Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>CCCCO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:13][N:12]=1
Reactant: CC(=O)c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1n[nH]c2ncccc12
Temperature: 120 °C
Reaction time: 0.83 h

Procedure:
To a solution of the above crude 1-(2-chloropyridin-3-yl)ethanone (XIII) in n-BuOH (512 L) was added 85% hydrazine hydrate (78 L, 1360 mol). The reaction was heated at refluxed (˜120° C.) for 48 hours. The reaction was cooled and evaporated under vacuum. The crude material was taken up in DCM (834 L) and washed with 2× aqueous 25% NaCl (214 L) by adding aqueous 25% NaCl, stirring for 50 min, allowing to stand for 50 min, separating the layers and then repeating. The organic layer was evaporated to produce 3-methyl-1H-pyrazolo[3,4-b]pyridine (XIV) as a solid (13.2 Kg, 99 mol, 94.1% purity, 36.3% assay yield for 3 steps). 1H NMR (DMSO-d6, 400 MHz) δ ppm 2.50 (s, 3H), 7.13 (dd, J=4.4 Hz, J=8 Hz, 1H), 8.19 (dd, J=1.2 Hz, J=8 Hz, 1H), 8.47 (dd, J=1.6 Hz, J=4.8 Hz, 1H), 13.18 (brs, 1H); ESIMS found C7H7N3 m/z 133.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]([CH3:13])[C:6](=[O:12])[NH:7]2.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.Cl>C1(C)C=CC=CC=1.CO.O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH3:14])([CH3:13])[C:6](=[O:12])[NH:7]2
Reactant: COc1cccc2c1C(C)C(=O)N2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: COc1cccc2c1C(C)(C)C(=O)N2
Temperature: -78 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of 4-methoxy-3-methyl-1,3-dihydro-indol-2-one (41.73 g, 235.5 mmol) and tetrahydrofuran (1000 mL) is cooled to −78° C. Potassium bis(trimethylsilyl)amide (989.0 mL, 494.3 mmol, 0.5 M in toluene) is added over 45 minutes so as to maintain the reaction temperature between −71° C. and −66° C. Iodomethane (36.71 g, 258.7 mmol) is added over 15 minutes between −75° C. and −70° C. The mixture is stirred at −78° C. for 1 hour then −60° C. for 30 minutes. Methanol (25 mL) is added at −60° C. Aqueous hydrochloric acid (1N, 420 mL) is added rapidly allowing the temperature to rise to −7° C. The solution is transferred to a separatory funnel with aqueous hydrochloric acid (1N, 420 mL) and toluene (50 mL). The organic layer is extracted with a saturated sodium bicarbonate solution (250 mL), washed with a saturated sodium chloride solution (200 mL), dried over magnesium sulfate, and filtered. The filtrate is stirred with DARCO (25 g) for 1 hour then filtered. The filtrate is concentrated by rotary evaporation. The residue is refluxed for 1 hour in tert-butyl methyl ether (300 mL). After distilling out 100 mL of solvent, the slurry is stirred for 10 hours at 24° C. The solid is isolated by vacuum filtration rinsing twice with cold (−40° C.) tert-butyl methyl ether. After vacuum drying for 12 hours at 50° C./5 Torr, 23.9 g (58%) of 4-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one is obtained. mp 143-144° C. MS (ES+) m/z 192 (M++1).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:21][CH:20]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2)cc1
Yield: 85.5 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 3 of Example 1, 270 mg (0.9 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylsulfonyl)benzene (Step 1) was reacted with 300 mg (1.8 mmol) of 4-methylthiophenylboronic acid (Example 1, Step 1). Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (4:1) gave 265 mg (86%) of 1-[2-(4-methylthiophenyl)cyclopenten-1-yl)-4-(methylsulfonyl)benzene as a colorless solid: mp 138°-139° C.; NMR (CDCl3) d 2.08 (m, J=7 Hz, 2H), 2.47 (s, 3H), 2.90 (t, J=7 Hz, 4H), 3.04 (s, 3H), 7.06 (d, J=8 Hz, 2H), 7.11 (d, J=8 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H); MS (EI) m/e (rel intensity) 344 (100), 297 (4), 218 (33); HRMS. Calc'd for C19H20O2S2 : 344.0905. Found: 344.0907. Anal. Calc'd for C19H20O2S2 : C, 66.24; H, 5.85; S, 18.16. Found: C, 66.28; H, 5.81; S, 18.95.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:11][O:12][CH2:13][CH2:14][OH:15])[CH3:10])=[CH:5][N:4]=1.O[C:17]1[CH:49]=[CH:48][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:47])=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:11][O:12][CH2:13][CH2:14][O:15][C:17]2[CH:49]=[CH:48][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[N:24]([C:28]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]3=[O:47])=[CH:19][CH:18]=2)[CH3:10])=[CH:5][N:4]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(C)=NOCCO)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 78.2 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 346 mg of 2-[1-(2-methoxy-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 31), 766 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 475 mg of triphenylphosphine and 301 mg of diethyl azodicarboxylate, 846 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Br:14]N1C(=O)CCC1=O>C(#N)C>[Br:14][C:7]1[CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:2]([OH:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(C(F)(F)F)c1O
Solvent: CC#N
Product: O=Cc1cc(Br)cc(C(F)(F)F)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
2-hydroxy-3-trifluoromethylbenzaldehyde (59.16 g) was dissolved in acetonitrile (500 mL), and N-bromosuccinimide (57.56 g) was added to the solution, and then the mixture was stirred at 0° C. for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained crystal was washed with n-hexane (50 mL) to obtain the title compound (63.98 g) as a pale yellow crystal.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3([CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:14](=[O:16])[CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O[I:27](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II>ClCCl>[I:27][C:15]1[C:14](=[O:16])[C:13]2([CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[O:12][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C2=CC(=O)C3(CCOCC3)O2)cc1
Agent: II
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C2=C(I)C(=O)C3(CCOCC3)O2)cc1
Yield: 77.5 %

Procedure:
A mixed solution of 2-{4-(methylsulfonyl)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one (0.55 g), [bis(trifluoroacetoxy)iodo]benzene (0.84 g) and iodine (0.45 g) in 50 ml dichloromethane was stirred for 6 hours at room temperature. Then the reaction was quenched by adding 10 ml aqueous saturated sodium thiosulfate. The organic layer was washed with brine and was concentrated under reduced pressure. The resulting crude product was purified by column chromatography (hexane/ethylacetate) to afford 0.6 g of 3-iodo-2-{4-(methylsulfonyl)phenyl}-1,8-dioxa-spiro[4,5]dec-2-en-4-one. mp: 210-213° C. NMR: δ1.60-1.72 (m, 2H), 2.11-2.44 (m, 2H), 3.12 (s, 3H), 3.80-3.90 (m, 2H), 4.04-4.14 (m, 2H), 8.21 (d, J=9 Hz, 2H), 8.41 (d, J=9 Hz, 2H). IR (cm−1): 1690, 1580, 1146, 912, 744.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[O:8]=[S:9]1(=[O:37])[CH2:14][CH:13]=[C:12]([C:15]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:30]2[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=2)=[O:29])[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C.CCOC(C)=O>C(Cl)Cl.CN(C=O)C>[C:3]([N:24]1[CH2:25][CH2:26][CH:21]([C:19]2[CH:18]=[CH:17][C:16]([NH:27][C:28]([C:30]3[NH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=3)=[O:29])=[C:15]([C:12]3[CH2:13][CH2:14][S:9](=[O:8])(=[O:37])[CH2:10][CH:11]=3)[CH:20]=2)[CH2:22][CH2:23]1)(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCS(=O)(=O)CC2)n1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCS(=O)(=O)CC3)c2)CC1
Reaction time: 0.08 h
Yield: 94.7 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [2-(1,1-dioxo-1,2,3,6-tetrahydro-1λ6-thiopyran-4-yl)-4-piperidin-4-yl-phenyl]-amide trifluoroacetic acid salt (as prepared in Example 36, step (e), 62 mg, 0.115 mmol) in 4 mL of 1:1 DCM/DMF at RT was added DIEA (60 μL, 0.345 mmol). The mixture was stirred for 5 min, then acetic anhydride (11 μL, 0.121 mmol) was added slowly to the mixture, and the resulting mixture was stirred at RT for 0.5 h. Treated with 40 mL of EtOAc, the mixture was washed with H2O (2×20 mL). The aqueous layers were extracted with EtOAc (4×10 mL). The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography on silica gel (1-4% MeOH/DCM) yielding 50.9 mg (95%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 13.0 (s, 1H), 9.10 (s, 1H), 8.13 (d, 1H, J=8.4 Hz), 7.77 (d, 1H, J=2.3 Hz), 7.26 (dd, 1H, J=8.4, 2.0 Hz), 7.08 (d, 1H, J=2.0 Hz), 5.77 (t, 1H, J=4.3 Hz), 4.84 (dt, 1H, J=13.3, 2.1 Hz), 4.00 (dt, 1H, J=13.3, 2.1 Hz), 3.89 (br s, 2H), 3.31 (t, 2H, J=6.2 Hz), 3.23 (td, 1H, J=13.2, 2.5 Hz), 3.02 (m, 2H), 2.77 (dddd, 1H, J=11.9, 11.9, 3.4, 3.4 Hz), 2.68 (ddd, 1H, J=12.6, 12.6, 2.9 Hz), 2.18 (s, 3H), 1.70-1.97 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C23H25N5O4S, 468.2 (M+H). found 468.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24](O)=[O:25]>>[CH3:18][C:19]1[O:20][CH:21]=[CH:22][C:23]=1[C:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:25]
Reactant: Cc1occc1C(=O)O
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: Cc1occc1C(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 99.1 %

Procedure:
Beginning with 8.7 mg (0.038 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 11 mg (0.087 mMol) 2-methylfuran-3-carboxylic acid, 12.7 mg (99%) of the title compound were recovered as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[C:7]([F:24])[C:6]=1F)[CH3:2].[CH:27]1([NH2:30])[CH2:29][CH2:28]1>CN(C)C(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)=[C:7]([F:24])[C:6]=1[NH:30][CH:27]1[CH2:29][CH2:28]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1F
Reactant: NC1CC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)c(F)c1NC1CC1
Yield: 76.9 %

Procedure:
A solution of 4-[3-(tert-butoxycarbonylamino)pyrrolidin-1-yl]-2,3-difluorobenzoic acid ethyl ester (Example 2h, 1.85 g, 5.01 mmol) and cyclopropylamine (14.0 mL, 201 mmol) in N,N-dimethylacetamide (5 mL) is heated in a sealed glass tube for 48 hours at 100° C. The solution is then concentrated under high vacuum and purified by column chromatography (1:9 ethyl acetate/hexanes) to afford the title compound (1.57 g). 1H NMR (CDCl3): δ 7.59 (bs, 1H), 7.57 (dd, 1H), 6.00 (dd, 1H), 4.82–4.68 (bd, 1H), 4.39–4.18 (m, 3H), 3.80–3.49 (m, 3H), 3.41–3.30 (m, 1H), 3.00–2.88 (m, 1H), 2.31–2.11 (m, 1H), 2.00–1.85 (m, 1H), 1.45 (s, 9H), 1.37 (t, 3H), 0.73–0.50 (m, 4H).
Reaction SMILES: [N:1]1([CH:10]2[CH2:15][CH2:14][N:13](C(OCC)=O)[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CC(O)C>[NH:13]1[CH2:14][CH2:15][CH:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[CH2:11][CH2:12]1
Reactant: CCOC(=O)N1CCC(N2CCc3ccccc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: c1ccc2c(c1)CCN2C1CCNCC1
Yield: 91.4 %

Procedure:
A mixture of intermediate 6 (95 g) and potassium hydroxide (194 g) in 2-propanol (1300 ml) was stirred and refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in H2O/CH2Cl2. The organic layer was separated, dried over MgSO4, filtered and evaporated, yielding 64 g (90.4%) of 2,3-dihydro-1-(4-piperidinyl)-1H-indole. A sample (4.5 g) was crystallized from CH3OH and converted into the hydrochloric acid salt (1:1) in 2-propanol and filtered off, yielding 3.0 g of 2,3-dihydro-1-(4-piperidinyl)-1H-indole monohydrochloride (intermediate 7).
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[C:7]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:8]([CH3:14])=[C:9]([NH:11]C=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>CO>[NH2:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]2[O:19][C:16]([CH3:18])([CH3:17])[CH2:15][C:7]=2[C:8]=1[CH3:14]
Reactant: C=C(C)Cc1c(C)c(NC=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N)cc(C(C)(C)C)c2c1CC(C)(C)O2
Temperature: 0 °C
Yield: 67.3 %

Procedure:
To a solution of N-[5-(tert-butyl)4-hydroxy-2-methyl-3-(2-methyl-2-propenyl)phenyl]formamide (10.45 g, 40 mmol) in methanol (100 ml) was added concentrated hydrochloric acid (40 ml) and the mixture was heated under reflux for 3 hours under argon atmosphere. After cooling to 0° C., the mixture was made weakly basic using 12N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by a column chromatography on a silica gel (hexane:ethyl acetate=1:1) and crystallized from hexane to obtain 6.28 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:21][OH:22])[CH:20]=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]>O=[Mn]=O.C(Cl)(Cl)Cl.CO>[N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH:21]=[O:22])[CH:20]=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCn2nc(CO)cc2C1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1cc2n(n1)CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
MnO2 (activated) (84.2 g) was added to the CHCl3-MeOH (95:5, 253 mL) solution of 2-hydroxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylic acid 4-nitrobenzyl ester (8.42 g), and the mixture was refluxed for 1 h under a nitrogen atmosphere. The reaction mixture was filtered through a pad of Celite. Silica-gel (20 g) was added to the filtrate and the solvent was removed under reduced pressure to give the silica-gel coating with crude reactant. The above silica-gel was adsorbed to silica-gel column chromatography and the column was eluted with CHCl3-MeOH (49/1 to 19/1). The titled compound was obtained as yellow crystals (2.82 g, 34%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:12][C:13](O)([CH3:15])[CH3:14].CCN=C=NCCCN(C)C.O>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[C:1]([C:4]1[S:8][C:7]([C:9]([O:11][C:13]([CH3:15])([CH3:14])[CH3:12])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: CC(=O)c1ccc(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (7 g, 41 mmol) in DMA (100 mL) was treated with 2-methyl-2-propanol (54 mL, 576 mmol), DMAP (3 g, 25 mmol), and EDCI (9.9 g, 51.5 mmol). The resulting mixture was stirred at 25° C. for 16 h. Water (200 mL) was added and the mixture was extracted with ethyl ether (350 mL). The organic phase was washed with 1 N HCl (100 mL), water (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL); dried (Na2SO4); filtered; and evaporated to afford 6.7 g (72%) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.53 (s, 9H) 2.58 (s, 3H) 7.75 (d, J=3.68 Hz, 1H) 7.92 (d, J=3.68 Hz, 1H); MS (DCI) 227 m/z (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.Cl.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1.C(N(CC)C(C)C)(C)C>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([N:27]3[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCCNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCCC(N)C3)c2c1
Temperature: 160 °C
Yield: 22.3 %

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (0.2 g, 0.54 mmol, prepared in analogy to the one in Example 2-1), piperidin-3-ylamine hydrochloric acid salt (0.275 g, 1.6 mmol) and N,N-diisopropylethylamine (1 mL) was heated at 160° C. under microwave irradiation for 1 hour. After being cooled to room temperature, the mixture was purified by preparative HPLC and SPE. After SPE separation, the eluent was concentrated in vacuo to remove the organic solution. The residue was dried by lyophylization to give 52.3 mg of the desired product (yield was 22.3%). MS obsd. (ESI+) [(M+H)+] 437, 1H NMR (400 MHz, CD3OD) δ ppm 8.09-8.07 (d, J=8 Hz, 1 H), 7.87-7.85 (q, J=7.2 Hz, 1 H), 7.85-7.82 (m, 1 H), 7.73-7.68 (q, J=14 Hz, 2 H), 7.62-7.55 (m, 2 H), 6.56 (s, 1 H), 5.37 (s, 2 H), 4.57 (s, 2 H), 3.90-3.88 (d, J=9.6 Hz, 1 H), 3.75 (s, 2 H), 3.67-3.66 (m, 1 H), 3.51-3.48 (d, J=11.6 Hz, 1 H), 3.26-3.24 (d, J=9.6 Hz, 1 H), 3.24-3.14 (m, 1 H), 2.49 (s, 3 H), 2.26-2.22 (m, 1 H), 2.14-2.10 (m, 1 H), 1.99-1.92 (m, 1 H), 1.91-1.78 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[CH2:21][OH:22].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([S:9]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][OH:22])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: OCC1CCCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N1CCCCC1CO
Temperature: 25 °C
Yield: 28 %

Procedure:
3-(Trifluoromethyl)benzenesulfonic acid chloride (1 eq), dissolved in methylene chloride (65 ml), was added dropwise to a cooled solution (0° C.) of 2-piperidinemethanol (40 mmol, 1.1 eq) in methylene chloride (160 ml) and triethylamine (2.5 eq). When the addition was complete, the cooling bath was removed and the reaction mixture was stirred at room temperature until, according to thin layer chromatography control, the reaction was complete (90 min). Hydrogen chloride solution (0.5 mol/l, 75 ml) was added, the mixture was stirred for 15 min, the phases were separated and the organic phase was washed with water, dried over sodium sulfate and concentrated in vacuo. Yield: 28%
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[CH3:12][CH:13]([CH2:18][C:19]([O:21]C)=[O:20])[C:14]([O:16]C)=[O:15].[OH-].[Na+]>C1(C)C=CC=CC=1.O.CO>[F:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[C:18](\[CH:13]([CH3:12])[C:14]([OH:16])=[O:15])/[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC(C)C(=O)OC
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C(=O)O)/C(=C\c1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (60% in paraffin oil, 31 g, 775 mmol) in toluene (150 mL) was added a solution of 4-fluorobenzaldehyde (30 g, 242 mmol) and dimethyl methylsuccinate (58 g, 362 mmol) in toluene (150 mL) over 1 hour at 0° C. under nitrogen. The reaction was initiated by addition of a drop of methanol at room temperature and was stirred at room temperature for 2 hours. A 2.0 N aqueous NaOH solution (300 mL) was added slowly at 0° C. The resulting mixture was stirred at 110° C. for 4 hours. The mixture was then cooled to room temperature and the aqueous layer was diluted with water (300 mL) and washed with Et2O (2×300 mL). The aqueous phase was cooled in an ice-water bath. Addition of concentrated HCl was followed by extraction with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (50 mL) followed by brine (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from ethyl acetate-hexanes to give 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid. The procedure above was repeated using a separate amount of 4-fluorobenzaldehyde (30 g, 242 mmol). The products of the two reactions were combined to provide 2-[1-(4-fluoro-phenyl)-meth-(E)-ylidene]-3-methyl succinic acid as a pale yellow solid (28 g, 24% overall). MS calcd. for C12H12FO4 [(M+H)+] 239, obsd. 239.2.
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=[S:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[C:34]([NH2:38])=[CH:33][CH:32]=[CH:31]2.CCN(CC)CC>C(Cl)Cl>[N:38]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:35]=1[CH:36]=[CH:37][C:28]([O:27][C:18]1[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][CH:19]=1)=[CH:29]2)=[C:1]=[S:2]
Reactant: COc1cc2nccc(Oc3ccc4c(N)cccc4c3)c2cc1OC
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4c(N=C=S)cccc4c3)c2cc1OC
Reaction time: 0.25 h

Procedure:
Thiocarbonyl diimidazole (108 mg, 0.606 mmol) was added to a solution of 6-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-1-amine (210, 0.606 mmol) and NEt3 (84.5 μL, 0.606) in DCM (1.52 mL) in one portion at RT. After 15 minutes of stirring, LCMS and TLC indicated that the reaction was complete. The crude mixture was purified by silica gel chromatography (Hex:EtOAc). MS (ESI, pos. ion) m/z: 389.0 (M+1). Mass Calc'd for C18H15NO3: 388.45.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[Cl:23][C:24]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][O:29]2>>[Cl:23][C:24]1[C:33]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][CH2:28][O:29]2
Reactant: CC1(C)OB(c2ccc3c(c2Cl)CCCO3)OC1(C)C
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1ccc2c(c1Cl)CCCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2-(5-chlorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.