Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16]Br)=[CH:11][C:10]=1[NH:19][C:20]([NH2:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH:30][CH:31]([CH3:43])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:35][CH:34]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>CCOCC>[CH2:23]([N:30]([CH:31]([CH3:43])[CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:38]=1)[CH2:16][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([NH:19][C:20]([NH2:22])=[O:21])[CH:11]=1)=[O:18])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)Nc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(CC(C)NCc2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1ccc(CC(C)N(CC(=O)c2ccc(OCc3ccccc3)c(NC(N)=O)c2)Cc2ccccc2)cc1

Procedure:
1-(4-Benzyloxy-3-ureidophenyl)-2-bromoethanone (3.1 g) and N-benzyl-(2-[4-carbomethoxyphenyl]-1-methylethanamine) (4.85 g) were heated in refluxing acetonitrile (50 ml) for 2 hours. The solution was diluted with an equal volume of ether, filtered and the filtrate diluted further with ether (200 ml). The solution was washed with water, dried and evaporated to give the title compound, mp 140°-145° (ethyl acetate). τ (CDCl3) 9.00 (3H, d, J=6 Hz), 6.70-7.60 (3H, m), 6.0-6.4 (4H, m), 6.20 (3H, s), 4.90 (2H, s), 6.32 (2H, b), 2.1-3.3 (17H, m), 1.20 (1H, d, J=2 Hz).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:18]([Li])CCC.[C:23]([Si:27]([CH3:57])([CH3:56])[O:28][C:29]1[CH:30]=[CH:31][C:32]2[C:33]3[C:46](=[O:47])[O:45][C:44]4[CH:43]=[C:42]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH:41]=[CH:40][C:39]=4[C:34]=3[CH2:35][O:36][C:37]=2[CH:38]=1)([CH3:26])([CH3:25])[CH3:24].C[Mg]Br>C1COCC1>[N:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:16]=[CH:17][C:2]([C:46]([C:33]3[C:32]4[C:37](=[CH:38][C:29]([O:28][Si:27]([C:23]([CH3:25])([CH3:24])[CH3:26])([CH3:56])[CH3:57])=[CH:30][CH:31]=4)[O:36][CH2:35][C:34]=3[C:39]3[CH:40]=[CH:41][C:42]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])=[CH:43][C:44]=3[OH:45])([OH:47])[CH3:18])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCc1c-2c(=O)oc2cc(O[Si](C)(C)C(C)(C)C)ccc12
Reactant: Brc1ccc(OCCN2CCCCCC2)cc1
Reactant: [Li]CCCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(C1=C(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O)COc2cc(O[Si](C)(C)C(C)(C)C)ccc21)c1ccc(OCCN2CCCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(4-bromophenoxy)ethyl]-azepane (356 mg, 1.19 mmol) in THF (7.5 mL) at −78° C., was added n-butyl lithium (2.5 M in hexane, 466 μL, 1.17 mmol). The reaction mixture was stirred at −78° C. for 0.5 hours. To the mixture was then added 2,8-bis-(tert-butyl-dimethyl-silyloxy)-11H-chromeno[4,3-c]chromen-5-one, prepared as in Example 22, (149 mg, 0.29 mmol) in THF (3 mL) and the reaction mixture stirred at −78° C. for 1.5 hours. To the mixture was then methyl magnesium bromide (3 M in diethyl ether, 1 mL, 3 mmol) at −78° C. and then stirred at room temperature overnight. The reaction was quenched with aqueous NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. The remaining solvent was evaporated to yield the crude title product as a yellow oil, which was carried on to the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[C:10]#[CH:11]>C(N(CC)CC)C.CCOC(C)=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.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C#Cc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
To a mixture of 1,4-diiodobenzene (1.0 g, 3.03 mmol), Pd(PPh3)2Cl2 (580 mg, 0.606 mmol) and CuI (115 mg, 0.606 mmol) in triethylamine (20 mL), ethyl propiolate (590 mg, 6.06 mmol) was added under N2. The resulting mixture was stirred at 80° C. for 16 h under N2. The reaction mixture was diluted with EtOAc (50 mL) and filtered. The filtrate was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified on a silica gel column using 0-10% EtOAc in petroleum ether to afford the title compound (360 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (d, 2H), 7.45 (d, 2H), 4.24 (q, 2H), 1.25 (t, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[CH2:13][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:25].C(N(CC)CC)C.[F:33][C:34]([F:52])([F:51])[C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1>ClCCl>[CH2:18]([O:17][N:11]1[C@@H:12]([CH:14]([CH3:16])[CH3:15])[CH2:13][C@@H:9]([NH:8][S:47]([C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH:39]=[CH:40][C:35]([C:34]([F:33])([F:51])[F:52])=[CH:36][CH:37]=3)=[CH:46][CH:45]=2)(=[O:49])=[O:48])[C:10]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(C)[C@H]1C[C@@H](N)C(=O)N1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1C[C@@H](NS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)N1OCc1ccccc1
Temperature: 22 °C
Reaction time: 1 h
Yield: 56.3 %

Procedure:
To a solution of (3R,5R)-3-amino-1-(Benzyloxy)-5-isopropyl-2-pyrrolidinone trifluoroacetate (0.036 g, 0.10 mmoles), triethylamine (0.070 mL, 0.50 mmoles) and dry dichloromethane (0.70 mL) was added in small portions 4′-(trifluoromethyl)[1,1′-biphenyl]-4-sulfonyl chloride (0.034 g, 0.11 mmoles) during two minutes. The mixture was stirred under dry nitrogen at 22° C. for 60 minutes, concentrated by rotary evaporation, re-dissolved in dichloromethane (2 mL), mixed with a silica (1 g), concentrated again and then applied on a silica column. Elution with ethyl acetate/n-heptane (1:4 through 1:3) and concentration of pure fractions gave 0.030 g (57% yield) of the title compound as a white solid. LC-MS (APCI) m/z 533 (M+1). 1H NMR (CDCl3) δ 8.02 (d, J=8 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 7.72 (d, J=8 Hz, 2H) 7.70 (d, J=8 Hz, 2H), 7.40–7.30 (m, 5H), 5.43 (d, J=3 Hz, 1H), 4.99 (d, J=10 Hz, 1H), 4.88 (d, J=10 Hz, 1H), 3.76 (dt, J1=3 Hz, J2=9 Hz, 1H), 3.31 (ddd, J1=4 Hz, J2=6 Hz, J3=9 Hz, 1H), 2.40 (ddd, J1=7 Hz, J2=9 Hz, J3=13 Hz, 1H), 2.20–2.08 (m, 1H), 1.76 (dt, J1=9 Hz, J2=13 Hz, 1H), 0.85 (d, J=7 Hz, 3H) and 0.83 (d, J=7 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH:11]([OH:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].Cl.O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[O:8][CH3:9])[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)[O:13][CH:11]([CH3:12])[CH2:10]2
Reactant: COc1ccc(CC(C)O)cc1Br
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc2c(cc1Br)CC(C)OC2c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
18.04 g (132.4 mmol) of freshly melted zinc chloride is added to a solution of 32.46 g (132.4 mmol) of 1-(3-bromo-4-methoxyphenyl)-propan-2-ol and 20.01 g (132.4 mmol) of 4-nitrobenzaldehyde in 166 ml of dry benzene, and then dry hydrogen chloride gas is introduced for 3 hours. The reaction mixture is then heated to boiling for 1 hour and stirred with 150 ml of water. The organic phase is separated and washed in succession with water (2×50 ml), 20% sodium hydrogen sulfite solution (100 ml), 8% sodium bicarbonate solution (50 ml) and water (2×50 ml) and dried. After concentration by evaporation, a thick oil, which during treatment with hot ethanol (450 ml) yields crystalline 6-bromo-3-methyl-7-methoxy-1-(4-nitrophenyl)-isochroman, is obtained: 20.39 g (41%), melting point 128-129° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[S:10]1[CH:11]=[CH:12][C:8]([C:6]2[N:5]=[C:4]3[CH2:13][CH2:14][CH2:15][C:3]3=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[CH:7]=2)=[CH:9]1
Reactant: Clc1cc(-c2ccsc2)nc2c1CCC2
Reactant: Nc1ccc(CCO)cc1
Product: OCCc1ccc(Nc2cc(-c3ccsc3)nc3c2CCC3)cc1
Yield: 29.7 %

Procedure:
Following general procedure B1, 4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060 g, 0.25 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.041 g, 0.30 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.025 g, 27%) as a white solid. MW=356.85. MW=372.91. 1H NMR (DMSO-d6, 500 MHz) δ 13.91 (s, 1H), 9.68 (s, 1H), 8.37-8.32 (m, 1H), 7.80-7.76 (m, 1H), 7.59-7.55 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.03 (s, 1H), 4.67 (s, 1H), 3.65 (t, J=7.0 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); APCI MS m/z 337 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1)[CH3:17].O>O1CCOCC1.CO>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1ccc(I)cc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCOc1ccc(-c2ccncc2)cc1
Reaction time: 48 h

Procedure:
Under inert gas atmosphere 88 mg (0.12 mmol) PdCl2(dppf)xCH2Cl2, 13.6 mL (27.2 mmol) 2N sodium carbonate solution and 1.64 g (13.3 mmol) pyridine-4-boronic acid are added to 3.00 g (12.1 mmol) 1-ethoxy-4-iodo-benzene in 18 mL 1,4-dioxane and 6 mL methanol. The mixture is stirred for 2 d at reflux. After that time, water is added. The precipitate is filtered off, taken up in DCM and extracted with water. The organic layer is dried over sodium sulphate and the solvent is evaporated. The residue is purified by column chromatography (silica gel; gradient DCM:MeOH 100:0->95:5) to yield the desired product which is directly used in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:24][CH2:23][CH2:22][C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1ccncc1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: Clc1nccc(-c2cccc(CNCCc3ccncc3)c2)n1

Procedure:
Intermediate 1 was coupled with 2-pyridin-4-yl-ethylamine following procedure B. LC-MS showed the product had the expected M+H+ of 325.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1.[OH-].[Na+]>O.C(O)C>[CH3:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[N:2][OH:3])=[CH:7][CH:6]=1
Reactant: NO
Reactant: Cc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=NO)cc1
Yield: 68.7 %

Procedure:
Hydroxylamine hydrochloride (41.7 g) in 70 ml of water was added to a solution of 36.1 g of 4-methylbenzaldehyde in 180 ml of absolute ethanol. A solution of 18 g of sodium hydroxide in 36 ml of water was added in portions during 5 to 10 minutes. The reaction mixture was then heated to boiling and filtered hot, and the filtrate was cooled in a dry ice-acetone bath. Water was added to the cooled filtrate until solid product precipitated. The solid was separated by filtration, air-dried overnight, and recrystallized from hexane to give 27.9 g of 4-methylbenzaldoxime, m.p. 73°-77°.
Reaction SMILES: C(CC(Cl)=O)#N.COC1C=CC([NH:15][C:16](=O)[CH2:17][C:18]([NH:20][C:21]([CH3:37])([CH2:27][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])=CC=1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([CH2:17][C:18]([NH:20][C:21]([CH3:37])([CH2:27][C:28](=[O:36])[C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:19])#[N:15]
Reactant: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC(=O)Nc1ccc(OC)cc1
Agent: CN(C)c1ccncc1
Agent: N#CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)(CC(=O)c1ccc(C)cc1)NC(=O)CC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of Intermediate 3C (2.192 g, 21.18 mmol) in DCM (30 mL) under argon was added Intermediate 102C (1.2 g, 4.81 mmol), pyridine (0.779 mL, 9.63 mmol) and DMAP (0.059 g, 0.481 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was loaded onto silica gel (25 g) and washed with EtOAc (4×50 mL). The filtrate was concentrated in vacuo to a dark red oil. The oil was dissolved in EtOAc (100 mL) and washed with water (2×50 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (80 g silica gel, eluted with EtOAc in hexanes) to afford the desired product (1.28 g, 84%) as yellow oil. LCMS Anal. Calc'd for C17H20N2O4 316.1, found [M+H] 317.1. 1H NMR (500 MHz, CDCl3) δ 7.82 (d, J=8.0 Hz, 2H), 7.39 (s, 1H), 7.24-7.29 (m, 2H), 4.45 (d, J=18.2 Hz, 1H), 4.22-4.31 (m, 2H), 3.47 (d, J=18.2 Hz, 1H), 3.28-3.38 (m, 2H), 2.42 (s, 3H), 1.74 (s, 3H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[C:25]([CH2:26][CH3:27])=NN=[C:22]2[CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:20]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:17][CH2:18][CH3:19])=O)=[CH:11][CH:10]=1)=O.[OH2:40].[NH2:41][NH2:42]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:21]3[C:25]([CH2:26][CH3:27])=[N:41][N:42]=[C:22]3[CH2:28][N:29]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([CH2:17][CH2:18][CH3:19])=[O:40])=[CH:13][CH:14]=3)[C:6]=2[CH:20]=1
Reactant: O
Reactant: CCCS(=O)c1ccc(C(=O)c2cc(F)ccc2-n2c(CC)nnc2CN2C(=O)c3ccccc3C2=O)cc1
Reactant: NN
Solvent: CCO
Product: CCCS(=O)c1ccc(C2=NCc3nnc(CC)n3-c3ccc(F)cc32)cc1

Procedure:
In the manner given in Example 5, 5-fluoro-4'-(propylsulfinyl)-2-[3-(phthalimidomethyl)-5-ethyl-4H-1,2,4-triazol-4-yl]benzophenone was heated in ethanol with hydrazine hydrate to give 8-fluoro-1-ethyl-6-[p-(propylsulfinyl)phenyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[NH3:15]>C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:15])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc2cccnc12
Temperature: -60 °C
Reaction time: 8 h
Yield: 47.2 %

Procedure:
Quinoline-8-sulfonyl chloride (1.0 g, 4.39 mmol) was slurried into DCM (20 mL) and cooled to −60° C. Then ammonia (˜5 g, 294 mmol) was bubbled into the reaction over 5 min (volume increased by ˜5 mL). The reaction was stirred and allowed to come to rt overnight. The residue was partitioned between water (50 mL) and EtOAc (50 mL) and the organic layer was washed with brine (20 mL) and diluted with hexanes (˜50 mL). The solution was stirred 20 min and the solids were collected by filtration to yield quinoline-8-sulfonamide (432 mg, 2.07 mmol, 47% yield) as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.25 (s, 2H), 7.73 (dd, J=8.3, 4.3 Hz, 1H), 7.76 (dd, J=8.6, 7.3 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.31 (d, J=7.3 Hz, 1H), 8.56 (br d, J=8.6 Hz, 1H), 9.08 (dd, J=4.3, 0.9 Hz, 1H). LC-MS retention time: 1.27 min; m/z 209 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][C:4](O)=O.C(OC(=O)C)(=[O:13])C.C(O)(=O)C>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:3][CH2:4][O:10][C:8](=[O:9])[C:7]1=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(=O)O)CC(=O)O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CN1CCOC(=O)C1=O
Yield: 77.1 %

Procedure:
A round-bottom flask equipped with a PTFE-coated magnetic stir bar was charged with N-methyliminodiacetic acid (25.0 g, 170 mmol, 1.0 equiv), acetic anhydride (85 mL, ˜850 mmol, ˜5 equiv.), and pyridine (274.9 μL, 3.4 mmol, 0.02 equiv). The flask was capped with a rubber septum which was pierced with an 18 gauge needle (alternatively a reflux condensor could be used). The reaction was lowered into a preheated 70° C. oil bath and stirred until the mixture became clear and dark orange (about 1.5 h). The acetic acid, pyridine, and remaining acetic anhydride were then removed by vacuum distillation (37° C. to 42° C. at 30 Torr). The resulting brown-black liquid was azeotroped three times with toluene (50 mL) to remove residual acetic acid and then transferred to an Erlenmeyer flask. To this flask was added enough diethyl ether to dissolve the crude N-methyl morpholine dione product (˜400 mL). The resulting mixture was filtered to remove a black-brown precipitate, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was then recrystallized from a minimum amount of hot diethyl ether to yield N-methyl morpholine dione (MIDA anhydride; 16.9 g, 131 mmol, 77%) as an off-white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(-c3ccccc3F)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-5,6-dimethoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 379(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[S:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:29]3[CH2:30][CH2:31][S:26][CH2:27][CH2:28]3)[CH2:24][CH2:25]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: O=C1CCSCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCN(C2CCSCC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 80 %

Procedure:
A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.44 g, 1.2 mmol) in methanol-acetic acid (95:5) (10 mL) was treated with tetrahydrothiopyran-4-one (1.34 g, 11.5 mmol) and sodium cyanoborohydride (4.6 mL of a 1 M solution in tetrahydrofuran). The reaction mixture was stirred at room temperature for 48 h, then heated at 50° C. for an additional 60 h. After cooling to room temperature, the solvent was removed in vacuo; the resulting residue was redissolved in methanol and directly applied to 5×10 g SCX columns, washed with methanol and eluted with dichloromethane-2 N ammonia in methanol (1:1). The product fractions were concentrated in vacuo and the residue was purified via silica gel chromatography. Elution with ethyl acetate followed by ethyl acetate-methanol (9:1) afforded the title compound (0.46 g, 84%) as a yellow solid, which was further purified via trituration in acetonitrile followed by separation of the yellow mother liquor.
Reaction SMILES: N[C:2]1[O:6][N:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N([O-])=O.[Na+]>C(O)(=O)C.O.O1CCCC1>[C:12]1([C:3]2[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][O:6][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1noc(N)c1-c1ccccc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1nocc1-c1ccccc1
Yield: 54.9 %

Procedure:
In an analogous manner to that described in J. Org. Chem. 50 (13) 1985, 2372-2375, 7.6 g (32.72 mmol) of ethyl 5-amino-4-phenyl-3-isoxazolecarboxylate in 160 ml of glacial acetic acid, 50 ml of water and 80 ml of tetrahydrofuran were treated portionwise at 15°-20° while stirring within 1 hour with a total of 22.6 g of sodium nitrite. The reaction mixture was thereafter poured into 1 liter of water and extracted 3 times with 400 ml of methylene chloride each time. The organic phases were combined and first washed twice with 1 liter of saturated sodium bicarbonate solution each time and then once with 1 liter of water, dried, filtered and concentrated in a vacuum, whereby after chromatography on silica gel and elution with methylene chloride there were obtained 3.9 g (55%) of ethyl 4-phenyl-3-isoxazolecarboxylate as a yellow oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([F:11])[CH:3]=1.[CH3:12][CH:13]([CH3:36])[CH:14]([NH:19][C:20]([C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=2)[N:26]=1)=[O:21])[C:15]([O:17][CH3:18])=[O:16]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:33][C:30]2[CH:31]=[CH:32][C:27]([C:25]3[N:26]=[C:22]([C:20]([NH:19][C@@H:14]([CH:13]([CH3:36])[CH3:12])[C:15]([O:17][CH3:18])=[O:16])=[O:21])[S:23][CH:24]=3)=[CH:28][CH:29]=2)=[C:4]([F:11])[CH:3]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C(C)C
Reactant: O=C=Nc1ccc(Cl)cc1F
Product: COC(=O)[C@@H](NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(Cl)cc3F)cc2)cs1)C(C)C

Procedure:
The title compound was synthesized analogous to Example 23, using 4-chloro-2-fluoro-1-isocyanatobenzene and intermediate 3. 1HNMR (DMSO-d6, 300 MHz): δ 9.281 (s, 1H), 8.824-8.796 (d, J=8.4 Hz, 1H), 8.703 (s, 1H), 8.330 (s, 1H), 8.227-8.168 (t, J=8.7, 9 Hz, 1H), 8.069-8.040 (d, J=8.7 Hz, 2H), 7.589-7.560 (s, J=8.7 Hz, 2H), 7.508-7.463 (d, J=2.1, 11.1 Hz, 1H), 7.268-7.238 (d, J=9 Hz, 1H), 4.395-4.343 (t, J=7.8 Hz, 1H), 3.700 (s, 3H), 2.341-2.273 (m, 1H), 1.000-0.953 (t, J=6.9, 7.2 Hz, 6H); MS (ESI) m/z 503 (M−H), 505 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H:23]2[C@@H:14]([CH2:15][N:16]3[C@H:21]([CH2:22]2)C2NC4C=C(OC)C=CC=4C=2CC3)[CH2:13][C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O.C(#[N:55])C>>[F:1][C:2]1[C:7]([O:8][C:15]2[N:16]=[CH:21][CH:22]=[CH:23][C:14]=2[C:13]#[N:55])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Reactant: Oc1cccnc1F
Reactant: CC#N
Product: N#Cc1cccnc1Oc1cccnc1F

Procedure:
The title compound was synthesized by General Procedure 9 using 2-fluoro-3-hydroxypyridine. 1H NMR (DMSO-d6. 400 MHz) δ 7.41 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 7.51 (ddd, 1H, J=1.1 Hz, J=4.9 Hz, J=7.8 Hz), 8.09 (ddd, 1H, J=1.7 Hz, J=7.8 Hz, J=9.7 Hz), 8.19 (td, 1H, J=1.6 Hz, J=4.9 Hz), 8.42 (dd, 1H, J=1.9 Hz, J=5.0 Hz), 8.50 (dd, 1H, J=1.9 Hz, J=7.6 Hz); RP-HPLC (Hypersil®1-100 C18, 5 μm, 100 Å, 10 cm; 5%-100% acetonitrile-0.1M ammonium acetate over 5 min. 2 mL/min), then 100% acetonitrile isocratic 1 minutes, Rt 3.62 min.