Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[C:14]2[C:15]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]=1[CH3:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:30]>CN(C)C=O.C(OCC)(=O)C>[ClH:27].[CH2:3]([C:10]1[C:14]2[C:15]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][C:13]=2[N:12]([CH3:30])[C:11]=1[CH3:28])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Cc1[nH]c2ccnc(NCc3ccc(Cl)cc3)c2c1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cc2ccccc2)c2c(NCc3ccc(Cl)cc3)nccc2n1C
Product: Cl
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
The compound (30 mg, 0.12 mmol) prepared in Example 73 was treated with a saturated sodium bicarbonate solution to obtain 3-benzyl-2-methyl-4-(4-chlorobenzylamino)-1H-pyrrolo[3,2-c]pyridine (24 mg, 0.065 mmol). Sodium hydride (60%, 4.9 mg, 0.118 mmol) was added at room temperature to a solution of 3-benzyl-2-methyl-4-(4-chlorobenzylamino)-1H-pyrrolo[3,2-c]pyridine (24 mg, 0.065 mmol) in N,N-dimethylformamide (1 ml) and then the reaction mixture was stirred for 30 minutes. Iodomethane (0.007 ml, 0.118 mmol) was added to the reaction mixture, which was then stirred for 1 hour at room temperature. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml) three times. The separated organic layer was dried on anhydrous magnesium sulfate, and then concentrated. The resulting residue was dissolved in ethyl acetate (1 ml), saturated with hydrochloric acid gas, and then filtered to give the titled compound as a white solid. (Yield: 58.2%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:20]([CH3:23])([O-:22])=[O:21]>>[CH2:11]([N:10]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[CH:23][N+:20]([O-:22])=[O:21])=[CH:3][C:2]=1[Cl:1])[CH2:13][CH3:14])[CH3:12]
Reactant: CCN(CC)c1ccc(C=O)cc1Cl
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCN(CC)c1ccc(C=C[N+](=O)[O-])cc1Cl
Temperature: 100 °C
Yield: 39 %

Procedure:
A solution was prepared by dissolving 34 grams (0.16 mol) of 3-chloro-4-(N,N-diethyl)aminobenzaldehyde in 150 ml of nitromethane, and added with 5 grams of ammonium acetate. The mixture was heated at 100° C. for 5 hours under agitation. The reaction solution was then cooled on a dry ice-acetone bath until crystallization had been completed. The separated solid (crystal) was filtered off and dried in vacuum. The obtained product was recrystallized from acetonitrile for two times. An amount of 16 grams of red crystal was obtained. The yield was 39%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[C:11]([CH3:22])[CH:12]=[C:13]([C:20]#[N:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[C:20]([C:13]1[CH:14]=[C:15]2[C:10](=[C:11]([CH3:22])[CH:12]=1)[NH:9][CH:8]([C:4]1[CH:3]=[C:2]([NH:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])[CH:7]=[CH:6][CH:5]=1)[CH2:17][C:16]2([CH3:19])[CH3:18])#[N:21]
Reactant: CC(C)(N)C(=O)O
Reactant: Cc1cc(C#N)cc2c1NC(c1cccc(Br)c1)CC2(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(C#N)cc2c1NC(c1cccc(NC(C)(C)C(=O)O)c1)CC2(C)C
Temperature: 25 °C
Yield: 23 %

Procedure:
A solution of 2-(3-bromo-phenyl)-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (355.0 mg, 1.0 mmol), copper(I) iodide (57.0 mg, 0.3 mmol), 2-amino-2-methyl-propionic acid (309.0 mg, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 120° C. for 16 h. Then the reaction mixture was cooled to room temperature and extracted with ethyl acetate (150 mL×2), washed with water (50 mL×2) and saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-(6-cyano-4,4,8-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamino]-2-methyl-propionic acid (86.7 mg, 23%) as a white solid: LC/MS m/e obsd. (ESI+) [(M+H)+] 378.1.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([OH:66])[CH:63]=[CH:64][CH:65]=1)[CH2:56][CH2:57][CH3:58]>C1COCC1.CN(C=O)C>[CH2:55]([O:59][C:60]1[CH:61]=[C:62]([CH:63]=[CH:64][CH:65]=1)[O:66][CH2:36][CH2:37][N:28]1[CH:29]=[CH:30][N:31]=[C:26]([N:23]2[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]2)[C:27]1=[O:32])[CH2:56][CH2:57][CH3:58]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: CCCCOc1cccc(O)c1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCOc1cccc(OCCn2ccnc(N3CCNCC3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
TMAD (0.060 g, 0.35 mmol) was dissolved in THF (1 mL) and DMF (0.5 mL) and the solution was added dropwise to a mixture of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.100 g, 0.310 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and 3-n-butyloxyphenol (0.166 g, 1.00 mmol) in THF (0.5 mL). The reaction mixture was stirred overnight at room temperature, concentrated, and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 97 mg (7%) of the title compound. HRMS m/z calcd for C20H28N4O3 (M)+ 372.2161, found 372.2149.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:30]O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:30][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCC1CCCCCCC1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCCCCCC2)c1

Procedure:
Mitsunobu reaction of phenol 58 with cyclooctane Methanol gave 2-(3-(3-(cyclooctylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.920 g, 65%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.86 (m, 2H), 7.68-7.73 (m, 2H), 7.10-7.13 (m, 1H), 6.72-6.79 (m, 2H), 6.64-6.68 (m, 1H), 3.65 (d, J=6.4 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 1.98-2.06 (m, 4H), 1.65-1.78 (m, 7H), 1.56-1.64 (m, 5H), 1.30-1.40 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[S:15](Cl)(=[O:17])=[O:16])([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[S:15]([NH:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:23]2[C:24]=1[N:19]=[CH:20][CH:21]=[CH:22]2)(=[O:17])=[O:16])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Reactant: c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 35 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoqunoline (500 mg, 3.47 mmol), 2-nitro-4-trifluoromethoxy-benzenesulfonyl chloride (Intermediate 221) (1.4 g, 4.51 mmol), pyridine (5 ml), DMAP (cat.) and DCM (3 ml) gave the title compound (500 mg, 35%) after purification by column chromatography with n-hexane/EtOAc (90:10) as the eluent.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[NH:5][C:4](=[O:17])[CH:3]=1.[CH3:18][N:19]([CH3:22])[CH:20]=O.CN(C(OC)OC)C.C(O)(C)C>O>[F:15][C:9]1[CH:10]=[C:11]([I:14])[CH:12]=[CH:13][C:8]=1[N:7]1[C:2]([N:1]=[CH:18][N:19]([CH3:22])[CH3:20])=[CH:3][C:4](=[O:17])[NH:5][C:6]1=[O:16]
Reactant: CN(C)C=O
Reactant: Nc1cc(=O)[nH]c(=O)n1-c1ccc(I)cc1F
Agent: COC(OC)N(C)C
Solvent: O
Solvent: CC(C)O
Product: CN(C)C=Nc1cc(=O)[nH]c(=O)n1-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 67.7 %

Procedure:
To a mixture (21.8 g) of 6-amino-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 80 and 78 was added N,N-dimethylformamide (42.0 ml) and N,N-dimethylformamidedimethylacetal (21.0 ml) and the mixture was stirred at room temperature for 4.5 hrs. With stirring at room temperature, isopropyl alcohol (20.0 ml) was added, and water (100 ml) was added dropwise. The mixture was stirred at room temperature for 45 min, and the precipitated crystals were collected by filtration, washed with water and dried to give N′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine 81 (21.7 g, yield 67.7% from 78) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][NH:18][CH:19]([CH:25]([CH3:27])[CH3:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:37](Cl)(Cl)=[O:38]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([CH:19]([CH:25]([CH3:26])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:37]2=[O:38])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)C(NCCNc1ccc(OCc2ccccc2)cc1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(C)C)N1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 0 °C
Yield: 81.5 %

Procedure:
Ethyl 2-(2-(4-benzyloxyphenylamino)ethylamino)-3-methylbutyrate (100 mg; 0.27 mmol) was dissolved in toluene (5 ml) and cooled to 0° C. DIEA (141 μl; 0.81 mmol) and phosgene (20% strength in toluene; 202 μl; 0.40 mmol) were added thereto. The mixture was allowed to reach RT over the course of 3 h, and then the solvent was removed under reduced pressure. The residue was partitioned between water (10 ml) and EtOAc (10 ml). The phases were separated and the aqueous phase was extracted with EtOAc (2×; 5 ml). The combined organic phases were dried over MgSO4. After removal of the solvent whilst under reduced pressure, ethyl 2-(3-(4-benzyloxyphenyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (90 mg; 0.22 mmol) was obtained. MS: 397.15 (M+H); Rt: 1.90 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: O[CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[O:20]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:25])[N:19]1[CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:4][S:5][CH3:6]
Reactant: CSCC(CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCC(CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [1-hydroxy-3-(methylsulfanyl)propan-2-yl]carbamate (14.0 g, 63.3 mmol) in THF (200 mL) was added phthalimide (11.2 g, 76.0 mmol) and triphenylphosphine (25.3 g, 94.9 mmol) under a nitrogen atmosphere. Diethylazodicarboxylate was added dropwise and the reaction mixture was stirred at room temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford tert-butyl [1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(methylsulfanyl)propan-2-yl]carbamate. MS ESI calc'd. for C17H22N2O4SNa [M+Na]+ 373. found 373. 1H NMR (400 MHz, CD3OD) δ 7.85-7.77 (m, 4H), 4.16-4.05 (m, 1H), 3.92-3.68 (m, 2H), 2.69-2.15 (m, 2H), 2.15 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C@@H:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1/[CH:11]=[CH:12]/[C:13](/[CH3:42])=[CH:14]/[CH:15]=[CH:16]/[C:17](/[CH3:41])=[CH:18]/[CH:19]=[CH:20]/[CH:21]=[C:22](\[CH3:40])/[CH:23]=[CH:24]/[CH:25]=[C:26](\[CH3:39])/[CH:27]=[CH:28]/[C:29]1[C:34]([CH3:36])([CH3:35])[CH2:33][C@H:32]([OH:37])[CH2:31][C:30]=1[CH3:38].Br([O-])(=O)=[O:44].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH2:57]>C(Cl)(Cl)Cl>[CH3:38][C:30]1[C:31](=[O:57])[C@@H:32]([OH:37])[CH2:33][C:34]([CH3:36])([CH3:35])[C:29]=1/[CH:28]=[CH:27]/[C:26](/[CH3:39])=[CH:25]/[CH:24]=[CH:23]/[C:22](/[CH3:40])=[CH:21]/[CH:20]=[CH:19]/[CH:18]=[C:17](\[CH3:41])/[CH:16]=[CH:15]/[CH:14]=[C:13](\[CH3:42])/[CH:12]=[CH:11]/[C:3]1[C:4]([CH3:9])([CH3:10])[CH2:5][C@H:6]([OH:8])[C:7](=[O:44])[C:2]=1[CH3:1]
Reactant: O
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C(=O)[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1=O
Temperature: 50 °C

Procedure:
To a suitable flask was added 20 grams of a natural product mixture containing 12.2 grams zeaxanthin (21.4 mmoles) slurried in 200 ml of chloroform. To this mixture was added a solution of 8.05 gms (53.3 mmoles) of sodium bromate. To this mixture was added dropwise over three hours at temperatures between 20 to 30° C., 8 ml of a solution prepared by dissolving 6.66 gms of sodium metabisulfite in 24 ml of water. After addition, the reaction mixture was filtered through Celite and the aqueous phase was separated. The chloroform was removed by vacuum evaporation at 40-42° C. The resulting slightly wet solid was added to 190 ml of warm (50° C.) 95% ethanol. The mixture was stirred and cooled slowly to −10° C. The resulting solid was filtered off and dried under vacuum to produce 8.8 grams (72.14%) yield of astaxanthin product containing greater than 25% astaxanthin.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[CH:3].[C:10]([O-])(O)=O.[Na+].[O:15](C)[S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17].CCOCC>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[S:16]([O-:18])(=[O:17])=[O:15].[C:2]([C:4]1[CH:9]=[CH:8][N+:7]([CH3:10])=[CH:6][CH:5]=1)#[CH:3]
Reactant: O=C([O-])O
Reactant: C#Cc1ccncc1
Reactant: COS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C#Cc1cc[n+](C)cc1
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91 %

Procedure:
Prepared according to Rubinsztajn et al. Tetrahedron Lett. 1992, 33, 14, 1821-1824. To a suspension of 4-ethynylpyridine hydrochloride (500 mg, 3.58 mmol) in DCM (50 mL) at 0° C. was slowly added NaHCO3 solution (aq, satd, 10 mL). After stirring for 5 min, the layers were separated and the aqueous was extracted with DCM (2×10 mL). The combined organic layers were dried over Na2SO4, concentrated in vacuo and subjected to high vacuum for 10 min. The crude residue was dissolved in DCM (10 mL), cooled to 0° C. and methyl triflate (450 μL, 3.94 mmol) was added drop-wise. After stirring for 30 min at 0° C., ether was added and the precipitate was collected and dried, affording the title compound (870 mg, 91%) as a light brown solid. Analytical data was identical to literature reported values.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.O.ClCCl>ClCCl>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)=[CH:24][N:25]=1
Reactant: COc1ccc(O)cn1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(OC2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
10.1 g (119.9 mmol, 1.5 eq.) of 3,4-dihydro-2H-pyran and 1.4 g (8.0 mmol, 0.1 eq.) of 4-toluenesulphonic acid were added to a solution of 10.0 g (79.9 mmol) of 6-methoxypyridin-3-ol in 150 ml of dichloromethane, and the mixture was stirred at RT for 5 d. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. Yield: 17.3 g (100% of theory)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[OH:34][CH2:35][C@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:37]5[CH2:38][CH2:39][CH2:40][CH:36]5[CH2:35][OH:34])[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: OC[C@H]1CCCN1
Agent: OC1CCNC1
Product: OCC1CCCN1c1cc(-c2ccc(Sc3ccc4c(c3)OCCO4)c(C(F)(F)F)c2)ccn1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-2-(hydroxymethyl)pyrrolidine. A yellow solid 120 was obtained (0.027 g, 55%). 1H-NMR (CDCl3, 400 MHz) δ 2.06–2.11 (m, 2H), 2.16–0.21 (m, 2H), 3.46–3.53 (m, 1H), 3.63–3.76 (m, 3H), 4.28–4.34 (m, 4H), 4.61–4.66 (m, 1H), 6.78 (s, 1H), 6.92 (dd, J=1.4 Hz, 6.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.05 (dd, J=2.2 Hz, 8.0 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, 8.4 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([NH2:12])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>N1C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23]([NH:12][C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)(=[O:24])=[O:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Nc1nc(-c2ccccc2)ns1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)ns2)cc1OC
Temperature: 25 °C
Reaction time: 46 h
Yield: 14.4 %

Procedure:
3-Phenyl-1,2,4-thiadiazol-5-amine (326 mg, 1.84 mmol) was dissolved in dry pyridine (10 mL). Then 3,4-dimethoxybenzenesulfonyl chloride (529 mg, 2.23 mmol) was added. The solution was stirred at room temperature under Argon. After 46 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between EtOAc and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with EtOAc. After drying over Na2SO4, the solvent was removed in vacuo to give a solid (100 mg) which was crystallized from EtOAc. Yield was 29.3 mg; mp 170-171° C.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:22][OH:23]>CCO>[NH2:2][C:1](=[N:22][OH:23])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C(N)=NO)cc2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
tert-Butyl 3-(7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (11.85 g; 41.38 mmol; 1 eq.) was suspended in EtOH (237 mL). Hydroxylamine (6.1 mL; 206.90 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum to give the title compound as a yellow oil. Diisopropyl ether (50 mL) was added. The resulting mixture was sonicated and concentrated under vacuum. This process was repeated 3 times, affording Intermediate 35 as a yellowish solid (13.2 g; quantitative). 1H NMR: (DMSO-d6, 400 MHz) δ 9.51 (br s, 1H), 7.43-7.34 (m, 2H), 7.09-7.06 (d, J=8.17 Hz, 1H), 5.71 (br s, 2H), 3.56 (s, 2H), 2.79-2.64 (m, 6H), 2.47-2.42 (t, J=6.93 Hz, 2H), 1.39 (s, 9H), traces of EtOH by NMR. HPLC/MS: 320.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.[CH3:14]C(C)([O-])C.[K+].CI.[Na+].[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:14])[C:8](=[O:13])[CH2:7][CH2:6]2
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(n1)CCC(=O)N2
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(n1)CCC(=O)N2C
Reaction time: 0.17 h
Yield: 64.4 %

Procedure:
A solution of 1.2 g (6.7 mmol) 6-methoxy-3,4-dihydro-1H-[1,5]naphthyridin-2-one in 15 ml of DMF was cooled to 5° C. and to this solution was slowly added 6.7 ml (6.7 mmol) of potassium t-butoxide (1M solution in THF). The mixture was stirred for 10 minutes followed by addition of 0.46 ml (7.4 mmol) methyl iodide. After addition was complete, the reaction mixture was stirred for 1 hour at 5° C. The reaction mixture was poured into saturated NaCl. The mixture was extracted with ethyl acetate. The ethyl acetate extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.83 g of 6-methoxy-1-methyl-3,4-dihydro-1H-[1,5]naphthyridin-2-one. TLC Rf=0.6 (1:10 ethyl acetate/chloroform). 1H NMR (CDCl3) δ 7.2 (d, 1H), 6.6 (d, 1H), 3.9 (s, 3H), 3.3 (s, 3H), 3.0 (m, 2H), 2.7 (m, 2H). Mass Spectrum: m/e 193.2 (p+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([CH3:15])=[CH:12][CH:13]=2)[O:8][C:7](=[O:16])[CH:6]=1)=O.[C:17]([NH2:20])(=[O:19])[CH3:18].C(OCC)(=O)C>CN(C)C=O>[CH3:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([C:3]3[N:20]=[C:17]([CH3:18])[O:19][CH:2]=3)=[CH:6][C:7](=[O:16])[O:8]2)=[CH:13][CH:12]=1
Reactant: CC(N)=O
Reactant: Cc1ccc2c(C(=O)CBr)cc(=O)oc2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3coc(C)n3)cc(=O)oc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromoacetyl)-7-methyl-2H-chromen-2-one (750 mg, 2.67 mmol) in N,N-dimethylformamide (2.5 mL), acetamide (158 mg, 2.67 mmol) was added. The reaction was then stirred overnight at 100° C. After cooling, the reaction mixture was dissolved with ethyl acetate and washed with water and brine, dried over MgSO4, filtered and concentrated. The crude residue obtained was pre-adsorbed on silica gel and purified by column chromatography (EtOAc/hexanes, 30:70 to 80:20) to afford the title compound. 1H NMR (400 MHz, acetone-d6): 8.52 (s, 1H), 8.21 (d, 1H), 7.23 (s, 1H), 7.21 (d, 1H), 6.52 (s, 1H), 2.57 (s, 3H), 2.49 (s, 3H).