Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(F)cc3O)nccc2c1
Yield: 22 %

Procedure:
1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide was dissolved in DCM (1 ml) and TFA (1 ml) and stirred at ambient temperature for 2 h. The mixture was purified by reverse phase chromatography, eluting with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(4-fluoro-2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (20 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H) 10.19 (s, 1H) 8.65 (d, J=5.67 Hz, 1H) 8.51 (d, J=1.56 Hz, 1H) 8.06 (d, J=5.87 Hz, 1H) 7.78-7.91 (m, 2H) 7.34 (t, J=7.78 Hz, 1H) 7.26 (d, J=4.50 Hz, 1H) 6.76-6.88 (m, 3H). m/z (ESI) 402.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7]CC)=O.[CH2:14]([N:21]1[C:26]2[N:27]=[CH:28][CH:29]=[CH:30][C:25]=2C(=O)[O:23][C:22]1=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(N(C)C)=O>[CH2:14]([N:21]1[C:26]2[C:25](=[CH:30][CH:29]=[CH:28][N:27]=2)[C:5]([OH:7])=[C:4]([C:3]([O:11][CH2:12][CH3:13])=[O:10])[C:22]1=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=c1oc(=O)n(Cc2ccccc2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(O)c2cccnc2n(Cc2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
To a slurry of sodium hydride (60%, 0.118 g, 2.95 mmol) in anhydrous dimethylacetamide (6 mL) at 0° C. under N2 was added diethyl malonate (0.472 g, 2.95 mmol) dropwise over 5 minutes. The mixture was stirred at ambient temperature for 1 hour, reacted with the product of Example 15A (0.50 g, 1.97 mmol), and heated at 120° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and cold water, and adjusted to pH to 5 with 1 M HCl. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was recrystallized from methanol to give the title compound as a white solid (0.439 g, 68%). MS (ESI+) m/z 325.0 (M+H)+, 347.0 (M+Na)+; 1H NMR (300 MHz, DMSO-d6) δ 1.30 (t, J=7.17 Hz, 3H), 4.32 (q, J=7.23 Hz, 2H), 5.55 (s, 2H), 7.23 (m, 5H), 7.37 (dd, J=7.91, 4.60 Hz, 1H), 8.45 (dd, J=7.91, 2.02 Hz, 1H), 8.71 (dd, J=4.78, 1.84 Hz, 1H), 13.00 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](=[N:8][OH:9])[Cl:7].[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>CCOCC>[CH3:10][S:11]([O:9][N:8]=[C:6]([Cl:7])[CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)(=[O:13])=[O:12]
Reactant: ON=C(Cl)C1CCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)ON=C(Cl)C1CCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A 500 mL round-bottomed flask was charged with tetrahydrofuran-2-carbonyl chloride oxime (2.6 g, 17.4 mmol), methanesulfonyl chloride (1.4 ml, 17.4 mmol), and Et2O (200 mL). Triethylamine (2.4 ml, 17.4 mmol) was added dropwise over about 1 minute and stirred at ambient temperature for 10 minutes. The resultant solids were filtered and the filtrate was concentrated. The resultant residue was purified on silica gel (100% DCM) to afford N-(methylsulfonyloxy)tetrahydrofuran-2-carbimidoyl chloride (2.1 g, 53.07% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[C:12][Si](C)(C)C)[CH3:2]>CN(C=O)C.[F-].[K+].CCOCC>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[C:11]#[CH:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#Cc1ncccc1C(=O)OCC
Temperature: 25 °C

Procedure:
6.2 g of 2-(2'-trimethylsilylethynyl)-nicotinic acid ethyl ester are dissolved in 50 ml of DMF and 3 g of KF.2H2O are added. After stirring at RT, the reaction mixture is diluted with 300 ml of ether filtered through celite, shaken with 150 ml of water and refiltered. The aqueous phase is extracted four times with 100 ml ether and the combined ether extracts dried over MgSO4, filtered and dried under vacuum. The intermediate can be further purified by chromatography over silica with ethylacetate/hexane.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][C:17](=[O:18])[C:13]=2[CH:12]=1>ClCCl>[CH3:9][O:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][C:16](=[CH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:17](=[O:18])[C:13]=2[CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CO2
Solvent: ClCCl
Product: COc1ccc2c(c1)C(=O)C(=Cc1ccccc1)O2
Temperature: 25 °C

Procedure:
36.5 mmol (3.9 g) of benzaldehyde are added to a solution of 30.5 mmol (5 g) of 5-methoxy-3-benzo[b]furanone in 150 ml of dichloromethane. With vigorous stirring and at ambient temperature, 25 g of basic alumina are then added. Stirring is maintained at ambient temperature for 30 minutes. The mixture is then filtered, the filtrate is concentrated and the residue obtained is washed with a minimum amount of ethanol to yield the expected compound. Melting point: 134° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][CH2:20][C:21]#[N:22]>>[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=1[CH2:19][C:20]1[C:21]([NH2:22])=[N:1][C:2]2[C:7]([CH:8]=1)=[CH:6][N:5]=[CH:4][CH:3]=2
Reactant: Nc1ccncc1C=O
Reactant: COc1cccc(Cl)c1CCC#N
Product: COc1cccc(Cl)c1Cc1cc2cnccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 4-aminonicotinaldehyde and 3-(2-chloro-6-methoxyphenyl)propionitrile.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[C:10](=[O:19])[C:9]2=[O:20])(=[O:4])=[O:3].[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[N+:24]([O-:47])[CH:25]=[C:26]([Cl:46])[C:27]=1[CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH:38]([F:40])[F:39])=[C:33]([O:41][CH2:42][CH:43]2[CH2:45][CH2:44]2)[CH:32]=1)[O:17][C:16](=[O:18])[CH2:15][N:11]1[C:12]2[C:8](=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:14][CH:13]=2)[C:9](=[O:20])[C:10]1=[O:19]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
A mixture of 2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid (141 mg, 0.473 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (166 mg, 0.394 mmol), EDC (227 mg, 1.182 mmol) and DMAP (24.06 mg, 0.197 mmol) in DCM (25 ml) was stirred at room temperature overnight. The solvent was evaporated, DMF (10 ml) was added, and the resulting solution was stirred at 80° C. for 6 hours. DMAP (48.1 mg, 0.394 mmol) was added, and stirring at 80° C. was continued for 2 days. The solvent was evaporated, DCM was added, and the mixture was washed with NaHCO3 5% and 1N HCl; the organic layer was dried over Na2SO4, filtered and evaporated affording a crude that was purified by flash chromatography on silica gel (DCM:Ethyl acetate from 50:50 to 30:70; then 100% DCM and then DCM:MeOH from 99:1 to 97:3). The product was further purified by Preparative HPLC (Method 3) affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)-phenyl)-2-(2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetoxy)ethyl)pyridine 1-oxide (0.012 g, 0.017 mmol, 4% yield). MS/ESI+ 700.16 [MH]+; [αD]=+63.50, c=0.12 in DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 9.75 (br. s., 1H), 8.43 (s, 2H), 7.45 (dd, 1H), 7.41 (d, 1H), 7.18 (d, 1H), 7.07 (d, 1H), 7.05 (d, 1H), 6.95 (dd, 1H), 7.07 (t, 1H), 6.03 (dd, 1H), 4.64 (d, 1H), 4.56 (d, 1H), 3.91 (d, 2H), 3.40 (dd, 1H), 3.22 (dd, 1H), 3.02 (s, 3H), 1.12-1.31 (m, 1H), 0.54-0.63 (m, 2H), 0.31-0.44 (m, 2H).
Reaction SMILES: [OH-].[Al+3:2].[OH-].[OH-].[C:5]([OH:10])(=[O:9])[CH:6]([CH3:8])[OH:7]>O>[C:5]([O-:10])(=[O:9])[CH:6]([CH3:8])[OH:7].[Al+3:2].[C:5]([O-:10])(=[O:9])[CH:6]([CH3:8])[OH:7].[C:5]([O-:10])(=[O:9])[CH:6]([CH3:8])[OH:7]
Reactant: CC(O)C(=O)O
Agent: [Al+3]
Agent: [OH-]
Solvent: O
Product: CC(O)C(=O)[O-]
Temperature: 69.85000000000002 °C
Reaction time: 70 h

Procedure:
Aluminum(III) hydroxide (2.21 g) was suspended with stirring (340 rpm) in water (10.8 g) maintained at 343 K, lactic acid (6.97 g) added over 1 minute, and stirring continued at 343 K for 70 hours. A white suspension was obtained, and this was diluted to 6% w/w solids for testing.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][C:11]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:9]2=[O:21])[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N:8]3[CH2:13][CH2:12][C:11]([CH3:20])([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:10][C:9]3=[O:21])[N:3]=2)=[CH:25][CH:24]=1
Reactant: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1
Product: CC1(c2ccccc2)CCN(c2nccc(-c3ccc(F)cc3)n2)C(=O)O1

Procedure:
The title compound was prepared following procedures analogous to those in Example 56 using 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one and 4-fluorophenylboronic acid. LC-MS Method 3, tR=1.193 min, m/z=363.9. 1H NMR (CDCl3) 1.60 (s, 1H), 1.80 (s, 3H), 2.48-2.53 (m, 1H), 2.62-2.71 (m, 1H), 3.60-3.67 (m, 1H), 4.30-4.40 (m, 1H), 7.20-7.55 (m, 10H), 7.60-7.62 (m, 1H), 8.05-8.15 (m, 3H), 8.80-8.85 (m, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[C:18]2[O:17][C:16]([C:19]([NH2:21])=O)=[CH:15][C:14](=[O:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]>CN(C)C=O>[N+:6]([C:9]1[C:18]2[O:17][C:16]([C:19]#[N:21])=[CH:15][C:14](=[O:22])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: NC(=O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 78 %

Procedure:
Phosphorous oxychloride (2.86 ml) was added very slowly at 0° C. to dry N,N-dimethylformamide (40 ml) and the mixture was left under stirring at room temperature for 35 minutes. After that a solution of 8-nitro-4-oxo-4H-1-benzopyran-2-carboxamide (1.515 g, 6.47 mmol) in N,N-dimethylformamide (10 ml) was added and the mixture was left under stirring at room temperature for 18 h. After this time, the reaction mixture was poured onto an ice-water mixture (100 ml) and extracted with ethyl acetate (4×40 ml). After drying and removing the solvents under reduced pressure, a residue was obtained which was purified by chromatography through a silica gel column. Eluting with hexane:chloroform, 7:3, 1.094 g of the title product were recovered (78% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Si](C)(C)C)=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[O:23][CH3:24].[I:25]Cl>ClCCCl>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([I:25])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[O:23][CH3:24]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)cc2)c(F)c(N)c1OC
Reactant: ClI
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(I)cc2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.9 %

Procedure:
Methyl 4-amino-5-fluoro-3-methoxy-6-(4-(trimethylsilyl)phenyl)picolinate (239 mg, 0.686 mmol) was dissolved in 1,2-dichloroethane (3.4 mL) and iodine monochloride (78 μL, 1.557 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was quenched with 10% Na2S2O3 (2 mL) and stirred at room temperature for 1 h. The mixture was extracted with CH2Cl2 (3×5 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The product was purified via RP-HPLC (CH3CN/H2O) to yield the title compound as an orange solid (270 mg, 98%): 1H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J=8.5 Hz, 2H), 7.65-7.53 (m, 2H), 6.54 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −140.64; ESIMS m/z 403.61 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N1C=CC=CC=1.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:14]2[CH:15]=[C:16]([Cl:20])[CH:17]=[N:18][CH:19]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:31]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1cc(N)ccc1Oc1cncc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(NC(=O)c2ccc(Cl)cc2Cl)ccc1Oc1cncc(Cl)c1
Reaction time: 1.5 h
Yield: 79.6 %

Procedure:
To a solution of the aniline produced in Example 1 (100 mg, 0.34 mmol) in CH2Cl2 (2 mL) was added pyridine (81 μL, 1 mmol) and 2,4-dichlorobenzoyl chloride (140 mg, 0.68 mmol). The mixture was stirred for 90 min. The product was purified by column chromatography on silica gel (gradient elution: 30:1 hexane/ethyl acetate to 7:1 hexane/ethyl acetate) followed by recrystallization from Ch2Cl2/hexanes to yield 126 mg (79%) of the title compound. mp 125-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[C:17](Cl)=[O:18].C(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].CCOC(C)=O>C(Cl)Cl.CC[Mg+].[Br-].[Cl-].[Cl-].[Zn+2].CCCCCC>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]([C:16]3[CH:20]=[C:21]([O:25][CH3:26])[C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=3)=[O:18])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: CC[Mg+]
Agent: [Al+3]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c[nH]c2c1
Reaction time: 1 h
Yield: 72 %

Procedure:
To a mixture of 6-methoxyindole (0.3 g, 2.03 mmol) and anhydrous ZnCl2 (0.56 g, 4.07 mmol) in CH2Cl2 (10 mL), EtMgBr (0.9 ml, 3 M) was added over 10 min at room temperature. The obtained suspension was stirred for 1 hr. To the suspension, the solution of 3,4,5-trimethoxybenzoyl chloride/CH2Cl2 (10 ml) was added dropwisely during 5 min for a coupling reaction. The reaction mixture continued stirring for another 1 hr and AlCl3 (0.27 g, 2.03 mmol) was added. The resultant thick mixture was vigorously stirred for 5 hr while monitoring by TLC (EtOAc:n-hexane=1:1). The reaction was quenched with H2O (10 ml) and extracted with CH2Cl2 (10 mL×3). The combined extracts was dried by MgSO4, and evaporated to give a brown oil which was chromatographed (silica gel; EtOAc:n-hexane=1:1) to afford Compound 1 (0.5 g, 72%) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)=[CH:9][CH:10]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Oc1ccc(Nc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Nc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 72.6 %

Procedure:
To a solution of 4-hydroxydiphenylamine (200 mg, 1.08 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (80 mg, 2 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (387 mg, 1.09 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (289 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:34])[C:25]=4[NH:26]C(OC(C)(C)C)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]>Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:34])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Agent: Cl
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[4′-(5-tert-Butoxycarbonylamino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.49 g, 1.1 mmol) was dissolved in HCl (4 N in dioxane, 3 mL) and stirred at room temperature for 30 minutes. The reaction was concentrated to dryness to yield the title compound as the hydrochloride salt.
Reaction SMILES: C1([C@H]([N:9]2[CH2:15][C@H:14]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH2:13][O:12][CH2:11][CH2:10]2)C)C=CC=CC=1.ClC(OC(Cl)C)=O.CO>ClCCCl>[O:12]1[CH2:13][C@@H:14]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: C[C@H](c1ccccc1)N1CCOC[C@@H](c2ccc(C#N)cc2)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCCl
Product: N#Cc1ccc([C@H]2CNCCOC2)cc1
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To a solution of (S)-4-(4-((R)-1-phenylethyl)-[1,4]oxazepan-6-yl)benzonitrile (0.662 g, 2.16 mmol) in 1,2-dichloroethane (3.60 ml) was added 1-chloroethyl chloroformate (0.772 g, 5.40 mmol) at room temperature. The mixture was refluxed for 8 hours. Methanol (15 ml) was added to the mixture cooled to room temperature. The mixture was refluxed again for 2 hours. The mixture was concentrated in vacuo. The residue was partitioned between aqueous sodium hydrogen carbonate and chloroform. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=96/4) to afford (S)-4-([1,4]oxazepan-6-yl)benzonitrile as pale yellow solid (312 mg, 70%).
Reaction SMILES: C[CH:2]([CH:6]1[C:11]2=[CH:12][C:13]3[C:18]([N:10]2[CH2:9][CH2:8][CH2:7]1)=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[C:3]([O-:5])=[O:4].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([C:12]2[C:13]3[C:18](=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[CH:20]([CH3:22])[CH3:21])[N:10]3[CH2:9][CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:11]=23)=[O:29])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)c1cc(F)cc2c1cc1n2CCCC1C(C)C(=O)[O-]
Product: CC(C)c1cc(F)cc2c1c(C(=O)c1ccc(Cl)cc1)c1n2CCCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl(3-fluoro-1-isopropyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (Example 122, Step 4) and 4-chlorobenzoyl chloride, the title compound was synthesized following the procedures described in Step 1 of Example 61 and Step 10 of Example 7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[C:7]([CH3:15])[C:6]=2[CH:16]=1.[BH4-].[Na+].O>CO.O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])=[C:7]([CH3:15])[C:6]=2[CH:16]=1
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(O)C(C)C)oc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.1 %

Procedure:
1-(5-Fluoro-3-methyl-1-benzofuran-2-yl)-2-methylpropan-1-one (11.66 g) synthesized above was dissolved in methanol (4 mL)-tetrahydrofuran (20 mL), and sodium tetrahydroborate (90%) (446 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (1.193 g, 100%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:17])C(=O)C1>C(O)(=O)C>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[I:17])[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cc(O)ncn1
Solvent: CC(=O)O
Product: CCc1nc[nH]c(=O)c1I
Temperature: 25 °C
Reaction time: 30 h

Procedure:
To a stirred solution of 70 g (0.56 mol) 4-hydroxy-6-ethyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min The reaction is stirred for 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a solid (90 g; 64%) which is used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+:7].[C:8]1(=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1>CO.[Pd]>[Na+:7].[CH:8]1([NH:1][CH2:2][C:3]([O-:5])=[O:4])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: NCC(=O)O
Reactant: O=C1CCc2ccccc21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CNC1CCc2ccccc21
Reaction time: 24 h
Yield: 29.7 %

Procedure:
Glycine (5.1 g, 0.068 mole) was dissolved in a solution of NaOH (2.72 g, 0.068 mole) and methanol (125 ml). To this was added 1-indanone (10.0 g, 0.076 mole, 10% excess) and 5% Pd/C dry (2.0 g). This mixture was subjected to hydrogen at room temperature on a Parr shaker for 24 hours. The catalyst was removed by filtration and fresh 5% Pd/C dry (2.0 g) added. Hydrogenation was resumed for 20 hours. A total of 55 psi of H2 (68 psi theory) was taken up. The catalyst was removed by filtration and the filtrate concentrated under reduced pressure to an oily residue. This residue was dissolved in H2O (100 ml) and extracted with ethyl acetate (3×25 ml). The aqueous solution was cooled on an ice bath and a white solid precipitated. This solid was collected and air dried to give 5.0 g of crude product. A second crop was obtained by concentrating the filtrate under reduced pressure to a solid residue. This residue was recrystallized from 70% isopropanol/H2O (40 ml), collected and air dried to give 4.3 g of product. The two crops were combined, triturated in 80% isopropanol/H2O (50 ml), collected, air dried and dried in vacuo at 60° to give 6.8 g (0.037 mole, 47% yield), melting point 196°-200° (dec.).