Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].Cl.[NH2:22][C@@H:23]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=1)[CH3:24]>C(N(CC)CC)C>[C:6]([C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:22][C@@H:23]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[C:27]([CH3:36])[CH:26]=2)[CH3:24])=[O:18])=[CH:19][CH:20]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc([C@@H](C)NC(=O)COc2ccc(C(C)(C)C)cc2)ccc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a tetrahydrofuran (THF) (2.0 ml) solution of (4-tert-butylphenoxy)acetic acid (140 mg, 0.7 mmol) 1,1′-dicarbonyldiimidazole (110 mg, 0.7 mmol) was added and the mixture was stirred for 1 hour at ambient temperature. N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.7 mmol) and triethylamine (0.5 ml) were added to the mixture. After being stirred for 1 hour at ambient temperature, white precipitate appeared. It was filtered and the solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with methylene dichloride/ethyl acetate=1/1 to furnish 90 mg (31% yield) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=2)=[CH:4][CH:3]=1.I[CH3:21]>C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:19])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][N:12]([CH3:21])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCOC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1cn(C)cc(-c2ccc(F)cc2)c1=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
A mixture of ethyl 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (1.5 g, 5.7 mmol) and iodomethane (0.9 g, 6.3 mmol) in saturated NaHCO3 (25 mL) was stirred at 60° C. overnight. The mixture was filtered. The solid was concentrated under vacuum to afford ethyl 5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxylate (1.1 g, 69.9% yield). The mixture was used directly without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].FC1C=C(C=CC=1F)CN1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(O)=O)C=4)NC=3)C=CC=2)=O)C1=O.[CH3:77][O:78][CH2:79][CH2:80]N>>[CH3:77][O:78][CH2:79][CH2:80][NH:33][C:31]([C:28]1[CH:29]=[C:30]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:8]4[C:7](=[O:34])[N:6]([CH2:5][C:4]5[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:10][CH:9]=4)=[O:13])[CH:17]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:32]
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: COCCN
Agent: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Product: COCCNC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (2-methoxy-ethyl)-amide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and 2-methoxyethylamine (22 uL, 0.00025 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.168 (s, 1H) 10.063 (t, J=5.8 Hz, 1H) 8.794 (m, 1H) 8.686 (m, 1H) 8.403 (d, J=7.1 Hz, 1H) 8.236 (d, J=6.3 Hz, 1H) 8.141 (s (br), 1H) 7.855 (d, J=2.5 Hz, 1H) 7.475-7.353 (m, 3H) 7.287 (d, J=3.4 Hz, 1H) 7.184-7.131 (m, 1H) 7.046 (d, J=3.4 Hz, 1H) 6.595 (t, J=7.1 Hz, 1H) 5.194 (s, 2H) 4.683 (d, J=5.7 Hz, 2H); MS m/z=572.41 M+H.
Reaction SMILES: CS[C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.[Cl:13][C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([O:21][CH3:22])=[C:18]([CH:20]=1)[NH2:19]>C(O)CCC>[Cl:13][C:14]1[C:15]([O:23][CH3:24])=[CH:16][C:17]([O:21][CH3:22])=[C:18]([CH:20]=1)[NH:19][C:3]1[S:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1
Reactant: COc1cc(OC)c(Cl)cc1N
Reactant: CSC1=Nc2ccccc2CS1
Solvent: CCCCO
Product: COc1cc(OC)c(NC2=Nc3ccccc3CS2)cc1Cl
Yield: 43 %

Procedure:
A mixture of 2-methylthio-4H-3,1-benzothiazine (48.8 g, 0.25 mole) and 5-chloro-2,4-dimethoxyaniline (46.8 g, 0.25 mole) in n-butanol (200 ml) was refluxed overnight. After cooling in ice, the solid was collected by filtration and recrystallized from ethanol to give 36 g (43.4%) of product. Recrystallization from ethanol gave an analytical sample, m.p. 157°-158°.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[SiH:15]([C:30]2[C:31]4[C:36]([CH:37]=[C:38]5[C:43]=2[CH:42]=[CH:41][CH:40]=[CH:39]5)=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:16]2[C:17]4[C:22]([CH:23]=[C:24]5[C:29]=2[CH:28]=[CH:27][CH:26]=[CH:25]5)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Mn]([O-])(=O)(=O)=[O:45].[K+]>O1CCCC1>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[Si:15]([C:16]2[C:29]4[C:24]([CH:23]=[C:22]5[C:17]=2[CH:18]=[CH:19][CH:20]=[CH:21]5)=[CH:25][CH:26]=[CH:27][CH:28]=4)([C:30]2[C:31]4[C:36]([CH:37]=[C:38]5[C:43]=2[CH:42]=[CH:41][CH:40]=[CH:39]5)=[CH:35][CH:34]=[CH:33][CH:32]=4)[OH:45])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c([SiH](c3c4ccccc4cc4ccccc34)c3c4ccccc4cc4ccccc34)c3ccccc3cc2c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O[Si](c1c2ccccc2cc2ccccc12)(c1c2ccccc2cc2ccccc12)c1c2ccccc2cc2ccccc12
Reaction time: 15 h

Procedure:
The oxidation of the tris(9-anthracenyl)silane is carried out analogously to Example 1.1 with 5 molar equivalents of potassium permanganate in boiling tetrahydrofuran. The reaction is interrupted after 15 h and, after filtration over silica gel to separate off pyrolusite from the solution, the silanol formed is obtained as a yellowish solid by concentration of the reaction mixture, yield: 10.75 g with a purity of 85% (GC-MS). Further purification is carried out by crystallization from boiling ethanol.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:13])[C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=2.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:14][C:15]1[N:16]=[C:17]([C:21]2[N:25]([CH2:2][C:3]3[N:4]([CH3:13])[C:5]4[C:10]([N:11]=3)=[CH:9][N:8]=[C:7]([CH3:12])[N:6]=4)[CH:24]=[CH:23][N:22]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ncc2nc(CCl)n(C)c2n1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc2nc(Cn3ccnc3-c3cccc(F)n3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 8-Chloromethyl-2,9-dimethyl-9H-purine (40 mg, 0.2 mmol), 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine (40 mg, 0.25 mmol) and K2CO3 (55 mg, 0.4 mmol) in 2 mL of DMF is stirred at room temperature for four hours. The mixture is diluted with water (10 mL), and extracted with ethyl acetate three times. The combined extract is washed with brine, dried and concentrated. The residue is purified by preparative thin layer chromatography to give the title compound. 1H NMR(CDCl3): δ 8.92 (s, 1H), 8.18 (dd, 1H), 7.88 (q, 1H), 7.25 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 6.83 (dd, 1H), 6.22 (s, 2H), 3.89 (s, 3H), 2.8 (s, 3H). LRMS calcd 323, found 324 (MH+).
Reaction SMILES: [CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=[O:10])[C:5]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2].Cl.[CH3:16]O>>[CH:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([O:11][CH3:16])=[O:10])[C:5]=1[N+:12]([O-:14])=[O:13])([CH3:3])[CH3:2]
Reactant: CC(C)c1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Product: COC(=O)c1n[nH]c(C(C)C)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 91 %

Procedure:
5-Isopropyl-4-nitropyrazole-3-carboxylic acid was added to a 4.5M solution of HCl in absolute methanol. The reaction mixture was heated at 60° C. for 7 hours. The title compound was crystallized from ethyl acetate; yield 91%; mp=78-80° C. 1H NMR (300 MHz, CDCl3): 1.39 d (6H, J=7.1 Hz); 3.64 sept (1H, J=7.1 Hz), 3.98 s (3H). CHN required: C=45.07%; H=5.20%; N=19.70%; found: C=45.21%; H=5.23%; N=19.65%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:34])[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)=[O:20])[CH:12]=1)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:34])[C:19]([N:21]2[CH2:22][CH2:23][CH:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)=[O:20])[CH:14]=[CH:15][CH:16]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1cccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of 0.5 g (1 mmol) of ({3-[2-(4-benzyl-piperidin-1-yl)-2-oxo-acetyl-amino]-phenylcarbamoyl}-methyl)-carbamic acid tert-butyl ester (Example 69) and 20 ml of 2.5 N hydrochloric acid in ethyl acetate is stirred at room temperature for 1 hour. The precipitated product is filtered off and washed with ethyl acetate to yield 0.41 g (95.1%) of the title compound. Melting Point: 85-90° C. (ethyl acetate)
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[C:48]([CH3:49])=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][C:40]=4[CH3:50])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O1CCOCC1>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([F:29])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[C:40]([CH3:50])=[CH:41][C:42]([C:43]([OH:45])=[O:44])=[CH:47][C:48]=4[CH3:49])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cc(F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: COc1ncc(-c2c(C)cc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 60 °C
Yield: 75.4 %

Procedure:
To a stirred solution of methyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoate (Step A, 82 mg, 0.118 mmol) in dioxane (2.4 mL) was added an aqueous solution of lithium hydroxide (1.2 mL, 0.5 M). The mixture was heated at 60° C. for one hour. The reaction mixture was cooled and acidified by the addition of TFA (0.090 mL, 1.17 mmol). Volatiles were removed under reduced pressure and the residue was purified by preparative HPLC reverse phase (C-18) to give 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-5-[3-fluoro-5-(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3,5-dimethylbenzoic acid (60.7 mg, 0.089 mmol) as a white solid following lyophilization. LCMS (M+H)+: 684.1. 1H NMR (500 MHz, CD3OD): δ 8.19 (s, 1H), 8.03 (s, 1H), 7.80 (s, 2H), 7.50 (m, 3H), 7.40 (m, 1H), 5.80 (d, 1H, J=8.4 Hz), 5.49 (br s, 0.5H), 5.42 (br s, 0.5H), 4.64 (d, 1H, J=16.9 Hz), 4.50 (m, 2H), 4.40 (m, 1H), 4.24 (m, 2H), 4.14 (d, 1H, J=16.9 Hz), 4.02 (s, 3H) 2.17 (s, 3H), 2.16 (s, 3H), 0.76 (d, 3H, J=6.6 Hz). RTA IC50: 15 nM.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21]C)[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].C[Si](I)(C)C.C(O)C.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:21])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:25])([F:26])[F:27])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Agent: C[Si](C)(C)I
Solvent: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(OC(F)(F)F)ccc1CNC(=O)c1cn(CC(F)(F)F)c2c(O)c(N3CCC(C(=O)O)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 92.6 %

Procedure:
150 mg (0.237 mmol) of the compound of Example 47 are provided in 3 ml of dichloromethane, 943 μl of trimethylsilyliodide (6.63 mmol) are added and the mixture is stirred for 4 days at room temperature. In order to destroy the excess trimethylsilyliodide the reaction mixture is cooled to 0° C., and a mixture of 414 μl of Ethanol (7.1 mmol) and 575 μl of pyridine (7.1 mmol) is added. After 5 min the volatile components are removed on a rotary evaporator. The residue is stirred in 5 ml of a water-acetonitrile mixture (1:1) and the solid is collected by filtration. It is dried under high vacuum. 136 mg of the title compound are obtained (91% of theory).
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:65]([NH:68][NH2:69])(=[O:67])[CH3:66]>CN(C)C=O>[C:65]([N:68]([C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:23]=1[CH:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH3:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:7](=[O:21])[N:6]1[CH3:22])[NH2:69])(=[O:67])[CH3:66]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Reactant: CC(=O)NN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)N(N)C(C)=O
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-m 4-yl]-5-cyano-benzoic acid (intermediate 6) (47.0 mg, 0.10 mmol)) and triethylamine (35.8 μL, 0.26 mmol) are suspended in N,N-dimethylformamide (2 mL), stirred for 5 min and O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (41.0 mg, 0.11 mmol) is added. The mixture is stirred for 10 min and acetic acid hydrazide (12.2 mg, 0.16 mmol) is added. The mixture is stirred overnight at room temperature. Another equivalent of acetic acid hydrazide is added to bring the reaction to completion. The crude product is purified by reversed phase HPLC. Yield 15 mg; ESI mass spectrum [M+H]+=514; Retention time HPLC: 0.95 min (HPLC method Z018_S04).
Reaction SMILES: [C:1]1([C:7]2[S:14][C:13]3[CH:12]=[N:11][N:10](C(=O)C)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:7]2[S:14][C:13]3[CH:12]=[N:11][NH:10][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)n1ncc2sc(-c3ccccc3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2cc3[nH]ncc3s2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92.6 %

Procedure:
To a mixture of 1-(5-phenyl-thieno[3,2-c]pyrazol-1-yl)-ethanone [3.82 g, 15.8 mmol, Intermediate (44)] and ethanol (50 mL) was added 6 N hydrochloric acid (50.0 mL, 300 mmol) in one portion and the resulting mixture heated at 70° C. After 18 hours, the reaction was cooled to ambient temperature and neutralized with 25% aqueous potassium carbonate. The mixture was diluted with water (200 mL) and aged at 0° C. for 1 hour. The resulting solid was collected, washed three times with water (50 mL), and then dried under vacuum to give 5-phenyl-1H-thieno[3,2-c]pyrazole [2.93 g, 92%, Intermediate (45)] as a beige powder. LC/MS: 201.0 (M+H), RT=3.15 minutes).
Reaction SMILES: NCCC1C=CC(O)=CC=1.C1C(C(O)CN)=CC=C(O)C=1.[CH:22]1[C:27]([C@@H:28](O)[CH2:29][NH2:30])=[CH:26][C:25]([OH:32])=[C:24]([OH:33])[CH:23]=1>>[NH2:30][CH2:29][CH2:28][C:27]1[CH:22]=[CH:23][C:24]([OH:33])=[C:25]([OH:32])[CH:26]=1
Reactant: NC[C@H](O)c1ccc(O)c(O)c1
Agent: NCC(O)c1ccc(O)cc1
Agent: NCCc1ccc(O)cc1
Product: NCCc1ccc(O)c(O)c1

Procedure:
Tyramine (TA), octopamine (OA) and norepinephrine (NE), naturally occurring monoamines that have a similar structure to DA, were tested together with DA for their ability to inhibit 3H-DA uptake. The concentration range of an unlabeled competitive inhibitor was selected according to the expected IC50 value. The IC50 values obtained were 0.39±0.11 μM for TA, 1.92±0.28 μM for OA, 4.10±1.02 μM for DA and 22.04±2.94 μM for NE. The apparent Ki values (calculation based on Cheng et al., (1973) Biochem Pharmacol 22:3099) were 0.35±0.10 μM for TA, 1.74±0.25 μM for OA, 3.72±0.92 μM for DA and 20.04±2.67 μM for NE. The rank order of apparent Ki on OA/TAT for potential substrates was: TA<OA<DA<NE.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:15]2=[O:27])=[CH:9][CH:8]=1)[CH3:2].[C:29]1([CH3:38])[C:30]([N:35]=[C:36]=[O:37])=[CH:31][CH:32]=[CH:33][CH:34]=1>ClCCl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:36]([NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[CH3:38])=[O:37])=[CH:22][CH:21]=3)[C:15]2=[O:27])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(N)cc3)c2=O)cc1
Reactant: Cc1ccccc1N=C=O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(NC(=O)Nc4ccccc4C)cc3)c2=O)cc1

Procedure:
3-{4-[3-(4-Aminophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}propionic acid ethyl ester (P8, 60 mg, 0.16 mmol) and o-tolyl isocyanate (40 [2 L, 0.32 mmol) were stirred at room temperature in dichloromethane (5 mL) for 3 hours, then the reaction mixture was concentrated. Trituration with diethyl ether afforded the title compound as a solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:37]=[CH:36][C:25]([C:26]([NH:28][NH:29][C:30]([CH:32]3[CH2:35][CH2:34][CH2:33]3)=O)=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]3[O:27][C:30]([CH:32]4[CH2:33][CH2:34][CH2:35]4)=[N:29][N:28]=3)=[CH:36][CH:37]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(-c4nnc(C5CCC5)o4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide (0.2 g, 0.40 mmol) in CH2Cl2 (3 mL) was added pyridine (0.08 mL, 1.0 mmol). The reaction mixture was cooled to −78° C. Triflic anhydride (0.14 mL, 0.84 mmol) was added dropwise. The mixture was stirred at −78° C. for 1 hour and at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (3 mL). The aqueous layer was washed with CH2Cl2 (3×5 mL) and the combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatograpy with EtOAc afforded 0.19 g (quantitative yield) of 1-Benzyl-4-[4-(5-cyclobutyl-[1,3,4]oxadiazol-2-yl)-phenyl]-4-(3-methoxy-phenyl)-piperidine. 1HNMR (400 MHz, CDCl3) δ 7.92 (d, 2H), 7.37 (d, 2H), 7.36-7.16 (comp, 6H), 6.83 (d, 1H), 6.80 (s, 1H), 6.60 (d, 1H), 3.81-3.78 (m, 1H), 3.77 (s, 3H), 3.45 (s, 2H), 2.82-2.38 (comp, 10H), 2.21-2.19 (comp, 2H); MS (M+1) 480.2.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([OH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:16]([O:19][CH:20]=[CH2:21])(=[O:18])[CH3:17].C(OCCCCCCCC)=C.C(OCCCCCCCC)(=O)C>C1(C)C=CC=CC=1>[C:16]([O:19][CH:20]([O:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH3:21])(=[O:18])[CH3:17]
Reactant: C=COC(C)=O
Reactant: CCCCCCCCO
Agent: C=COCCCCCCCC
Agent: CCCCCCCCOC(C)=O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCCCCCCOC(C)OC(C)=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of di-1-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (0.01 mmol) and sodium carbonate (0.1 mmol) in toluene (1.0 ml), 1-octanol (130 mg, 1 mmol) and vinyl acetate (5 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 2 hours. The reaction mixture was analyzed by gas chromatography to find that 1-octyl vinyl ether, octyl acetate, and 1-(1-octyloxy)ethyl acetate were produced in yields of 58%, 3%, and 21%, respectively, with a conversion from 1-octanol of 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[NH:6]2.N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([CH2:15][O:14][C:13]3[CH:16]=[C:17]4[C:21](=[CH:22][C:12]1=3)[CH2:20][CH2:19][O:18]4)[C:5](=[O:11])[N:6]2[CH2:36][C@H:33]1[CH2:32][CH2:25][CH2:35][O:34]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2cccc(Cl)c2C12COc1cc3c(cc12)CCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2cccc(Cl)c2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4′-chloro-5,6-dihydrospiro[benzo[1,2-b:5,4-b']difuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 4′-chloro-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (80%) as a colorless solid: mp 78-82° C.; 1H NMR (300 MHz, DMSO-d6) δ7.32-7.09 (m, 1H), 7.05-6.92 (m, 1H), 6.44 (s, 1H), 6.35 (s, 1H), 4.96 (dd, J=9.1, 1.1 Hz, 1H), 4.85 (d, J=9.1 Hz, 1H), 4.51 (t, J=8.7 Hz, 1H), 4.31-4.16 (m, 1H), 4.00-3.59 (m, 1H), 2.98 (t, J=8.6 Hz, 1H), 2.12-1.80 (m, 1H), 1.76-1.61 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.0 (2), 162.1 (2), 162.0, 144.7, 131.1 (2), 129.8 (2), 128.7 (2), 123.9, 119.4 (2), 118.4 (2), 117.5 (2), 108.1 (2), 92.9, 77.5, 76.9 (2), 72.3, 68.2 (2), 58.1 (2), 44.9 (2), 29.1 (2), 29.0 (2), 25.6 (2); MS (ES+) m/z 397.9 (M+1), 399.9 (M+1).