Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:4]2[C:5]([O:7][C:8](=[O:10])[NH:9][C:3]=12)=O.[C:14]1([N:20]2[C:24](C(Cl)=O)=[CH:23][C:22]([C:28]([F:31])([F:30])[F:29])=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:32]([NH2:35])([CH3:34])[CH3:33]>N1C=CC=CC=1.ClCCl.CCOCC>[CH3:1][C:2]1[CH:13]=[CH:12][CH:11]=[C:4]([C:5]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:7])[C:3]=1[NH:9][C:8]([C:24]1[N:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:21]=[C:22]([C:28]([F:29])([F:30])[F:31])[CH:23]=1)=[O:10]
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ccccc1
Reactant: CC(C)N
Reactant: Cc1cccc2c(=O)oc(=O)[nH]c12
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1cccc(C(=O)NC(C)C)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ccccc1
Temperature: 95 °C

Procedure:
A sample of 3-methylisatoic anhydride (0.30 g, 1.7 mmol) partially dissolved in pyridine (4.0 mL) was treated with 1-phenyl-3-(trifluoromethylpyrazole)-5-carboxyl chloride (i.e. the product of Step C) (0.55 g, 1.9 mmol). The mixture was heated to ˜95° C. for a period of 2 hours. The resulting orange solution was cooled to 29° C., then was treated with isopropylamine (1.00 g, 16.9 mmol). The reaction mass exothermically warmed to 39° C. It was further heated to 55° C. for a period of 30 minutes, whereupon much precipitate formed. The reaction mass was dissolved in dichloromethane (150 mL). The solution was washed with aqueous acid (5 mL of conc. HCl in 45 mL of water), then with aqueous base (2 g sodium carbonate in 50 mL of water). The organic layer was dried over MgSO4, filtered, then concentrated on a rotary evaporator. Upon reduction to ˜4 mL, product crystals had formed. The slurry was diluted with ˜10 mL of ether, whereupon more product precipitated. The product was isolated by filtration, washed with ether (2×10 mL), then washed with water (2×50 mL). The wet cake was dried for 30 minutes at 70° C. in vacuo. The product, a compound of the present invention, consisted of 0.52 g of an off-white powder melting at 260-262° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>C(Cl)Cl.CCOCC>[ClH:43].[CH:38]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: CCOCCOc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOCCOc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-ethoxy-ethoxy)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (70 mg, 0.12 mmol) was dissolved in CH2Cl2 (2.5 mL) and 2 M HCl in ether (2.5 mL) was added. This mixture was stirred for 2 h at room temperature and a yellow precipitate formed. The solvents were removed under reduced pressure and the resulting solid was suspended in ether and collected by filtration then dried overnight in vacuo at 50° C. to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt (30 mg, 52%). MS (APCI); M++1: Calc'd, 480.3. Found 480.4. Anal. Calc'd for C25H33N7O32HCl 3.44H2O: C, 48.87; H, 6.87; N, 15.96. Found; C, 48.48; H, 6.66; N, 15.66.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4](F)[CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[C:4]([S:12][CH3:11])[CH:3]=1
Reactant: CSc1ccc(Br)cc1F
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cc1SC
Temperature: 0 °C
Reaction time: 48 h
Yield: 87.9 %

Procedure:
Combine 4-bromo-2-fluoro-1-methylsulfanyl-benzene (4.8 g, 22 mmol) and sodium methanethiolate (1.6 g, 22 mmol) in DMF (50 mL). Stir for 48 hours. Pour the reaction mixture into ice (10 g). Separate the layers and wash the organic layer with aqueous saturated NaHCO3 and brine. Dry with MgSO4, filter and concentrate in vacuo. Chromatograph the residue on a column eluting with diethyl ether in hexane (0 to 5%) to give 4.82 g of 4-bromo-1,2-bis-methylsulfanylbenzene (89%).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1>O1CCOCC1.C(OCC)(=O)C>[CH3:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[N:5]=[C:6]([N:52]2[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1c(-c2ccc(C)cc2)nc(=O)[nH]c1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a stirred solution of ethyl 6-methyl-2-oxo-4-p-tolyl-1,2-dihydropyrimidine-5-carboxylate (2 g; 7,34 mmol) in dioxane (35 mL) were added PyBrOP (3,77 g; 8,08 mmol), triethyl amine (2,06 mL; 14,69 mmol) and piperidine (0,945 mL; 9,55 mmol) and the mixture was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 2 g (80%) of the title as a yellow oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[C:11](C(OC(=O)CCCC2C=CC(C)=CC=2)=CCCC2C=CC(C)=CC=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2].C(C1C=CC(CCCC(O)=O)=CC=1)(C)(C)C>>[C:1]([O:4][CH2:5][C@@:6]([NH:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH2:7][CH2:8][C:9]1[N:10]([CH3:38])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C(=CCCc2ccc(C)cc2)OC(=O)CCCc2ccc(C)cc2)n1C)COC(C)=O
Agent: CC(C)(C)c1ccc(CCCC(=O)O)cc1
Product: CC(=O)N[C@](C)(CCc1cccn1C)COC(C)=O

Procedure:
The reaction was carried out in the similar manner to (1a) using 4-(4-t-butylphenyl)butyric acid obtained in Reference example 7 and (2R)-1-acetoxy-2-acetylamino-2-methyl-4-(1-methylpyrrol-2-yl)butane obtained in Reference example 1 to obtain the title compound (yield: 59%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=1[C:33]([NH:35][O:36][CH3:37])=[O:34]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:41]=[CH:40][CH:39]=[CH:38][C:32]=3[C:33](=[O:34])[NH:35][O:36][CH3:37])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: CONC(=O)c1ccccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NOC)n2)c(OC)c1)OCC
Yield: 73.4 %

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (0.060 g, 0.13 mmol) and 2-amino-N-methoxybenzamide (Compound 259A, 0.0242 g, 0.145 mmol). The crude material was purified on an Isco Combiflash unit using 0→5% MeOH in DCM as eluent to afford 55.7 mg of the title compound (72%). 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.70 (br. s., 1H), 8.79 (br. s., 1H), 8.38 (s, 1H), 7.48-7.57 (m, 2H), 7.42 (t, J=7.71 Hz, 1H), 7.09 (t, J=7.33 Hz, 1H), 7.01 (s, 1H), 6.83 (td, J=2.02, 8.08 Hz, 1H), 3.91-4.04 (m, 4H), 3.76 (s, 3H), 3.70 (s, 3H), 3.18-3.28 (m, 2H), 1.19 (t, J=7.07 Hz, 6H); MS (ES+): m/z: 585.1915 [MH+]. HPLC: tR=1.41 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O=[C:8]1[CH:17]=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9]1.C(OC(=O)C)C>C1COCC1>[NH:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:16][CH2:17][CH2:8]1
Reactant: O=c1cnc2ccccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCN2
Temperature: 0 °C
Yield: 66 %

Procedure:
Basically, a 500 ml, three-necked flask was charged with lithium aluminum hydride (300 ml, lM in THF, 300 mmol) under an inert atmosphere. To the lithium aluminum hydride was added 2-keto-1,2-dihydroquinoxaline (22 g, 0.15 mol) in dry THF (100 ml) in small portions to prevent a sharp rise of temperature. After the addition was complete, the mixture was heated at the refluxing temperature of THF for 4 hours. The excess lithium aluminum hydride was decomposed by a slow addition of ethylacetate (10 ml) at room temperature. The resulting mixture was dropped slowly into ice water and extracted with diethyl ether. The diethyl ether solution was dried over anhydrous MgSO4, filtered and the solvent evaporated to give a yellow solid. The solid was recrystallized in hexane to give 1,2,3,4-tetrahydroquinoxaline in 66% yield.
Reaction SMILES: [N:1]([C@@H:4]([CH2:25][OH:26])[C@@H:5]([OH:24])[C@H:6]([OH:23])[C@@H:7](OS(C)(=O)=O)[C@@H:8]([OH:17])[C@@H:9]([OH:16])[CH2:10]OS(C)(=O)=O)=[N+]=[N-].C(OCC)(=O)C.CO.C([O-])(=O)C.[Na+]>O.[Pd]>[OH:26][CH2:25][C@@H:4]1[N:1]2[C@H:7]([C@@H:8]([OH:17])[C@@H:9]([OH:16])[CH2:10]2)[C@@H:6]([OH:23])[C@@H:5]1[OH:24]
Reactant: CS(=O)(=O)OC[C@H](O)[C@H](O)[C@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](CO)N=[N+]=[N-]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: OC[C@H]1[C@@H](O)[C@H](O)[C@H]2[C@@H](O)[C@@H](O)CN21

Procedure:
7-Azido-7-deoxy-1,4-di-O-methanesulphonyl-L-threo-L-talo-octitol (Qi, 1.6 g, 3.78 mmol) was dissolved in water (30 ml) and was treated with 10% palladium on carbon (400 mg) under an atmosphere of hydrogen for 16 h. T.l.c analysis (ethyl acetate:methanol, 9:1) indicated the disappearance of starting material (Rf 0.75) and the presence of a more polar product (Rf 0.05). Palladium was removed by filtration and the filtrate was treated with sodium acetate (930 mg, 11.34 mmol) at 60° C. for 16 h. The reaction mixture was cooled and the solvent removed in vacuo. The crude brown oil was purified by ion-exchange chromatography (Dowex 50WX8-100, eluting with 2M ammonium hydroxide) to afford (1R,2R,3S,6S,7R,7aR)-3-(hydroxymethyl)-1,2,6,7-tetrahydroxypyrrolizidine [3,7-diepi-Casuarine] Qj as a brown glass (671 mg, 87%): δH (D2O) 2.81-2.92 (m, 2H, H-5, H-5a), 3.16 (dd, 1H, J3,2 5.91 Hz, J3,8 10.74 Hz, H-3), 3.30 (app t, 1H, J 3.78 Hz, H-7), 3.76 (dd, 1H, J8,8a 6.35 Hz, H-8), 3.87 (dd, 1H, H-8a), 4.01 (d, 1H, J2,1 3.55 Hz, H-2), 4.04-4.12 (m, 2H, H-6, H-7), 4.29 (app t, 1H, H-1); δC (D2O) 49.32, 57.29, 63.78, 70.41, 72.59, 72.65, 74.47, 78.25; [α]D −21.1 (c 0.5, H2O).
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])[S:9][C:5]=2[CH:4]=1)#[N:2].[N:18]([Sn](CCCC)(CCCC)CCCC)=[N+:19]=[N-:20]>O1CCCC1>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([C:1]3[N:18]=[N:19][NH:20][N:2]=3)[CH:17]=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CCNC(=O)Nc1nc2ccc(C#N)cc2s1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2ccc(-c3nn[nH]n3)cc2s1
Reaction time: 0.5 h

Procedure:
About 30 mg N-(6-cyano-1,3-benzothiazol-2-yl)-N′-ethylurea was charged into about 5 mL dry tetrahydrofuran. Added about 2 g of azidotributylstannane then refluxed for about 48–72 hours. The solvent was removed under reduced pressure then the crude oil was taken up in dichloromethane. About 0.5 mL of dilute aqueous hydrochloric acid was added and a white precipitate formed. This was allowed to sit for about 30 minutes then the precipitate was collected by filtration, washed with warm THF then dried under vacuum. 1H NMR 1.10 (t, 3H), 3.2 (m, 2H), 6.76 (br s, 1H), 7.78 (d, 1H), 8.0 (d, 1H), 8.58 (s, 1H), 10.91 (s, 1H); LC/MS 1.37 min, 290 (M+1).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:53][C:54]([F:60])([F:59])[CH2:55][C:56](O)=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([C:56](=[O:57])[CH2:55][C:54]([F:60])([F:59])[F:53])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=C(O)CC(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(C(=O)CC(F)(F)F)C4)c3)n2)cn1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 58.8 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62, 50.0 mg, 0.116 mmol) and HATU (52.8, 0.139 mmol) in dry DMF (0.50 mL) was added 3,3,3-trifluoropropanoic acid (19.3 mg, 0.150 mmol) and the mixture was stirred at ambient temperature for 2 minutes. DIEA (80.6 μL, 0.463 mmol) was added and the resulting homogeneous solution was stirred at ambient temperature for 18 hours. The reaction mixture was added to H2O (5.0 mL) and extracted with EtOAc. The combined extracts were washed with H2O, saturated aqueous NaHCO3 and dried over MgSO4. The solution was eluted through a silica gel column eluting with EtOAc then with 10% MeOH/EtOAc. The 10% MeOH/EtOAc pool was concentrated to give the title compound (32 mg, 59% yield) as a white solid. MS (apci) m/z=470.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=3)[NH2:17])=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35]Br.O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]([CH2:13][C:14]3[CH:20]=[CH:19][CH:18]=[C:16]([N:17]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:15]=3)=[N:10][C:9]=2[C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][CH:25]=[CH:24]3)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(-c2[nH]c(Cc3cccc(N)c3)nc2-c2ccc3ncccc3c2)n1
Reactant: BrCCCCBr
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2[nH]c(Cc3cccc(N4CCCC4)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 120 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
To a solution of 6-(5-(6-methylpyridin-2-yl)-2-(3-nitrobenzyl)-1H-imidazol-4-yl)quinoline (500 mg, 1.186 mmol, prepared according to the method described in US 2008/0319012 A1) in MeOH (5 mL) was added Pd/C (0.5 mg, 10% w/w) and the mixture was stirred under H2 at atmospheric pressure for 5 hours. The reaction mixture was filtered through celite and the filterate was concentrated under reduced pressure. The residue was purified by MPLC on silica gel (MeOH:CH2Cl2=1:50) to afford the 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (424 mg, 91%). The obtained compound, 3-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)aniline (30 mg, 0.077 mmol) was dissolved in DMF (3 mL), treated with 1,4-dibromobutane (17 mg, 0.080 mmol), and stirred at 120° C. for 12 hours. The reaction mixture was cooled to room temperature, added H2O (30 mL), and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:20 (v/v)) and on NH silica gel (MeOH:CH2Cl2=1:100 (v/v)) to afford the title compound (7 mg, 20.5%). (300 MHz, CDCl3) δ 2.50 (3H, s), 4.09 (2H, s), 6.64-6.72 (2H, m), 6.91-6.98 (2H, m), 7.31 (1H, d), 7.39 (1H, t), 8.13 (2H, d), 8.41 (1H, s), 8.84 (2H, dd), MS (ESI) m/z 411 (MH+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[N:22]([C:1]([Cl:4])=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH:38]([CH3:40])[CH3:39])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Phosgene (2.95 mL, 5.69 mmol, 1.93 M in toluene) was added dropwise to a cooled mixture of triethylamine (1.3 mL, 9.4 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-1H-imidazole (0.80 g, 1.88 mmol, example 6) in methylene chloride (15 mL) at 0° C. The reaction mixture was stirred for 30 min at 0° C. and evaporated. The residue was kept under high vacuum for 30 min. Chromatography of the residue over silica gel using 60-80% methylene chloride in hexanes gave 4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (0.71 g, 77%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2Cl.[CH3:19][N:20]([CH3:28])[C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])=[C:5]2[NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([N:20]([CH3:28])[CH3:19])[CH2:22][CH2:23]1
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Reactant: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(C)CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure B, 1-(6-bromo-4-chloroquinolin-3-yl)-3-methylbutan-1-one (44 mg, 0.14 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine (92 mg, 0.43 mmol) to afford the desired product (13 mg, 21%) as an off-white solid: ESI MS m/z 433 [C22H30BrN3O+H]+.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Br[C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].N#N.Cl[CH2:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1>CC(N(C)C)=O.O.[Pd](Cl)Cl>[C:1]([O:4][CH2:18][C:19]1[C:23]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=[O:10])=[C:22]([CH3:24])[O:21][N:20]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(CCl)no1
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: N#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)OCc1noc(C)c1-c1ccccc1C=O
Temperature: 130 °C
Yield: 76.9 %

Procedure:
To a resealable vial was added palladium(II) chloride (4.49 mg, 0.025 mmol), potassium acetate (1.24 g, 12.7 mmol), and 2-bromobenzaldehyde (0.59 mL, 5.07 mmol). The vial was sealed and evacuated/backfilled with N2 (3×) before addition of 3-(chloromethyl)-5-methylisoxazole (1.00 g, 7.60 mmol) as a solution in DMA (25 mL). The vial was then heated to 130° C. overnight. The reaction was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (4-(2-formylphenyl)-5-methylisoxazol-3-yl)methyl acetate (1.01 g, 3.90 mmol). LC/MS m/z 260 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:31])[NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=4)[CH:17]=[CH:16][C:15]=3[F:32])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[F:33][C:34]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O.COCCOC>[F:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[F:29])[CH2:22][NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:32])=[C:14]([NH:13][C:11]([C:8]2[N:5]3[CH:6]=[CH:7][C:2]([C:42]4[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([F:33])[CH:43]=4)=[CH:3][C:4]3=[N:10][CH:9]=2)=[O:12])[CH:19]=1)=[O:31]
Reactant: O=C(NCc1ccc(F)c(F)c1)c1ccc(F)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCc5ccc(F)c(F)c5)ccc4F)cnc3c2)cc1F

Procedure:
7-Bromo-N-(5-(3,4-difluorobenzylcarbamoyl)-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (Intermediate 3A) (500 mg, 0.993 mmol), methyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (306 mg, 1.093 mmol) and cesium carbonate (1295 mg, 3.97 mmol) in water (2 ml)/DME (5 ml) were mixed to give a suspension. The mixture was degassed with nitrogen and PdCl2(dppf).CH2Cl2 adduct (40.6 mg, 0.050 mmol) was added. The reaction mixture was heated using microwave radiation at 100° C. for 1 hr and partitioned between EtOAc and water. The organic portion was separated, dried (MgSO4) and concentrated in vacuo. The crude product was triturated with MeOH/diethyl ether to afford the title compound;
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:10]([OH:12])=O)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Cl:27][CH2:28][CH2:29][NH2:30]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][NH:30][C:10]([C:6]1[NH:7][C:8]([CH3:9])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[CH3:13])=[O:12]
Reactant: NCCCl
Reactant: CC(=O)c1c(C)[nH]c(C(=O)O)c1C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)[nH]c(C(=O)NCCCl)c1C
Temperature: 0 °C
Yield: 49 %

Procedure:
4-Acetyl-3,5-dimethylpyrrole carboxylic acid (15.731 g, 86.82 mmol), was taken up in anhydrous DMF (40 mL) and cooled to 0° C. Carbonyldiimidazole (14.512 g, 86.82 mmol) was added to this slurry and stirred until the evolution of gas ceased and a clear solution formed. 2-Chloroethyl amine hydrochloride (10.574 g, 91.16 mmol) was added in one portion. The reaction mixture was left to stir overnight at room temperature. The reaction mixture was extracted in water (50 mL) from DCM (4×20 mL). The aqueous layer (containing precipitate) was filtered off and washed with cold water. The white solid was found to be the target compound. (10.316 g, 42.51 mmol, 49% yield).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].[O:15]=O>Cl[Cu].CN(C=O)C>[N+:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:4]=[O:15])([O-:13])=[O:12]
Reactant: O=O
Reactant: CN(C)C=Cc1ccccc1[N+](=O)[O-]
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
20 g of β-dimethylamino-2-nitrostyrene, 1 g of CuCl and 300 ml of DMF were initially introduced into a 300 ml autoclave equipped with an aerating stirrer. The autoclave was heated to 50° C. and pressurized to 10 bar with air, and a pressure of 20 bar was then maintained using oxygen. After 2 h, the experiment was discontinued and 87.2% of o-nitrobenzaldehyde was obtained after working-up.