Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13](S)=[N:12][C:11]=2[CH:16]=1>>[Cl:4][C:13]1[S:14][C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:16][C:11]=2[N:12]=1
Reactant: Sc1nc2cc(Cl)ccc2s1
Reactant: O=S(=O)(Cl)Cl
Product: Clc1ccc2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (10 mL) was added to 5-chloro-2-mercaptobenzothiazole at 0° C. After complete addition, the reaction mixture was allowed to warm to rt. After 2 h, the reaction mixture was poured into ice water (100 mL). This was allowed to warm to rt and was extracted with EtOAc (3×). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was used without further purification. LC-MS: RT=10.03 min., compound does not ionize.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)=[O:8])([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(C(F)(F)F)cs1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Solvent: CO
Product: Nc1ccc(C(=O)Nc2nc(C(F)(F)F)cs2)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of 3,4-dinitro-N-(4-trifluoromethyl-thiazol-2-yl)-benzamide using 10% palladium on charcoal in methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10]1([OH:16])C=CC=CC=1>>[OH:9][C:3]1[C:4]([CH:10]=[O:16])=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(C)c(O)c1
Reactant: Oc1ccccc1
Product: Cc1ccc(C)c(C=O)c1O

Procedure:
6-Hydroxy-2,5-dimethylbenzaldehyde was prepared by the method of Example 104 Step 1 except that 2,5-dimethylphenol was used as the starting phenol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-])=O)=[C:6]([CH:24]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:25][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=2[C:9]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(OC)ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(OC)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(5-fluoro-2-nitroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-5-fluoroanilino)-6-methoxybenzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:18](OCC)(=O)C.CCCCCC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
(R)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (Sigma-Aldrich) (1.04 g, 5.55 mmol) was methylated and purified in a similar way to Preparation 67 using 60% sodium hydride dispersion (267 mg, 6.68 mmol) and methyl iodide (0.5 mL, 8.06 mmol) in DMF (15 ml). δH (CDCl3): 1.50 (9H, s), 1.94-2.02 (2H, m), 3.37 (3H, s), 3.38-3.58 (4H, m), 3.95 (1H, m); Rf 0.47 (ethyl acetate/hexane: 1/1).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH2:32])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH:32][C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 81.6 %

Procedure:
39 g calcium carbonate and 36.8 g phenyl chloroformate in 250 mL THF was added to a stirred solution of 50 g 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester in 1 L THF. The reaction mixture was allowed to stir for 15 h at RT. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was washed with 20% ethyl acetate in hexane to give 60 g of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][NH:8][C:5]2=[CH:6][N:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1n[nH]c2cnc(Br)cc12
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1n[nH]c2cnc(-c3cccc(F)c3)cc12
Temperature: 130 °C
Yield: 34.8 %

Procedure:
Under nitrogen protection, to 6 mL of dioxane was added 5-bromo-3-methyl-1H-pyrazolo[3,4-c]pyridine from Example 102 (0.21 g, 1 mmol), 3-fluorophenylboronic acid (0.28 g, 2 mmol), PdCl2(dppf) (87 mg, 0.1 mmol) and 2 M Na2CO3 (2 mmol, 1 mL). The suspension was heated under microwave radiation at 130° C. for 1 hour. It was cooled to room temperature and the solvent was removed the solvent. The crude product was purified by SGC (EtOAc/Petroleum:1/1) to afford 79 mg (34%) of 122 as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.98 (s, 1H), 7.75-7.82 (m, 2H), 7.44-7.47 (m, 1H), 7.08-7.09 (m, 1H), 2.67 (s, 3H). ESI MS m/z=229 (M+1)
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of the compound from Example 8, step 2 (100 mg 0.3 mmol) in CH2Cl2 was added acetic anhydride (0.1 mL) and triethylamine (0.4 mL) sequentially at rt. The reaction mixture was stirred at it for 1 h and poured onto water (100 mL). The precipitate was collected by filtration and washed with water to give the title compound (58 mg, 64%) as an off-white solid: MS (ESI) m/z 297 (M+H); 1H NMR (400 MHz, CDCl3) δ 2.15 (s, 3H), 3.12 (m, 4H), 3.63 (t, J=5.2 Hz, 2H), 3.78 (t, J=5.2 Hz, 2H), 6.91-6.99 (m, 6H), 7.05 (m, 1H), 7.28-7.32 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH2:32][CH2:31][CH2:30][C@@:7]2([CH2:11][C@H:10]([O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=1)=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1>[Si:13]([O:12][C@@H:10]1[CH2:9][CH2:8][C@:7]2([CH2:30][CH2:31][CH2:32][C:5]([CH2:3][OH:2])=[CH:6]2)[CH2:11]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1=C[C@]2(CCC1)CC[C@@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C2
Agent: COCCO[Al+]OCCOC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C=C(CO)CCC2)C1)(c1ccccc1)c1ccccc1
Yield: 93.5 %

Procedure:
To a solution of (2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en e-7-carboxylic acid methyl ester (615 mg) obtained in Step 6 in toluene (7 mL) was added dropwise sodium bis(2-methoxyethoxy)aluminum hydride (65% toluene solution; 486 mg) under ice-cooling, followed by stirring the mixture under ice-cooling for 0.5 hour. To the reaction mixture was added dropwise 1M aqueous Rochelle salt solution (10 mL), followed by stirring at room temperature for 2 hours, and the reaction mixture was extracted with toluene. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:6 to 1:5) to give [(2R,5R)-2-(tert-butyldiphenylsilanyloxy)-spiro[4.5]dec-6-en-7-yl]-methanol (539 mg).
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:31]([NH:33][CH2:34][CH2:35][C:36]3[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=3)=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(O)(=O)/[CH:45]=[CH:46]/[C:47]1[CH:54]=[CH:53][C:51]([OH:52])=[C:49]([OH:50])[CH:48]=1>>[C:16]([NH:18][C@H:19]([C:31]([NH:33][CH2:34][CH2:35][C:36]1[CH:43]=[CH:42][C:40]([OH:41])=[C:38]([OH:39])[CH:37]=1)=[O:32])[CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])(=[O:17])/[CH:45]=[CH:46]/[C:47]1[CH:54]=[CH:53][C:51]([OH:52])=[C:49]([OH:50])[CH:48]=1
Reactant: CCCCOC(=O)NCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Reactant: O=C(O)/C=C/c1ccc(O)c(O)c1
Product: CCCCOC(=O)NCCC[C@H](NC(=O)/C=C/c1ccc(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-butoxycarbonyl-L-ornithyl]dopamine (1.0 g, 1.75 mmol) was deprotected following the indications of general procedure G. The free amino groups thus obtained were coupled with caffeic acid (472 mg, 2.6 mmol) following the general procedure D. The crude material was purified by flash chromatography using a solvent gradient from 30% to 90% EtOAc/CH2Cl2/1% AcOH. The desired product was obtained as white crystals (370 mg, 40%).
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[Zn+2].[C-]#N>[NH2:8][C:7]1[C:2]([C:9]#[N:10])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cccnc1Cl
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ncccc1N
Temperature: 90 °C
Reaction time: 7 h

Procedure:
2-Chloro-pyridin-3-ylamine (2.0 g) was dissolved in DMF (24 mL) and zinc cyanide (1.83 g) was added to the solution. The solution was degassed in vacuum 5×, tetrakis(triphenylphosphine) palladium(0) (901 mg) was added and the reaction mixture was stirred at 90° C. for 7 h. After the reaction mixture was cooled to room temperature, the solid was removed by filtration and the filter cake was washed with ethyl acetate. Water was added to the filtrate, the layers were separated and the aqueous layer was 2× extracted with ethyl acetate. The combined organic layer was washed 3× with water, washed with brine, dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography (silica 60, chloroform/ethyl acetate 3:1, Rf=0.25) to afford 755 mg of the title compound of the formula
Reaction SMILES: C([O:3][C:4](=[O:40])[C@@H:5]([NH:36][C:37](=[O:39])[CH3:38])[CH2:6][NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:35])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[CH2:21][CH2:20]2)[CH2:11]1)=[O:9])C.[OH-].[Li+].OS([O-])(=O)=O.[K+]>C(O)C.O1CCCC1.O>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][CH2:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][CH2:6][C@H:5]([NH:36][C:37](=[O:39])[CH3:38])[C:4]([OH:40])=[O:3])=[O:9])[CH2:11]2)=[O:35])[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)NC(C)=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)C(=O)O
Temperature: 0 °C
Yield: 54.3 %

Procedure:
To a solution of N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S) -acetylamino-β-alanine ethyl ester (130 mg) in a mixture of ethanol (1.5 ml) and tetrahydrofuran (1.5 ml) was added a solution of lithium hydroxide (11 mg) in water (1.5 ml) under stirring at 0° C. After stirring at ambient temperature for 1 hour, the mixture was acidified with 10% KHSO4 aqueous solution and extracted with ethyl acetate. The extract was washed with water, brine and dried over MgSO4 and evaporated in vacuo to give N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine as an oil (67 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:9][C:6]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:4]([F:20])[C:3]([CH2:2][N:1]2[C:31](=[O:32])[C:30]3[NH:29][CH:28]=[N:27][C:26]=3[N:25]=[CH:24]2)=[CH:8][CH:7]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Solvent: Oc1ccccc1
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.15 g, 0.422 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.098 g, 0.464 mmol) and phenol (0.052 g, 0.548 mmol) in DCM (2 mL) to give 0.070 (34%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.15 (t, 1H), 5.28 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3ccccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 35.9 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.18 mmol), 2-(tributylstannyl)pyridine (99 mg, 0.27 mmol), and PdCl2(PPh3)2 (25 mg, 0.036 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 3 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (50 mL) were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 25 mg of the title compound. MS: (+) m/z 388.33 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH:6]=[O:7].[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].[OH-].[Na+].C(O)(=O)C>CO>[F:11][C:10]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH:15]([N+:12]([O-:14])=[O:13])[CH3:16])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(O)C(C)[N+](=O)[O-])ccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a flame dried 100 mL round bottom flask was added 3-methoxy-4-fluorobenzaldehyde (367 mg, 2.38 mmol) and this was dissolved in methanol (23 mL). The reaction solution was cooled to 0° C. and nitroethane (357 mg, 4.76 mmol) was added to it followed by 5M NaOH (0.476 mL, 2.38 mmol). The solution was stirred for 80 min at 0° C. after which acetic acid (2% solution, 32 mL) was added and stirred for an additional 30 min. The reaction mixture was concentrated and water (10 mL) was added. The solution was extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentration to give afford an oil which was purified by silica gel flash chromatography using dichloromethane as eluant. Product (391 mg, 72%) product Was obtained as a colorless oil in a 1.88:1 ratio (A:B) of diastereomers. Pair A: 1H NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 5.34 (t, 1H, J=3 Hz), 4.65 (d of q, 1H, J=3.6, 6.6 Hz), 3.9 (s, 3H), 2.697 (d, 1H, J=3.6 Hz), 1.5 (d, 3H, J=6.6 Hz). 13C NMR (75 MHz, CDCl3): δ 153.3, 150.1, 147.44 (d, J=10.8 Hz), 134.1, 117.7 (d, J=7 Hz), 115.7 (d, J=18.6 Hz), 110.6, 86.8, 72.8, 55.8, 11.7. Pair B: NMR (600 MHz, CDCl3): δ 7.07 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 4.9 (d Of d, 1H, J=3.6, 9 Hz), 4.72 (m, 1H), 3.9 (s, 3H), 2.57 (d, 1H, J=4.2 Hz), 1.33 (d, 3H, J=5.4 Hz). 13C NMR (75 MHz, CDCl3): δ 153.8, 150.5, 147.76 (d, J=10.8 Hz), 134.1, 119 (d, J=7 Hz), 115.8 (d, J=18.6 Hz), 111, 87.7, 75.3, 55.8, 15.9. HRMS: Calc'd for C10H12FNO4 (M+Na): 252.0642; Found: 252.0643.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[OH:18][CH2:19][CH:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21]>>[OH:18][CH2:19][CH:20]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([C:2]2[C:3]3[C:4]4[CH:17]=[CH:16][S:15][C:5]=4[C:6](=[O:14])[NH:7][C:8]=3[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH3:21]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(CO)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(S(=O)(=O)NC(C)CO)cc1
Yield: 20 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-thieno[2,3-c]quinolin-4(5H)-one) (530 mg, 1.8 mmol) was reacted with N-(1-hydroxypropan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (750 mg, 2.02 mmol) to afford the desired product (150 mg, 20%) as a yellow solid: ESI MS m/z 445 [C21H20N2O5S2+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]1[CH2:58][C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12](=[O:14])[NH:46][CH2:47][CH:48]([OH:59])[CH2:49][N:50]2[CH2:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH2:51]2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCC(O)CN1Cc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCC(O)CN2Cc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (300 mg, 1.3 mmol) in DCM (8 mL) was added EDCI (383 mg, 2.0 mmol), HOBt (270 mg, 2.0 mmol), Et3N (263 mg, 2.6 mmol), 1-amino-3-(isoindolin-2-yl)propan-2-ol (499 mg, 2.6 mmol), and the mixture was stirred at 25° C. for 16 h. The crude reaction mixture was washed with water and extracted with DCM. The combined organic layers were concentrated, and the residue was purified by column chromatography (DCM:MeOH=10:1). (260 mg, yield 49%) MS (ESI+) e/z: 412.2 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 7.87 (s, 1H), 7.58-7.50 (m, 1H), 7.45-7.38 (m, 1H), 7.34-7.28 (m, 1H), 7.25-7.14 (m, 4H), 4.08-3.96 (m, 5H), 3.63-3.53 (m, 1H), 3.45-3.37 (m, 1H), 2.94-2.80 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: BrN1C(=O)CCC1=O.[C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:19][C:18]([CH3:21])([CH3:20])[CH2:17][CH:16](Br)[C:15]=2[CH:23]=1)#[N:10]>>[C:9]([C:11]1[CH:12]=[CH:13][C:14]2[O:19][C:18]([CH3:20])([CH3:21])[CH:17]=[CH:16][C:15]=2[CH:23]=1)#[N:10]
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: O=C1CCC(=O)N1Br
Product: CC1(C)C=Cc2cc(C#N)ccc2O1

Procedure:
The compound of the formula (II) is brominated in the benzyl position by N-bromo-succinimide in haloalkanes in the presence of a trace of peroxide and 6-cyano-3,4-dihydro-2,2-dimethyl-4-bromo-2H-1-benzopyran of the formula (X) ##STR12## is almost quantitatively formed and this can be similarly with almost quantitative yield dehydrobrominated with alkali alcoholates to produce 6-cyano-2,2-dimethyl-2H-1-benzopyran of the formula (III).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[F:22][C:20]([F:21])([F:23])[C:17]1[CH:16]=[CH:15][C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3ccc(C(F)(F)F)cc3)c2O1

Procedure:
Treatment of (±)-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (3.3 g, 7.34 mmol) with sodium azide (1.91 g, 29.38 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.205 g, 10 wt. %) generally according to the procedure described for Example 1 provided 1.82 g (75%) of (±)-1-{7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl methanamine as a white solid, hydrochloride salt. mp >250° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 57.47; H, 4.82; N, 3.65.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34]O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH3:34])[C:23]=4[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Reactant: CO
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2C)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60) and methanol.