Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>C(O)(=O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=Cc1cccc(O)c1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cccc(O)c1
Yield: 76 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (1 g, 0.008 mol), malonic acid (1.69 g, 0.016 mol), piperidine (1 to 3 mL) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask and irradiated under microwave for 2–8 minutes in parts. The cooled mixture was poured into ice cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain crude solid which was recrystallised with methanol, provided a white solid in 76% yield; 193° C. (lit mp 194° C.); 1H NMR (CDCl3) δ 6.73(1H, s, H-3 and H-5), 6.62 (1H, dd, H-7), 5.61(1H, d, J=10.9 Hz trans, H-8), 5.16(1H, d, J=17.6, cis-H-8).; 13C NMR (CDCl3) δ 147.4 (C-2 and C-6), 137.2 (C-1), 135.1 (C-7), 129.5 (C-4), 112.2 (C-8), 103.3 (C-3 and C-5), 56.0 (2 OMe). This experiment clearly indicates that utilization of microwave technique as well as presence of hydroxy at 4-position of phenylaldehydes is important for the preparation of 4-vinylphenols (Example I, II and III).
Reaction SMILES: C1O[C:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][C:8]2=[O:17])([NH:5]O)[O:3]C1.C1C=CC=CC=1.C(OCC)(=O)C.[K+].[Br-]>Cl.CO.C1C=CC=CC=1.C(OCC)(=O)C.C(O)=O.C(O)=O>[OH:3][C:4]1[C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][C:8]=2[O:17][N:5]=1
Reactant: COC(=O)N1CCC(C2(NO)OCCO2)C(=O)C1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)N1CCc2c(O)noc2C1

Procedure:
A solution of 1-methoxycarbonyl-3-oxopiperidine-4-carbohydroxamic acid ethylene acetal (750 mg; 2.9 mmol) in concentrated hydrochloric acid (13 ml) was heated to 70° C. for 10 minutes. The mixture was evaporated in vacuo to give a black oil. CC [silica gel (Woelm 0.063-0.1 mm): 60 g; eluents: benzene to which ethyl acetate (40-70%) and formic acid (1%) was added] gave crystalline and TLC-pure Va (244 mg; 43%) [RF : 0.27; eluent: benzene-ethyl acetate-formic acid (50:50:1)]. An analytical sample was recrystallized (benzene-cyclohexane) to give pure Va as colourless crystals, m.p. 136.0-138.0° C. IR (KBr): 3700-3300 (m), 3300-2500 (several bands, w-m), 1655 (s), 1525 (m), 1490 (s) cm-1. UV [methanol (log ε)]: 212 (3.64) nm. 1H NMR (CDCl3): δ10.6 (1H, (s), 4.43 (2H, s), 3.70 (s) and 3.8-3.5 (t) (a total of 5H), 2.6-2.3 (2H, t).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23].C(N(CC)CC)C>CC#N>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of chlorobis(4-chlorophenyl)methane (407 mg, 1.5 mmol) in MeCN was added piperazin-2-one (601 mg, 6.0 mmol) followed by triethylamine (626 μl, 4.5 mmol) and the resulting mixture was refluxed overnight. After cooling to rt, the solvent was evaporated to dryness and the residue was submitted to column chromatography (SiO2, DCM to DCM/MeOH=100:5) to give 4-(bis(4-chlorophenyl)methyl)piperazin-2-one (420 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1.CN(C=O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[I:23])[CH:13]=[CH:12][O:11]3)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(-c2nc3occn3c2I)cc1
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A solution of 6-(4-fluorophenyl)imidazo[2,1-b]oxazole (4.92 g, 24.3 mmol; prepared according to WO2004110990A2, Example 1, Steps 1-3), NIS (5.75 g, 25.6 mmol), and DMF (100 mL) was stirred at ambient temperature. After about 3 h, the reaction was poured into water (300 mL) and the resulting precipitate was filtered, washing with additional water, and dried in a vacuum oven at about 55-65° C. to give the title compound (7.21 g, 89%): LC/MS (Table 1, Method b) Rt, =2.09 min; MS m/z: 329.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)(=O)C>O1CCCC1>[Br:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NCCc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccc(Cl)cc1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a solution of 2-(4-chlorophenyl)ethylamine (2.83 g) and triethylamine (1.46 ml) in tetrahydrofuran (50 ml), 4-(bromomethyl)benzenesulphonyl chloride (1.63 g) was added, and the mixed solution was stirred at room temperature for one hour. Ethyl acetate was added thereto, and the solution was washed with a saturated solution of ammonium chloride and then washed with water. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (neutral OH type silica gel, ethyl acetate/n-hexane=10 to 30%) to give 4-(bromomethyl)-N-[2-(4-chlorophenyl)ethyl]benzene sulfonamide (2.04 g) as a colorless solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Ca+2].[CH2:6]([OH:15])[C@@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8]>>[OH:15][CH2:6][C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:1][OH:4])[OH:14])[OH:12])[OH:10])[OH:8]
Reactant: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Yield: 22 %

Procedure:
A stabilized, substantially non-volatile mixture of 15 grams of a medium chain triglyceride and 22.5 grams of menthol crystals was formed. To this mixture was added 0.45 grams of F, D and C Blue No. 1 H.T. Lake. A second mixture comprising 22.5 grams of polyethylene glycol (8,000 carbowax) with 12 grams of hydrogenated cottonseed oil was heated separately. An additional mixture of 129.6 grams of corn sugar solids (maltodextrose M-365), 45 grams of hydroxypropylmethyl cellulose, 1.5 grams of lecithin, 15 grams of calcium carbonate, 0.4 grams of capsicum, 30 grams of xylitol and 6 grams of sorbitol was formed. The separate mixtures were then combined and placed in a spinning machine having a 7" cable heater head with a 0.030" gap between heating cables. The mixture was then flash flowed to produce a delivery system containing menthol flavor crystals.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:3]1[CH:2]=[C:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: BrCCCBr
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: BrCCCOc1cccc(-c2ccccc2)c1
Reaction time: 24 h
Yield: 57.9 %

Procedure:
To a solution of 3-biphenylol (0.0574 g, 0.337 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.340 mL, 3.35 mmol) followed by Cs2CO3 (0.172 g, 0.529 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0568 g, 57.8%). EI-MS Rt (2.59 min).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[CH2:29]([NH2:32])[CH:30]=[CH2:31]>C(Cl)Cl>[CH2:29]([NH:32][C:4]1[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)[CH:30]=[CH2:31]
Reactant: C=CCN
Reactant: CC1(c2ccc(F)cc2)CCc2c(Cl)nc(Cl)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNc1nc(Cl)nc2c1CCC2(C)c1ccc(F)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation U, 1.00 g, 3.37 mmol) in DCM (13.46 mL) was added DIPEA (1.176 ml, 6.73 mmol), then allylamine (0.303 ml, 4.04 mmol). The reaction solution was allowed to stir at rt. The reaction was concentrated in vacuo. The residue was applied to silica gel and eluted with a 0 to 50% EtOAc/Hexane gradient to afford N-allyl-2-chloro-7-(4-fluorophenyl)-7-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (896.2 mg, 2.82 mmol, 84% yield) as a white solid. LC-MS (M+H)+=316.2. 1H NMR (500 MHz, CDCl3) δ ppm 7.18-7.23 (2H, m), 6.91-6.98 (2H, m), 5.90-6.00 (1H, m), 5.26 (1H, dd, J=17.2, 1.4 Hz), 5.20 (1H, dd, J=10.1, 1.2 Hz), 4.62 (1H, br. s), 4.17 (1H, td, J=5.7, 1.7 Hz), 2.56-2.62 (2H, m), 2.43-2.50 (1H, m), 2.19-2.28 (1H, m), 1.63 (3H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:49][S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)Cc3ccccc3Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 37.7 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0313 g, 0.0678 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0570 mL, 0.407 mmol) and (2-chlorophenyl)methanesulfonyl chloride (0.0460 g, 0.203 mmol) to obtain 4-[(2-chlorophenyl)methanesulfonyloxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0166 g, yield 29%).
Reaction SMILES: [N:1]1([C:5]2[S:6][C:7]3[C:13](OS(C(F)(F)F)(=O)=O)=[C:12]([C@H:22]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]([CH3:33])=[CH:10][C:8]=3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[O:35]1[C:46]2[C:47]3[C:42]([C:43](B(O)O)=[CH:44][CH:45]=2)=[N:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36]1.[F-].[Cs+].C([O-])(O)=O.[Na+]>CC(OC)(C)C.COC1C=CC=C(OC)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].COCCOC>[N:1]1([C:5]2[S:6][C:7]3[C:13]([C:43]4[C:42]5[C:47]6=[C:38]([CH2:37][CH2:36][O:35][C:46]6=[CH:45][CH:44]=4)[CH:39]=[CH:40][N:41]=5)=[C:12]([C@H:22]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:11]([CH3:33])=[CH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: OB(O)c1ccc2c3c(ccnc13)CCO2
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCC3)sc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd+]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: COCCOC
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCC3)sc2c1-c1ccc2c3c(ccnc13)CCO2
Temperature: 110 °C
Yield: 52.7 %

Procedure:
To a solution of 33 (38 mg, 0.075 mmol) in freshly distilled DME (1 mL) was added 2,3-dihydropyrano[4,3,2-de]quinolin-7-ylboronic acid hydrochloride (24 mg, 0.097 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(II) methyl-t-butylether adduct, [SPhos Palladacycle] (5 mg, 0.0075 mmol), and cesium fluoride (46 mg, 0.3 mmol). The reaction mixture was heated in the microwave at 110° C. for 45 min. A saturated solution of NaHCO3 (3 mL) was added, and the layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer were dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give 21 mg of 34. LCMS-ESI+: calc'd for C30H33N3O4S: 532.2 (M+H+); Found: 532.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)=[O:11].B(Br)(Br)Br.S([O-])([O-])(=O)=S>ClCCl>[NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)=[O:11]
Reactant: COc1cccc(C(=O)c2ccc(C(C)C)cc2)c1N
Agent: BrB(Br)Br
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)c2cccc(O)c2N)cc1
Reaction time: 48 h

Procedure:
To a solution of 0.5 g (1.64 mmol) (2-amino-3-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 5 ml dichloromethane is added under inert atmosphere 3.3 ml (3.3 mmol) 1M solution of BBr3 in dichloromethane. After stirring for 48 h the reaction mixture is poured onto 1M aqueous thiosulfate solution and extracted with dichloromethane to yield (2-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone.
Reaction SMILES: Br[C:2]1[CH: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@@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[CH3:32][O:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][C:35]=1[OH:49]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@@H:18]2[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:38]2[CH:37]=[CH:36][C:35]([OH:49])=[C:34]([O:33][CH3:32])[CH:39]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3c2)ccc1O

Procedure:
Following general procedure F, tert-butyl cis-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (40 mg, 0.082 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.124 mmol) to afford the crude product (43 mg) as a yellow solid: ESI MS m/z 532 [C31H37N3O5+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:25]([CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH2:13][N:14]2[CH2:18][CH2:17][N:16]([CH:25]([CH:31]([CH3:33])[CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2=[O:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCN1Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(C)C)N1CCN(Cc2ccc(OCc3ccccc3)cc2)C1=O
Temperature: 40 °C
Reaction time: 4 h
Yield: 26 %

Procedure:
1-(4-Benzyloxybenzyl)imidazolidin-2-one (1.0 g; 3.54 mmol) was dissolved in dimethylformamide (DMF, 10 ml). NaH (60% in mineral oil; 0.085 g; 3.54 mol) was added, and the mixture was heated at 40° C. for 1 h. Then ethyl 2-bromoisovalerate (0.74 g; 3.54 mmol) were added, and heating was continued at 60° C. for 4 h. The reaction was stopped by slow addition of water (1 ml). The solvent was removed under reduced pressure, and the residue was partitioned between water (50 ml) and EtOAc (50 ml). Dilute HCl was added until the pH of the aqueous phase was about 4. The phases were then separated, and the aqueous phase was extracted with EtOAc (2×; 30 ml). The combined organic phases were dried over MgSO4. The solvent was removed under reduced pressure. Purification of the residue by column chromatography on silica gel (SiO2) resulted in ethyl 2-(3-(4-benzyloxybenzyl)-2-oxoimidazolidin-1-yl)-3-methylbutyrate (0.38 g; 0.92 mmol). MS: 411.15 (M+H); Rt: 1.87 min (method: gradient 0 min 90% H2O (0.05% TFA) 1.9 min 95% acetonitrile, 95% acetonitrile to 2.4 min, 10% acetonitrile 2.45 min; flow rate 1 ml/min; column 0.4 μL (YMC J'sphere ODS H80 20X2 1.4μ); 30° C.)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]>N1C=CC=CC=1>[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][N:24]([C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]
Reactant: O=C(Cl)c1cccs1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 28 (282 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 277 mg (70%) of white solids. M.P. 214° C. 1H NMR (DMSO-d6): δ 2.41 (s, 3H), 3.55 (s, 3H), 3.63 (m, 4H), 3.92 (m, 4H), 7.16 (t, J=4.1 Hz, 1H), 7.47 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.68 (s, 1H), 7.80 (d, J=4.9 Hz, 1H). EIMS m/z 393 (M+1), 415 (M+23). Anal. (C21H20N4O2S) C,H, N.
Reaction SMILES: NC1C=CC(OC2C3C(=CC(OC)=C(OC)C=3)N=C(N)C=2)=C(F)C=1.COC1C=C2C(=CC=1OC)N=C(SC)C=C2OC1C=CC([NH:48][C:49]([C:51]2([C:54]([NH:56]C3C=CC(F)=CC=3)=[O:55])[CH2:53][CH2:52]2)=[O:50])=CC=1F>>[C:51]1([C:54]([NH2:56])=[O:55])([C:49]([NH2:48])=[O:50])[CH2:53][CH2:52]1
Reactant: COc1cc2nc(SC)cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OC
Agent: COc1cc2nc(N)cc(Oc3ccc(N)cc3F)c2cc1OC
Product: NC(=O)C1(C(N)=O)CC1

Procedure:
N-(4-{[2-amino-6,7-bis(methyloxy)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-fluorophenyl)cyclopropane-1,1-dicarboxamide was synthesized from 4-(4-amino-2-fluoro-phenoxy)-6,7-dimethoxy-quinolin-2-ylamine in a similar manner as N-(4-{[6,7-bis(methyloxy)-2-(methylthio)quinolin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. It was purified by preparatory HPLC using ammonium acetate and isolated as a white solid (4.0% yield). 1H NMR (DMSO-d6) δ 10.34 (s, 1H), 9.95 (s, 1H), 7.82 (d, 1H), 7.58 (m, 2H), 7.44 (d, 1H), 7.33 (t, 1H), 7.25 (s, 1H), 7.09 (t, 2H), 7.07 (s, 1H), 6.17 (br s, 2H), 5.66 (s, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 1.40 (d, 4H). LCMS: m/z 535 (M+H)+.
Reaction SMILES: [OH2:1].O.[Cl-].[Ca+2:4].[Cl-].[Cl:6][C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][C@@H:13]([F:31])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C@H:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[C:9]([C:34]#[N:35])[CH:8]=1.[OH-].[Na+]>O.CO.CC(C)=O>[OH2:11].[OH2:1].[OH2:11].[Cl:6][C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][C@@H:13]([F:31])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C@H:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[C:9]([C:34]#[N:35])[CH:8]=1.[Cl:6][C:7]1[CH:33]=[CH:32][C:10]([O:11][CH2:12][C@@H:13]([F:31])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:22][C@H:23]([O:27][CH:28]([CH3:30])[CH3:29])[C:24]([O-:26])=[O:25])[CH:19]=[CH:20][CH:21]=2)=[C:9]([C:34]#[N:35])[CH:8]=1.[Ca+2:4]
Reactant: CC(C)O[C@@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)C(=O)O
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)O[C@@H](Cc1cccc(OC[C@H](F)COc2ccc(Cl)cc2C#N)c1)C(=O)[O-]
Temperature: 15 °C
Yield: 177 %

Procedure:
A methanol solution (500 mL) of calcium chloride dihydrate (23.8 g, 0.16 mol) was added to an acetone (1750 mL) solution of (2S)-3-[3-[(2S)-3-(4-chloro-2-cyanophenoxy)-2-fluoropropoxy]phenyl]-2-isopropoxypropionic acid (140 g, 0.32 mol) at 40° C. After confirming the dissolution, methanol (1,250 mL) was added to the reaction mixture. The reaction mixture was heated to 40° C., to which a 5N sodium hydroxide aqueous solution (64 mL, 0.32 mol) was then added dropwise over a period of 8 minutes and then water (134 ml) was added dropwise over a period of 29 minutes. The reaction mixture was cooled to 15° C., followed by filtering the precipitated crystal before vacuum drying at 40° C. to obtain 136.5 g of the title compound (yield: 93%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH:8]([CH3:12])[C:9]([O-:11])=O)=[CH:4][CH:3]=1.[Li+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][NH2:22])=[N:19][CH:20]=1.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][NH:22][C:9](=[O:11])[CH:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:12])=[N:19][CH:20]=1
Reactant: NNc1ccc(Br)cn1
Reactant: CC(C(=O)[O-])c1ccc(Cl)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
A mixture of lithium 2-(6-chloropyridazin-3-yl)propanoate (7.2 g, 37.4 mmol), 5-bromo-2-hydrazinylpyridine (7.03 g, 37.4 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (5.05 g, 37.4 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (7.89 g, 41.1 mmol) in DMF (Volume: 320 ml) was stirred for 4 hrs at 25° C. The reaction was poured into H2O (2 L) and extracted with EtOAc (3×500 mL). The organic phase was dried over MgSO4, filtered, and evaporated to dryness. The resulting residue was purified by MPLC CHCl3:MeOH (9:1) to provide the title compound, N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)propanehydrazide 48C (5.5 g, 15.42 mmol, 41.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=7.33 Hz, 3 H) 4.17 (d, J=7.07 Hz, 1 H) 6.52 (d, J=8.84 Hz, 1 H) 7.67 (dd, J=8.84, 2.53 Hz, 1 H) 7.87 (d, J=9.09 Hz, 1 H) 7.94 (d, J=8.84 Hz, 1 H) 8.11 (d, J=1.77 Hz, 1 H) 8.66 (d, J=1.52 Hz, 1 H) 10.20 (d, J=1.52 Hz, 1 H). ESI-MS:m/z 356.1 (M+H)+.