Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[C:21]([C:23]1[C:24]([SH:31])=[N:25][CH:26]=[C:27]([C:29]#[N:30])[CH:28]=1)#[N:22]>CN(C=O)C.C(OCC)(=O)C>[C:29]([C:27]1[CH:28]=[C:23]2[C:21]([NH2:22])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:31][C:24]2=[N:25][CH:26]=1)#[N:30]
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Reactant: N#Cc1cnc(S)c(C#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2ncc(C#N)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (1.18 g, 8.55 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.34 g, 5.12 mmol) and 3,5-dicyano-2-mercaptopyridine (0.55 g, 3.42 mmol) in dry DMF (8 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 196° C.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17](CC(OC)=O)[CH:18]([C:23]([O:25][CH3:26])=[O:24])[C:19](OC)=O)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O>Cl>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH:18]([CH2:19][CH2:18][C:23]([O:25][CH3:26])=[O:24])[C:23]([O:25][CH3:26])=[O:24])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: COC(=O)CC(c1ccc2c(c1)CCN2C(=O)OC(C)(C)C)C(C(=O)OC)C(=O)OC
Agent: Cl
Product: COC(=O)CCC(Cc1ccc2c(c1)CCN2)C(=O)OC
Yield: 84.6 %

Procedure:
A mixture of dimethyl 3-(1-boc-2,3-dihydro-1H-indol-5-yl)-2-methoxycarbonyl-pentanedioate [530 mg, Reference Example 10(a)] and concentrated hydrochloric acid (20 ml) was stirred at reflux overnight then evaporated. The residual clear foam (370 mg) was treated with methanol (20 ml), then with concentrated sulphuric acid (10 drops). The resulting solution was stirred at reflux for 2 hours then evaporated. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer and extracts were washed with brine, then dried and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:1, v/v) to give the title compound (150 mg) as a clear oil. MS (ES+) 278 (MH+).
Reaction SMILES: [CH2:1]([S:3][CH2:4][CH:5]([C:7]1[N:8](S(C)(=O)=O)[C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)[OH:6])[CH3:2].[OH-].[Na+]>>[CH2:1]([S:3][CH2:4][CH:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([C:19]([F:22])([F:20])[F:21])[CH:10]=2)[OH:6])[CH3:2]
Reactant: CCSCC(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CCSCC(O)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2[nH]1

Procedure:
This compound was prepared using the general de-protection procedure described in General Procedures Example B, starting from 2-ethylsulfanyl-1-(1-methanesulfonyl-5-nitro-6-trifluoromethyl-1H-indol-2-yl)-ethanol (1.52 g, 3.69 mmol) and 4M sodium hydroxide as base (1.8 mL, 7.38 mmol) to yield the title compound as a bright yellow solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([O:16][C:17]([N:19]([C:39]1[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=1)[S:20]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([CH3:38])=[CH2:37])=[CH:31][CH:30]=2)=[N:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21])=[O:18])[CH:13]([CH3:15])[CH3:14]>>[O:6]1[CH2:37][C:36]1([CH3:38])[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[C:23]([S:20]([N:19]([C:17]([O:16][CH2:12][CH:13]([CH3:14])[CH3:15])=[O:18])[C:39]3[C:44]([O:45][CH3:46])=[N:43][C:42]([CH3:47])=[CH:41][N:40]=3)(=[O:22])=[O:21])=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:30][CH:31]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(CC2(C)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
3-Chloroperoxybenzoic acid (50%, 2.4 g) was added over 5 minutes to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-[4-(2-methylprop-2-enyl)phenyl]pyridine-3-sulphonamide (1.8 g) in dichloromethanc (75 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred a further 1 hour. The mixture was washed with saturated aqueous sodium hydrogen carbonate solution (20 ml), water and saturated sodium chloride solution then dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by suction flash chromatography followed by gradient elution with 0-40% ethyl acetate/hexane through a silica gel Mega Bond Elut column to give 2-[4-(2,3-epoxy-2-methylpropyl)phenyl]-N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.16 g) as a solid, 1H NMR (CDCl3): 0.65 (d, 6 H), 1.3 (s, 3 H), 1.7 (m, 1 H), 2.5 (s, 3 H), 2.65 (dd, 2 H), 2.9 (q, 2 H), 3.85 (d, 2 H), 4.0 (s, 3 H), 7.3 (d, 2 H), 7.5 (dd, 1 H), 7.6 (d, 2 H), 7.95 (s, 1 H), 8.85 (dd, 1 H), 8.95 (dd, 1 H); mass spectrum (+ve ESP): 527 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH:25]4[CH2:28][O:27][CH2:26]4)[CH2:21][CH2:20]3)=[CH:15][N:14]=2)[C:5]2[N:9]=[CH:8][N:7]([CH3:10])[C:6]=2[CH:11]=1.C([O:32][CH2:33][C:34]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][C:37]([F:49])=[CH:36][C:35]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=O)C.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:49][C:37]1[CH:38]=[C:39]([C:2]2[CH:3]=[C:4]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH:25]5[CH2:26][O:27][CH2:28]5)[CH2:23][CH2:24]4)=[CH:15][N:14]=3)[C:5]3[N:9]=[CH:8][N:7]([CH3:10])[C:6]=3[CH:11]=2)[C:34]([CH2:33][OH:32])=[C:35]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])[CH:36]=1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(Cl)cc21
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1cnc2c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)cc(-c3cc(F)cc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cc21
Temperature: 110 °C
Yield: 14 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 109e (300 mg, 0.75 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-Hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 101l (545 mg, 1.13 mmol), potassium carbonate (414 mg, 3.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (68 mg, 0.075 mmol), and tricyclohexylphosphine (210 mg, 0.75 mmol). After bubbling nitrogen through the suspension for 5 minutes, the reaction was heated at 110° C. for overnight. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 109 as a white solid (71 mg, 14%). LCMS: [M+H]+ 677.3. 1H NMR (500 MHz, DMSO) δ 8.64 (s, 1H), 8.23 (d, J=1.0, 1H), 8.18 (s, 1H), 7.88 (d, J=2.5, 1H), 7.38-7.39 (m, 1H), 7.33-7.35 (m, 1H), 7.24 (d, J=9.0, 1H), 7.18-7.19 (m, 2H), 6.52 (s, 1H), 4.85 (bs, 1H), 4.56 (t, J=6.0, 2H), 4.46 (t, J=6.0, 2H), 4.29 (s, 2H), 4.16-4.18 (m, 3H), 3.93-3.94 (m, 1H), 3.84 (s, 3H), 3.44-3.45 (m, 1H), 3.07 (t, J=4.0, 4H), 2.61-2.62 (m, 2H), 2.47 (t, J=6.0, 2H), 2.39 (t, J=4.0, 4H), 1.79-1.80 (m, 2H), 1.70-1.71 (m, 2H)
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC=C(Cl)C=2Cl)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:25]1([CH2:24][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[Cl:23])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:8][N:9]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2Cl)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: Clc1cccc(NCC2CCCC2)c1Cl
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(Cl)c2Cl)s1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(2,3-dichloro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2,3-dichlorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][CH2:21][C:11]2[N:12]([CH3:20])[C:13]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]([C:15]3[CH:16]=[CH:17][C:18]4[C:10]5[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][CH2:21][C:11]=5[N:12]([CH3:20])[C:13]=4[CH:14]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: COc1ccc(-c2cc[nH]c(=O)c2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: COc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cc1
Temperature: 133 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
tert-Butyl-7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.19 g, 0.54 mmol), 4-(4-methoxyphenyl)pyridin-2(1H)-one (90 mg, 0.45 mmol) and Cs2CO3 (0.16 g, 0.49 mmol) were suspensed in DMSO (2.0 mL) and degassed under vacuum for 15 min. The system was then flushed with Ar and 8-hydroxyquinoline (19 mg, 0.13 mmol) and copper iodide (0.10 g, 0.54 mmol) were added. The degassing/Ar flushing process was repeated twice more, and the reaction mixture was heated at 133° C. for 18 h under N2. The suspension was cooled, diluted with 20% NH4OH/MeOH (25 mL) and stirred at ambient temperature for 30 min. The suspension was further diluted with CH2Cl2 (100 mL). The solution was filtered through silica gel and concentrated under reduced pressure. The concentrate was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic phase was dried over Na2SO4, filtered and concentrated to dryness. Flash column chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 10 column volumes, increased to 50:50 over 20 column volumes and then hold for 5 column volumes) gave the title compound (75 mg, 34%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.0 Hz, 1H), 7.46 (d, J=7.5 Hz, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.86 (d, J=2.0 Hz, 1H), 6.50 (dd, J=7.0, 2.0 Hz, 1H), 4.66-4.64 (m, 2H), 3.87 (s, 3H), 3.85-3.84 (m, 2H), 3.64 (s, 3H), 2.84-2.83 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: CO[N:3]=[C:4]([CH3:22])[CH2:5][C:6]1[C:7](=[O:21])[NH:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[H][H]>C(O)C.[Ni]>[NH2:3][CH:4]([CH3:22])[CH2:5][C:6]1[C:7](=[O:21])[NH:8][CH2:9][CH2:10][CH2:11][C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: CON=C(C)CC1=C(c2ccc(OC)cc2)CCCNC1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2=C(CC(C)N)C(=O)NCCC2)cc1

Procedure:
The solution of 6.5 g of 3-(2-methoxyiminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone in 150 ml of ethanol is hydrogenated at room temperature and atmospheric pressure in the presence of 10 g of Raney nickel until the uptake of 2 mole equivalents of hydrogen is complete. The mixture is filtered, the filtrate evaporated and the residue dissolved in 100 ml of water and 10 ml of 6 N hydrochloric acid. The acidic solution is washed with diethyl ether, filtered, basified with 30 ml of 3 N aqueous sodium hydroxide and repeatedly extracted with chloroform. The extract is dried, evaporated and the residue is purified by suspension in diethyl ether, to give the 3-(2-aminopropyl)-4-(4-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone melting at 131°-133°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:28][C:29]1[CH:44]=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:45])[CH:30]=1>O1CCCC1>[F:45][C:31]1[CH:30]=[C:29]([NH:28][C:14]([C:11]2([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:12][CH2:13]2)=[O:16])[CH:44]=[CH:43][C:32]=1[O:33][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (5.58 g) in tetrahydrofuran (60 ml) was added dropwise triethylamine (4.18 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 15 min. To the reaction mixture, was then added thionyl chloride (2.0 ml), followed by stirring at the same temperature for 60 min. To the reaction mixture was added a suspension of 4-(4-amino-2-fluorophenoxy)pyridine-2-carboxamide (4.945 g) and triethylamine (4.18 ml) in tetrahydrofuran (50 ml) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 2 hr. The reaction was allowed to warm up to room temperature, followed by stirring overnight. The reaction mixture was partitioned after addition of ethyl acetate (100 ml) and a 1N aqueous solution of sodium hydroxide (100 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (100 ml, 3 times), 1N hydrochloric acid (100 ml, twice) and brine (100 ml) in this order, and dried over anhydrous sodium sulfate. The organic layer was filtered and the filtrate was concentrated under reduced pressure. To the resultant residue (8.3 g) were added ethyl acetate (20 ml) and heptane (5 ml) to precipitate a solid. After diluting with addition of ethyl acetate (20 ml), the solid was collected by filtration with suction, washed with ethyl acetate-heptane (16 ml-2 ml). Drying under aeration with suction on a paper filter provided the titled compound as pale brown powder (3.73 g, 41%). The filtrate was concentrated under reduced pressure, and ethyl acetate (20 ml) and heptane (4 ml) were again added to the residue (3.6 g) to precipitate a solid. The solid was collected by filtration with suction. Drying under aeration with suction on a paper filter provided the titled compound as pale brown powder (216 mg, 2.4%). The filtrate was further concentrated under reduced pressure, and the residue (3.06 g) was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as pale brown powder (885 mg, 9.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](O)[CH:6]=[CH:5]2.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: Oc1ccc2cc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Yield: 90 %

Procedure:
180 mg 6-chloro-2-hydroxy quinoline was treated by 3 ml POCl3, the mixture was refluxed for 3 hours, the remaining POCl3 was evaporated out. After cooling to room temperature, the residue was treated by cold water, the solid was filtered out and dried as green powder, yield: 90%. Following the general procedure in claim 5, the listed compounds were achieved. Mass calculated for C9H5Cl2N: 198; LCMS: 200.1 (M+2)+; 1HNMR (400 MHZ), DMSO-d6) δ ppm 8.04 (1H, d, J=7.8 Hz), 7.97 (1H, d, J=8.8 Hz), 7.81 (1H, d, J=1.9 Hz), 7.68 (1H, dd, J=9.8 Hz, J=2.9 Hz), 7.42 (1H, d, J=8.8 Hz).
Reaction SMILES: [C:1]12([CH2:15][C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.Cl.O([NH2:20])C.N1C=CC=CC=1>CO.Cl>[C:1]12([CH2:15][CH:14]([NH2:20])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2
Reactant: O=C1CC2(CCCCC2)Oc2ccccc21
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: NC1CC2(CCCCC2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Example 1A (3.022 g, 13.99 mmol) in methanol (50 mL) was added methoxylamine hydrochloride (1.17 g, 14.0 mmol) and pyridine (5.7 mL, 70.5 mmol). The mixture was stirred overnight at room temperature and was then evaporated in vacuo. The residue was partitioned between ethyl acetate and H2O, and the organic layer was dried over Na2SO4, filtered and evaporated in vacuo. The residue thus obtained was dissolved in methanol (50 mL) and was hydrogenated (balloon) over 10% Pd-on-carbon in the presence of 4 drops of conc. HCl overnight at room temperature. After this time, the catalyst was filtered off (Celite), and the filtrate was evaporated in vacuo. The residue was taken up in ether (50 mL) and was extracted with 1N HCl (3×20 mL). These acidic extracts were then basified to pH 10 with 2N NaOH and were extracted with ethyl acetate (3×20 mL). The organic extracts were dried over Na2SO4, filtered and evaporated in vacuo to yield the title compound as a yellow oil, 880 mg (29%). 1H NMR (300 MHz, DMSO-d6) δ ppm 7.52 (m, 1H), 7.06 (m, 1H), 6.82 (td; J=7.4, 1.3 Hz; 1H), 6.69 (dd; J=8.1, 1.3 Hz; 1H), 3.83 (dd; J=11.1, 6.3 Hz; 1H), 2.08 (dd; J=13.5, 6.3 Hz; 1H), 1.90 (m, 1H), 1.74 (m, 2H), 1.31-1.57 (m, 8H); MS (ESI) m/z 218 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[NH:21]1[CH2:25][CH2:24][C@@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.Cl>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:21]3[CH2:25][CH2:24][C@@H:23]([NH2:26])[CH2:22]3)=[O:18])=[CH:19][CH:20]=2)=[N:2]1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CO
Product: N[C@@H]1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)C1
Temperature: 60 °C
Yield: 57.4 %

Procedure:
The product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (700 mg, 2.65 mmol) obtained in Step 6 of Example 1, tert-butyl (R)-(pyrrolidin-3-yl)carbamate (740 mg, 3.98 mmol), 1-hydroxybenzotriazole monohydrate (470 mg, 3.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (710 mg, 3.72 mmol) and N-methylmorpholine (0.608 mL, 5.32 mmol) in a similar manner to Example 5, was dissolved in methanol (1.5 mL), and the solution was added with a 4 mol/L solution of hydrogen chloride in methanol (1.50 mL), followed by heating under reflux at 60° C. for 60 minutes. The reaction mixture was concentrated under reduced pressure, the residue was added with saturated aqueous potassium carbonate solution and ethyl acetate and was extracted. The crude product was crystallized from ethyl acetate to obtain Compound 158 (506 mg, 58%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[N:27]([CH2:28][CH3:29])[N:26]=[CH:25][CH:24]=2)=[C:12]([F:30])[C:11]=1[F:31])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH2:28]([N:27]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][N:33]=3)(=[O:8])=[O:9])=[C:11]([F:31])[C:12]=2[F:30])=[CH:24][CH:25]=[N:26]1)[CH3:29]
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)c(F)c1F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1nccc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 83.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-2,3-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (0.060 g, 0.09 mmol) prepared in Example 41a, triethylsilane (0.07 mL), trifluoroacetic acid (0.09 mL) and dichloromethane (0.9 mL), to yield the title compound (34.9 mg, 82%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:19]1[CH:29]=[N:28][C:22]2[NH:23][C:24](=[O:27])[O:25][CH2:26][C:21]=2[CH:20]=1.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH2:7][C:8]1[N:9]([CH3:17])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3](=[O:6])/[CH:4]=[CH:5]/[C:19]1[CH:29]=[N:28][C:22]2[NH:23][C:24](=[O:27])[O:25][CH2:26][C:21]=2[CH:20]=1
Reactant: O=C1Nc2ncc(Br)cc2CO1
Reactant: C=CC(=O)N(C)Cc1cc2ccccc2n1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)COC(=O)N2
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a stirred solution of N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (1.19 g, 5.2 mmole) in propionitrile (50 mL) was added 6-bromo-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]-1,3-oxazine (1.1 g, 4.9 mmole), DIEA (1.75 mL, 10 mmole), palladium(II) acetate (112 mg, 0.5 mmole), and tri-o-tolylphosphine (304 mg, 1.0 mmole). The reaction was purged with argon and heated at reflux for 16 hr, then was cooled to RT and concentrated under vacuum. The residue was taken up in CHCl3 and the solution was filtered through a pad of silica gel (3% methanol/CHCl3). The filtrate was concentrated and the residue was triturated with ethyl acetate, collected by suction filtration, and dried under vacuum gave the title compound (1.02 g, 55%) as an off-white solid: LCMS (ES) m/e 377 4 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:31][CH2:30]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(N2CCN(CCCc3cc(-c4ccccc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
106 mg (74%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.289 mmol), 1-(4-chlorophenyl)piperazine (78 mg, 0.289 mmol), DIPEA (76 mL, 0.434 mmol) and NaBH(OAc)3 (184 mg, 0.868 mmol).