Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[N:14](COCC[Si](C)(C)C)[CH:13]=2)=[O:11])[CH3:8])=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=5)[N:23]([CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)[N:22]=4)[N:19]=3)[NH:14][CH:13]=2)=[O:11])[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(F)ccc34)nc12)c1ccncc1
Solvent: ClCCl
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Product: CC(NC(=O)c1c[nH]c2ncc(-c3nn(CCN4CCOCC4)c4cc(F)ccc34)nc12)c1ccncc1
Reaction time: 2 h
Yield: 45.9 %

Procedure:
2-[6-Fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide (70 mg, 0.11 mmol) was combined with dichloromethane (1 mL) then trifluoroacetic acid (0.24 ml, 3.26 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (1 mL) and ethylenediamine (0.22 ml, 3.26 mmol) was added. The reaction mixture was stirred for 20 min then concentrated in vacuo. The residue was diluted with water then extracted with CH2Cl2 (2×20 ml). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo to afford 26 mg (44%) of 2-[6-fluoro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-4-yl-ethyl)-amide as a yellow solid. MS: (M+H)+=515; 1H NMR (DMSO-d6) δ: 9.13 (s, 1H), 8.44-8.62 (m, 4H), 8.35 (dd, J=8.9, 5.4 Hz, 1H), 7.73 (dd, J=10.0, 2.0 Hz, 1H), 7.45 (d, J=6.0 Hz, 2H), 6.98 (d, J=2.0 Hz, 1H), 5.29 (t, J=7.2 Hz, 1H), 4.62 (t, J=6.4 Hz, 2H), 3.42-3.59 (m, 4H), 3.30 (m, 4H), 2.85 (t, J=6.4 Hz, 2H), 1.65 (d, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[CH3:39][C:40]1[O:44][N:43]=[C:42]([C:45](Cl)=[O:46])[CH:41]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:45]([C:42]1[CH:41]=[C:40]([CH3:39])[O:44][N:43]=1)=[O:46])[CH:29]=3
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C(=O)Nc2cc3cc(c2)Nc2nc(ncc2Cl)Nc2cccc(c2)CC3)no1
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example B26, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 5-methylisoxazole-3-carbonyl chloride as the starting materials in 42% yield. LCMS for C23H20ClN6O2(M+H)+: m/z=447.2. 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 9.59 (s, 2H), 8.17 (s, 1H), 7.88 (m, 1H), 7.59 (m, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.11 (dd, 1H), 6.89 (m, 1H), 6.84 (m, 1H), 6.64 (m, 1H), 2.88 (m, 4H), 2.48 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.C[O:47][C:48](=[O:51])[CH2:49][NH2:50].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:50][CH2:49][C:48]([OH:51])=[O:47])=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COC(=O)CN
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CC(=O)NCC(=O)O)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.7 %

Procedure:
A stirred solution of [3-methoxy-4-(3-o-tolylureido)phenyl]-acetic acid (7.53 g, Reference Example 5) in a mixture of dimethylformamide (15 ml) and dichloromethane (150 ml) was treated with 1-(3-dimethylaminoprop-1-yl)-3-ethylcarbodiimide (4.98 g), then with 1-hydroxybenzotriazole (3.57 g), then with glycine methyl ester hydrochloride (3.01 g) and then with diisopropylethylamine (4.10 ml). After stirring at room temperature for 20 hours the reaction mixture was diluted with water (100 ml). The organic phase was washed with saturated sodium bicarbonate (100 ml), then with hydrochloric acid (1M) and then with brine, then dried over magnesium sulphate and then evaporated. The residue was triturated with petroleum ether and the resulting cream coloured solid (6.25 g) was dissolved in tetrahydrofuran (200 ml). The solution was treated with water (50 ml) and then with lithium hydroxide hydrate (0.75 g). The mixture was stirred at room temperature for 4 hours and then the tetrahydrofuran was removed under vacuum. The aqueous phase was acidified by addition of hydrochloric acid (12M). The resulting solid was washed with diethyl ether and then dried to give the title compound (5.76 g), m. p. 130-134° C. (with decomposition). MS: 370 [M−1]−. HPLC: RT=10.16 minutes (gradient clution using a mixture of acetonitrile and water 4:1 to 1:4 v/v).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][CH2:41][O:40][CH2:39]1)(=O)=O.O>CN(C)C=O>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:36][CH2:37][CH:38]2[CH2:43][CH2:42][CH2:41][O:40][CH2:39]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Reactant: CS(=O)(=O)OCCC1CCCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A stirring mixture of 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt (200 mg) and potassium carbonate (236 mg) in dry N,N-dimethylformamide (2 ml) was heated with stirring at 60° C. for 1 h. 2-(Tetrahydro-2H-pyran-3-yl)ethyl methanesulfonate (142 mg) was added and the stirring mixture heated at 60° C. for 3 h. Water was added and the mixture extracted three times with ethyl acetate. The combined extracts were washed with water then brine, dried by passing through a phase separation cartridge and stripped to give a brown oil. This was purified by C18 reverse phase chromatography using water (0.1% formic acid)-acetonitrile (0.05% formic acid) as eluent (20-70%) and the appropriate fractions combined and evaporated to remove acetonitrile. The remaining aqueous mixture was made basic with saturated sodium hydrogen carbonate, extracted three times with dichloromethane and the combined extracts dried by passing through a phase separation cartridge then evaporated to afford the title compound as a brown oil, yield 108 mg.
Reaction SMILES: [N:1]([C@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([O:19]C(OCC)C)[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[N:1]([C@H:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: CCOC(C)OC1COc2ccc3cnn(C[C@@H](C)N=[N+]=[N-])c3c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Cn1ncc2ccc3c(c21)CC(O)CO3)N=[N+]=[N-]
Yield: 92.5 %

Procedure:
To a mixture of the product from Step H (0.30 g, 0.87 mmol) in THF (50 mL) was added 1 N HCl (20 mL). After stirring for 40 min a saturated solution of sodium bicarbonate (80 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried and evaporated to a residue, which was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to give an oil (0.22 g, 92%).
Reaction SMILES: [C:1]([OH:5])(=O)[C:2]#[CH:3].[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.ClCCl.CO.N>>[Cl:6][C:7]1[CH:13]=[CH:12][C:10]([NH:11][C:1](=[O:5])[C:2]#[CH:3])=[CH:9][CH:8]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: C#CC(=O)O
Agent: N
Solvent: CO
Solvent: ClCCl
Product: C#CC(=O)Nc1ccc(Cl)cc1

Procedure:
Prepared analogously to Example 1.1.b. from propynoic acid and 4-chloroaniline. Yield: 0.56 g (31.2% of theory); C9H6ClNO (M=179.60); calc.: molecular ion peak (M−H)−: 178/180; found: molecular ion peak (M−H)−: 178/180; Rf value: 0.53 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([SH:32])=[N:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu](I)I>[CH3:24][O:25][C:26]1[N:27]=[CH:28][C:29]([S:32][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:30][CH:31]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COc1cnc(S)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 80 °C
Yield: 75.1 %

Procedure:
A mixture of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (25-1, 173.5 mg, 0.40 mmol), 5-methoxypyrazine-2-thiol (25-2, 170 mg, 17.5 mmol), copper iodide (3.8 mg, 0.02 mmol), and potassium carbonate (165.3 mg, 1.2 mmol) in DMF (2 mL) was heated at 80° C. for 16 h. The solution was added with water and extracted with ethyl acetate. The organic layer was collected, dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes as eluant) to provide N-{4-(4-(5-methoxypyrazin-2-ylthio)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (25, 135 mg) as yellow solids in 24% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 2 H), 8.28 (s, 1 H), 8.18 (s, 1 H), 7.94-7.95 (m, 2 H), 7.14-7.21 (m, 3 H), 3.88 (s, 3 H), 2.03 (s, 6 H). ESI-MS: m/z 450.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[O:4].N1C=CC=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O1CCCCO1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:8][C:9]=1[N:10]1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH:11]1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(CCCC(=O)O)C1CCCCC1
Agent: C1CCOOC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)c1sc(-c2ccccc2)cc1N1C(=O)CCCC1C1CCCCC1
Temperature: 65 °C
Yield: 39.3 %

Procedure:
To a vial containing a solution of 3-(4-Carboxy-1-cyclohexyl-butylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (40 mg, 0.096 mmol, 1.0 equiv) in 1,2-dioxane (1.0 mL) was added pyridine (3.8 mg, 0.048 mmol, 0.5 equiv) and Boc2O (25 mg, 0.166 mmol, 1.2 equiv). The vial was then sealed and heated at 65° C. for 18 hours. The solution was concentrated and the residue was purified by silica gel column chromatography, EtOAc/Heptane 5% to 100% to give product 15 mg (yield 39%).
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)O.S(Cl)([Cl:23])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:13]([Cl:23])[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2oc(C(O)C3CCCCC3)c(Br)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(Cl)C3CCCCC3)c(Br)c2c1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution (20 mL) of (3-bromo-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methanol (1.82 g) synthesized above in toluene was added thionyl chloride (469 μL) and the mixture was stirred at 100° C. for 1.5 hr. The reaction mixture was poured into ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (1.73 g, 90%) as a yellow solid.
Reaction SMILES: O[C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][CH:5]=1)=[O:3].[NH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C1C2C(=CC=CC=2)C=CC=1C(O)=O.IC1C=CC(N)=CC=1>>[CH:8]([C:7]1[CH:11]=[CH:12][C:4]([C:2]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:3])=[CH:5][CH:6]=1)([CH3:10])[CH3:9]
Reactant: Nc1cccnc1
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: Nc1ccc(I)cc1
Agent: O=C(O)c1ccc2ccccc2c1
Product: CC(C)c1ccc(C(=O)Nc2cccnc2)cc1

Procedure:
This compound was synthesized by the same procedure as for Example 15 except cuminic acid and 3-aminopyridine were used instead of 2-napthoic acid and 4-iodoaniline. White needles. M+241.3
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.[ClH:20].[N:21]1([C:28](=[NH:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CC(C)([O-])C.[K+]>C(O)C.O>[ClH:20].[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][N:29]=[C:28]([N:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:30]=1
Reactant: N=C(N)N1CCCCCC1
Reactant: Cc1occc1C(=O)C(=CN(C)C)c1ccccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1occc1-c1nc(N2CCCCCC2)ncc1-c1ccccn1
Temperature: 25 °C
Yield: 22.6 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-furanyl)-2-(2-pyridinyl)-2-propen-1-one (205 mg, 0.8 mmol) and hexahydro-1H-azepine-1-carboximidamide hydrochloride (213 mg, 1.200 mmol) in ethanol (4 ml) was stirred at room temperature. Potassium tert-butoxide (180 mg, 1.600 mmol) was added and the mixture was heated at reflux for 45 minutes. After cooling to room temperature the reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by mass-directed automated HPLC. The product was dissolved in a mixture of dichloromethane (2 ml) and methanol (0.5 ml) and hydrogen chloride (1M in ether, 0.5 ml) was added and the solvent was evaporated. The residue was co-evaporated with ether and triturated with ether. The solid was collected and dried to give the title compound (67 mg, 23%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.74 (2H, d), 8.54 (1H, s), 8.12-8.10 (1H, m), 7.65-7.55 (2H, m), 7.43 (1H, d), 5.74 (1H, d), 3.84-3.80 (4H, m), 2.41 (3H, s), 1.85-1.70 (4H, m), 1.60-1.48 (4H, m).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1C=O.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:8]1([CH:21]=[O:22])[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22]
Reactant: O=Cc1ccc2c(c1)C(=O)c1ccccc1C2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: OCCCO
Solvent: Cc1ccccc1
Product: O=Cc1cccc2c1C(=O)c1ccccc1C2=O

Procedure:
A mixture of anthraquinone-2-aldehyde (12.0 g), 1,3-propanediol (10 ml), and p-toluenesulfonic acid (20 mg) in toluene (300 ml) was heated under reflux with a removal of water formed from the condensation of anthraquinone aldehyde and 1,3-propane diol for 4 hours. The mixture was then cooled to room temperature, filtered off with suction, washed with water and diethyl ether, and dried under vacuum to afford anthraquinone-2-propaneacetal (12.5 g, 84%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:21])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:6]2.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:9]1[C:10]2[C:5](=[C:4]([CH3:21])[C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2c1C
Product: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1C
Temperature: 150 °C

Procedure:
A 10˜20 mL process vial was charged with 500 mg 6-Methoxy-5-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one in 15 mL POCl3. The vial was heated at 150° C. for 30 min under microwave irradiation. After cooling, POCl3 was removed under reduced pressure. MeOH was carefully added to the residue during which the precipitate was formed. The solid was collected as crude product for the next reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:12][C:13](N)=[O:14]>>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:13](=[O:14])[NH:12][C:4]2=[O:5]
Reactant: NC(N)=O
Reactant: Nc1ccc(I)cc1C(=O)O
Product: O=c1[nH]c(=O)c2cc(I)ccc2[nH]1

Procedure:
Prepared according to general method B from 2-amino-5-iodobenzoic acid (5.0 g) and urea (11.4 g). Yield: 5.34 g (98%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 8.04 (d, J=2.0 Hz, 1H), 7.77 (dd, J=2.1 Hz, J=8.6 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C:20]=3[NH:21]2)=[CH:17][CH:16]=1.CCOC(C)=O>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][C:20]=3[N:21]2[S:3]([C:6]2[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=2)(=[O:5])=[O:4])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3cc(Br)ccc23)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
6 N NaOH solution (6 mL), (Bu4N)2SO4 (50% wt. solution in H2O, 0.20 mL), and TsCl (646 mg, 3.39 mmol) were added to a suspension of tert-butyl 7-bromo-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (991 mg, 2.82 mmol) in toluene (20 mL) and the resulting suspension was stirred at 25° C. for 1.5 h. H2O and EtOAc were added to the suspension and the phases were separated. The organic phase was washed with H2O, dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (1.285 g, 90%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 8.32 (d, J=1.5 Hz, 1H), 7.78-7.66 (m, 2H), 7.36 (dd, J=8.4, 1.5 Hz, 1H), 7.25-7.21 (m, 2H), 7.21-7.13 (m, 1H), 4.92-4.81 (m, 2H), 3.74-3.63 (m, 2H), 2.70-2.61 (m, 2H), 2.37 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:14])([CH3:13])[O:4][C:5]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:6]=12.[NH3:15]>C(O)C>[NH2:15][C@@H:7]1[C:6]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:5]=2[O:4][C:3]([CH3:14])([CH3:13])[C@H:2]1[OH:1]
Reactant: Cc1ccc2c(c1)C1OC1C(C)(C)O2
Reactant: N
Solvent: CCO
Product: Cc1ccc2c(c1)[C@@H](N)[C@H](O)C(C)(C)O2

Procedure:
A solution of 3,4-epoxy-3,4-dihydro-2,2,6-trimethyl-2H-1-benzopyran (7 g, see J. Med. Chem. 26, 1582, 1983) in concentrated ammonia solution (90 ml) and ethanol (160 ml) was stirred at room temperature for 5 days. Evaporation of solvent gave the title compound (7 g) as a crude solid which was used directly, without purification.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([C:11](OCC)=[O:12])[CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>O1CCCC1.O>[CH2:1]1[CH:10]2[N:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH:3]([CH2:11][OH:12])[CH2:2]1
Reactant: CCOC(=O)C1CCC2CCCCN2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCC2CCCCN2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Ethyl octahydro-2H-quinolizine-3-carboxylate (2.35 g, 11.1 mmol) was added dropwise to a stirred suspension of lithium aluminum hydride (1 M solution in tetrahydrofuran, 33 mL, 33 mmol) in tetrahydrofuran (50 mL) at 0° C. The reaction was stirred at room temperature for 3 h. The mixture was cooled in an ice bath and ethyl acetate (6 mL) was added slowly, followed by water (1.25 mL), 15% aqueous sodium hydroxide solution (5 mL) and water (1.25 mL). The mixture was filtered through a pad of celite and washed with ether. The filtrate was concentrated in vacuo and dried rigorously to afford octahydro-2H-quinolizin-3-ylmethanol as a yellow oil (1.66 g, 9.82 mmol, 88% yield). MS (EI) for C10H19NO: 170 (MH+).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[C:20]1([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:29]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][NH:28][C:2]2[N:10]=[C:9]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(NCCN2CCCCC2)nc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1ccc(C(CNc2nc(NCCN3CCCCC3)nc3[nH]cnc23)c2ccccc2)cc1

Procedure:
A mixture of Intermediate 38 (5.000 g, 17.8 mmol), 2,2-diphenylethylamine (5.200 g, 27 mmol) and N,N-diisopropylethylamine (6.2 ml, 36 mmol) in isopropanol (100 ml) was heated to reflux overnight. Upon cooling the solvent was removed in vacuo and the residue was purified using flash column chromatography with a Biotage column (90 g, SiO2) eluting with 5% methanol/chloroform/1% ammonia gave the title compound as an off white solid (4.500 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:23])C>>[C:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][CH:13]2[C:18]([NH2:20])=[O:19])(=[O:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCc2c(Cc3ccccc3)cccc21
Reactant: CC(=O)O
Product: NC(=O)C1CCCc2c(C(=O)c3ccccc3)cccc21

Procedure:
To 100 ml. of acetic acid is added 6.6 g. of 5-benzyl-1,2,3,4-tetrahydro-1-naphthamide and, under cooling with ice, 3.4 g. of chromic anhydride is added. The mixture is stirred well. After stirring overnight, the reaction mixture is poured over 500 g. of ice and the resultant crystals are collected by filtration. This is subjected to column chromtography on silica gel using chloroform as the eluent and the eluate is recrystallized from cyclohexane. The procedure gives 5-benzoyl-1,2,3,4-tetrahydro-1-naphthamide, melting point: 145.5°-147.5°C.