Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][NH:5][S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C.O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:20][CH3:21])[S:6]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:19])[CH:15]=2)[CH:10]=1)(=[O:8])=[O:7])[CH3:30]
Reactant: COC(CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1)OC
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)CN(CC(OC)OC)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(2,2-Dimethoxyethyl)-6-chloro-2-naphthalenesulfonamide was dissolved in DMF (100 ml) and combined with sodium hydride (1.16 g, in oil), cooled to 0° C., treated dropwise with a solution of ethyl bromoacetate (4.843 g) in tetrahydrofuran (15 ml) and then stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain N-(2,2-dimethoxyethyl)-N-(6-chloro-2-naphthalenesulfonyl)glycine ethyl ester as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([F:40])[C:35]=2[CH3:41])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:42]([OH:48])([C:44]([F:47])([F:46])[F:45])=[O:43]>C(Cl)Cl>[F:40][C:36]1[C:35]([CH3:41])=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2.[F:45][C:44]([F:47])([F:46])[C:42]([OH:48])=[O:43].[F:40][C:36]1[C:35]([CH3:41])=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][C:17]1[N:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:19]2[C:24]([C:16]=1[C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2
Reactant: COc1ccc2c(c1)c(C(=O)N1CCN(C(=O)OC(C)(C)C)CC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1)c(C(=O)N1CCNCC1)c(Cc1cccc(F)c1C)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound of step 6 (72.0 mg, 129 μmol) in DCM (8 ml) was added TFA (2 ml), and the reaction mixture was stirred at room temperature for 2 h. The solvents were evaporated. The solid was dissolved in MOH and water and lyophilized to give the title compound in the form of the [2-(3-fluoro-2-methyl-benzyl)-5-methoxy-1-phenyl-1H-indol-3-yl]-piperazin-1-yl-methanone trifluoroacetic acid salt as a white solid. Yield: 70.0 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]1([C:22]2[O:23][CH:24]=[N:25][N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: c1ccc(-c2nnco2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 19, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-[1,3,4]oxadiazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:11]2[N:12]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:13]=[C:14]([CH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[N:15]=2)[OH:10])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([Sn](C)(C)C)=[N:33][CH:34]=1>COCCOC.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:20][C:17]([CH3:21])([CH2:18][CH3:19])[CH2:16][C:14]1[N:15]=[C:11]([CH:9]([OH:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)=[CH:3][CH:4]=2)[N:12]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:13]=1
Reactant: C[Sn](C)(C)c1ccc(F)cn1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(Br)cc2)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
Palladium tetrakis(triphenylphosphine) (16 mg, 0.01 mmol) was added to a degassed, ambient temperature solution of 2-[2-(4-bromophenyl)-1-hydroxyethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (65 mg, 0.14 mmol) and 5-fluoro-2-(trimethylstannyl)pyridine (solution from the previous step containing 1.7 mmol) in 1,2-dimethoxyethane (10 mL). After stirring at 95° C. for 8 h, the reaction mixture was diluted with ethyl acetate and washed with water, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-hydroxyethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[N:15]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:13]=[C:12]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[C:9]=1[C:10]#[N:11].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O.C(OCC)(=O)C>[CH2:28]([O:27][C:24]1[CH:23]=[CH:22][C:21]([C:12]2[C:9]([C:10]#[N:11])=[C:8]([Cl:7])[N:15]=[C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)[CH:13]=2)=[CH:26][CH:25]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(-c2ccc(O)cc2)cc(C2CCCC2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)cc(C2CCCC2)nc1Cl
Reaction time: 16 h
Yield: 85.7 %

Procedure:
Cesium carbonate (39.3 mg, 0.120 mmol) was added to a solution of 2-chloro-6-cyclopentyl-4-(4-hydroxyphenyl)nicotinonitrile (18 mg, 0.060 mmol) and benzyl bromide (0.014 mL, 0.120 mmol) in DMSO (1 mL). After 16 h at room temperature, the mixture was diluted with ethyl acetate (80 mL), washed with saturated sodium bicarbonate (5 mL), brine (5 mL), dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-15% ethyl acetate in hexanes, gave 4-(4-(benzyloxy)phenyl)-2-chloro-6-cyclopentylnicotinonitrile as a white solid (20 mg, 85% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.50-7.74 (2H, m), 7.30-7.48 (5H, m), 7.19 (1H, s), 7.00-7.15 (2H, m), 5.13 (2H, s), 3.10-3.34 (1H, m), 2.00-2.32 (2H, m), 1.64-1.95 (6H, m), MS (ES+) m/z: 389 (M+H); LC retention time: 4.431 min (analytical HPLC Method A).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[O:16]([C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: N#Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1Oc1ccccc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
To a suspension of 2-fluorobenzonitrile (10.0 g, 82.6 mmol) and phenol (7.7 g, 5.1 mmol) in DMF (80 mL) was added K2CO3 (22.8 g, 165 mmol) at rt. The reaction was stirred at 130° C. for 10 h. The reaction mixture was diluted with water, extracted with EtAOAc (100 mL×3), washed with brine (100 mL), dried (Na2SO4), and concentrated to give 15.0 g, (93%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 6.85 (1H, d, J=8.4 Hz), 7.07-7.14 (3H, m), 7.22 (1H, t, J=7.2 Hz), 7.40 (2H, t, J=8.0 Hz), 7.47 (1H, td, J=2.0, 8.4 Hz), 7.65 (1H, dd, J=1.2, 8.0 Hz).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=O)=[CH:4][C:3]=1[CH2:12][O:13]C.O[N:16]=[C:17]([C:19]1[CH:20]=[N:21][C:22]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:23][CH:24]=1)[NH2:18]>>[CH3:9][O:8][CH2:6][C:5]1[CH:4]=[C:3]([C:12]2[O:13][N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:21][CH:20]=3)[N:16]=2)[CH:2]=[CH:11][C:10]=1[C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[CH3:12]
Reactant: NC(=NO)c1ccc(N2CCCC2)nc1
Reactant: COCc1cc(C(=O)OC)ccc1Br
Product: COCc1cc(-c2nc(-c3ccc(N4CCCC4)nc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described in Method B starting from Intermediate A1 and N′-hydroxy-6-pyrrolidin-1-ylpyridine-3-carboximidamide (UkrOrgSynthesis, BBV-073346). After purification by flash chromatography (silica, EtOAc/cHex) followed by a crystallization from a mixture of MTBE and heptane, the title compound was obtained as an off-white powder. HPLC (Method A), Rt: 4.1 min (purity: 99%). UPLC/MS, M+(ESI): 417.1, M−(ESI): 415.2. Elemental analysis: [C26H26N4O2-0.2H20] calculated: C, 72.60%; H, 6.19%; N, 13.03%. found: C, 72.68%; H, 6.45%; N, 13.05%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14](I)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[C:38]([N:42]3[CH2:47][CH2:46][CH:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:44][CH2:43]3)[CH:39]=[N:40][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]2[C:14]([C:36]3[CH:37]=[C:38]([N:42]4[CH2:43][CH2:44][CH:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:53])([CH3:52])[CH3:54])[CH2:46][CH2:47]4)[CH:39]=[N:40][CH:41]=3)=[CH:15][N:16]([S:17]([C:20]3[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[C:11]2=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccccc4F)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(N4CCC(NC(=O)OC(C)(C)C)CC4)c3)c3nc(-c4ccccc4F)ccc32)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
A suspension of 5-(2-fluorophenyl)-3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridine (155 mg, 0.315 mmol), tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (222 mg, 0.551 mmol) Pd(PPh3)4 (36.4 mg, 0.031 mmol, Strem) and Na2CO3, 2.0 M (0.315 mL, 0.630 mmol) in Toluene (2 mL) and EtOH (2 mL) was capped, degassed and backfilled with argon. The reaction was heated to 100° C. After 18 h, the reaction was cooled to 23° C., diluted with EtOAc (75 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 0-4% MeOH/DCM), affording tert-butyl 1-(5-(5-(2-fluorophenyl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (134 mg, 66%). MS (ESI, pos. ion) m/z: 642.4 (M+1).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.CCN(CC)CC.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:6][CH:1]2[CH2:5][CH:4]=[CH:3][CH2:2]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: OC1CC=CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OC1CC=CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
To a solution of 3-cyclopentene-1-ol (7.0 g, 83.0 mmol) and Et3N (14.5 g, 143.0 mmol) in CH2Cl2 (200 mL) was added 4-nitrobenzoyl chloride (18.5 g, 100.0 mmol) as solid in several portions over a period of 30 min. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off and the filtrate was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1; column 40M; TLC method: n-hexane/ethyl acetate 9/1; Rf=0.50), affording the title product (15.6 g, yield 81%): 1H NMR (500 MHz, CDCl3) δ 8.28 (d, J=8.9 Hz, 2H), 8.20 (d, J=8.9 Hz, 2H), 5.81 (m, 2H), 5.69 (m, 1H), 2.95 (m, 2H), 2.61 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:3]1.[Br:23]Br.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: BrBr
Reactant: Cn1cc(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Br)c(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
7-methyl-5-(pyridin-3-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.28 g, 0.908 mmol) was dissolved in DMF (8 ml). The solution was cooled down to 0° C. Bromine (0.056 ml, 1.09 mmol) was added in dropwise. After 30 min, the reaction mixture was diluted with a aqueous mixture (3:1:4 water, saturated sodium bicarbonate solution and 20% w/w sodium thiosulfate solution, 80 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phase was washed with water (4×60 ml), brine and concentrated to give title compound (0.13 g, 37%). LCMS RT=0.81 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][CH2:26][O:27][CH2:28][CH:29]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 282.3 ({37Cl}[M+H−Me2C═CH2]+, 49%), 280.3 ({35Cl}[M+H−Me2C═CH2]+, 100%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19](=[CH:11][C:8]3[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=3[CH3:13])[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Reactant: O=C1Cc2ccc(O)cc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(CCC(=O)O)c[nH]c1C=C1C(=O)Nc2cc(O)ccc21

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (543 mg), 450 mg 6-hydroxy-2-oxindole, and 450 μL piperidine in 10 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 2 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:27]=[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:38][CH2:39][C:40]([NH:42][NH2:43])=[O:41])[CH:34]=2)[NH:29]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:43][NH:42][C:40](=[O:41])[CH2:39][O:38][C:33]2[CH:34]=[C:35]3[C:30](=[CH:31][CH:32]=2)[NH:29][C:28](=[O:27])[CH:37]=[CH:36]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NNC(=O)COc1ccc2[nH]c(=O)ccc2c1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(COc1ccc2[nH]c(=O)ccc2c1)NNC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a stirred solution of 2-(3,4-dichlorophenyl)acetic acid (0.440 g, 2.144 mmol) in DMF (15 mL), EDC (0.616 g, 3.22 mmol) and HOBT (0.328 g, 2.144 mmol) were added. The reaction mixture was stirred at room temperature for 10 min. To this suspension was added 2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetohydrazide (0.5 g, 2.144 mmol) and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated and ice cold water was added and stirred for 10 min. The solid which separated was filtered, washed with water, and dried to afford crude 2-(3,4-dichlorophenyl)-N′-(2-((2-oxo-1,2-dihydroquinolin-6-yl)oxy)acetyl)acetohydrazide as a brown solid (0.7 g, 78%). LCMS: RT 1.581 min. LCMS (ES-API), m/z 420.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3F)[N:10]=2)=[CH:5][CH:4]=1.[CH3:48][O:49][C:50]1[N:55]=[CH:54][C:53]([NH2:56])=[CH:52][N:51]=1.O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][C:6]([CH2:7][N:8]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[CH:19]=[N:20][C:21]=3[NH:56][C:53]3[CH:52]=[N:51][C:50]([O:49][CH3:48])=[N:55][CH:54]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Reactant: COc1ncc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3Nc3cnc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
A solution of tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (0.500 g, 0.777 mmol) and 2-methoxypyrimidin-5-amine (0.117 g, 0.932 mmol) (ACES PHARMA) in tetrahydrofuran (10 mL, 123 mmol) was stirred at 0° C. and treated dropwise via syringe with lithium bis(trimethylsilyl)amide (1.0 M solution in tetrahydrofuran; 2.330 mL, 2.330 mmol). The solution was stirred at 0° C. for 1 h. The solution was quenched with water (10 mL) and diluted with water (15 mL) and EtOAc (100 mL). The organic layer was separated and dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(2-methoxypyrimidin-5-ylamino)pyridin-3-yl)methyl)piperazine-1-carboxylate (0.420 mg, 0.561 mmol, 72% yield). m/z (ESI, +ve ion) 749.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.[O-:20][C:21]#[N:22].[K+].CC(O)=O>O>[F:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[N:4][C:3]=1[C:15]1[CH:16]=[N:17][N:18]([C:21]([NH2:22])=[O:20])[CH:19]=1
Reactant: N#C[O-]
Reactant: Cc1cccc(Nc2nc(-c3cn[nH]c3)c(F)s2)n1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc(Nc2nc(-c3cnn(C(N)=O)c3)c(F)s2)n1
Yield: 2.5 %

Procedure:
According to Scheme 19: A solution of N-(5-fluoro-4-(1H-pyrazol-4-yl)thiazol-2-yl)-6-methylpyridin-2-amine (1.22 mmol, 337 mg), potassium cyanate (1.47 mmol, 119 mg), AcOH (5 mL) and water (5 mL) was stirred for 2.5 hours at room temperature. The reaction mixture was quenched with water (100 mL) and the precipitate was filtered. The resulting crude product was purified by flash chromatography over silica gel using DCM/EDA (80:20; EDA: DCM/EtOH/NH3 90:9:1) as eluent to yield 4-(5-fluoro-2-(6-methylpyridin-2-ylamino)thiazol-4-yl)-1H-pyrazole-1-carboxamide (31 μmol, 10 mg, 3%) as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].C(O)(=O)C.[BrH:20].Br.[NH+]1C=CC=CC=1>O>[Br:20][CH2:2][C:1]([C:4]1[S:8][C:7]([NH:9][CH3:10])=[N:6][C:5]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:3]
Reactant: Br
Reactant: CCOC(=O)c1nc(NC)sc1C(C)=O
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nc(NC)sc1C(=O)CBr
Reaction time: 2.5 h

Procedure:
To a mixture of ethyl 5-acetyl-2-methylamino-4-thiazolecarboxylate (7.1 g), 30% acetic acid solution of hydrogen bromide (10 ml) and acetic acid (50 ml) was added pyridinium hydrobromide perbromide (9.9 g) at ambient temperature and stirred for 2.5 hours. The reaction mixture was poured into water (300 ml) and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and water and the resultant mixture was adjusted to pH 7.0 with 20% aqueous potassium carbonate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with ethyl ether to give ethyl 5-(2-bromoacetyl)-2-methylamino-4-thiazolecarboxylate (6.6 g). mp 130°-131.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (95 mg, 0.348 mmol), 2,5-dimorpholinoaniline (92 mg, 0.348 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.348 mmol) in MeOH (2.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-8-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72 (1H, dd, J=4.7, 1.6 Hz), 7.87-8.00 (2H, m), 7.64-7.71 (1H, m), 7.31-7.45 (4H, m), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=7.4 Hz), 6.04 (1H, br. s.), 3.90 (4H, t, J=4.9 Hz), 3.68-3.79 (4H, m), 2.99-3.14 (4H, m), 2.86-2.98 (4H, m), 2.42 (3H, s). Mass Spectrum (ESI) m/e=500.2 (M+1).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15]([CH:16]=O)=[CH:14][CH:13]=[CH:12][N:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:15]2[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:23]1[CH3:32]
Reactant: O=Cc1cccnc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 1c using 2-benzenesulfonylpyridine-3-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[NH2:27][C:28]1[NH:29][CH:30]=[CH:31][N:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:27][C:28]2[NH:29][CH:30]=[CH:31][N:32]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: Nc1ncc[nH]1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ncc[nH]1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-aminoimidazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(1H-imidazol-2-yl)terephthalamide. MS (Q1) 452 (m)+.