Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH:23]=[N:24][C:25]2[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2].CO.[BH3-]C#N.[Na+]>C(O)=O.O>[C:1]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[N:22]=[C:21]([CH2:23][NH:24][C:25]2[C:30]([CH:31]([CH3:32])[CH3:33])=[CH:29][CH:28]=[CH:27][C:26]=2[CH:34]([CH3:36])[CH3:35])[CH:20]=[CH:19][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1N=Cc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: O=CO
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(-c2c(CNC(C)(C)C)ccc3ccccc23)n1

Procedure:
To a solution of 2.45 g (5.10 mmol) of N-[(6-{2-[(tert-butylamino) methyl]-1-naphthyl}pyridin-2-yl)methylene]-2,6-diisopropylaniline in 50 ml of hot methanol 0.53 g (8.40 mmol) of NaBH3CN was added in one portion followed by the addition of four drops of 88% formic acid. The resulting mixture was refluxed under inert atmosphere for 1 hour and then poured into 50 ml of water. The crude product was extracted with 3×20 ml of ether. The combined extract was washed by 2×50 ml of water, dried over K2CO3, and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: dichloromethane-methanol-triethylamine=100:5:1, vol.). Yield 1.60 g (65%) of orange oil. Anal. calc. for C33H41N3: C, 82.63; H, 8.61; N, 8.76. Found: C, 82.74; H, 8.79; N, 8.60. 1H NMR (CDCl3): 7.89 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.86 (m, 1H, 8-H in naphthyl), 7.82 (m, 1H, 4-H in Py), 7.65 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.47 (m, 11-1, 3-H in Py), 7.44 (m, 1H, 7-H in naphthyl), 7.33-7.40 (m, 3H, 5-H in Py and 5,6-H in naphthyl), 7.04-7.11 (m, 3H, 3,4,5-H in Ph), 4.37 (d, J=14.7 Hz, 1H, CHH′N′Bu), 4.25 (d, J=14.7 Hz, 1H, CHH′NtBu), 3.56 (m, 2H, CH2NAr), 3.33 (sept, J=7.1 Hz, 2H, CH2Me2), 2.04 (s, 1H, NHAr), 1.18 (d, J=7.1 Hz, 6H, CHMeMe'), 1.16 (d, J=7.1 Hz, 6H, CHMeMe′), 0.96 (s, 9H, tBu).
Reaction SMILES: C=O.[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:30])[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)#[N:4].[C:31](=O)(O)[O-].[Na+]>C(O)(=O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:12](=[O:30])[N:13]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH3:31])[CH:24]=2)[CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:16]=1)#[N:4]
Reactant: O=C([O-])O
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1cccc(-n2cc(-c3ccccn3)cc(-c3ccccc3C#N)c2=O)c1
Temperature: 25 °C

Procedure:
Paraformaldehyde (41 mg) and 119 mg of triacetoxy sodium borohydride were added to a solution of 50 mg of 3-(2-cyanophenyl)-5-(2-pyridyl)-1-(3-aminophenyl)-1,2-dihydropyridin-2-one in 3 ml of acetic acid followed by stirring at room temperature for one night. To this was added an aqueous solution of sodium bicarbonate, the mixture-was extracted with ethyl acetate, the organic layer was washed with water, dried and concentrated and the residue was purified by a silica gel column chromatography (ethyl acetate/hexane system) to give 11 mg of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][NH:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15](CCO)[CH:14]=1.NC1C=CC(N)=CC=1C=CCNC1C(CCO)=CC(N)=CC=1.NC1C=CC(N)=CC=1C=CCNC1C=CC(N)=C(Cl)C=1.NC1C=CC(N)=CC=1C=CCNC1C=CC(N)=C(C)C=1.NC1C=CC(N)=CC=1C=CCNC1C=CC(N)=CC=1Cl.NC1C=CC(N)=CC=1C=CCNC1C=CC(N)=CC=1C.NC1C(CCO)=CC(N)=CC=1C=CCNC1C=CC(N)=CC=1.NC1C(Cl)=CC(N)=CC=1C=CCNC1C=CC(N)=CC=1.NC1C=CC=CC=1.NC1C=CC(N)=C(C)C=1C=CCNC1C=CC(N)=CC=1.NC1C=C(CCO)C(N)=CC=1C=CCNC1C=CC(N)=CC=1.NC1C=C(Cl)C(N)=CC=1C=CCNC1C=CC(N)=CC=1.NC1C=C(C)C(N)=CC=1C=CCNC1C=CC(N)=CC=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH:9]=[CH:10][CH2:11][NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH2:17])=[CH:18][CH:19]=1
Reactant: Nc1ccc(N)c(C=CCNc2ccc(N)c(CCO)c2)c1
Agent: Cc1c(N)ccc(N)c1C=CCNc1ccc(N)cc1
Agent: Cc1cc(N)c(C=CCNc2ccc(N)cc2)cc1N
Agent: Cc1cc(N)ccc1NCC=Cc1cc(N)ccc1N
Solvent: Nc1ccccc1
Product: Nc1ccc(NCC=Cc2cc(N)ccc2N)cc1

Procedure:
4-[3-(2,5-diaminophenyl)allylamino]-2-(2-hydroxyethyl)-aniline; 4-[3-(2,5-diaminophenyl)allylamino]-5-(2-hydroxyethyl)aniline; 4-[3-(2,5-diaminophenyl)allylamino]-2-chloroaniline; 4-[3-(2,5-diaminophenyl)allylamino]-2-methylaniline; 4-[3-(2,5-diaminophenyl)allylamino]-3-(2-hydroxyethyl)aniline; 4-[3-(2,5-diaminophenyl)allylamino]-3-chloroaniline; 4-[3-(2,5-diaminophenyl)allylamino]-3-methylaniline; 4-{3-[2,5-diamino-3-(2-hydroxyethyl)phenyl]allylamino}-aniline; 4-[3-(2,5-diamino-3-chlorophenyl)allylamino]aniline; 4-[3-(2,5-diamino-3-methylphenyl)allyl]-amino]aniline; 4-[3-(2,5-diamino-6-methylphenyl)allylamino]aniline; 4-{3-[2,5-diamino-4-(2-hydroxyethyl)phenyl]allylamino}aniline; 4-[3-(2,5-diamino-4-chlorophenyl)allylamino]aniline; 4-[3-(2,5-diamino-4-methylphenyl)allylamino]aniline; 4-[3-(N2,N2-bis-methyl-2,5-diaminophenyl)allylamino]-2-aniline; 4-{3-[N2,N2-bis-(2-hydroxyethyl)-2,5-diaminophenyl]allylamino}-2-aniline; 4-[3-(N5,N5-bis-methyl-2,5-diaminophenyl)allylamino]-2-aniline; 4-{3-[N5,N5-bis-(2-hydroxyethyl)-2,5-diaminophenyl]-allylamino}-2-aniline; 4-[3-(2,5-diaminophenyl)allylamino]-2-N,N′-bis-methylaniline; 4-[3-(2,5-diaminophenyl)allylamino]-2-N,N′-bis-(2-hydroxyethyl)aniline or a physiologically tolerated salt thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][N:15]([C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)[C@H:14]([C:29]([NH:31][C:32]2([C:35]#[N:36])[CH2:34][CH2:33]2)=[O:30])[CH2:13]1)(=[O:11])=[O:10].[C:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)([CH3:40])([CH3:39])[CH3:38]>>[C:35]([C:32]1([NH:31][C:29]([C@@H:14]2[CH2:13][C@@H:12]([S:9]([C:3]3[CH:4]=[CH:5][C:6]([N:44]4[CH2:45][CH2:46][N:41]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:42][CH2:43]4)=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:10])[CH2:16][N:15]2[C:17]2[N:21]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:20]=[C:19]([CH3:28])[CH:18]=2)=[O:30])[CH2:34][CH2:33]1)#[N:36]
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1
Reactant: CC(C)(C)N1CCNCC1
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C(C)(C)C)CC4)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCOCC2)n1

Procedure:
In analogy to the procedure described in example 389, (2S,4R)-4-(2-chloro-4-fluorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-carboxamide (example 464d) was reacted with 1-tert-butylpiperazine (CAS Reg. No. 38216-72-7) to give the title compound as colorless oil. MS (ESI): m/z=658.4 [M+H]+.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[CH3:7][C:8]1([CH2:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]1.[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=O>C(Cl)Cl>[CH2:21]([O:20][C:16](=[O:19])[CH:17]=[N:15][CH2:14][C:8]1([CH3:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]1)[CH3:22]
Reactant: CC1(CN)C=CC=CC1
Reactant: CCOC(=O)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)C=NCC1(C)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 989.9 %

Procedure:
To a suspension of magnesium sulfate (150 g) and 1-methylphenylmethylamine (37.87 g, 32.9 mmol) in methylene chloride was added dropwise a solution of ethyl glyoxylate (33.55 g; 32.9 mmol) in methylene chloride, and the mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was concentrated in vacuo to afford 67.5 g (quantitative) of N-[(1-methyl)phenylmethyl]imino-acetic acid ethyl ester, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]([C:22]2[C:23]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][C:24]=3[S:25][C:26]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][Si](C(C)C)(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]([C:22]2[C:23]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:41][C:24]=3[S:25][C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:31][CH:32]=2)=[O:21])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Reaction time: 0.17 h

Procedure:
A solution of 6-benzyloxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-methoxy-4-triisopropylsilyloxyphenyl ketone (Part C; 4.89 g; 6.64 mmol) in 65 mL of dry THF was treated with tetrabutylammonium fluoride (1 M solution in THF; 7.3 mL) in a dropwise fashion. After 10 min, the reaction mixture was poured into 100 mL of saturated NaHCO3 (aq). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over K2CO3, filtered and concentrated in vacuo to give a quantitative yield of the title compound as a orange foam. An analytical sample was purified by radial chromatography (SiO2; gradient of 1% to 3% MeOH in CHCl3).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH2:20])=[O:19])[NH:13]2)C1C=CC=CC=1.[H][H]>CO.[Pd].CCCCCC>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([NH2:20])=[O:19])[NH:13]2
Reactant: NC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cc2c(O)cccc2[nH]1

Procedure:
4-(benzyloxy)indole-2-carboxamide (4.98 g) in 300 ml of methanol is stirred under 1 atm of hydrogen with 0.75 g of 10% palladium on carbon for 16 hr. The catalyst is filtered off through Celite filter aid, the filtrate concentrated, the residue taken up in ethyl acetate (300 ml) and filtered again. The clear filtrate is concentrated to 200 ml and hexane added to a volume of 450 mi. The cooled solution gives a small amount of gummy, dark material. The filtrate is diluted with hexane and cooled overnight to give a solid. Recrystallization from ethyl acetate/hexane then ethyl acetate gives 4-hydroxyindole-2-carboxamide, mp 219-221.
Reaction SMILES: [Li]N1C(C)(C)CCC[C:3]1(C)C.CC1CCCN(C)C1(C)C.CN(CCN(C)C)C.[Li]CCCC.[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[CH:48][C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.CI>C1COCC1>[NH:35]([C:42]1[N:43]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:44]2[C:49]([C:50](=[O:52])[CH:51]=1)=[C:48]([CH3:3])[C:47]([F:53])=[C:46]([Cl:54])[N:45]=2)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=c1cc(Nc2ccccc2)n(-c2ccccc2)c2nc(Cl)c(F)cc12
Reactant: [Li]N1C(C)(C)CCCC1(C)C
Agent: CC1CCCN(C)C1(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)c(Cl)nc2c1c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of LTMP [freshly prepared at 0° C. from tetramethylpiperidine (227.2 mg, 1.62 mmol), TMEDA (188.3 mg, 1.62 mmol) and n-BuLi (1 mL, 1.62 mmol)) in THF (5 mL) was added to a cooled (40° C.) and stirred solution of 2-anilino-7-chloro-6-fluoro-1-phenyl-1,8-naphthyridin-4(1H)-one (200 mg, 0.54 mmol) in THF (10 mL). The reaction mixture was warmed to 0° C., for 1 h and then re-cooled to 40° C. MeI (766 mg, 5.35 mmol) was added and the reaction mixture was allowed to warm to room temperature and was stirred overnight. The reaction was quenched carefully with water (50 mL) and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. Silica gel flash chromatography of the residue using 1:1 EtOAc:Hex afforded 2-anilino-7-chloro-6-fluoro-5-methyl-1-phenyl-1,8-naphthyridin-4(1H)-one (184 mg, 88%) as a white solid: LCMS RT: 2.74 min, MH+: 380.3. This transformation can also be accomplished by using other amide bases such as LDA.
Reaction SMILES: [OH:1][CH:2]([CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1.[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([N:30]=[C:31]=[O:32])=[CH:24][C:23]=2[O:22]1>>[CH2:21]1[O:29][C:28]2[CH:27]=[CH:26][C:25]([NH:30][C:31]([O:1][CH:2]([CH3:20])[CH2:3][N:4]3[CH2:5][CH2:6][CH:7]([C:10]4[C:18]5[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=5)[NH:12][N:11]=4)[CH2:8][CH2:9]3)=[O:32])=[CH:24][C:23]=2[O:22]1
Reactant: CC(O)CN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Reactant: O=C=Nc1ccc2c(c1)OCO2
Product: CC(CN1CCC(c2n[nH]c3cc(F)ccc23)CC1)OC(=O)Nc1ccc2c(c1)OCO2
Yield: 8.3 %

Procedure:
Starting from 3-[1-(2-hydroxyprop-1-yl)-4-piperidinyl]-6-fluoro-1H-indazole (300 mg, 1.1 mmol) and 3,4-methylenedioxyphenylisocyanate (380 mg, 2.2 mmol) using the procedure described in example 12A was prepared 40 mg (9%) of the title compound as an amorphous solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH:16][CH:17]=O)=[O:15])=[CH:12][N:11]=[C:10]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>CN1CCCC1=O>[CH:1]1([N:7]2[C:8]3[C:9]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[C:10]=4[N:11]=[CH:12][C:13]=3[C:14](=[O:15])[N:16]=[CH:17]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCCCC3)c(C(=O)NC=O)cnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)ncn(C3CCCCC3)c12
Temperature: 25 °C
Yield: 74 %

Procedure:
4-(Cyclohexylamino)-N-formyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (12.4 mg, 0.0311 mmol) in N-methyl-2-pyrrolidinone (0.5 mL) was stirred at 200° C. for 30 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous ammonium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)) to give the title compound as a pale yellow amorphous (9.2 mg, yield 74%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=O)[CH3:15].[I-].[Na+].C(=O)(O)[O-].[Na+]>C(O)CCC>[N:17]1[CH:14]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=3)[CH2:19][CH2:18]2)=[CH:15][CH:18]=1
Reactant: NS(=O)(=O)c1ccc(CCCl)cc1
Reactant: CC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: NS(=O)(=O)c1ccc(CCN2CCN(c3ccncc3)CC2)cc1
Reaction time: 66 h
Yield: 69.6 %

Procedure:
A mixture of 4-(2-chloroethyl)benzenesulphonamide (2.00 g), 1-acetylpiperazine (1.17 g), sodium iodide (1.37 g) and sodium bicarbonate (0.84 g) in n-butanol was heated under reflux with stirring for 66 hours. The mixture was cooled slightly and filtered. The filtrate was allowed to stand and the solid that crystallised out was filtered off and recrystallised from ethyl acetate/methanol to give the title compound (1.10 g), m.p. 203°-204.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:31])=[N:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[C:21]=4[CH3:22])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:32]1[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[C:18]([CH3:31])=[N:19][N:20]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=5)[C:21]=4[CH3:22])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:4][C:3]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)c(F)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)c(F)c3)cc12
Yield: 9.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(2-fluoro-4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (110 mg, 0.184 mmol) was deprotected in TFA/DCM (3/0.5 mL) to afford 9 mg (8.1% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.6 (s, 1H), 8.14-8.13 (d, 1H), 7.55 (s, 1H), 7.50-7.30 (m, 4H), 7.05-6.95 (td, 2H), 6.90-6.85 (d, 1H), 5.37 (s, 2H), 3.52-3.49 (d, 2H), 3.24-3.14 (m, 3H), 2.20 (s, 3H), 2.18 (s, 3H), 2.10-1.95 (m, 4H). MS: m/z=497.8 (M+1), HPLC: 96.3% in method A.
Reaction SMILES: NC(N)=O.S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][CH:14]=1.C([O:35][C:36](=O)[NH:37][S:38]([C:41]1[S:42][C:43]([Cl:46])=[CH:44][CH:45]=1)(=[O:40])=[O:39])C>>[Cl:46][C:43]1[S:42][C:41]([S:38]([NH:37][C:36]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=4[O:21][CH2:20]3)=[CH:17][N:18]=2)=[O:35])(=[O:40])=[O:39])=[CH:45][CH:44]=1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Agent: NC(=O)N=S(=O)=O
Agent: NC(N)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)nc1)CO2
Yield: 23.6 %

Procedure:
Analogous to the sulfonylurea urea formation described in Ex 5, 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.017 g, 0.058 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (0.026 g, 0.096 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-2-yl)urea (0.007 g, 24%). RP-HPLC: 2.7 min; ES-MS (M+H)+=512.0; 1H-NMR (MeOH-d4) δ (ppm): 2.82 (s, 3), 5.4 (s, 2), 6.2 (d, 1), 6.9 (d, 1), 7.3 (d, 1), 7.6 (dd, 1), 8.0 (d, 1), 8.1 (d, 1).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:12][C:11]1[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(N)c1NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a solution of 500 mg (3.0 mmol) of methyl 2,3-diaminobenzoate 9w and 730 mg (6.0 mmol) of benzoic acid 9x in 8 mL of CH2Cl2 was added 620 mg (3.0 mmol) of dicyclohexylcarbodiimide (DCC) and 4 mg (0.033 mmol) of DMAP. The reaction was stirred overnight and the solid was filtered off. The solid was purified by flash column chromoatography (silica gel, 10-30% gradient of EtOAc in heptanes) to give 220 mg (27%) of methyl 3-Amino-2-benzoylamino-benzoate, 9y. MS m/z (M+H+) 271.2
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5]([O:8]C)=[CH:6][CH:7]=1.B(Br)(Br)Br.[OH-].[Na+].Cl>C(Cl)Cl.O>[OH:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: COc1ccc(Br)cc1OC
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1ccc(Br)cc1O
Temperature: 0 °C
Yield: 92 %

Procedure:
4-Bromoveratrole (30 g, 0.138 mol) was placed in a three-neck reaction flask and cooled in an ice bath. Boron tribromide, as described Bhatt et al., Synthesis, 249, (1968) the description of which is incorporated by reference herein, (1.0M in CH2Cl2, 0.2 mol) was slowly introduced through a dropping funnel. After the addition was complete, the reaction mixture was refluxed overnight (20 h). The solution was chilled to 0° C. and water was added slowly. The residue was hydrolyzed with a minimum amount of 10% NaOH(aq). The resulting solution was acidified with hydrochloric acid and extracted with ether. The extracts were washed with H2O and brine, then dried over anhydrous MgSO4 and concentrated in vacuo to afford compound 7 (24 g, 92%). The product was used in the next step without purification (only one spot by TLC). 1H-NMR (CDCl3) δ7.02 (d, 1H, Jmeta =2.26 Hz), 6.92 (dd, Jortho =8.45 Hz, Jmeta =2.26 Hz), 6.74 (d, Jortho =8.45 Hz).
Reaction SMILES: C(C1C=C(NC(=O)CCCC2C=CC([B:25]([OH:27])[OH:26])=CC=2)C=CC=1S(CC)(=O)=O)#N.Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][CH2:38][C:39]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([S:58]([CH2:61][CH3:62])(=[O:60])=[O:59])=[C:46]([CH:57]=2)[CH2:47][N:48]([CH3:56])[C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:40])=[CH:32][CH:31]=1.CC1(C)COB(B2OCC(C)(C)CO2)OC1.B(O)O>>[C:51]([O:50][C:49]([N:48]([CH2:47][C:46]1[CH:57]=[C:42]([NH:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][C:33]2[CH:34]=[CH:35][C:30]([B:25]([OH:27])[OH:26])=[CH:31][CH:32]=2)[CH:43]=[CH:44][C:45]=1[S:58]([CH2:61][CH3:62])(=[O:60])=[O:59])[CH3:56])=[O:55])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(Br)cc2)cc1CN(C)C(=O)OC(C)(C)C
Agent: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: OBO
Product: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1CN(C)C(=O)OC(C)(C)C
Yield: 76 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 17C (0.428 g, 0.76 mmol) was coupled to 5,5,5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] (0.202 g, 0.894 mmol) and then hydrolyzed to the free boronic acid to give 17D (0.260 g, 76%) as a white solid. MS (ESI) m/z 519.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])(=[O:4])[C:2]#[CH:3].C([Li])CCC.[CH2:16]1[O:26][C:25]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[O:17]1.[Cl-].[NH4+]>O1CCCC1>[OH:22][CH:21]([C:20]1[CH:23]=[CH:24][C:25]2[O:26][CH2:16][O:17][C:18]=2[CH:19]=1)[C:3]#[C:2][C:1]([O:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])=[O:4]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: C#CC(=O)OCC=C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)=CCOC(=O)C#CC(O)c1ccc2c(c1)OCO2
Reaction time: 0.17 h

Procedure:
A solution of 10 g (72 mmol) of 3-methyl-2-butenyl propiolate in 100 ml of tetrahydrofuran was treated at -78° under argon with 47 ml of n-butyllithium (1.6M in hexane). The mixture was stirred at -78° for 10 minutes and then a solution of 10.9 g (72 mmol) of 3,4-methylenedioxybenzaldehyde in 120 ml of tetrahydrofuran was added within 30 minutes. The reaction mixture was stirred at -78° for a further 30 minutes then brought to room temperature and treated with 120 ml of saturated ammonium chloride solution. The aqeuous phase was extracted twice with ether; the organic phases were washed in succession with saturated sodium chloride solution and with water, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent methylene chloride/ethyl acetate 9:1). There was obtained 3-methyl-2-butenyl 4-hydroxy-4-[3,4-(methylenedioxy)phenyl]-2-butynoate as a yellow oil.