Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=[NH:78])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[NH2:78][C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.05 g, 3.30 mmol), Pd2(dba)3 (8 mg, 0.00825 mmol), BINAP (15 mg, 0.0248 mmol) and benzophenone imine (0.662 mL, 3.95 mmol) were combined in a dry flask. The flask was charged with 40 mL of dry toluene, followed by sodium tert-butoxide (0.444 g, 4.62 mmol). Argon was bubbled through the solution for 5 minutes. The reaction solution was heated to 110° C. and stirred under argon. After 2.5 hours, the reaction was concentrated, 20 mL of THF and 1 mL of 6N hydrochloric acid were added and the resulting solution was stirred. After 2 hours, the solution was poured into 300 mL of ethyl acetate, 100 mL of saturated sodium bicarbonate and 200 μL of water. The organic layers were separated, dried with magnesium sulfate, filtered, concentrated, and purified by flash column chromatography (0-30% ethyl acetate/hexanes gradient) to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.77 (d, 1H); 8.55 (d, 1H); 7.58 (d, 1H); 7.44 (d, 1H); 7.18 (d, 1H); 7.14 (d, 1H); 7.01 (dd, 1H); 4.15 (s, 2H). LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1. Method B: 3-chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.1 g, 2.7 mmol) was dissolved in 8 mL methanol and 30 mL dichloromethane. Then 10 mL of trifluoroacetic acid was added and the solution was stirred at ambient temperature. After 1 hour, reaction was concentrated, dissolved in 500 mL of ethyl acetate and washed with 200 mL saturated sodium bicarbonate. The organic layer was separated, dried with magnesium sulfate, filtered, and purified by flash column chromatography (0-10% methanol/dichloromethane gradient) and reverse phase HPLC (20-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford title compound. LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257.0; found 257.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(F)cc2)OC1(C)C
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(F)cc4)cn23)cc1

Procedure:
The title compound, white solid (79 mg, 64%), MS (ISP) m/z=433.6 [(M+H)+], mp 226° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (intermediate O) (0.1 g, 0.285 mmol) and 1-(4-fluoro-phenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate A) (0.11 mg, 0.37 mmol).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]([CH3:28])[C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1.[H-].[Na+].[CH3:31]I>CN(C)C=O>[CH3:31][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C@H:10]1[CH2:15][CH2:14][C@H:13]([CH2:16][N:17]([CH3:28])[C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][CH2:11]1
Reactant: CN(C[C@H]1CC[C@H](c2nc3ccccc3[nH]2)CC1)C(=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C[C@H]1CC[C@H](c2nc3ccccc3n2C)CC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.2 g (0.019 mol) of benzyl [[trans-4-(2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate in 160 ml of dimethylformamide is treated at 15°-20° under argon with 0.023 mol of sodium hydride (1.0 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 2.3 ml (0.038 mol) of methyl iodide in 10 ml of dimethylformamide is added thereto at 15°-20° within 15 minutes and the mixture is stirred at room temperature for a further 3 hours. After concentration under reduced pressure the residue is partitioned between ice-water and ethyl acetate. The organic phase, dried over sodium sulphate, is evaporated and the solid residue is recrystallized from ethyl acetate/ether. There are obtained 5.9 g (79%) of benzyl [[trans-4-(1-methyl-2-benzimidazolyl)cyclohexyl]methyl]methylcarbamate, m.p. 141°-142°, as a colourless crystalline powder.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C:10]2[CH:9]=[C:8]([OH:21])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Br[CH2:23][CH:24]([F:28])[CH2:25][CH2:26]Br.C(N(CC)CC)C.O>C(#N)C.C(OC(=O)C)C>[Cl:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[Cl:19])[CH2:12][CH:11]1[C:10]2[CH:9]=[C:8]([OH:21])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[N:1]1[CH2:26][CH2:25][CH:24]([F:28])[CH2:23]1
Reactant: FC(CBr)CCBr
Reactant: NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Oc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N1CCC(F)C1)CC2
Yield: 39 %

Procedure:
7-Amino-8-(3,4-dichlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-ol (691 mg, 2.146 mmol, example 34), 2 eq of 1,4-dibromo-2-fluorobutane, and 3 eq of triethylamine were dissolved in acetonitrile (10 ml) and heated in the microwave for 2 h. Addition of water with ethylacetate, washing of the organic phase with saturated NaHCO3, NaCl, drying over Na2SO4 and flash chromatography (silica gel, CH2Cl2/MeOH 95:5) gave 8-(3,4-dichlorobenzyl)-7-(3-fluoropyrrolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-ol (330 mg, 39%). The ethylene sulfonamide side chain was added in analogy to examples 1, 7, 8 to give 1-cyclopropyl-N-[2-({8-(3,4-dichlorobenzyl)-7-[3-fluoropyrrolidin-1-yl]-5,6,7,8-tetrahydronaphthalen-2-yl}oxy)ethyl]methanesulfonamide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1>>[O:9]1[CH2:10][CH:11]=[C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:14]1
Reactant: C#Cc1ccccn1
Reactant: O=C1CCOCC1
Product: C(#Cc1ccccn1)C1=CCOCC1

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), tetrahydro-4H-pyran-4-one (6.0 mmol, 600 mg); yields 2-(3,6-dihydro-2H-pyran-4-ylethynyl)pyridine as a transparent oil (200 mg, 18% overall yield). 1H NMR (CDCl3, 300 MHz) Δ8.57 (m, 1H), 7.63 (m, 1H), 7.44 (m, 1H), 7.21 (m, 1H), 6.29 (m, 1H), 4.25 (m, 2H) 3.81 (m, 2H), 2.36 (m, 2H). MS (EI ionization) 185 (M+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2[CH2:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([Li:21])CCC>CCCCCC>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2([Li:21])[CH:12]=[CH:11][CH:10]=[CH:9]2)=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Reactant: FC(F)(F)c1ccc(CC2=CC=CC2)cc1
Solvent: CCCCCC
Product: [Li]C1(Cc2ccc(C(F)(F)F)cc2)C=CC=C1
Yield: 80 %

Procedure:
2.5 g of 4-trifluoromethylbenzylcyclopentadiene (10 mmoles) and 30 ml of hexane are charged, in an argon atmosphere, into a tailed test-tube equipped with magnetic stirring. The same procedure is then carried out as in paragraph 2 of example 1 above, using 4.5 ml of a 2.5 M solution of butyllithium in hexane. At the end, 2.1 g of the desired salt are obtained with a yield of 80%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.C([N-]C(C)C)(C)C.[Li+].[Cl:19]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>C1COCC1>[Cl:19][CH2:9][C:4]1[O:3][C:2]([CH3:10])([CH3:1])[O:7][C:6](=[O:8])[CH:5]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C=C(CCl)O1
Temperature: -25 °C
Yield: 81.9 %

Procedure:
A solution of 2,2,6-trimethyl-1,3-dioxin-4-one (16.0 g, 0.11 mol) in THF (50 ml) was added dropwise over 20 min to a solution of lithium diisopropylamide (75 ml, 2.0 M solution in heptane/THF/ethylbenzene, 0.15 mol) at the temperature of −78° C. During the addition, a fine yellow suspension formed. Subsequently, the enolate solution was stirred at −78° C. for another 1 h and then cannulated to a solution of hexachloroethane (39 g, 0.16 mol) in THF (200 ml) at −50° C. over 30 min. The resulting reaction mixture was then allowed to warm slowly to −25° C., and poured into ice-cold aqueous 10% hydrochloric acid (200 ml). The organic layer extracted with ether was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 15.9 g of yellow oil. The product was used without further purification. 1H NMR (CDCl3, ppm): δ 5.57 (s, 1H), 4.00 (s, 2H), 1.96 (s, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].[CH3:8][S:9](Cl)(=[O:11])=[O:10].O>N1C=CC=CC=1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][S:9]([CH3:8])(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CCCO1
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)OC[C@H]1CCCO1

Procedure:
To a solution of (S)-1-(tetrahydrofuran-2-yl)methanol (7.95 g) in pyridine (35 ml) was added, at −15° C., methanesulfonyl chloride (7.47 g), and the reaction was stirred at 0° C. for 5 hours. After the addition of water, the mixture was extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The product was thus obtained with the molecular weight of 180.22 (C6H12O4S); MS (ESI): 181 (M+H+). Analogously, methanesulfonic acid (R)-1-(tetrahydrofuran-2-yl)methyl ester was synthesized.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([OH:18])=O)=[N:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])=[CH:6][CH:7]=1.[NH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[N:26]1[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@H:28]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:27]1>>[NH2:1][C:2]1[C:3]([C:16]([NH:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[N:26]2[CH2:31][CH2:30][C@@H:29]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@H:28]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:27]2)=[O:18])=[N:4][C:5]([C:8]2[C:9]([F:15])=[CH:10][CH:11]=[CH:12][C:13]=2[F:14])=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2NC(=O)c2nc(-c3c(F)cccc3F)ccc2N)CC[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
3-amino-6-(2,6-difluorophenyl)picolinic acid and tert-butyl (3R,4R)-1-(3-aminopyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate were coupled following method 11 (example 249), to yield tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate after HPLC purification. Alternatively, tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)-piperidin-3-ylcarbamate could be obtained starting with tert-butyl (3R,4R)-1-(3-(3-amino-6-bromo-picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate and 2,6 difluorophenylboronic acid following the Suzuki procedure outlined in method 14. The TBDMS deprotection of tert-butyl (3R,4R)-1-(3-(3-amino-6-(2,6-difluorophenyl)picolinamido)pyridin-4-yl)-4-(tert-butyldimethylsilyloxy)piperidin-3-yl-carbamate was performed with 6N HCl, THF, methanol (1:2:1) at room temperature for 2 h. After volatile materials were removed, the crude material was stirred in 30% TFA in dichloromethane for 2 hours. After volatile materials were removed in vacuo, purification and lyophilization yielded 3-amino-N-(4-((3R,4R)-3-amino-4-hydroxy-piperidin-1-yl)pyridin-3-yl)-6-(2,6-difluorophenyl)picolinamide. HPLC. LCMS (m/z): 441.2 (MH+); LC Rt=2.03 min.
Reaction SMILES: [CH2:1]([N:8]([CH3:34])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][O:26]CC3C=CC=CC=3)[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([N:8]([CH3:34])[C:9]([CH:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][OH:26])[C:15]=2[CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccccc1)C(=O)C1CCCc2c1c1ccccc1n2CCO
Reaction time: 24 h
Yield: 19.9 %

Procedure:
To a solution of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid benzyl-methyl-amide (27) (246 mg, 0.5 mmol) in methanol (15 mL) was added a slurry of Pd/C (200 mg) in methanol (10 mL). The mixture was placed on the Parr hydrogenator and shaken for 24 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and concentrated in vacuo to afford 36 mg (20%) of 9-(2-hydroxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid benzyl-methyl-amide (28) as a green oil which was used in the next step without purification. The structure was confirmed by 1H NMR (CDCl3) δH 1.80-2.20 (4H, m), 2.70-3.00 (2H, m), 3.20-4.30 (10H, m), 6.90-7.50 (9H, m).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8]2)=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[C:18]=[O:19]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][CH2:13][NH:14][C:18]([NH:17][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=3)=[O:19])[CH2:8]2)=[CH:15][CH:16]=1
Reactant: NCCCN1CC(Oc2ccc(F)cc2)C1
Reactant: COc1cccc(N=C=O)c1
Solvent: C1COCCO1
Product: COc1cccc(NC(=O)NCCCN2CC(Oc3ccc(F)cc3)C2)c1

Procedure:
A solution of 3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propylamine (0.07 g, 0.31 mmol) and 1-isocyanato-3-methoxy-benzene (0.041 g, 0.31 mmol) in dioxane (15 ml) is heated to 100° C. for 3 hours. The reaction mixture is evaporated and the crude product purified by flash silica chromatography (elution with a 1:9 methanol/dichloromethane) to afford 1-{3-[3-(4-fluoro-phenoxy)-azetidin-1-yl]-propyl}-3-(3methoxy-phenyl)-urea. [MH]+ 374.0.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=O)C.[OH-].[NH4+:16]>C(O)C>[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)(=[O:3])[NH2:16]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1ccn2nccc12
Agent: [OH-]
Solvent: CCO
Product: NC(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (35 g) in ethanol (180 ml) was added 28% ammonium hydroxide solution (110 ml). The mixture was stirred at room temperature for two hours. The resultant precipitate was collected by filtration, washed with isopropyl ether and dried to give 1-carbamoylmethyl-1H-imidazo[1,2-b]pyrazole (18.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](O)=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:35])[CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:22][CH2:21]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(CCc3ccc(F)cc3)sc2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)c2nc(CCc3ccc(F)cc3)sc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.5 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-piperazin-1-yl-thiazolo[5,4-d]pyrimidine (50 mg, 0.14 mmol) and 4-chlorophenylacetic acid (0.21 mmol) in DMF (2 ml) was added TBTU (0.21 mmol) followed by diisopropylethylamine (0.21 mmol, 35 μL). The reaction was stirred at room temperature for 24 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (44 mg) which was characterized by its mass spectrum: MS m/z (%): 511 ([M+H]+, 100).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10]1>C1COCC1>[Br:8][C:13]1[NH:9][CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=1
Reactant: COC(=O)c1cc[nH]c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c(Br)c1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
NBS (Aldrich; 1.201 g, 6.75 mmol) was added in one portion to a solution of methyl 1H-pyrrole-3-carboxylate (Aldrich; 0.844 g, 6.75 mmol) in THF (10 mL), and the resulting solution was stirred at 23° C. for 1.5 h. THF was removed in vacuo, and the residue was taken up in DCM (50 mL) and washed with 10:1 water/sat. aq. NaHCO3 (50 mL). The organic layer was separated, and the aq. layer was extracted with DCM (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-50% EtOAc/hexanes) furnished methyl 5-bromo-1H-pyrrole-3-carboxylate (924.2 mg, 4.53 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.41 (1H, br. s.), 7.36 (1H, dd, J=2.9, 1.8 Hz), 6.60 (1H, dd, J=2.5, 1.8 Hz), 3.81 (3H, s). m/z (ESI, +ve) 203.9/205.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:8]=[C:9]([C:24]([OH:26])=O)[C:10](=[CH:14][C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[CH:14]=[C:10]3[C:11](=[O:13])[O:12][C:24](=[O:26])[C:9]3=[CH:8][C:7]=2[NH:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1OC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
A steady stream of argon is passed through a suspension of 4.49 g (11.68 mmol) of 4,5-bis(4-fluoroanilino)phthalic acid in 75 ml of toluene and 3.32 ml (35.12 mmol, 3 eq) of acetic anhydride is added. The reaction mixture is heated to 60°-65° for 90 minutes with vigorous stirring. The reaction mixture is cooled to 10° for 15 minutes, theyellow orange crystals are filtered off and washed with toluene/hexane to yield the title compound in the form of yellow orange crystals, FAB-MS: 367 [M+ +H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:12][CH3:13].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:11]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[CH3:31])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:12][CH3:13]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75.9 %

Procedure:
Oxalyl chloride (4.99 mL, 57.28 mmol) was added to a mixture of methyl sulfoxide (DMSO) (5.54 g, 71.46 mmol) in dichloromethane (50 mL) at −78° C. and stirred for 5 minutes. 5-(2-Propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-ol (14.2 g, 47.74 mmol) was added dropwise, followed by the addition of triethylamine (19.96 mL, 143.2 mmol). The reaction was allowed to warm to ambient temperature and the reaction was stirred for 2 hours. Saturated aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, filtered over magnesium sulfate, and concentrated under reduced pressure to afford 10.7 g of 5-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one as a brown oil.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[NH:14][CH:13]=[C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24](N)[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH:42][S:43]([N:46]2CCOC2=O)(=[O:45])=[O:44])[CH2:41][CH2:40]1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:38]=[CH:37][C:18]3[N:19]([C:22]4[CH:23]=[C:24]([CH:40]5[CH:39]([NH:42][S:43](=[O:44])(=[O:45])[NH2:46])[CH2:41]5)[CH:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=5[F:35])[CH:27]=4)[CH:20]=[N:21][C:17]=3[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1S(=O)(=O)NC1CC1
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(C4=CNC(OCc5ccccc5)C=C4)ccc32)c1
Solvent: c1ccncc1
Product: NS(=O)(=O)NC1CC1c1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(OCc5ccccc5)nc4)ccc32)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 10 %

Procedure:
To a solution of 5-(5-(6-(benzyloxy)-1,6-dihydropyridin-3-yl)-1H-benzo[d]imidazol-1-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (120 mg, 0.2380 mmol) in pyridine was added N-cyclopropyl-2-oxooxazolidine-3-sulfonamide (78 mg, 0.380 mmol, 1.6 eq.). The mixture was stirred at 50° C. for 16 h, quenched with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with 1 N HCl and 1N NaOH, water, brine and dried over sodium sulphate. The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 10% yield (15 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][C:9]([C:17]#[N:18])=[C:8]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:4]1([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:14]=2[O:15][CH3:16])[N:11]=[CH:10][C:9]([C:17]#[N:18])=[C:8]3[NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:3][CH2:2]1
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N1CC1
Temperature: 75 °C
Yield: 103 %

Procedure:
To a solution of 0.202 g (0.5 mmol) of 6-[(2-chloroethyl) amino]-4-(3-chloro-4-fluoroanilino)-7-methoxy-3-quinolinecarbonitrile in 4 ml of dimethylformamide, were added 0.075 g of sodium iodide (0.5 mmol) and 0.069 g of potassium carbonate (0.5 mmol). After the reaction solution was heated at 75° C. overnight, it was decanted into cold saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate. The solvent was removed to yield 0.19 g of a light brown solid. The crude product was washed with hexane to give 0.1 g of a yellow solid, mp 197-199° C.; high resolution mass spectrometry (EI, m/e): M 368.0888.