Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[F:2][C:3]([F:22])([F:21])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]([O-:20])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:64]([F:67])([F:66])[F:65])([O-:50])=[O:49].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][CH:58]2[CH2:59][CH2:60][N:61]([C:18](=[O:20])[CH2:17][CH2:16][CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:21])([F:2])[F:22])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:62][CH2:63]2)=[CH:53][C:52]=1[C:64]([F:67])([F:65])[F:66])([O-:50])=[O:49]
Reactant: O=C([O-])CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CCC1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of 3-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-propionic acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 140) in tetrahydrofuran (1.0 mL) is added tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (12 mg; 0.021 mmol). The structure was confirmed using Protocol I-D. Calculated mass=572; observed mass=573; HPLC retention time=1.13 min.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:6]=1[CH2:7]Cl)([O-:4])=[O:3].[OH-:19].[Na+]>>[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]([N+:16]([O-:18])=[O:17])[C:6]=1[CH:7]=[CH:7][C:6]1[C:5]([N+:2]([O-:3])=[O:19])=[CH:12][C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([O-:4])=[O:3]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(CCl)c([N+](=O)[O-])c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(C=Cc2c([N+](=O)[O-])cc([N+](=O)[O-])cc2[N+](=O)[O-])c([N+](=O)[O-])c1
Reaction time: 0.02 h
Yield: 50 %

Procedure:
Two methods of preparing 2,2',4,4',6,6'hexanitrostilbene (HNS) are disclosed in U.S. Pat. No. 3,505,413, entitled "Hexanitrostilbene," issued to Kathryn, G. Shipp on Apr. 7, 1970. In the first 2,4,6-trinitrotoluene was reacted with 5 percent sodium hypochlorite (Clorox) at 0° C. in a tetrahydrofuran (THF)-methanol solvent mixture to produce HNS in a single step (disclosed yield 42%). In the second method, the above conditions were used except that the reaction was stopped after one minute by drowning the reaction mixture in very dilute hydrochloric acid. The reported yield of 2,4,6-trinitrobenzyl chloride was 85 percent. Next the 2,4,6-trinitrobenzyl chloride was reacted at room temperature with sodium hydroxide to give HNS (reported yield 50%). Thus, the yield of HNS using the two step method was 0.85×0.50 =0.425 or 42.5%. It would be desirable to find a method of substantially increasing this yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[C:9]([C:13]#[N:14])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.BrC1C2N(CC(O)=[O:27])C=NC=2C=CC=1>>[C:13]([C:9]1[C:8]2[N:4]([CH2:3][C:2]([OH:27])=[O:1])[CH:5]=[N:6][C:7]=2[CH:12]=[CH:11][CH:10]=1)#[N:14]
Reactant: O=C(O)Cn1cnc2cccc(Br)c21
Reactant: N#Cc1cccc2ncn(CCO)c12
Product: N#Cc1cccc2ncn(CC(=O)O)c12

Procedure:
(7-Cyano-1H-benzimidazol-1-yl)acetic acid was prepared starting from 1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile (89 mg) according to the procedure described for the synthesis of (7-bromo-1H-benzoimidazol-1-yl)acetic acid. Yield 38 mg (39 %). MS (ESI) m/z 202.0 [M+H). 1H NMR (400 MHz, DMSO-D6) δ ppm: 5.31 (s, 2 H), 7.37 (dd, J=8.1, 7.7 Hz, 1H), 7.75 (dd, J=7.6, 0.8 Hz, 1H), 8.04 (dd, J=8.1, 1.1 Hz, 1H), 8.38 (s, 1H), 13.43 (bs, 1H).
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].CC([O-])=O.[Na+].Cl.[NH2:26][OH:27].C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.O>[CH2:1]([CH:5]1[C:10](=[N:26][OH:27])[CH2:9][CH2:8][N:7]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCC1CN(CCc2ccccc2)CCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CCCCC1CN(CCc2ccccc2)CCC1=NO

Procedure:
3-Butyl-1-phenethyl-piperidine-4-one (300 mg), NaOAc (878 mg) and hydroxylamine hydrochloride (708 mg) were suspended in ethanol/water (1:1, 10 ml) and the mixture was heated to reflux for 5 hours. The clear solution that resulted from this treatment was cooled, diluted with water and basified with 10% aq. Na2CO3 to pH 10. The suspension was extracted with DCM and the organic layer was washed with brine, dried (MgSO4) and evaporated. The product was sufficiently pure for the next step. Yellowish glass, mixture of cis and trans diastereomers (332 mg). MS (ESI): 261.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.Br[CH2:26][C:27]([NH:29][C@H:30]([C:35]([O:37][CH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:26][C:27]([NH:29][C@H:30]([C:35]([O:37][CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])=[CH:12][CH:13]=2)[C:6](=[O:15])[CH:5]=[CH:4][C:3]=1[C:16](=[O:24])[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1
Reactant: Nc1c(C(=O)c2ccc(F)cc2)ccc(=O)n1-c1ccc(O)cc1
Reactant: CC(C)C[C@H](NC(=O)CBr)C(=O)OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)COc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC1CCCC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
To a solution of 6-amino-5-(4-fluorobenzoyl)-1-(4-hydroxyphenyl)pyridin-2(1H)-one [WO 03/076405] (100 mg, 0.31 mmol) in anhydrous DMF (3 ml) under an atmosphere of nitrogen was added cyclopentyl N-(bromoacetyl)-L-leucinate (109 ml, 0.34 mmol, 1.1 eq) and potassium carbonate (51 mg, 0.37 mmol, 1.2 eq). The mixture was heated at 40 C for 16 hours, before being allowed to cool to room temperature and added to water (20 ml). The mixture was extracted with EtOAc (3×15 ml), and the combined extracts washed with water (2×40 ml) and brine (40 ml). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by column chromatography (2-3% MeOH in DCM) followed by trituration with minimal MeOH afforded the title compound as a white solid (91 mg, 52% yield).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][CH2:7][C:8]([NH:10][C:11]1[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]([O:21][CH3:22])[C:14]([NH:23][C:24](=O)[CH2:25][Cl:26])=[C:13]([C:28](=[O:31])[NH:29][CH3:30])[C:12]=1[O:32][CH3:33])=O.C([O-])(=O)C.[Na+].[K+].[Br-]>C(OCC)(=O)C.CO.O.C(O)(=O)C>[Cl:26][CH2:25][C:24]1[N:29]([CH3:30])[C:28](=[O:31])[C:13]2[C:14]([N:23]=1)=[C:15]([O:21][CH3:22])[C:16]1[C:17](=[O:20])[N:18]([CH3:19])[C:8]([CH2:7][Cl:6])=[N:10][C:11]=1[C:12]=2[O:32][CH3:33]
Reactant: CNC(=O)c1c(NC(=O)CCl)c(OC)c(C(=O)NC)c(NC(=O)CCl)c1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1c2nc(CCl)n(C)c(=O)c2c(OC)c2nc(CCl)n(C)c(=O)c12
Temperature: 110 °C

Procedure:
To a solution consisting of 15 mL of acetic acid and 0.5 mL of sulfuric acid, was added 333 mg (0.766 mmol) of 12. The resulting mixture was heated at 110° C. for 5.5 hours. After cooling the reaction mixture to room temperature, the solution was poured over ca 50 mL of water and then buffered to pH 6 with sodium acetate. The resulting yellow precipitate was filtered, washed with water, and then dried. The dried solid was recrystallized from ethanol: 219 mg (72%) yield; mp 273°-274° C.; TLC (ethyl acetate/methanol [9:1]), Rf =0.34; IR (KBr) 1677, 1607, 1434, 1347, 1324, 1269, 1071, 1032, 795, 690 cm-1 ; 1H NMR (dimethyl-d6 sulfoxide) δ4.92 (4H, s, methylenes), 3.95 (6H, s, methoxys), 3.59 (6H, s, 3- and 8- methyls); mass spectrum (EI), m/z 398 (P+, 35Cl35Cl), 400 (P+, 37Cl35Cl), 402 (P30, 37Cl37Cl37). Anal. Calcd for C16H16Cl2N4O4 : C, 48.14; H, 4.04; N, 14.03. Found: C, 48.40; H, 4.03; N, 14.14.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].FC(F)(F)C(O)=O.ClCCl.CO>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[CH3:33])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(CCC(=O)O)ccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1

Procedure:
tert-Butyl 3-(4-(5-(3-Cyano-4 isopropyloxyphenyl)-1,2,4-thiadiazol-3-yl)-3-methylphenyl)propanoate (110 mg, 0.23 mmol, from Step D) was treated with 20% solution of trifluoroacetic acid in dichloromethane (10 mL) for 3 h at rt. The solvents were removed under reduced pressure, residual solids dissolved in toluene and concentrated again. Pure product was isolated by a column chromatography using a Biotage 40S column (eluent: dichloromethane/methanol=9/1): 1H NMR (500 MHZ, CDCl3) δ 1.49 (d, J=6.5, 6H), 2.65 (s, 3H), 2.77 (t, J=8.0, 2H), 3.03 (t, J=8.0, 2H), 4.79 (sep, J=6.5, 1H), 7.11 (d, J=9.0, 1H), 7.21 (d, J=9.0, 1H), 7.24 (s, 1H), 7.70 (d, J=8.0, 1H), 8.17 (d, J=2.0, 1H), 8.25 (dd, J=8.0, 2.0, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Cl>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: COc1cccc(CCl)c1
Product: COc1cccc(CN2CCC(=O)CC2)c1

Procedure:
1-(3-Methoxybenzyl)-4-piperidone is prepared from 4-piperidone and 3-methoxybenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([Br:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[CH2:18]([N:14]1[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]([OH:25])=[C:8]2[C:16]([Br:17])=[CH:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2Cc2ccccc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Br)cn(Cc3ccccc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-1-benzyl-3-bromo-7-cyano-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 429 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43]([S:48][CH3:49])=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[C:43]([S:48][CH3:49])=[N:42][N:41]=5)=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnc(SC)n4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnc(SC)n4CCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylthio)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (0.80 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.41 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 1 hour at −78° C. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), which was further recrystalized from ethyl acetate-hexane, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(5-methylthio-4-propyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 149) (617.6 mg) as yellow crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13]Br)(=[O:4])=[O:3].[CH3:15][O-:16].[Na+]>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[C:6]=1[CH2:13][O:16][CH3:15])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Br)c(Cl)c1CBr
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension comprising 8.5 g of 4-bromo-2-bromomethyl-3-chlorophenyl methyl sulfone and 100 ml of methanol, 1.5 g of sodium methoxide (95%) was added under cooling with ice, and then the mixture was stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:23][CH3:24])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7]1=[O:25].[H-].[Na+].I[CH3:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:23][CH3:24])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[N:16]([CH3:33])[S:17]([CH3:20])(=[O:18])=[O:19])[C:7]1=[O:25]
Reactant: COc1c2c(c(NS(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c2c(c(N(C)S(C)(=O)=O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 25 °C

Procedure:
A cold (0° C.) solution of N-[6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]methanesulfonamide (60 mg, 0.14 mmol) in anhydrous DMF (1 mL) was treated with sodium hydride (6.8 mg, 0.17 mmol; 60% dispersion in oil). The resultant mixture was stirred at the same temperature for 30 minutes, and treated with iodomethane (38 mg, 0.27 mmol). The reaction mixture was allowed to slowly warmed up to room temperature. The product mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to provide the title compound. ES MS M+1=458
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=[O:6].[C:20]1([O:28][CH3:29])[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:22][CH3:23].O1CCCC1>O1CCCC1>[CH3:23][O:22][C:21]1[C:20]([O:28][CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:11][CH2:12]1)=[O:6]
Reactant: COc1ccccc1OC
Reactant: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Temperature: -17 °C
Reaction time: 3 h

Procedure:
Into a 500-mL jacketed-bottom-drain resin pot fitted with a five-joint head equipped with a mechanical stirrer, a thermocouple, a reflux condenser topped with a nitrogen bubbler, a septum, and a stopper was placed 28.9 g (0.092 mol) of 4-[(methoxymethylamino)carbonyl]-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (15) (28.9 g, 0.092 mol, 87% pure) and 80 g of tetrahydrofuran. The solution was cooled to −17° C. and the cold lithiated veratrole/tetrahydrofuran slurry was added via cannula while maintaining the internal reaction temperature below −10° C. (15 minutes addition). The reaction mixture was then warmed to 10° C. and stirred for 3 hours. The solution may be used directly in Scheme L, step a, Example 109.
Reaction SMILES: Br[C:2]1(Br)[C@H:12]2[C@@H:3]1[CH2:4][O:5][C:6]1[C:11]2=[CH:10][CH:9]=[C:8]([CH2:13][O:14][CH3:15])[C:7]=1[C:16]([O:18][CH3:19])=[O:17].[Cl-].[NH4+]>C(O)C.[Zn]>[CH3:15][O:14][CH2:13][C:8]1[C:7]([C:16]([O:18][CH3:19])=[O:17])=[C:6]2[C:11]([C@H:12]3[CH2:2][C@H:3]3[CH2:4][O:5]2)=[CH:10][CH:9]=1
Reactant: COCc1ccc2c(c1C(=O)OC)OC[C@H]1[C@@H]2C1(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: COCc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21
Yield: 97.2 %

Procedure:
A mixture of methyl cis-(1aRS,7bSR)-1,1-dibromo-5-methoxymethyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 8, 1.06 g), zinc dust (4.14 g), and ammonium chloride (1.75 g) in absolute ethanol (100 mL) was stirred and heated at reflux for 6 hours. Further zinc dust (2.0 g) and ammonium chloride (0.9 g) were added and the mixture was stirred and heated at reflux overnight. After cooling, the mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was partitioned between DCM and water and the organic layer was dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(1aRS,7bSR)-5-methoxymethyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.63 g) as an oil.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[CH:13]([CH:15]1[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]([CH3:26])[CH2:16]1)=[O:14].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1COCC1.C([O-])(O)=O.[Na+].S([O-])([O-])=O.[Na+].[Na+].ClCCl>[CH3:26][CH:17]1[CH2:16][CH:15]([C:13]([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)=[O:14])[CH2:20][CH2:19][CH:18]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C1CCC(C=O)CC1C
Reactant: c1cscn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(C(=O)c2nccs2)CC1C
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of iPrMgCl—LiCl (1.3 M in THF, 187 mL, 243 mmol) at −5° C. was added thiazole (17.4 mL, 243 mmol) at such a rate that the internal temperature did not exceed 5° C. The resulting slurry was warmed to 15° C. over 15 minutes, and then cooled to −10° C. To the reaction mixture was added ethyl 4-formyl-2-methylcyclohexanecarboxylate (41 g, 207 mmol) as a solution in THF (100 mL) at such a rate the internal temperature did not exceed 5° C. The reaction mixture was stirred for 30 minutes at 0° C., and then quenched with water (100 mL) and diluted with EtOAc (500 mL) and 1N HCl (500 mL). The organic layer was separated, and the aqueous layer extracted again with EtOAc (700 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was diluted with DCM (500 mL), and to this mixture was added Dess-Martin periodinane (88 g, 208 mmol). During the addition, the temperature was controlled such that the internal temperature did not exceed 35° C. After 1 hour, the reaction mixture was cooled to room temperature and then diluted with saturated aqueous NaHCO3 (600 mL), aqueous 5% sodium sulfite (600 mL), and dichloromethane (600 mL). The heterogeneous mixture was stirred until both layers were clear. The layers were separated and the aqueous layer was extracted a second time with dichloromethane (600 mL). The organic layers were combined, dried over MgSO4, filtered, absorbed on silica, and purified by silica gel chromatography to afford ethyl 2-methyl-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate. MS ESI calc'd. for C14H20NO3S [M+H]+ 282. found 282.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C1CCN2C(=NCCC2)CC1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1COCC1>[CH3:20][C:19]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: [C-]#[N+]CC(=O)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1C
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A stirred mixture of methyl isocyanoacetate (7.0 g, 70 mmol, 1 eq) and DBU (10.06 g, 70 mmol, 1 eq) in THF was cooled to 0° C., and a solution of acetic anhydride (7.14 g, 70 mmol, 1 eq) in THF was added dropwise over 15 min. The reaction mixture was stirred for 12 h at room temperature. The solvent was removed by Rota-vapor and water was added. The mixture was extracted with EtOAc. The crude product was purified by silica gel (230-400) column chromatography using 30% EtOAc/hexane. Yield: 6.8 g (98%). 1H NMR (400 MHz, CDCl3): δ 2.54 (s, 3H), 3.80 (s, 3H), 7.69 (s, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]([OH:19])=[O:18])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].[C:22](=O)(O)[O-].[Na+]>CO>[N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:16][C:17]([O:19][CH3:22])=[O:18])=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cc1ccc2ncccc2c1
Yield: 98 %

Procedure:
As shown in step i of Scheme 1, concentrated sulfuric acid (206 mL, 3.868 mol) was added dropwise to a solution of 2-(quinolin-6-yl)acetic acid (compound 1001, 658.2 g, 3.516 mol, Okeanos Tech Co., Cat. No. OK-J-05024) in 6.5 liters of methanol. During the addition, a slight exotherm was observed. After the addition was complete, the reaction was stirred at reflux for 4 hours. After cooling, the volatiles were removed under reduced pressure, the resulting residue was diluted with 4 liters of ethyl acetate, cooled in an ice bath, treated with 2N NaOH (2.1 liters, 1.2 equiv.) until a pH of 4 was achieved, and then treated with saturated sodium bicarbonate until a pH of 8 was achieved. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate, washed with water, washed with brine, dried over anhydrous MgSO4, filtered, and evaporated under reduced pressure to afford methyl 2-(quinolin-6-yl)acetate as a clear brown oil (compound 1002, 696.8 g, 98% yield): ESMS (M+1), 202.14; 1H NMR (300.0 MHz, DMSO-d6) δ 8.90 (1H, dd, J=1.7, 4.2 Hz), 8.14-8.10 (1H, m), 8.08 (1H, d, J=8.7 Hz), 7.72 (1H, d, J=1.4 Hz), 7.65 (1H, dd, J=2.0, 8.7 Hz), 7.40 (1H, dd, J=4.2, 8.3 Hz), 3.83 (2H, s), 3.73 (3H, s).