Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:16][CH3:17])=[CH:10][C:9]=1[CH3:18])(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>ClCCl>[CH2:16]([O:15][C:11]1[C:12]([CH3:14])=[CH:13][C:8]([NH2:7])=[C:9]([CH3:18])[CH:10]=1)[CH3:17].[C:22]([OH:24])([C:21]([F:26])([F:25])[F:20])=[O:23]
Reactant: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C)c(N)cc1C
Reaction time: 2 h

Procedure:
To a solution of 36 (950 mg, 3.6 mmol) in 10 mL dichoromethane, trifloroacetic acid (5 mL) was added. The reaction mixture was stirred for 2 h. At this point, LC-MS showed the reaction to be complete. The reaction flask was concentrated to remove the solvent and most of the TFA. The residue was then dried further in a high vacuum oven over 24 h to give the title compound 37 as TFA salt.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:5].[CH2:17](OC(OCC)(OCC)C)[CH3:18]>O>[CH3:17][C:18]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:4](=[O:5])[C:3]2[C:2](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccn1
Reactant: CCOC(C)(OCC)OCC
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccccn1
Yield: 70.2 %

Procedure:
A mixture of 72 (3 g, 0.015 mol) and 1,1,1-triethoxy-ethane (5 g, 0.045 mol) were heated for 7 hours. The reaction mixture was poured into water, filtered, and the precipitate was washed with water and recrystallized from EtOH to yield 73 (2.5 g, 75%). M. Wt. 237. LCMS [M+H]+=238.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]2=3)[CH2:3][CH2:2]1.O.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:37][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][C:8]=2[N:17]2[CH2:22][CH2:21][O:20][C:19]3[CH:23]=[C:24]([S:27]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)(=[O:28])=[O:29])[CH:25]=[CH:26][C:18]2=3)[CH2:5][CH2:6]1
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4nccs4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
EXAMPLE 44 was prepared by charging a 10-mL round bottomed flask with 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide, (EXAMPLE 38, 0.040 g, 0.077 mmol). The reaction vessel was then flushed with N2 gas and the solid starting materials were dissolved in methanol (0.4 mL). To the resulting solution, formaldehyde 37% wt in water (0.085 mL, 1.148 mmol) was added and the mixture was stirred for 5 min at room temperature. Sodium triacetoxyborohydride (0.243 g, 1.148 mmol) was added portion wise and the resulting solution was stirred for 10 min. The reaction mixture was poured into a sep. funnel containing sat. NaHCO3 and EtOAc. The aqueous layer was washed with EtOAc (3×25 mL), the organic layers were combined and dried over Na2SO4. The organic layer was filtered and concentrated to give pure 4-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.030 g, 0.056 mmol) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18 (d, J=5.58 Hz, 3 H) 2.41 (br. s., 2 H) 2.91 (br. s., 2 H) 3.57 (br. s., 3 H) 4.25 (br. s., 2 H) 5.22 (s, 1 H) 5.80 (br. s., 1 H) 6.40 (t, J=8.61 Hz, 1 H) 6.60 (d, J=3.62 Hz, 1 H) 6.85 (d, J=4.70 Hz, 1 H) 7.03-7.12 (m, 1 H) 7.13-7.22 (m, 1 H) 7.35 (d, J=4.50 Hz, 1 H) 7.46-7.63 (m, 2 H) 7.64-7.78 (m, 1 H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[C:7]([O:15][CH3:16])[CH:6]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](/[CH:23]=[CH:24]/[C:25](O)=[O:26])[CH:18]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([O:15][CH3:16])[C:8]([O:13][CH3:14])=[C:9]([O:11][CH3:12])[CH:10]=1)[C:25](=[O:26])/[CH:24]=[CH:23]/[C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)/C=C/c1cccnc1
Reactant: CNCCc1cc(OC)c(OC)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CCN(C)C(=O)/C=C/c2cccnc2)cc(OC)c1OC
Yield: 93.5 %

Procedure:
N-Methyl-3,4,5-trimethoxyphenethylamine (1.60 g, 7.11 mmol) and trans-3-(3-pyridyl)acrylic acid (1.17 g) were dissolved in dimethylformamide (8 ml), and diethylphosphoric cyanide (1.3 ml) and triethylamine (2.2 ml) were sequentially added under ice-cooling and stirring and stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the reaction mixture was extracted with dichloromethane, washed with water and dried over potassium carbonate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=10:1) to yield amorphous (E)-N-methyl-3-(3-pyridyl)-N-(3,4,5-trimethoxyphenethyl)-2-propenoic acid amide (2.37 g, 94%). Then, hydrogen chloride-methanol was added to the product (1.80 g) to produce its hydrochloride, which was recrystallized in a mixed solvent of ethyl acetate-methanol to yield the titled compound (1.59 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:19][C:20]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1N
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-chloro-4-methoxy benzoic acid (Lancaster Synthesis Ltd., Windham, N.H.) (100 mg, 0.54 mmol) in CH2Cl2 (5 mL) was cooled to −40° C. DMF (one drop) was added followed by oxalyl chloride (0.32 mL, 0.64 mmol, and 2M solution in CH2Cl2). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was then concentrated to dryness and dried under high vacuum for several hours. The crude acid chloride (38 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL) and treated with a solution of 43B (48 mg, 0.18 mmol) in CH2Cl2 (2 mL). Triethylamine (0.13 mL, 0.9 mmol) was added and the reaction was stirred at room temperature until disappearance of the starting material was noted. The reaction was concentrated to dryness and purified by chromatography (SiO2, 5% EtOAc in hexanes) to afford 43C (72 mg, 95%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:33][CH2:34][CH2:35][OH:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([N:33]([CH2:34][CH2:35][OH:36])[C:23](=[O:24])[CH2:22][N:14]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCNCc1ccccc1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: Cc1ccc(N(CC(=O)N(CCO)Cc2ccccc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 2-benzylamino-ethanol
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[O:13])=[CH:4][CH:3]=1.[OH-].[Na+]>CCO>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]2)=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2cccn2Cc2ccc(F)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CCN(C(=O)c2cccn2Cc2ccc(F)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl 1-(1-(4-fluorobenzyl)-1H-pyrrole-2-carbonyl)piperidine-4-carboxylate (197 mg, 0.550 mmol) was dissolved in EtOH (6 mL), and 7M aq. NaOH was added (6 mL). The reaction was allowed to stir at 60° C. for 8 h. EtOH was then removed in vacuo, and the remaining aqueous solution was acidified (to ˜pH 2) by conc. HCl. The precipitate was filtered over a scintered glass filter and collected as a viscous oil. This material was dried overnight under high-vacuum to afford 169 mg of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[CH:5]2.[OH:14][C@:15]1([C:22]2[CH:23]=[C:24]([SH:27])[S:25][CH:26]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1>>[OH:14][C@:15]1([C:22]2[CH:23]=[C:24]([S:27][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH:6]=[CH:5]4)[S:25][CH:26]=2)[CH2:20][CH2:19][O:18][C@@H:17]([CH3:21])[CH2:16]1
Reactant: Cn1c(=O)ccc2cc(I)ccc21
Reactant: C[C@H]1C[C@@](O)(c2csc(S)c2)CCO1
Product: C[C@H]1C[C@@](O)(c2csc(Sc3ccc4c(ccc(=O)n4C)c3)c2)CCO1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2-dihydroquinolin-2-one (European Patent Application No. 0420511, Example 1 thereof) was reacted with (2S,4R)-4-hydroxy-4(2-mercaptothien-4-yl)-2-methyltetrahydropyran to give (2S,4R)-4-hydroxy-2-methyl-4-[2-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylthio)thien-4-yl]tetrahydropyran in 65% yield as a foam;
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[CH:15][C:16]([O:29][CH3:30])=[C:17]([C:19]([CH3:28])([CH3:27])[CH2:20][C:21]2([CH:24]([F:26])[F:25])[CH2:23][O:22]2)[CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CS(C)=O.C(OCC)(=O)C>[F:26][CH:24]([F:25])[C:21]([OH:22])([CH2:20][C:19]([C:17]1[CH:18]=[C:13]([F:12])[CH:14]=[CH:15][C:16]=1[O:29][CH3:30])([CH3:28])[CH3:27])[CH2:23][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH:3]=[CH:4]1
Reactant: Oc1ccnc2ccccc12
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)F)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cn1ccc(=O)c2ccccc21)C(F)F
Temperature: 25 °C
Reaction time: 360 h

Procedure:
To a solution of the 4-hydroxyquinoline and 2-[2-(5-fluoro-2-methoxyphenyl)-2-methylpropyl]-2-difluoromethyloxirane in DMSO (1.0 mL) stirred under nitrogen was added NaHMDS (1.2 mL, 1.0M in THF) dropwise. The mixture was stirred at room temperature for 15 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated in vacuo. Trituration of the residue with diethyl ether gave the product 1-[2-difluoromethyl-4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methylpentyl]-1H-quinolin-4-one as a crystalline solid that was collected by filtration and air dried (77.7 mg, 20%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12](O)=O)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.CS(Cl)(=O)=O.[N:20]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]#[N:20])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sc(C(=O)O)cc12
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Product: COc1cccc2sc(C#N)cc12
Reaction time: 2 h
Yield: 74 %

Procedure:
(Ref: Cheutin et al.; C.R. Hebd. Seances Acad. Sci; 261; 1965; 705.) A solution of 4-methoxy-1-benzothiophene-2-carboxylic acid (1.19 g, 5.7 mmol) in pyridine (25 mL) at 0° C. was treated with methanesulfonyl chloride (0.49 mL, 6.3 mmol) keeping the temperature at 0° C., stirring was continued for 2 h. Ammonia gas was then bubbled through the mixture for 5 minutes, followed by nitrogen for 10 mins. The reaction mixture was then treated with a large excess of mesyl chloride (4.43 mL, 57 mmol) and stirred for 16 h at room temperature. The solvent evaporated in vacuo to give a brown residue which was purified by flash chromatography with 10% ethyl acetate in hexane to give a colourless solid (800 mg, 74%); δH (300 MHz, CDCl3) 8.00 (1H, s, 3-ArH), 7.48-7.35 (2H, m, ArH), 6.80-6.77 (1H, m, ArH) and 3.92 (3H, s, OCH3).
Reaction SMILES: [OH:1][C:2]([CH3:38])([CH3:37])[CH2:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].[F-].[Cs+].C1OCCOCCOCCOCCOCCOC1.C(#N)C>C(OCC)(=O)C>[OH:1][C:2]([CH3:37])([CH3:38])[CH2:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: CC(CC(C)(C)O)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(CC(C)(C)O)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Yield: 21.2 %

Procedure:
In a 125 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide (25 mg, 0.046 mmol), cesium fluoride (70 mg, 0.46 mmol) and 18-crown-6 (12 mg, 0.046 mmol) were combined with acetonitrile to give an off-white suspension. The reaction was stirred at reflux for 72 h. A large excess of CsF and 18-crown-6 was added and the reaction was heated for an additional 24 h. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4 and concentrated. The crude material was suspended in water and collected by filtration then triturated with 1:2 dichloromethane/heptane to afford 4 mg (21%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-hydroxy-1,3-dimethyl-butyl)-amide as a yellow solid. MS: [M+Na]+=433, 1H NMR (300 MHz, DMSO-d6) δ: 12.83 (br. s., 1H), 9.10 (s, 1H), 8.57 (dd, J=8.9, 5.5 Hz, 1H), 8.41 (d, J=2.3 Hz, 1H), 8.15 (d, J=8.3 Hz, 1H), 7.71 (dd, J=9.8, 1.9 Hz, 1H), 7.20 (td, J=9.1, 2.3 Hz, 1H), 4.35 (s, 1H), 4.29-4.43 (m, 1H), 4.16 (s, 3H), 1.83 (dd, J=14.4, 7.9 Hz, 1H), 1.73 (dd, J=16.6, 4.9 Hz, 1H), 1.31 (d, J=6.4 Hz, 3H), 1.15 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.O>CN(C)C=O>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(c1ccc(OCCN3CCCC3)cc1)c1c-2ccc2ccccc12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A 7 g portion of the compound of Example 1 was dissolved in 100 ml of dry dimethylformamide, and to it was added 1.05 g of 50% mineral oil dispersion of sodium hydride and 4 g of 1-(2-chloroethyl)pyrrolidine. The mixture was then stirred at 60° C. for 3 hours and cooled. It was then poured over 500 ml of ice and water, and the mixture was extracted 3 times with 250 ml portions of ethyl acetate. The organic extract was washed with two 50 ml portions of brine, dried and concentrated under vacuum. The residue was chromatographed over a 5 cm×50 cm silica gel column with 3:1 ethyl acetate:toluene, followed by ethyl acetate. The product-containing fractions were combined and concentrated under vacuum to contain 4.5 g of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:27])[C:12]([C:15]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:17])[CH3:16])=[N:13][N:14]=1.CI.[C:30](=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH3:27])[C:12]([C:15]([N:18]([CH3:30])[C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([CH3:17])[CH3:16])=[N:13][N:14]=1
Reactant: O=C([O-])O
Reactant: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CI
Product: CN(C(=O)c1ccccc1)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 16 mg) was added to a DMF (10 ml) solution of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}benzamide (130 mg), followed by stirring at room temperature for 30 minutes. Then, methyl iodide (0.027 ml) was added thereto and the whole was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and chloroform were added to the reaction solution and then the organic layer was separated. Furthermore, the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting crude product was purified by flash column chromatography (chloroform:methanol=100:3) to obtain 104 mg of N-{1-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-1-methylethyl}-N-methylbenzamide (colorless solid).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[O:7])(C)(C)C.C([SiH](CC)CC)C.ClCCl>FC(F)(F)C(O)=O>[O:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8]([C:6]([OH:7])=[O:5])=[N:9][NH:10]3)=[CH:15][CH:14]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1n[nH]c2cc(C3CCOCC3)ccc12
Yield: 60 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was dissolved in trifluoroacetic acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid. The acid was coupled with the bicyclobase according to procedure A.
Reaction SMILES: [C:1](O)(=O)[C:2]1C(=CC=C[CH:8]=1)O.[C:11]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)(N1C=CN=C1)=O>O1CCCC1>[NH2:20][CH:21]1[CH:2]2[CH2:8][CH2:11][N:18]([CH2:19][CH2:1]2)[CH2:22]1
Reactant: O=C(O)c1ccccc1O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NC1CN2CCC1CC2
Reaction time: 1 h
Yield: 120 %

Procedure:
A solution of salicylic acid (3.46 g, 25 mmole) in anhydrous tetrahydrofuran (20 ml) under nitrogen is treated with 1,1'-carbonyldiimidazole (4.22 g, 26 mmole), stirred for one hour, then degassed with a stream of nitrogen. A solution of 3-aminoquinuclidine (from 30 mmole of dihydrochloride) in tetrahydrofuran (10 ml) is prepared, and the solution is added dropwise to the first solution. After 18 hours at room temperature, the reaction mixture is concentrated in vacuo and partitioned between methylene chloride (200 ml) and water (100 ml). The resultant organic layer is separated and the aqueous solution is extracted with methylene chloride (100 ml). The combined organic solutions are dried (Na2SO4), concentrated in vacuo, and passed through a short column of alumina (eluted first with 5% methanol/tetrahydrofuran, then with 25% methanol/tetrahydrofuran) to provide 3.20 g (52%) of product as a colorless foam.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)C.Cl>CC(C)=O>[C:11]12([CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[O:3])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: CCOC(CCCCOCC12CC3CC(CC(C3)C1)C2)OCC
Agent: Cl
Solvent: CC(C)=O
Product: O=CCCCCOCC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of the appropriate acetal 5, 6, (0.2 mmol) in 3 ml acetone and 1 ml 5% HCl was stirred at rt for 1h. Evaporation of the acetone, extraction of the residue with ether (3×7ml), drying on Na2SO4 and evaporation yielded the aldehyde (quant.) used for the next step without further purification.
Reaction SMILES: N1C2C(=CC=CC=2)C(=O)C1=O.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[C:15](=[O:23])[C:16](=[O:22])[NH:17]2.BrCCC1CC1.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][N:17]1[C:18]2[C:14](=[C:13]([Cl:12])[CH:21]=[CH:20][CH:19]=2)[C:15](=[O:23])[C:16]1=[O:22])[CH3:36]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: BrCCC1CC1
Agent: O=C1Nc2ccccc2C1=O
Product: CCOC(=O)CN1C(=O)C(=O)c2c(Cl)cccc21

Procedure:
Following the procedure as described in PREPARATION 2A, and making non-critical variations to replace isatin with 4-chloro-1H-indole-2,3-dione, and (2-bromoethyl)cyclopropane with ethyl bromoacetate, the title compound was obtained (95%) as a colorless solid: 1H NMR (300 MHz, CDCl3)δ 7.48 (t, 1H), 7.08 (d, 1H), 6.67 (d, 1H), 4.47 (s, 2H), 4.23 (q, 2H), 1.27 (t, 3H); MS (ES+) m/z 268.6 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:12]([N:14]([CH2:15][CH3:16])[C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)[CH3:13]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Methoxybenzoic acid (6 g, 39 mmol) was treated with diethylamine (4.45 mL, 43 mmol), TBTU (15 g, 46.8 mmol), disopropylethylamine (10.2 mL, 58.5 mmol) in DMF (40 mL). The mixture was stirred at ambient temperature overnight. The reaction was poured into ice water and the resulting mixture extracted several times with ethyl acetate. The organic layer was washed with a solution of saturated sodium bicarbonate, water and then brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 30 to 70% ethyl acetate in hexanes to obtain a brown oil. Yield=7.8 g. MS (M+H)+ 208.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9]2/[C:10](=[O:15])[NH:11][C:12](=[O:14])[S:13]/2)[CH:5]=[CH:4][N:3]=1.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[C:26](Cl)=[O:27].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[O:14]=[C:12]1[NH:11][C:10](=[O:15])/[C:9](=[CH:8]/[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=3)=[O:27])[N:7]=2)/[S:13]1
Reactant: O=C(Cl)c1ccc2ccccc2n1
Reactant: Nc1nccc(/C=C2\SC(=O)NC2=O)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1NC(=O)/C(=C/c2ccnc(NC(=O)c3ccc4ccccc4n3)n2)S1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)quinoline-2-carboxamide was prepared as follows. A 2-dram vial was charged with (Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg, 0.100 mmol), Pyridine (1 mL), quinoline-2-carbonyl chloride (74.6 mg, 0.389 mmol, 3.8 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9 equiv.), and the reaction was shaken at RT. After 16 h, the reaction was treated with saturated sodium bicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organic layer was concentrated under reduced pressure and the residue was purified using reverse phase HPLC to provide the desired product (3 mg, 37.7 mg theoretical, 8%). LC-MS m/z 378.4 (M+1).