Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(O)[C:27]1[CH:32]=[CH:31]C=[CH:29][CH:28]=1>OS(O)(=O)=O>[CH3:1][C:2]1[N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4]([CH3:19])=[C:5]([C:14]([O:16][CH2:17][C:18]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)=[O:15])[C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCC)c1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c(C)c(C(=O)OCc2ccccc2)c1=O

Procedure:
4 g. of 2,6-dimethyl-3,5-dicarboethoxy-N-phenyl-4-pyridone (prepared as described in Example 1) were dissolved in 20 ml. of benzyl alcohol, 4 drops of concentrated H2SO4 were added and the mixture was stirred and heated for 7 hours at 130°, at the same time distilling off the produce ethanol. The benzyl alcohol solution was washed with a saturated solution of sodium bicarbonate and the slurry was extracted several times with chloroform. The extracts were combined and dried over magnesium sulphate, and the chloroform was distilled off in vacuo. The oily residue was dissolved in 50 ml. of ether and 50 ml. of petrolether 40'-60° were added. After cooling in a dry ice-acetone bath and scratching, 2,5g. of 2,6-dimethyl-3-carboethoxy-5-carbobenzyloxy-N-phenyl-4-pyridone, m.p. 142° were obtained.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:10](=[O:11])[CH:9]=[CH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(O[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl.FC(F)(F)C(O)=O>[C:1]([O:4][CH:5]1[CH2:6][CH2:7][CH:8]2[CH:9]([CH2:17][N:18]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)[C:10]1=[O:11])(=[O:3])[CH3:2]
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CC(=O)OC1CCC=CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC1CCC2CN(Cc3ccccc3)CC2C1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 7.5 g of 6-acetoxy-2-cyclohexenone and 16.83 cm3 of N-butoxymethyl-N-trimethylsilylmethylbenzylamine in 150 cm3 of dichloromethane are added, at a temperature of 10° C., 12 drops of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 7 hours, then 2 g of potassium carbonate are added and the solution is filtered through a sinter funnel and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of dichloromethane and methanol (97.5-2.5 by volume) and collecting 60 cm3 fractions. Fractions 25 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 6.25 g of (3aRS,5RS,7aSR)-5-acetoxy-2-benzyl-4-perhydroisoindolone are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([NH:14][C:15]2[NH:19][N:18]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:16]=2)[N:11]=[C:10]([CH:23]2[CH2:27][C@@H:26]([O:28][CH2:29][CH:30]([F:32])[F:31])[CH2:25][C@H:24]2[C:33]([O:35][CH3:36])=[O:34])[N:9]=1>>[CH:20]1([C:17]2[CH:16]=[C:15]([NH:14][C:12]3[N:13]=[C:8]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:9]=[C:10]([CH:23]4[CH2:27][C@@H:26]([O:28][CH2:29][CH:30]([F:31])[F:32])[CH2:25][C@H:24]4[C:33]([O:35][CH3:36])=[O:34])[N:11]=3)[NH:19][N:18]=2)[CH2:22][CH2:21]1
Reactant: COC(=O)[C@@H]1C[C@H](OCC(F)F)CC1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: C1COCCN1
Product: COC(=O)[C@@H]1C[C@H](OCC(F)F)CC1c1nc(Nc2cc(C3CC3)n[nH]2)nc(N2CCOCC2)n1

Procedure:
124E was prepared from morpholine and 124D using the procedure described in 1. LC/MS [M+H]+: 495; Ret time (Method F): 2.61 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].I[CH3:14].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:14])[N:6]=[CH:5]2
Reactant: CI
Reactant: Brc1ccc2[nH]ncc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ncc2cc(Br)ccc21
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
5-Bromo-1H-indazole (1r) (10 g, 51 mmol) in THF was added slowly to a cold solution of NaH (2.2 g, 60% wt in oil, 56 mmol) in THF under nitrogen. After 15 minutes, iodomethane (10.8 g, 76 mmol) was added to the dark solution at 0° C. After 2 hours, the mixture was poured into 1N HCl (30 mL) and extracted with EtOAc (2×50 mL), and the combined extracts were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. Column chromatography (silica gel): hexane:EtOAc (10-40%) resulted in 8.2 g of final product (2r). 1H NMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.84 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 4.04 (s, 3H); MS (ESI) m/z 213 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][C:8]=1[CH:9]=O>C1(C)C=CC=CC=1>[CH2:1]([N:5]=[CH:9][C:8]1[CH:11]=[C:12]([CH:15]=[CH2:16])[CH:13]=[CH:14][C:7]=1[OH:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: C=Cc1ccc(O)c(C=O)c1
Solvent: Cc1ccccc1
Product: C=Cc1ccc(O)c(C=NCCCC)c1
Yield: 78.7 %

Procedure:
74 g (1 mole) of butylamine were added to a solution of 74 g (0.5 mole) of 2-hydroxy-5-vinylbenzaldehyde in 750 ml of toluene, and this mixture was refluxed for 2 hours. It was then extracted with twice 500 ml of ice water and the toluene was distilled off. 80 g (79%) of 2-butyliminomethyl-4-vinylphenol were obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and benzenesulfonyl chloride (105 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (108 mg, 76%) as a white foam. HRMS calcd. for C26H21ClNO4S [(M−H)−] 478.0885, obsd. 478.0884.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:32]=1[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]2.N1C=CC=CC=1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH2:33][C:34]([CH3:44])([C:40]([O:42][CH3:43])=[O:41])[CH2:35]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Reactant: COC(=O)C1(C)Cc2cccc(N)c2C1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)C1(C)Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C3CCCC3)c2C1

Procedure:
A solution of 200 mg (0.97 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2, Example 77A), 459 mg (1.2 mmol) of methyl 4-amino-2-methyl-2,3-dihydro-1H-indene-2-carboxylate (Example 95A), 556 mg (1.46 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU) and 5 ml of pyridine in 20 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, the phases were separated and the aqueous phase was extracted three times with tert-butyl methyl ether. The combined organic phases were dried over sodium sulfate, and after filtration the solvent was removed to dryness under reduced pressure. The crude product obtained was purified by preparative HPLC. This gave 448 mg (0.77 mmol, 79% of theory) of a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2].O[Li].O.C1COCC1>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)=[C:5]([CH3:26])[CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C#N)cc2C)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)ccc1COc1ccnn1-c1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Charged methyl 2-[5-[(4-cyano-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylate (112 mg, 0.32 mmol), LiOH.H2O (14 mg, 0.32 mmol), water (2 mL) and THF (2 mL) to a flask, then the mixture was stirred at room temperature for 30 min, added another 2 mL water, and the mixture was washed with ethyl acetate twice (6 mL×2). The aqueous phase was acidified with 1N HCl (pH=3), filtered and dried the solid to give the title compound. 1H NMR (300 MHz, DMSO-d6): δ 2.37 (3H, s), 5.37 (2H, s), 6.10 (1H, d, J=1.8 Hz), 7.62 (1H, d, J=1.5 Hz), 7.70-7.77 (4H, m), 8.08 (1H, s), 8.68 (1H, d, J=5.4 Hz). [M+H] Calc'd for C18H14N4O3, 335. Found, 335.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: FC(F)(F)c1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A mixture of 4-bromo-2-trifluoromethyl-phenylamine (0.88 g, 3.66 mmol), tetrahydro-4H-pyran-4-one (0.5 ml, 5.49 mmol), oven dried molecular sieves 4 Å (1 g) and sodium triacetoxyborohydride (1.15 g, 5.49 mmol) in 1,2-dichloroethane (30 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (aqueous saturated solution), dried over Na2SO4 and evaporated till dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/MeOH(NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to yield intermediate 13 as a yellow oil (1.11 g, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C1CCCCO1)[N:6]=[C:5]2[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:53]1([C:59]#[CH:60])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>C(#N)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:60]#[C:59][C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)[CH:3]=3)[NH:7][N:6]=2)=[CH:22][CH:21]=1
Reactant: C#Cc1ccccc1
Reactant: Fc1ccc(-c2nn(C3CCCCO3)c3ccc(Br)cc23)cc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2n[nH]c3ccc(C#Cc4ccccc4)cc23)cc1
Yield: 40.7 %

Procedure:
A mixture of 5-bromo-3-(4-fluorophenyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.375 g, 1.0 mmol), triethylamine (1.5 mL), tri-o-tolylphosphine (0.122 g, 0.4 mmol), tri(dibenzylideneacetone)dipalladium(0) (0.092 g, 0.1 mmol) and phenylacetylene (0.204 g, 2.0 mmol) in dried acetonitrile (10 mL) under nitrogen was heated to reflux overnight. It was quenched with water and extracted with ethyl acetate. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 10–15% ethyl acetate/hexane) to provide the title compound (0.127 g, 32% yield). 1H NMR (CDCl3) δ 8.16 (t, 1H), 7.93–7.97 (m, 2H), 7.54–7.64 (m, 4H), 7.34–7.37 (m, 3H), 7.21 (t, 2H) 5.77 (dd, 1H), 4.08 (m, 1H), 3.79 (m, 1H), 2.62 (m, 1H), 2.11–2.21 (m, 2H), 1.57–1.83 (m, 3H); ES-MS (m/z) 397 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C:5]([F:21])=[CH:4][C:3]=1[S:22]([N:25]([C:33]1[N:34]=[CH:35][S:36][CH:37]=1)C(=O)OC(C)(C)C)(=[O:24])=[O:23].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([O:8][C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]2[C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C:5]([F:21])=[CH:4][C:3]=1[S:22]([NH:25][C:33]1[N:34]=[CH:35][S:36][CH:37]=1)(=[O:23])=[O:24]
Reactant: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1F
Yield: 179.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl [(2,5-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamate (177 mg, 0.319 mmol) prepared in Example 5a, trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (260 mg, 87%) as a colorless solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([N:37]4[CH:49]=[CH:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[C:29]=3[CH:30]=[O:31])[CH:21]=2)=[N:17][CH:18]=1.[BH4-].[Na+].O>CO>[CH3:1][C@H:2]1[CH2:7][N:6]([CH:8]2[CH2:11][O:10][CH2:9]2)[C@H:5]([CH3:12])[CH2:4][N:3]1[C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20]2[C:25](=[O:26])[N:24]([CH3:27])[CH:23]=[C:22]([C:28]3[C:29]([CH2:30][OH:31])=[C:32]([N:37]4[CH:49]=[CH:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[CH:33]=[C:34]([F:36])[CH:35]=3)[CH:21]=2)=[N:17][CH:18]=1
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ccn6c7c(cc6c5=O)CCCC7)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ccn6c7c(cc6c5=O)CCCC7)c4CO)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a solution of 121h (150 mg, 0.22 mmol) in methanol (10 mL) was added NaBH4 (41.8 mg, 1.1 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The mixture was poured into water (30 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by prep-HPLC to afford 121 (60.3 mg, 40%) as white solid. MS: [M+H]+ 680. 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=2.0 Hz, 1H), 8.51 (s, 1H), 7.90 (d, J=3.0 Hz, 1H), 7.41 (m, 2H), 7.31-7.23 (m, 4H), 6.78 (d, J=1.0 Hz, 2H), 4.80 (m, 1H), 4.55-4.54 (m, 2H), 4.49-4.4.48 (m, 2H), 4.28-4.20 (m, 2H), 3.69-3.64 (m, 1H), 3.60 (s, 3H), 3.29-3.27 (m, 2H), 2.89-2.88 (m, 1H), 2.75-2.67 (m, 4H), 2.61 (m, 2H), 1.93-1.86 (m, 3H), 1.59 (m, 2H), 0.85-0.81 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].Cl[C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][O:8][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1
Reactant: CN1CCC[C@H]1CO
Reactant: FC(F)(F)c1cncc(Cl)c1
Solvent: CN(C)C=O
Product: CN1CCC[C@H]1COc1cncc(C(F)(F)F)c1

Procedure:
(S)-(-)-1-Methyl-2-pyrrolidinemethanol (Aldrich Chemical Co., 0.5 g, 4.34 mmol) was reacted with 3-chloro-5-trifluoromethylpyridine according to the method of Example 3, except using DMF in place of THF as solvent and reducing reaction time to less than 2 hours. The solvent was removed, the residue dissolved in ethyl acetate, and the product purified by chromatography over silica gel to give 170 mg of the title compound. MS (DCI/NH3) m/e: 261 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.50 (d, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.41 (dd, J=0.6, 3.0 Hz, 1H), 4.12-3.96 (m, 2H), 3.21-3.10 (m, 1H), 2.80-2.65 (m, 1H), 2.51 (s, 3H), 2.44 (m, 1H), 2.14-1.73 (m, 4H).
Reaction SMILES: Br.[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]=2[CH2:9][O:8]1.[NH3:26]>C(O)C.[Cu](Cl)Cl>[CH3:25][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[NH:26])[NH2:17])=[CH:15][C:10]=2[CH2:9][O:8]1
Reactant: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Reactant: N
Agent: Cl[Cu]Cl
Agent: Br
Solvent: CCO
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C(=N)N)ccc21
Temperature: 80 °C

Procedure:
A mixture of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile hydrobromide (citalopram hydrobromide, 300 mg, 1.0 equiv), copper(II) chloride (1.5 equiv) and ammonia (2.8 equiv) in ethanol (6 mL) was heated at 80° C. for 48 h. The mixture was cooled to room temperature and concentrated to dryness to give crude product (M/Z 342 [M++H]). This material was purified by re-suspending the crude product in fresh ethanol, filtration to remove insoluble material and slow evaporation under N2 to give the title product, 90 mg (23%) of a pale yellow powder.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:9][O-:10].[Na+]>>[CH2:7]([O:6][C:1](=[O:5])[CH:2]([CH:9]=[O:10])[CH2:3][CH3:4])[CH3:8]
Reactant: C[O-]
Reactant: CCCC(=O)OCC
Agent: [Na+]
Product: CCOC(=O)C(C=O)CC
Yield: 70.6 %

Procedure:
1200 g Ethyl butyrate was reacted with 130 g 85% sodium methylate substantially as in Example 1 to produce 245 g 2-formylbutyric acid ethyl ester (85% yield) boiling at 60°-64° C./14 torr. n20D =1.4300.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:4]=1.[H-].[Na+].[CH3:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([CH:19]([CH3:21])[CH3:20])[C:12]([N:14]([CH2:24][O:25][CH3:26])[S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])[N:6]=1
Reactant: COc1cc(OC)nc(C(C(=O)NS(C)(=O)=O)C(C)C)n1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCN(C(=O)C(c1nc(OC)cc(OC)n1)C(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
2.0 g of 2-(4,6-dimethoxypyrimidin-2-yl)-3-methyl-N-methylsulfonylbutyric acid amide was placed in a round bottomed flask, and was dissolved in 50 ml of DMF. To the resultant solution, was gradually added 0.28 g of 60% sodium hydride, and the mixture was stirred at room temperature for one hour. Thereafter, 1.0 g of chloromethyl methyl ether was added dropwise to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into ice water, and was extracted with 200 ml of diethyl ether, followed by drying with anhydrous sodium sulfate. After filtrating the inorganic salt, the solvent was distilled off under reduced pressure. An oily product thus obtained was purified by silica gel column chromatography (developing solvent: N-hexane/ethyl acetate=10/l ) to obtain 1.8 g of the aimed product of colorless transparent viscous liquid (yield=78.3%) having a refractive index (nD20) of 1.4976.
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:18])[C:7]=2[C:6]([O:19]C)=[CH:5][CH:4]=1.[N+]([O-])(O)=O>CC(C)=O>[CH:12]1[CH:13]=[C:14]2[C:15]([C:16]3[C:3](=[O:2])[CH:4]=[CH:5][C:6](=[O:19])[C:7]=3[C:8](=[O:18])[C:9]2=[CH:10][CH:11]=1)=[O:17]
Reactant: COc1ccc(OC)c2c1C(=O)c1ccccc1C2=O
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Product: O=c1ccc(=O)c2c(=O)c3ccccc3c(=O)c1=2

Procedure:
1,4-Dimethoxyanthraquinone (II) (0.596 g, 2 mmole) is dissolved in hot aceton (60 ml) and argentic oxide (1g, 8mmole) was added to this warm solution. Brief sonication forms a uniform dispersal of oxident. The mixture is heated up to boiling on steam bath again and the mixture stirred vigorously with magnetic stirrer. The oxidation is then initiated by the addition of 6N aqueous nitric acid (2 ml). After addition, the mixture is stirred while cooling for an extra 20 minutes and filtered. The residue is washed thoroughly with water and dried under reduced pressure to give quinizarinquinone (III) as a brown solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc2sc(S)nc2c1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: COc1ccc2sc(SCC(=O)N3CCCc4ccccc43)nc2c1
Yield: 83 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 5-methoxybenzo[d]thiazole-2-thiol as the nucleophile to yield 18 as a pale yellow solid (83%): MS m/z: 371 (M+H)+. Anal. Calcd. For, C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56; S, 17.31. Found: C, 61.40; H, 4.90; N, 7.48; S, 17.26.