3.00 (t, 2H), 1.59 (s, 9H), 1.23 (t, 3H).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22].O>C(#N)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:1])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: CC1C(=O)Nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1C(=O)N(CCCCl)c2ccccc21
Yield: 15.1 %

Procedure:
To a mixture of 3-methylindolin-2-one (1 g, 6.79 mmol, 1 equiv) in acetonitrile, potassium carbonate (1.877 g, 13.58 mmol, 2.5 equiv) followed by 1-bromo-3-chloropropane (2.01 ml, 20.38 mmol, 3 equiv) were added. The reaction was refluxed for 16 h. Upon cooling water was added and the mixture was extracted into ethyl acetate. The organic layer was further washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified using the Biotage flash chromatography system (SNAP 100 g cartridge, Rf=0.5, gradient—2%-20% ethyl acetate in hexanes) to afford the title compound as a yellow oil (230 mg, 15%); 1H NMR (400 MHz, DMSO-d6): δ 1.31 (d, 3H, J=7.6 Hz); 1.99-2.05 (m, 2H); 3.47-3.53 (m, 1H); 3.66 (t, 2H, J=6.4 Hz); 3.74-3.82 (m, 2H); 7.04 (d, 2H; J=7.6 Hz); 7.24-7.27 (m, 1H); 7.3-7.32 (m, 1H); MS for C12H14ClNO m/z 211.06 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[CH:64]1([NH2:71])[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1>CN(C)C=O>[NH3:11].[Si:1]([O:8][C@H:9]([C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH2:32][OH:33])[CH:26]=1)[CH2:10][NH:11][C@H:12]([CH3:24])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([NH:71][CH:64]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]2)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NC1CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@H](Cc1cccc(CC(=O)NC2CCCCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h
Yield: 117.2 %

Procedure:
A solution of (3-{(2R)-2-[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetic acid (Preparation 20) (250 mg, 0.45 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), hydroxybenzotriazole monohydrate (66 mg, 0.49 mmol) in N,N-dimethylformamide (4 ml) was treated with triethylamine (0.12 ml, 0.89 mmol) and cycloheptylamine (56 mg, 0.49 mmol) and the resulting suspension left to stir at room temperature under a nitrogen atmosphere for 18 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (10 ml) and saturated aqueous sodium bicarbonate (10 ml). The organic phase was separated, and the aqueous phase extracted with further ethyl acetate (2×10 ml). The combined organic extracts were washed with water (5 ml), brine (5 ml), dried (sodium sulfate) and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95:5:0.5 by volume) to give the title compound as a pale yellow oil (150 mg). 1H NMR (400 MHz, CD3OD): δ=7.20-6.98 (6H, m), 6.68 (1H, d), 4.60 (3H, m), 3.80 (1H, m), 3.40 (2H, s), 2.85 (2H, m), 2.63 (2H, m), 2.58 (1H, m), 1.80 (2H, m), 1.75-1.40 (10H, m), 1.03 (3H, d), 0.83 (9H, s), 0.00 (3H, s), −0.20 (3H, s) ppm. LRMS (electrospray): m/z [M+H]+ 569.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH:14]2[O:16][CH2:15]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cc(F)ccc1OCC1CO1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
A mixture consisting of 31.4 g of 4-fluoro-2-nitrophenol, 100 ml of epichlorohydrin, 9.1 g of sodium hydroxide, 40 ml of water, and 900 ml of ethanol was stirred at 80° C. for 10 hours. The reaction mixture was cooled to room temperature, and any insoluble matter was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in a 1:1 mixed solvent of diethyl ether and hexane, washed with water and then with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using a 3:1 mixture of chloroform and hexane as a developing solvent. The fraction containing the desired compound was concentrated to give 27.9 g of the title compound.
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][N:5]=1>C(O)C>[OH:2][N:1]=[C:8]([NH2:9])[C:7]1[CH:10]=[CH:11][C:4]([CH3:3])=[N:5][CH:6]=1
Reactant: Cc1ccc(C#N)cn1
Reactant: NO
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cn1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 0.765 g, 10 mmol) in ethanol (10 mL) was treated with a solution 6-methylnicotinonitrile (Aldrich, 12.8 g, 100 mmol) in ethanol (10 mL). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 2.2 (s, 3H), 6.02 (bs, 2H), 7.59 (m, 1H), 8.06-8.0 (m, 2H), 10.2 (s, 1H) ppm; MS (DCl/NH3) m/z 152 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[S:12][CH:13]=2)=[CH:5][CH:4]=1.CC(=CC)C.Cl([O-])=[O:24].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(O)(C)(C)C>[F:17][C:2]([F:16])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([C:14]([OH:24])=[O:15])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[4-(trifluoromethyl)phenyl]thiophene-2-carbaldehyde (intermediate 37, 1.23 g), t-butanol (20 ml) and 2-methyl-2-butene (10 ml) was cooled to 0° C. To this was added drop-wise, a solution of sodium chlorite (3.8 g) and sodium dihydrogen phosphate (4.03 g) in water (15 ml). After the addition was complete, the mixture was allowed to warm to room temperature and was stirred for 4 hours. The solution was then concentrated and partitioned between water and ethyl acetate. The aqueous layer was washed with a second ethyl acetate portion and the organic liquors were combined, washed with brine, then dried (MgSO4). The solution was then absorbed onto silica and loaded onto a SPE (Si) cartridge. The product was eluted with neat ethyl acetate to afford the title compound as a white solid.
Reaction SMILES: O[C@H:2]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)[CH2:3][CH2:4][C:5]([O:7]C)=[O:6]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([C@H:2]2[O:7][C:5](=[O:6])[CH2:4][CH2:3]2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)CC[C@H](O)c1cccc(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc([C@@H]2CCC(=O)O2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
The (S)-methyl 4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg) is dissolved in CH2Cl2 (10 mL), and the solution is cooled to 0° C. Trifluoroacetic acid (˜4 drops) is added and the mixture is stirred for 8 h at room temperature to complete the lactonization. The reaction is quenched with aqueous sodium bicarbonate, and the organic layer is washed with water, dried (Na2SO4), and concentrated to yield 827 mg (100%) of (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one as a colorless oil.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]1[CH:17]=[C:18]([C:31]2[C:32]([OH:38])=[CH:33][CH:34]=[C:35]([F:37])[CH:36]=2)[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[C:39]([O:44]C(C)(C)C)(=[O:43])[C@@H:40]([CH3:42])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:15][C:16]1[CH:17]=[C:18]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=2[O:38][C@@H:40]([CH3:42])[C:39]([OH:44])=[O:43])[CH:19]=[CH:20][C:21]=1[S:22]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2cc(F)ccc2O)cc1F
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropyl azodicarboxylate (0.19 ml) was added to a solution of the product of example 2 part (iii) (250 mg), tert-butyl(R)-(+)-lactate (141 mg) and triphenylphosphine (252 mg) in tetrahydrofuran (10 ml) at 0° C. After 20 minutes the ice bath was removed and the reaction stirred at room temperature overnight. The reaction mixture was then adsorbed onto silica and purified using flash column chromatography (eluent 10% ethylacetate/hexane) to give the subtitle compound as an oil, yield 140 mg.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH2:12][CH2:13][OH:14])=[CH:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:15][S:16]([O:14][CH2:13][CH2:12][CH2:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1cc(CCCO)c2ccccc21
Product: Cn1cc(CCCOS(C)(=O)=O)c2ccccc21

Procedure:
3-(1-methyl-3-indolyl)-1-propyl methanesulfonate was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (291 mg, 84%) from 3-(1-methyl-3-indolyl)-1-propanol (245 mg, 1.30 mmol) and methanesulfonyl chloride (223 mg, 1.94 mmol). 1H NMR (CDCl3, 300 MHz) δ2.15 (qu, 2H, J=7.0 Hz), 2.90 (t, 2H, J=7.0 Hz), 2.99 (s, 3H), 3.76 (s, 3H), 4.27 (t, 2H, J=6.2 Hz), 6.88 (s, 1H), 7.11 (dt, 1H, J=1.1, 6.9 Hz), 7.23 (dt, 1H, J=1.1, 7.0 Hz), 7.29 (d, 1H, J=8.5 Hz), 7.57 (d, 1H, J=8.1 Hz) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:27]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:28]
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1N
Product: Cc1cc(N2CC[C@H](CN3CCC[C@@H]3C)C2)ccc1NC(=O)C1CCCCC1
Yield: 45 %

Procedure:
The title compound was prepared in a manner substantially the same as example 20 by coupling (2S,3R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl-methyl)-pyrrolidin-1-yl]-phenylamine with cyclohexanecarbonyl chloride in 45% yield.