Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Cl)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][O:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[CH:24][CH:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: c1ccc(COc2ccc(COc3ccc4ncccc4c3)cc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 86.8 %

Procedure:
To a solution of quinoline-6-ol (37 mg, 0.25 mmol), 1-benzyloxy-4-chloromethyl-benzene (70 mg, 0.30 mmol) in dimethylsulfoxide (2.5 mL) was added potassium tert-butoxide (43 mg, 0.38 mmol) under nitrogen atmosphere, and the solution was stirred for 13 hours at room temperature. This reaction solution was purified by thin layer silica gel chromatography (hexane:ethyl acetate=1:1), and the title compound (74 mg, 0.217 mmol, 86%) was obtained as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH:25]1(P(C2CCCCC2)C2CCCCC2)CCCC[CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:17]1[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:16]=1[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:7]=2)[C:2]([CH:25]=[CH2:26])=[CH:3][N:4]=1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)OC)ccc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 326.7 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (292 mg), 2,4,6-trivinylboroxin-pyridine complex (89 mg), palladium acetate (19 mg), tricyclohexylphosphine (45 mg), tripotassium phosphate (280 mg), toluene (7 mL), and water (0.5 mL) was heated under stirring in an oil bath at 100° C. for 12 hours. The reaction mixture was returned to room temperature, diluted with water and ethyl acetate, and then the insoluble materials were separated by filtration. The filtrate was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 1-(2,4,6-trifluorophenyl)-4-vinylisoquinoline-7-carboxylate (180 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]4[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=4)=[O:20])[CH:17]=3)=[N:7][N:6]2[CH:29]=1.[CH:30]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH:30]1([C:34]([NH:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:13]=[CH:14][C:15]([CH3:28])=[C:16]([NH:18][C:19]([C:21]5[N:25]([CH3:26])[N:24]=[C:23]([CH3:27])[CH:22]=5)=[O:20])[CH:17]=4)=[N:7][N:6]3[CH:29]=2)=[O:35])[CH2:33][CH2:32][CH2:31]1
Reactant: O=C(Cl)C1CCC1
Reactant: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(N)cn4n3)ccc2C)n(C)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CCC5)cn4n3)ccc2C)n(C)n1
Yield: 77.1 %

Procedure:
In the same manner as in Example 264 and using N-{5-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]-2-methylphenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide hydrochloride (200 mg, 0.48 mmol), cyclobutanecarbonyl chloride (86 mg, 0.73 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (170 mg, 76%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:57][CH:58]1[CH2:64][CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]1>>[NH:61]1[CH2:62][CH2:63][CH2:64][CH:58]([NH:57][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:59][CH2:60]1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and tert-butyl 4-aminoazepane-1-carboxylate, where Boc was removed using TFA in DCM. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41-1.65 (m, 4H) 1.65-1.83 (m, 3H) 1.83-1.99 (m, 4H) 2.07 (m., 2H) 3.16 (s, 3H) 3.32 (s, 3H) 3.93 (s, 3H) 4.07 (t, J=13.8 Hz, 3H) 4.78 (t, J=8.1 Hz, 1H) 7.41-7.54 (m, 2H) 8.14-8.29 (m, 2H) 8.31 (d, J=7.6 Hz, 1H) 8.55 (br. s., 2H). [M+H] calc'd for C27H35F2N7O3, 544. found 544.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH:4]([NH2:19])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:8]=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.[Cl:29][C:30]1[S:34][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:32][CH:31]=1>C(Cl)Cl.CCOC(C)=O>[Cl:29][C:30]1[S:34][C:33]([S:35]([NH:19][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[N:8]=[CH:7][CH:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:20][CH3:21])(=[O:37])=[O:36])=[CH:32][CH:31]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ccnn1Cc1ccc(OC)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ccnn1Cc1ccc(OC)cc1
Yield: 51 %

Procedure:
To {2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}amine (0.500 g, 1.74 mmol) in CH2Cl2 (15 mL) was added triethylamine (0.29 mL, 2.1 mmol) and 5-chlorothiophene-2-sulfonyl chloride (0.450 g, 2.09 mmol). After 2 days the reaction mixture was diluted with EtOAc (30 mL), washed with 1 N HCl (30 mL), dried (Na2SO4) and concentrated. Column chromatography (EtOAc/hexane, 3:7, then 1:1) provided 5-chloro-N-{2-ethyl-1-[1-(4-methoxybenzyl)-1H-pyrazol-5-yl]butyl}thiophene-2-sulfonamide (0.415 g, 51%) as an oil.
Reaction SMILES: [OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[OH:1][C@@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[CH2:3]1
Reactant: C1CCNC1
Reactant: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Product: C[C@H]1CCC[C@@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCCC4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-Dichloro-quinoline-5-carboxylic acid ((1S,3S)-1-hydroxy-3-methyl-cyclohexyl methyl)-amide and pyrrolidine. 1H NMR (400 MHz, DMSO-d6): δ 8.50 (t, J=6.01 Hz, 1H), 7.80 (d, J=9.22 Hz, 1H), 7.47-7.54 (m, 2H), 6.96 (d, J=9.21 Hz, 1H), 4.16 (s, 1H), 3.51-3.53 (m, 4H), 3.26-3.28 (m, 2H), 1.97-1.98 (m, 4H), 1.71-1.73 (m, 1H), 1.45-1.61 (m, 6H), 1.00-1.07 (m, 1H), 0.83-0.84 (m, 3H), 0.73-0.79 (m, 1H). m/z: 402.2 [M+H]+
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](N)=[N:6][CH:7]=1.N([O-])=O.[Na+].[OH-].[NH4+].O.[ClH:19]>[Cu]Cl>[Cl:19][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]([I:1])=[CH:7][N:6]=1
Reactant: Cl
Reactant: Nc1ncc(I)cc1[N+](=O)[O-]
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [NH4+]
Solvent: O
Product: O=[N+]([O-])c1cc(I)cnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a solution of 5-iodo-3-nitropyridin-2-amine (1.3 g, 4.9 mmol) in concentrated HCl at 0° C. was added sodium nitrite (6.73 g, 97.13 mmol, 20 eq.) stepwise followed by the addition of copper(I) chloride (0.5 g, 4.9 mmol, 1 eq.) and the mixture was stirred at RT for 12 h. The mixture was then poured in to a mixture of ammonium hydroxide and water (1:1) and extracted with ethylacetate (3×150 ml). The combined organic layer was washed with water, aqueous sodium thiosulfate, brine and dried over sodium sulphate. The solvent was distilled off to afford the product in 43% yield (0.6 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)=[CH:8][C:7]([OH:18])=[CH:6][CH:5]=2.[CH2:19]([O:21][C:22](=[O:27])[C:23](Br)([CH3:25])[CH3:24])[CH3:20]>>[CH2:19]([O:21][C:22](=[O:27])[C:23]([CH3:25])([O:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2]([CH3:1])=[C:10]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=1)[CH3:24])[CH3:20]
Reactant: Cc1cccc(-c2c(C)[nH]c3ccc(O)cc23)c1
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1ccc2[nH]c(C)c(-c3cccc(C)c3)c2c1

Procedure:
The above compound was prepared from 2-methyl-3-(3-methyl-phenyl)-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8](=[O:10])[CH3:9].[Cr](Cl)([O-])(=O)=[O:13].[NH+]1C=CC=CC=1.N1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:13])[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)Cc1ccccc1C
Reactant: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)C(=O)c1ccccc1C
Yield: 15.4 %

Procedure:
A mixture of 7 g (47.23 mmol) 1-o-Tolyl-propan-2-one, 30.5 g (0.141 mol) pyridinium chlorochromate and 11.2 g (0.141 mol) pyridine in 200 ml DCM was heated to reflux for 16 h. The mixture was filtered through a pad of silica and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica eluting with ethyl acetate/n-hexane 1:4. The product fractions were evaporated to yield 1.178 g (15%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:43]1([O:52]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:19][N:18]=[C:17]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[N:16]=2)[CH2:11][C:12]([NH:43][OH:52])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCCC2)no1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[3-(1-pyrrolidinylcarbonyl)-1,2,4-oxadiazol-5-yl]hexanoic acid (Preparation 13) (288 mg, 0.79 mmol) and N,N-diisopropylethylamine (138 μl, 0.79 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (452 mg, 1.19 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Further N,N-diisopropylethylamine (552 μl, 3.16 mmol) was then added, followed by the hydroxylamine hydrochloride (165 mg, 2.38 mmol) and the mixture stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue wasa partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol (98:2) to afford the title compound as a foam (126 mg).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3][C:2]([F:11])([F:12])[F:1])(=[O:24])=[O:23])=[CH:20][CH:21]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1OC(F)(F)F
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ccccc2OC(F)(F)F)cc1
Temperature: 85 °C
Yield: 76.6 %

Procedure:
To a pre-cooled solution of 2-(trifluoromethoxy)aniline (1.8 g, 10.16 mmol) in pyridine (20 ml) was added 4-nitrobenzene-1-sulfonyl chloride (2.252 g, 10.16 mmol) in 5-10 mL of pyridine at 0° C. slowly. The reaction mixture was stirred and heated to 85° C. for 3 h, then cooled down to 45° C. and stirred at the same temperature over weekend. The solvent was removed under reduced pressure. The residue was diluted with methylene chloride and washed with 1N HCl (×2), water (×2), and brine. The organic layer was separated, dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 2.82 g of title product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:5]1[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: NCc1ccc(F)cc1F
Product: Fc1ccc(Cn2cccc2)c(F)c1

Procedure:
8.6 g (0.060 mol) of 2,4-difluorobenzylamine are heated in an autoclave with 8 g (0.060 mol) of 2,5-dimethoxytetrahydrofuran for 2 hours at 250° C. The reaction mixture is cooled and then purified by vacuum distillation. 9.2 g (79% of theory) of a colourless oil which boils at 110°-114° C. at 16 mbar are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:32])[CH:30]=[CH2:31])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:24]([O:28][C:29](=[O:32])/[CH:30]=[CH:31]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:23])[NH:19][S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (2.0 g, 4.49 mmol), Pd(OAc)2 (100 mg) and acrylic acid t-butyl ester (0.78 mL, 5.8 mmol) in acetonitrile (15 mL) in a pressure vessel is added triethylamine (3.13, 22.5 mmol) and the mixture is stirred at 100° C. for 6 h. The solution is filtered through Celite, washed with acetonitrile and concentrated to give the title compound. This is used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.C(O)(O)=O>CC#N.O>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[C:11]([CH:12]=[O:13])=[CH:10][C:9]3[C:4](=[C:5]([O:14][CH3:15])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: COc1cccc2cc(C=O)c(Cl)nc12
Agent: O=C(O)O
Solvent: CC#N
Solvent: O
Product: COc1cccc2cc(C=O)c(-c3cccc(F)c3)nc12
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-8-methoxyquinoline-3-carbaldehyde (1.8583 g, 8.384 mmol), 3-fluorobenzeneboronic acid (1.290 g, 9.223 mmol), tetrakis(tri-phenylphosphine)palladium (0.4844 g, 0.4192 mmol), and sodium carbonate anhydrous (4.443 g, 41.92 mmol) in 76 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 3 h, the mixture was cooled to room temperature and partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was washed with brine (100 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give an orange solid. The orange solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 25 min as eluent to give 2-(3-fluorophenyl)-8-methoxyquinoline-3-carbaldehyde as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (1 H, s), 8.94 (1 H, s), 7.80 (1 H, dd, J=8.2, 1.2 Hz), 7.66 (1 H, t, J=8.0 Hz), 7.53-7.64 (2 H, m), 7.47-7.53 (1 H, m), 7.36-7.44 (2 H, m), 4.00 (3 H, s); LC-MS (ESI) m/z 282.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C=O)C.C(OCC)(=O)C>[F:28][C:2]([F:27])([F:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1C(F)(F)F
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
40% Methanolic Triton B (0.18 mL, 0.4 mM) was added to a solution of the 9-[(2-trifluoromethylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (120 mg, 0.31 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (98.5 mg, 0.62 mM) was added and the resultant mixture stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate, washed four times with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate/THF) to afford 95 mg (67%) of the {9-[(2-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ7.7 (d, 1H, J=8 Hz), 7.5-7.2 (m, 6H), 6.95 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.45 (d, 1H, J=8 Hz), 6.3 (br s, 1H), 6.1 (br s, 1H), 5.7 (s, 2H), 4.9 (s, 2H), and 3.9 (s, 3H). IR (CHCl3, cm−1) 1763 and 1674. MS (ES) m/e 457.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC(O[CH:25](N(C)C)[N:26]([CH3:28])[CH3:27])(C)C.O.CCCC(C)C>C(OC)(C)(C)C>[C:1]([O:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:17])/[CH:16]=[CH:25]/[N:26]([CH3:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[O:18][CH3:19])(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: COc1ccc(C(C)=O)cc1COC(=O)C(C)(C)C
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CCCC(C)C
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(C(=O)/C=C/N(C)C)cc1COC(=O)C(C)(C)C
Temperature: 54 °C
Yield: 79.6 %

Procedure:
5-acetyl-2-methoxybenzyl pivalate (66.24 g, 251.7 mmol) was added to Bredereck's reagent (175.5 g, 1000.7 mmol) held under a nitrogen atmosphere. The resulting solution was heated at 54° C. for 240 minutes. Water (600 mL) was then added and the mixture allowed to stir for an hour. Methyl tert-butyl ether was then added (500 ml) and the mixture stirred and allowed to settle. The upper organic layer was separated off and retained. Further methyl-tert-butyl ether was then added (500 ml) and the mixture stirred and allowed to settle. The upper organic layer was separated off and combined with the original upper organic layer. The combined organic layers were washed twice with water (2×300 mL), discarding the two lower aqueous washes. Solvent (850 mL) is removed from the reaction by atmospheric distillation and iso-hexane (100 mL) added. The clear solution was allowed to cool to 20° C. whereby a white, crystalline solid was obtained. Further iso-hexane (50 mL) was added and the solid filtered off at around 20° C. The solid was washed twice with fresh iso-hexane (2×100 mL) and dried to constant weight to afford 64 g of the desired 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-methoxybenzyl pivalate (2).
Reaction SMILES: [CH3:1][C:2]1([C:7]([OH:9])=O)[CH2:6][S:5][S:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl.CCCCCCC.CCOC(C)=O.CN(C=O)C>[CH2:16]([N:18]([CH2:19][CH3:20])[C:7]([C:2]1([CH3:1])[CH2:6][S:5][S:4][CH2:3]1)=[O:9])[CH3:17]
Reactant: CC1(C(=O)O)CSSC1
Reactant: CCNCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)C1(C)CSSC1
Temperature: 0 °C

Procedure:
5 ml of anhydrous dichloromethane and 0.1 ml of anhydrous DMF are added to 2.26 mmol of Compound 1. The mixture is cooled to 0° C. and 2.7 mmol of oxalyl chloride are added. The mixture is stirred at 20° C. and then added at 0° C. to a mixture of 2.26 mmol of diethylamine, 5 ml of anhydrous dichloromethane and 6.8 mmol of diisopropylethylamine. The reaction medium is stirred for 3 hours at 20° C. When the reaction is complete, the medium is diluted in 50 ml of dichloromethane and then washed with 2×30 ml of water and 1×50 ml of saturated NH4Cl solution, dried over Na2SO4 and evaporated to dryness on a rotavapor. After flash chromatography (eluent: heptane/EtOAc), Compound 18 is isolated in the form of a yellow oil (48% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:46]1N=N[C:48]2C=CC=[CH:52][C:47]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(C)C>CN(C=O)C>[CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:46][CH:47]([CH3:52])[CH3:48])=[O:32])=[CH:29][CH:28]=2)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2ccc(C(=O)O)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2ccc(C(=O)NC(C)C)cc2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
To the compound 4-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (28 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and isopropylamine (7.03 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.1 mg, 53%). LC-MS m/z 549 (M+H)+.