Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30](Cl)=[O:31]>C(Cl)(Cl)Cl>[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[CH:35]=1)[C:30]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11][C:10]3[CH:22]=[CH:23][CH:24]=[N:25][C:9]2=3)[CH:5]=[CH:6][CH:7]=1)=[O:31]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Reactant: Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(Nc1cccc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 130.8 %

Procedure:
To a solution of 4-(3-aminophenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (329 mg) in chloroform (5 ml) was added 3,5-dichlorobenzoylchloride (220 mg). The mixture was stirred at room temperature for 15 minutes and concentrated. The residue was crystallized from methanol to give 4-[3-(3,5-dichlorobenzoylamino)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazinehydrochloride (370 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C(Cl)(=O)[C:9](Cl)=[O:10].[NH2:14][C:15]1[N:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]3[CH2:36][CH2:35][N:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])[CH:23]=2)=[CH:17][CH:16]=1>ClCCCl.C(Cl)Cl>[CH2:37]([N:34]1[CH2:33][CH2:32][N:31]([C:29]([NH:28][C:24]2[CH:23]=[C:22]([O:21][C:18]3[CH:19]=[N:20][C:15]([NH:14][C:9]([NH:5][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[O:10])=[CH:16][CH:17]=3)[CH:27]=[CH:26][N:25]=2)=[O:30])[CH2:36][CH2:35]1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)N3CCN(Cc4ccccc4)CC3)c2)cn1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)C(N)=O
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCN(Cc4ccccc4)CC3)c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a stirring suspension of trimethylacetamide (0.115 g, 1.141 mmol) in 1,2-dichloroethane (5 mL) at RT was added oxalyl chloride (0.100 mL, 1.141 mmol). The mixture was stirred 1 h at RT and then at 90° C. for 1 h. The mixture was cooled to RT and added slowly to a stirring solution of N-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-4-benzylpiperazine-1-carboxamide (0.355 g, 0.878 mmol) in CH2Cl2 (15 mL). Solids precipitated and the suspension was stirred overnight at RT. DIEA (0.6 mL) was added and the resulting solution stirred 45 min. It was washed with H2O (2×), brine (1×), dried (MgSO4), and evaporated. The crude product was purified by silica gel chromatography (0-6% MeOH/CH2Cl2) and then re-purified by silica gel chromatography (0-10% MeOH/EtOAc) to afford 4-benzyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)piperazine-1-carboxamide (0.151 g, 32%) as an off-white brittle foam. 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.24 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.11 (d, J=5.7 Hz, 1H), 8.08 (d, J=9.1 Hz, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.28-7.26 (m, 5H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.46 (s, 2H), 3.40 (m, 4H), 2.31 (t, J=4.7 Hz, 4H), 1.21 (s, 9H); MS (ESI) m/z: 532.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:25][CH2:24]1
Reactant: BrCC1CC1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CC2)c(=O)[nH]c1=O
Yield: 50.6 %

Procedure:
5-Ethyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and bromomethyl cyclopropane were reacted by the same way with the example 1 to obtain the titled compound (165 mg, yield: 50.6%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:15]([CH3:28])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[F:27])=[O:17])[CH2:11][CH2:12][CH2:13][OH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si]([O:36]C(CC(N(C)C(NCC1C=CC=C(F)C=1F)=O)C)C([O-])=O)(C(C)(C)C)(C)C.N1C=NN=N1.C(N(C(C)C)[P:67]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])(C)C.C1C=C(Cl)C=C(C(OO)=O)C=1>C1COCC1>[P:67]([O:14][CH2:13][CH2:12][CH2:11][C@H:10]([N:15]([CH3:28])[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[F:27])=[O:17])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3])([O:68][C:69]([CH3:70])([CH3:71])[CH3:72])([O:73][C:74]([CH3:75])([CH3:76])[CH3:77])=[O:36]
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Reactant: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Reactant: CC(CC(O[Si](C)(C)C(C)(C)C)C(=O)[O-])N(C)C(=O)NCc1cccc(F)c1F
Agent: O=C(OO)c1cccc(Cl)c1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of (S)-1-(1-(tert-butyldimethylsilyloxy)-5-hydroxypentan-2-yl)-3-(2,3-difluorobenzyl)-1-methylurea-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentanoate (6.1 g, 14.66 mmol) in THF (20 mL) was added tetrazole (0.34 M in acetonitrile, 172.0 mL, 58.64 mmol) followed by addition of di-tert-butyl diisopropylphosphoramidite (9.3 mL, 29.32 mmol) at RT The resulting solution was stirred at RT for 2 h. To this mixture was added MCPBA (70%, 7.3 g, 29.32 mmol) at RT. The reaction mixture was stirred at RT overnight and quenched with Na2SO3. The mixture was filtered and the filtrate was concentrated and dissolved in EtOAc. The organic mixture was washed with NaOH (1 N×2), NaHCO3 (sat.), and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-di-tert-butyl 5-(tert-butyldimethylsilyloxy)-4-(3-(2,3-difluorobenzyl)-1-methylureido)pentyl phosphate (4.1 g, 54%). LRMS (M+H+−2 tBu) m/z 491.2.
Reaction SMILES: O[C@@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:27]([OH:30])(=[S:29])[CH3:28].Cl>O1CCCC1>[C:27]([S:29][C@H:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH2:5][O:4][CH2:3]1)(=[O:30])[CH3:28]
Reactant: CCOC(=O)C1=CCOC[C@@H]1O
Reactant: CC(O)=S
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=CCOC[C@H]1SC(C)=O
Temperature: -45 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Under a nitrogen atmosphere, to a solution (500 mL) of ethyl (3R)-3-hydroxy-3,6-dihydro-2H-pyran-4-carboxylate (23.5 g) in tetrahydrofuran was added dropwise N,N-diisopropylethylamine (35.7 mL) at −70° C. Then, methanesulfonyl chloride (13.7 mL) was added dropwise, and the mixture was stirred at −45° C. for 2 hr. The mixture was again cooled to −70° C., N,N-diisopropylethylamine (14.6 mL) and thioacetic acid (35.7 mL) were respectively added, and the mixture was stirred at −45° C. for 2 hr. The reaction mixture was treated with 1N hydrochloric acid (300 mL) and extracted with diisopropyl ether (300 mL×2). The extract was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL) and water (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=6:1→4:1) to give the title compound (19.5 g, 62%).
Reaction SMILES: [N:1]1(NC(Cl)=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[Cl:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][Cl:22].[C:23](=O)([O-])[O-:24].[K+].[K+]>C(#N)C>[Cl:16][CH2:17][CH2:18][N:19]([CH2:20][CH2:21][Cl:22])[C:23]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:24]
Reactant: O=C([O-])[O-]
Reactant: ClCCNCCCl
Reactant: O=C(Cl)NN1CCCc2ccccc21
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: O=C(N(CCCl)CCCl)N1CCCc2ccccc21
Reaction time: 18 h
Yield: 29.1 %

Procedure:
A solution of 7 g of 3,4-dihydroquinoline-1(2H)-carbamic acid chloride in 180 ml of acetonitrile is introduced into a 500 ml round-bottomed flask. 9.6 g of bis(2-chloroethyl)amine hydrochloride and 14.83 g of potassium carbonate are subsequently added and the reaction mixture is stirred for 18 h. The acetonitrile is evaporated under reduced pressure and water and ethyl acetate are subsequently added. The aqueous phase is extracted with ethyl acetate and then the organic phases are combined, washed with water and dried over sodium sulfate and then the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol gradient from 1/0 to 95/5. 2.91 g of N,N-bis(2-chloroethyl)-3,4-dihydroquinoline-1(2H)-carboxamide are obtained.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].S(O[CH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1)(=O)(=O)C>CN(C=O)C>[C:46]([O:45][C:43]([N:40]1[CH2:41][CH2:42][CH:37]([CH2:36][O:17][C:11]2[CH:10]=[C:9]3[C:14]([C:5]([O:4][C:3]4[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:2]=4[F:1])=[CH:6][CH:7]=[N:8]3)=[CH:13][C:12]=2[O:15][CH3:16])[CH2:38][CH2:39]1)=[O:44])([CH3:49])([CH3:47])[CH3:48]
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-hydroxyquinoline (609 mg, 1.8 mmol) in DMF (9 mL) was added K2CO3 (1.24 g, 9.0 mmol) and N-Boc-4-piperidinemethanol mesylate (732 mg, 2.5 mmol). The mixture was then stirred at 80° C. for 2.5 h. After it was cooled to rt, the mixture was loaded directly to a Biotage column, and eluted with solvents (hexanes:EtOAc=1:3). The resulting product, 4-[4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester, was obtained as a solid (556 mg, 56%).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2]C.[OH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])[CH2:10][NH2:11].[CH2:22]1CCN2C(=NCCC2)CC1>C(Cl)Cl>[OH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])[CH2:10][NH:11][S:4]([CH:1]([CH3:2])[CH3:22])(=[O:5])=[O:6]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(O)(CN)c1ccc([N+](=O)[O-])cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
In a 500 mL, 3 neck flask fitted with a stirrer and thermometer, 2.98 g. of propanesulfonyl chloride was added dropwise to 3.92 g. of 2-hydroxy-2-(4-nitrophenyl)propylamine and 3.19 g. of DBU in CH2Cl2 (200 mL) while stirring at 0° C. under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred overnight at this temperature. In the morning, reaction was diluted with CH2Cl2 (100 mL) and the organic layer was washed two times with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield a viscous oil. This material was purified via silica gel chromatography employing the Water's Prep 2000 and eluting with a solvent of hexane/ethyl acetate 1:1 to yield the intermediate title compound (940 mg, 16%) as a viscous oil. Ion spray M.S. 302.1 (M*−1).
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])[CH3:2].CCCCC.C(I)C(C)C.[C:16]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(OCC)C>[CH2:2]([C:16]1([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:1]([CH3:4])[CH3:3]
Reactant: [Li]C(C)(C)C
Reactant: O=C1CCCCC1
Agent: CC(C)CI
Agent: Cl
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)CC1(O)CCCCC1
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
At −60° C., a solution of 1.7M tert-butyllithium in pentane (1000 ml, 1.7 mol, 2.1 eq.) in diethyl ether (800 ml) was treated dropwise within 1 h with isobutyl iodide (157 g, 0.81 mol, 1.0 eq.). The resulting solution was stirred at −70° C. for 45 min., warmed to 10° C., cooled to −70° C., and treated at this temperature within 4 h with cyclohexanone (100.7 ml, 0.971 mol, 1.2 eq.). At the end of the addition, the reaction mixture was allowed to reach room temperature before being poured into ice/H2O (500 ml) and acidified with concentrated HCl. The water phase was extracted with diethyl ether (300 ml) and the combined organic phases were washed with water (400 ml) and aqueous saturated NaCl solution (500 ml), dried (50 g MgSO4) and the solvent evaporated to give the crude 1-isobutylcyclohexanol (148 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[Cl:25][C:26]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:37])[F:36])[C:26]=2[Cl:25])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(-c4ccccc4)nnc4c(Cl)cccc34)c2)c1Cl

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 2-chloro-3-trifluoromethylbenzaldehyde according to the procedure of Step 5 Example 6. MS (ESI) m/z 522.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:27])[NH2:26])[CH:19]=3)=[CH:10][C:9]=2[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:2]1.[C:32](=O)([O:34]C1C=CC=CC=1)[NH2:33].CCN(CC)CC.FC(F)(F)C(O)=O>CO>[NH2:33][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:15][CH:16]=[CH:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([C:25](=[NH:26])[NH2:27])[CH:19]=3)=[CH:10][C:9]=2[C:28]([F:29])([F:30])[F:31])[CH2:3][CH2:2]1)=[O:34]
Reactant: NC(=O)Oc1ccccc1
Reactant: N=C(N)c1ccc(O)c(C=CCNc2ccc(OC3CCNCC3)c(C(F)(F)F)c2)c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N=C(N)c1ccc(O)c(C=CCNc2ccc(OC3CCN(C(N)=O)CC3)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 4-(piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine (75 mg) in MeOH was added phenyl carbamate (37 mg) and Et3N (0.073 mL). The reaction mixture was stirred at ambient temperature for 3 hours, acidified with trifluoroacetic acid and purified on HPLC (10-40% acetonitrile in water with 0.1% trifluoroacetic acid). The corresponding peak was collected and freezed dried to afford 4-(N′-(aminocarbonyl)piperidin-4-yl)oxy-3-trifluoromethyl-N-(3-(6-hydroxy-3-amidinophenyl)prop-2-en-1-yl)benzenamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]3[O:27][CH2:26]3)[C:20]([O:22]C)=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.[SH:35][C:36]1[S:37][CH:38]=[CH:39][N:40]=1>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH:19]([CH2:24][CH:25]([OH:27])[CH2:26][S:35][C:36]3[S:37][CH:38]=[CH:39][N:40]=3)[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Sc1nccs1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CSc3nccs3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-4,5-epoxypentanoate 1d (0.7 g, 1.79 mmol) in benzene (5 mL) and Et3N (0.33 mL, 2.3 mmol) at room temperature is added slowly 2-mercaptothiazole (0.52 g, 4.48 mmol). The reaction mixture is stirred for 4 h at room temperature. The resulting mixture is diluted with water, and the mixture is then extracted three times with EtOAc. The combined EtOAc layer is consecutively washed with water, and brine, dried over MgSO4 and concentrated to an oil under reduced pressure. Purification is accomplished by column chromatography with hexane/EtOAc (4:1 to 7:3 to 6:4) eluent to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1I.[CH3:10][N:11]1[CH2:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[C:14]1[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH:13]=1
Reactant: Fc1cncc(Cl)c1I
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CC=C(c2c(F)cncc2Cl)CC1
Temperature: 80 °C
Yield: 85.9 %

Procedure:
3-chloro-5-fluoro-4-iodo-pyridine (500 mg, 1.942 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (476.6 mg, 2.136 mmol) and Pd(PPh3)2Cl2 (68.15 mg, 0.09710 mmol) in DME (10.00 mL) were degassed using 3×vacuum/nitrogen cycles. Na2CO3 (2.913 mL of 2 M, 5.826 mmol) was added followed by further degassing and the reaction heated at 80° C. for 18 hours. The reaction was cooled to ambient temperature and diluted with EtOAc/water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic extracts were washed with brine (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was passed through a 10 g SCX-2 cartridge and washed with MeOH/DCM mixtures. The product was eluted by washing the cartridge with 2M NH3 in MeOH/DCM mixtures and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column, eluting with 0 to 10% MeOH/DCM+1% NH4OH, loaded in DCM) to give 3′-chloro-5′-fluoro-1-methyl-1,2,3,6-tetrahydro-4,4′-bipyridine as a red solid (378 mg, 86% Yield). MS (ES+) 227.1.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13]2.O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:22]([O:21][C:19]([C:14]1[NH:15][C:16]2[C:12]([C:13]=1[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)=[O:20])[CH3:23]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)c1c(C(=O)OCC)[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
A solution of 40 ml (313 mmol) of ethyl chloroglyoxylate and of 36 ml (313 mmol) of titanium tetrachloride in 1 l of dichloromethane is stirred for 15 min at room temperature. A solution of 50 g (241 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate in dichloromethane is added and the mixture is stirred for 2 h at room temperature. The mixture is poured into water and the organic phase is separated by settling, washed with dilute sodium hydroxide solution and dried over sodium sulphate. 31.5 g (102 mmol) of product are obtained, which product is used as is in the following stage.
Reaction SMILES: Cl.[C:2](#[N:4])[CH3:3].CO.C(N(CC)CC)C.C1C=[C:18]2[C:20]([C:22](O)([OH:25])[C:23](=[O:24])C2=CC=1)=[O:21]>C1COCC1>[NH2:4][CH2:2][CH2:3][CH2:18][CH:20]([CH:22]([CH2:23][OH:24])[OH:25])[OH:21]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC#N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: NCCCC(O)C(O)CO

Procedure:
3-Aminopropyl solketal (2.43 g, 12.8 mmole) was dissolved in THF (30 ml) and aqueous hydrochloric acid (1M, 30 ml) was added. After 1 hour at room temperature TLC (acetonitrile/methanol/triethlyamine 80/18/2) indicated that all starting material Rf 0.33 had been hydrolyzed to the diol Rf ca.0.0 (detection by ninhydrin spray). THF was evaporated in vacuo and the aqueous residue was applied to a Dowex 50 ion exchange column (100 ml, H form). The resin was washed with water to remove all Cl ion and the desired amine was eluted with aqueous ammonia. The ammonia soution was evaporated to remove all volatile material and the aqueous residue used for subsequent reactions without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH:16]2[CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1ccc(Br)cc1C(F)(F)F
Yield: 96.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclopropylamine (0.27 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-cyclopropyl-2-(trifluoromethyl)benzenesulfonamide (0.51 g, 96%) was provided after purification. MS (ESI) m/z 344. HPLC purity 100.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:36])[CH3:34])[CH2:25]4)=[N:22][CH:23]=2)=[N:3][C:2]([C:43]2[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)nc34)cn2)C1
Yield: 63.2 %

Procedure:
Following general procedure II, (S)-tert-Butyl 1-{5-[6-chloro-3-(cyclopropanecarbonyl)-1,5-naphthyridin-4-ylamino]pyridin-2-yl}piperidin-3-ylcarbamate (131 mg, 0.25 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102 mg, 0.38 mmol) to afford the desired product (100 mg, 63%) as an orange red solid. ESI MS m/z 633 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[NH4+:54]>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:54])[C:8]=2[N:17]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCC(=O)N1CCOCC1

Procedure:
2-(2-Methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline (4.55 g, 11.1 mmol) was treated with mCPBA (4.97 g, 21.6 mmol) followed by ammonium hydroxide (40 mL) and p-toluenesulfonyl chloride (3.69 g, 19.4 mmol) according to the method described in Part D of Example 8. The crude product was recrystallized twice from ethyl acetate to provide 1.17 g of 2-(2-methoxyethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinolin-4-amine as brown needles, mp 131-132° C.