Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([CH:30]=O)[NH:21][C:20]=1[CH3:32])=[O:18]>>[CH3:12][N:13]([CH3:33])[CH2:14][CH2:15][NH:16][C:17]([C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:22]([CH:30]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[NH:21][C:20]=1[CH3:32])=[O:18]
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1[nH]c(C=O)c(-c2ccccc2)c1C(=O)NCCN(C)C
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCN(C)C
Yield: 56 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (46 mg, 0.22 mmol) was condensed with 5-formyl-2-methyl-4-phenyl-1H-pyrrole-3-carboxylic acid (2-dimethylaminoethyl)amide (65 mg) to give 60 mg (55%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C([NH:64][C@H:65]([C:70](O)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:64][C@H:65]([C:70]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:31]=[CH:30][C:24]([C:25](=[O:26])[N:27]([CH3:28])[CH3:29])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:71])[CH2:66][CH:67]([CH3:69])[CH3:68]
Reactant: CN(C)C(=O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)N(C)C)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.9 %

Procedure:
To a solution of 4-{[(1′S,2′S)-1′-hydroxy-1′,3′-dihydro-1H,2′H-2,2′-biinden-2′-yl]methyl}-N,N-dimethylbenzamide (23, 100 mg, 0.24 mmol), DCC (56 mg, 0.28 mmol) and DMAP (3 mg, 0.024 mmol) in ethyl acetate (5 mL), was added Fmoc leucine (84 mg, 0.24 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (140 mg) was dissolved in dry THF (5 mL) and cooled to 0° C. Dimethylamine (5 mL, 20% in THF) was added drop wise and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 45 mg (36%) of the title compound as an off white solid.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH2:5][CH:6]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Product: O=C(O)[C@@H]1CCCN1C(=O)C(CS)Cc1ccccc1

Procedure:
1-(3-Acetylthio-2-benzylpropanoyl)-L-proline is treated with methanolic ammonia according to the procedure of Example 34 to obtain 1-(3-mercapto-2-benzylpropanoyl)-L-proline.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][C:12](=[O:16])C(O)=O.[OH2:17].OO>CO>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][C:12]([OH:16])=[O:17]
Reactant: O=C(O)C(=O)Cc1c(I)cccc1[N+](=O)[O-]
Reactant: O
Agent: OO
Solvent: CO
Product: O=C(O)Cc1c(I)cccc1[N+](=O)[O-]
Yield: 70 %

Procedure:
3-(2-Iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.086 g, 6.2 mmol) was dissolved in 6 ml of methanol under stirring, and added with 20 ml of water and 7 ml of hydrogen peroxide to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered, extracted with ethyl acetate (20 ml×2). The combined organic extracts were concentrated under reduced pressure, combined with the above filter cake, and dried to obtain the title compound (2-iodo-6-nitro-phenyl)-acetic acid 74d (1.77 g, yield 70%) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[N:6][C:7]=1[Cl:8].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:3][C:4]([CH3:9])=[CH:5][N:6]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cnc(Cl)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 5-amino-6-chloro-3-picoline (9.54 g, 66.9 mmol) in pyridine (200 mL) was added 2-nitrobenzoyl chloride (13.65 g, 73.6 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 18 h. The dark mixture was then diluted with water (1500 mL) and sat. sodium bicarbonate solution was added until pH=8. The precipitate was collected by filtration, rinsed with water (30 mL×3) and dried in oven to afford N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide as a pale solid (17.70 g, yield: 91%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(OCC)C.ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 5-phenylpentanol (3.7 mL), methyl 3-(4-hydroxyphenyl)propanoate (3.6 g), triphenylphosphine (5.77 g) and dichloromethane (200 mL) was added 1,1′-(azodicarbonyl)dipiperidine (5.55 g). The reaction mixture was stirred at room temperature for 4 days. Diethyl ether was added to the reaction mixture, which was filtered and the filtrate was concentrated. Hexane-diethyl ether (1:1) (200 mL) was added to the residue, which was filtered and the filtrate was concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=9:1→4:1) to give the title compound (6.16 g) having the following physical data.
Reaction SMILES: [CH:1]1([N:4]([C:23](=[O:30])[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2[C:6]([C:19]([O:21]C)=O)=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.[O-]CC.[Na+]>C(O)C>[CH:1]1([N:4]2[C:5]3[C:6](=[N:7][CH:8]=[C:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[C:19]([OH:21])=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:23]2=[O:30])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CC(=O)N(c1cc(Cc2ccc(F)cc2)cnc1C(=O)OC)C1CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C2CC2)c1=O
Temperature: 25 °C
Yield: 97.6 %

Procedure:
A solution of methyl 3-{cyclopropyl[3-(ethyloxy)-3-oxopropanoyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (402 mg, 0.97 mmol) in ethanol (20 mL) at 0° C. was treated with sodium ethoxide (165 mg, 2.4 mmol). The reaction mixture was allowed to warm to room temperature as the bath warmed overnight. Solvents were removed in vacuo and the residue was taken up in water. The pH was adjusted to ˜5 with 1 N HCl (aq) and the aqueous layer extracted with ethyl acetate. The organics were dried over sodium sulfate filtered and concentrated to give ethyl 1-cyclopropyl-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (362 mg, 98%) as a solid. 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=1.6 Hz, 1 H), 7.78 (s, 1 H), 7.18 (dd, J=8.7, 5.4 Hz, 2 H), 7.04 (t, J=8.7 Hz, 2 H), 4.50 (q, J=7.1 Hz, 2 H), 4.13 (s, 2 H), 2.77 (m, 1 H), 1.46 (t, J=7.3 Hz, 3 H), 1.22 (m, 2 H), 0.76 (m, 2 H); MS m/z 383 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: Clc1nccc2ccc(Br)cc12
Product: CCCN(CCC)c1nccc2ccc(Br)cc12
Yield: 62 %

Procedure:
A solution of 7-bromo-1-chloroisoquinoline from step 1 (500 mg, 2.1 mmol) and dipropylamine (2.8 mL, 21 mmol) was heated at 150° C. in a sealed tube for 2 d. The reaction mixture was cooled, and the solvent was removed under reduced pressure to provide 7-bromo-N,N-dipropylisoquinolin-1-amine (400 mg): 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.90 (d, J=6 Hz, 1H), 7.75-7.64 (m, 2H), 6.87 (d, J=6 Hz, 1H), 3.42 (q, J=7 Hz, 4H), 1.65 (q, J=7 Hz, 4H), 0.94 (t, J=7 Hz, 6H).
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:22][C@@H:23]([C@H:25]4[CH2:29][NH:28][C:27](=[O:30])[CH2:26]4)[CH3:24])=[N:10][C:11](B4OC(C)(C)C(C)(C)O4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.Br[C:32]1[S:36][C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])=[N:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.COCCOC>[C:37]([C:35]1[S:36][C:32]([C:11]2[N:10]=[C:9]([O:22][C@@H:23]([C@H:25]3[CH2:29][NH:28][C:27](=[O:30])[CH2:26]3)[CH3:24])[C:8]3[N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[N:6][C:7]=3[CH:12]=2)=[CH:33][N:34]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: C[C@@H](Oc1nc(B2OC(C)(C)C(C)(C)O2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)c1ncc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: C[C@@H](Oc1nc(-c2cnc(C(C)(C)C)s2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 100 °C
Yield: 5.7 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((3-cyclopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (167.0 mg, 0.405 mmol), 5-bromo-2-(tert-butyl)thiazole (133.8 mg, 0.608 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.55 mL, 0.55 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (10.6 mg, 0.009 mmol) was added. The tube was sealed and heated in an oil bath at 100° C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give off-white solids, 9.8 mg (yield 5.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.30 (s, 1H), 8.24 (s, 1H), 7.77 (s, 1H), 7.56 (broad s, 1H), 5.43 (m, 1H), 3.73-3.63 (m, 1H), 3.47-3.36 (m, 1H), 3.25-3.14 (m, 1H), 2.93-2.75 (m, 1H), 2.38-2.28 (m, 2H), 1.41 (s, 9H), 1.40-1.39 (m, 3H), 1.17-1.10 (m, 2H), 1.10-0.97 (m, 2H) ppm; MS (ESI+) m/z 426.61 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][NH:33][CH:34]=2)O1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:32]1[CH:31]=[C:30]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]4[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH:34]=[N:33]1
Reactant: N#Cc1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1ccc(C2(c3ccc(-c4cn[nH]c4)cc3)CCNCC2)cc1
Temperature: 100 °C

Procedure:
4-[4-(4-chloro-phenyl)-piperidin-4-yl]-benzonitrile was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole following the procedure set out in Example 1, but using tetrakis(triphenylphosphine)palladium (0) as the catalyst and heating at 100° C. for 15 minutes, to obtain the title compound. LCMS (PS-A3) Rt 6.68 min [M+H]+ 329. 1H NMR (Me-d3-OD) δ 2.65-2.73 (4H, m), 2.77-2.85 (4H, m), 3.75 (3H, s), 7.46 (2H, d), 7.59 (2H, d), 7.68 (2H, d), 7.71 (2H, d), 8.42 (2H, br.s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[CH:8]=1)[NH2:5]
Reactant: Brc1cncs1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(N)cc(-c2cncs2)c1
Temperature: 100 °C

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.98 g, 90 mmol), 5-bromothiazole (8.85 mL, 99 mmol), and sodium carbonate (90 mL, 180 mmol) were combined in a flask. 2-Methyl-THF (326 mL) was added and the flask was degassed with N2 for 1.5 h before 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.67 g, 4.50 mmol) was added. The reaction was heated to 100° C. overnight and was then cooled to room temperature. The reaction mixture was filtered though a pad of Celite, washing with ethyl acetate. The layers were separated and the aqueous layer was back-extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by chromatography (0-40% ethyl acetate in hexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as a yellowish brown solid (15.33 g, 81 mmol, 90%). MS ESI: [M+H]+ m/z 191.1. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1/[CH:17]=[C:6]1/[C:2](=[O:1])[N:3]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:4](=[S:7])[S:5]/1
Reactant: O=C(O)CCN1C(=O)CSC1=S
Reactant: COc1ccc(OC)c(C=O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(OC)c(/C=C2\SC(=S)N(CCC(=O)O)C2=O)c1
Yield: 87.4 %

Procedure:
3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (200 mg, 1 mmol), 2,5-dimethoxybenzaldehyde (168 mg, 1 mmol) and piperidine (0.3 mL) were combined in ethanol (3 mL) and irradiated in the microwave at 100° C. for 10 minutes. The reaction was cooled, the solid was collected by filtration, washed with ethyl acetate/hexanes (1/1) and recrystallized from ethanol to afford 85% yield of the title compound (309 mg, brown-orange solid). MS (M+H, 284); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.57 (t, 2H)), 3.74 (s, J=6.8 Hz, 3H), 3.84 (s, 3H), 4.19 (t, 2H), 6.90 (s, 1H), 7.10 (s, 2H), 7.86 (s, 1H).
Reaction SMILES: C[Si](I)(C)C.[CH:6]([C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([O:33]C)=[CH:31][CH:32]=3)=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:11][CH2:10]1)([CH3:8])[CH3:7].CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH:6]([C@H:9]1[CH2:10][CH2:11][C@H:12]([NH:15][C:16]2[N:25]=[CH:24][C:23]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([OH:33])=[CH:31][CH:32]=3)=[C:22]3[C:17]=2[CH:18]=[CH:19][CH:20]=[N:21]3)[CH2:13][CH2:14]1)([CH3:8])[CH3:7]
Reactant: COc1ccc(Cc2cnc(N[C@H]3CC[C@H](C(C)C)CC3)c3cccnc23)cn1
Agent: C[Si](C)(C)I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H]1CC[C@H](Nc2ncc(Cc3ccc(O)nc3)c3ncccc23)CC1
Reaction time: 12 h

Procedure:
Under a N2 atmosphere, 142 μl (1.02 mmol) of trimethylsilyl iodide are added to 400 mg (1.02 mmol) of trans 5-(4-isopropyl-cyclohexylamino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine in 7 ml of chloroform, and stirring is effected for 12 h at 70° C. The mixture is cooled, EtOAc and diluted NaHCO3 are added, stirring is effected until everything has dissolved, the organic phase is separated and washed with water and brine. The aqueous phases are extracted twice more with EtOAc. Drying (Na2SO4), concentrating by evaporation, column chromatography (SiO2, EtOAc/EtOH 5:1) and stirring with DIPE yield trans 5-(4-isopropyl-cyclohexylamino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine; m.p. 232-235° C.; FAB-MS: (M+H)+=377.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][S:19]([CH3:18])(=[O:21])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(O)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2ccc(OS(C)(=O)=O)cc2C1
Yield: 69 %

Procedure:
The title compound (2.3 g, 69%) was prepared from 2-(tert-butyloxycarbonyl)-5-hydroxy-2,3-dihydro-1H-isoindole (2.5 g) and methanesulfonyl chloride (1.7 ml) using the method of Description 6.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=[O:19])[CH2:8][N+:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(=O)(O)[O-].[Na+].[C:36](#[N:39])[CH:37]=[CH2:38]>CN(C)C=O>[C:36]([C:37]1[CH:38]=[C:8]([C:7](=[O:19])[C:6]2[CH:5]=[CH:4][C:3]([CH3:2])=[CH:21][CH:20]=2)[N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=12)#[N:39]
Reactant: Cc1ccc(C(=O)C[n+]2cccc3ccccc32)cc1
Reactant: C=CC#N
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2cc(C#N)c3ccc4ccccc4n23)cc1

Procedure:
The title compound was prepared from 1-(4-methyl-phenacyl)-quinolinium bromide (120 mg, 0.350 mmol), tetrapyridinecobalt(II) dichromate (229 mg, 0.376 mmol), sodium bicarbonate (74.7 mg, 0.889 mmol), acrylonitrile (120 μL, 1.82 mmol), and N,N-dimethylformamide (2.5 mL), similar to Example 1b, and yielded 30.6 mg (28%) as a yellow solid. 1H NMR (CDCl3): 8.05 (d, J=8.51 Hz, 1H), 7.98 (dd, J=6.60, 1.65 Hz, 2H), 7.84 (dd, J=7.83, 1.51 Hz, 1H), 7.71 (d, J=9.34 Hz, 1H), 7.67 (d, J=9.07 Hz, 1H), 7.60 (ddd, J=8.24, 7.08, 1.58 Hz, 1H), 7.52 (td, J=7.49, 1.19 Hz, 1H), 7.40 (s, 1H), 7.37 (d, J=7.97 Hz, 2H), 2.50 (s, 3H).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.C(N(CCCC)CCCC)CCC.[CH3:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.[CH2:27]=[O:28].Cl>C1(C)C=CC=CC=1.O>[OH:26][C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][C:23]=1[CH:27]=[O:28]
Reactant: C=O
Reactant: Cc1cccc(O)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Cc1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.4 %

Procedure:
109 μl (0.93 mmol) of tin-tetrachloride and 882 μl (3.70 mmol) of tri-n-butylamine were added to a solution of 1.0 g (9.25 mmol) of 3-methyl-phenol in toluene (12 ml) and the mixture was stirred for 30 min at RT. Then 611 g of paraformaldehyde were added and the resulting mixture was heated to 100° C. for 16 hours. After cooling to RT water (40 ml) was added and the pH was adjusted to 2 by addition of 1N HCl. This mixture was extracted with ether. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography (silica gel; ether/cyclohexane 1:15) to yield 131 mg (10%) of 2-hydroxy-4-methyl-benzaldehyde as colorless crystals. 1HNMR (CDCl3, 300 MHz): δ 2.38 (s, 3H), 6.80 (s, 1H), 6.82 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 9.83 (s, 1H), 11.04 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH:9]1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[N:31]([CH3:32])[C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[N:28]=3)[CH:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.Cl>ClCCl.CCOCC>[CH3:32][N:31]1[C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[N:28]=[C:27]1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH:9]3[CH2:10][O:11][CH2:12][CH2:13][NH:8]3)[CH2:20][CH2:19]2)[CH:22]=1
Reactant: Cn1c(-c2cccc(N3CCN(CC4COCCN4C(=O)OC(C)(C)C)CC3)c2)nc2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1c(-c2cccc(N3CCN(CC4COCCN4)CC3)c2)nc2ccccc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of 3-{4-[3-(1-methyl-1H-benzoimidazol-2-yl)-phenyl]-piperazin-1-ylmethyl}-morpholine-4-carboxylic acid tert-butyl ester (0.07 g, 0.15 mmol) in dichloromethane (1 mL) was added 2M HCl in Et2O (3 mL) and the resulting solution was stirred for 7 h at room temperature.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH2:29][NH:28][CH2:27][CH2:26][C:24]=3[N:25]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.OCC=O.C([BH3-])#N.[Na+]>CO>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([NH:19][C:20]2[N:21]=[C:22]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:23]3[CH2:29][N:28]([CH2:2][CH2:1][OH:4])[CH2:27][CH2:26][C:24]=3[N:25]=2)[CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CNCC3)ccc1-n1cnc(C)c1
Agent: O=CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(Nc2nc3c(c(Nc4ccccc4)n2)CN(CCO)CC3)ccc1-n1cnc(C)c1
Reaction time: 0.17 h
Yield: 381.7 %

Procedure:
Acetic acid (0.803 μL, 0.01 mmol) was added to a solution of N2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)-N4-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-diamine (Example 7, 0.03 g, 0.07 mmol) and 2-hydroxyacetaldehyde (4.21 mg, 0.07 mmol) in MeOH (5 mL). The reaction mixture was stirred for 10 min and sodium cyanoborohydride (4.41 mg, 0.07 mmol) added. The reaction was stirred for an additional 15 min and solvent evaporated under reduced pressure. The crude product was dissolved in MeOH/DMSO and purified by preparative HPLC to give 2-(2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (0.018 g, 53.5%). MS (ESI+)/(ESI−) m/z 472/470
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH:30][CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:30]([CH3:31])[CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Reactant: CNC
Product: CCOC(=O)c1c(CN(C)C)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with dimethyl amine as described in Example 86.1. to give 3-dimethylaminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 375.5 ([M−H]−).