Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([O:40][CH2:41][CH2:42][S:43][CH3:44])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:55])C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:27]=3)[C:22]([O:40][CH2:41][CH2:42][S:43]([CH3:44])=[O:55])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:45][CH3:46])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCSC)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCCS(C)=O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-methylsulfanyl-ethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in chloroform (1 ml), then thereto is added m-chloroperbenzoic acid (60 mg) is added thereto, and the mixture is stirred at room temperature for 2 hours. After addition of a saturated aqueous sodium hydrogen carbonate solution, the reaction mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=19:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(2-methylsulfinylethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (125 mg). MS (m/z): 690 [M+H]+
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:8][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=2)[CH:30]=1)(=[O:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: C/C=C/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: C/C=C/C=C/C(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h

Procedure:
To a solution of 2.0 g of sorbic acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methanesulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed with ethyl ether, then with acetone, dissolved in methanol, and filtered to remove the insolubles. The filtrate was concentrated under reduced pressure and recrystallized from an ethanol-methanol mixture to yeild 2.4 g of colorless granular crystals 6-amidino-2-naphthyl sorbate methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH3:10])[NH2:9])=[N:6][CH:7]=1
Reactant: COc1ccccc1C(=O)O
Reactant: NNc1ccc(Br)cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)N(N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
To a solution of 5-bromo-2-hydrazinylpyridine (7.1 g, 38 mmol) and 2-methoxybenzoic acid (7.0 g, 46 mmol) in dichloromethane (DCM, 100 mL) were added benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, 25.2 g, 57 mmol) and N-methylmorpholine (NMM, 13.4 g, 0.10 mol), and it was stirred at room temperature for 2 h. The mixture was filtered and the solids were washed with DCM (50 mL×3), dried to give the title compound (8.23 g, 67.5% yield) as yellow solids. MS: m/z 322.1 [M+H+].
Reaction SMILES: [C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][CH2:11][CH3:12])[C:6]1=O)([O:3][CH3:4])=[O:2].Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[C:1]([CH:5]1[CH2:9][S:8][CH:7]([CH2:10][CH2:11][CH3:12])[C:6]1=[N:15][OH:16])([O:3][CH3:4])=[O:2]
Reactant: NO
Reactant: CCCC1SCC(C(=O)OC)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCC1SCC(C(=O)OC)C1=NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 94.0 g (0.465 mole) of 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene in 250 ml of dry pyridine was treated with 40.0 (0.576 mole) of hydroxylamine hydrochloride at 25°. The reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1 N HCl and methylene chloride. The organic phase was dried over sodium sulfate and evaporated to afford 100 g (0.461 mole, 99%) of pure 4-carbomethoxy-3-keto-2-propyl-tetrahydrothiophene oxime as a colorless oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9](Cl)=[O:10])=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][CH:15]1[CH2:16][CH2:17][N:12]([C:9]([O:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)=[O:10])[CH2:13][CH2:14]1)[CH3:23]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 98.7 %

Procedure:
Benzyl chloridocarbonate (10.5 g, 61.3 mmol) was added to a solution of ethyl piperidin-4-ylacetate (10.0 g, 58.4 mmol) and sodium carbonate (46.2 g, 438 mmol) in dichloromethane (320 mL). After 18 h, the reaction mixture was filtered and concentrated. Purification by silica gel chromatography [75% hexanes/ethyl acetate→50% hexanes/ethyl acetate)] gave the title compound (17.6 g). MS 306.1 (M+1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC)=O)=[C:17]([Cl:27])[CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22](=[O:24])[N:3]([CH2:1][CH3:2])[C:4]3[N:5]=[C:6]([S:12][CH3:13])[N:7]=[CH:8][C:9]=3[CH:10]=2)=[C:17]([Cl:27])[CH:16]=1
Reactant: CCOC(=O)Cc1ccc(Br)cc1Cl
Reactant: CCNc1nc(SC)ncc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCn1c(=O)c(-c2ccc(Br)cc2Cl)cc2cnc(SC)nc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
To a solution of 4-ethylamino-2-(methylthio)pyrimidine-5-carbaldehyde (9, 1.00 g, 5.07 mmol) in anhydrous dimethylacetamide (10 mL) was added ethyl 4-bromo-2-chlorophenylacetate (1.70 g, 6.12 mmol) and cesium carbonate (3.30 g, 10.13 mmol). The reaction mixture was stirred at 100° C. for 2 h. The mixture was poured into ice water and the orange solid was collected, washed with water, dried and purified by Teledyne-Isco using a hexane:ethyl acetate gradient (1:0→4:1) to afford the title compound as a white solid (0.30 g, 0.73 mmol, 14%). ESMS m/z 410 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.65 (s, 1H), 7.66 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.47 (dd, J=8.3, 1.5 Hz, 1H), 7.26 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.0 Hz, 2H), 2.66 (s, 3H), 1.37 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[K+]>[CH2:9]([O:16][C:17]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
10 g of L-valine (85 mmol) are dissolved in 4 M KOH (40 ml) and the mixture is cooled in ice. 21.9 g of benzyloxycarbonyl chloride (128 mmol) are added thereto over 5 minutes and a white solid forms. The mixture is stirred at 0° C. for one hour, the temperature is then allowed to rise and stirring is continued for another hour at room temperature. The reaction mixture is then diluted with 4 M KOH (200 ml) and is extracted with ether (2×100 ml). The aqueous phase is then brought to an acidic pH<1 with concentrated hydrochloric acid and is then extracted with ethyl acetate (3×200 ml). The extracts are combined and dried (Na2SO4) and the solvent is evaporated off. A clear oil is obtained.
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=1>>[C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:44]3[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:55])([CH3:54])[CH3:56])[CH:45]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ccn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccnc(NC(=O)OC(C)(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (686 mg, 1.10 mmol) is coupled to pyridyl bromide 155 (300 mg, 1.10 mmol) using Method A to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([F:18])[F:17])=[CH:12][CH:11]=2)=[C:4]([OH:20])[CH:3]=1.P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]([F:17])[F:18])=[CH:14][CH:15]=3)[O:20][C:4]=2[CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1O)c1ccc(C(F)F)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)c1ccc(-c2nc3ccc(Br)cc3o2)cc1
Yield: 26.7 %

Procedure:
N-(4-Bromo-2-hydroxyphenyl)-4-(difluoromethyl)benzamide (0.5 g, 1.5 mmol) was dissolved in 1,4-Dioxane (10 ml) and added Phosphorus oxychloride (0.4 ml, 4.4 mmol). This mixture was refluxed for 2 h. 1,4-Dioxane removed on rotavapour to obtain the residue. Residue was washed with water to obtain solid. Solid was purified by column on 60-120 mesh silica gel using DCM as eluent to obtain the titled compound (130 mg) as an off-white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.28 (d, J 8.4, 2H), 7.74 (d, J 1.7, 1H), 7.65-7.58 (m, 3H), 7.46 (dd, J 1.8, 8.4, 1H), 6.68 (t, J 56.2, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[O:37])[CH2:28][N:27](CC3C=CC=CC=3)[CH2:26]2)=[O:24])=[CH:18][CH:17]=1.C(O)(=O)C>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2([C:36]([NH:38][C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[O:37])[CH2:26][NH:27][CH2:28]2)=[O:24])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CN(Cc5ccccc5)C4)cc3)c2cc1OC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2nccc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CNC4)cc3)c2cc1OC
Reaction time: 16 h
Yield: 31.8 %

Procedure:
To a solution of ′N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-1-(phenylmethyl)azetidine-3,3-dicarboxamide (300 mg, 0.5 mmol) in MeOH (50 mL) was charged with Pd/C (50% wet, 10% mmol, 265 mg) and acetic acid (2 mL). The reaction mixture was subjected to hydrogenolysis condition under H2 (50 psi) on a Parr Hydrogenator for 16 hr. The reaction mixture was filtered through celite and washed with MeOH. After removal of solvent in vacuo, the crude product was purified using preparative HPLC (solvent system: MeCN/H2O/NH4OAc), affording N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)azetidine-3,3-dicarboxamide (82 mg, 32% yield) as a white solid. 1HNMR (DMSO-d6): 8.46 (d, 1H), 7.84 (d, 2H), 7.70 (m, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 7.24 (d, 2H), 7.20 (t, 2H), 6.44 (d, 1H), 4.03 (s, 4H), 3.95 (s, 6H), 1.90 (s, 3H, acetate salt). LCMS (POS): 517.3 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=2)[N:10]=1.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:24][CH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[O:7][C:8]=1[CH3:21]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(CO)c1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccco2)nc1COc1cccc(CCl)c1
Yield: 98.6 %

Procedure:
To a mixture of (3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol (8.0 g) and toluene (100 mL) was added thionyl chloride (4.00 g), and the mixture was heated under reflux for 2 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:4, v/v) to give {4-[(3-chloromethylphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole as a colorless oil (8.40 g, yield 99%).
Reaction SMILES: [CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4].[CH3:23][NH2:24]>O>[CH3:1][N:2]([CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:24][CH3:23])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1)(=[O:5])=[O:4]
Reactant: CN
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Solvent: O
Product: CNc1ccc(S(=O)(=O)N(C)C2CCN(C)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.6 g (4.6 mmol) of 4-chloro-3-nitrobenzenesulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)amide was mixed with 30 mL of 40% methylamine solution and stirred in a sealed flask for four hours at room temperature. Then the mixture was diluted with about 40 mL of water, the product precipitated was suction filtered, washed with water, and dried. Yield: 1.5 g (95% of theory), C14H22N4O4S (343.4); Rf value: 0.45 (silica gel; dichloromethane/ethanol=4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@@:13]2([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[C:14]([OH:16])=O)=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.O=S(Cl)Cl>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:13]23[CH2:17][CH2:18][CH2:19][N:12]2[C:10](=[O:11])[N:9]([C:4]2[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:14]3=[O:16])=[CH:22][CH:23]=1)([OH:29])=[O:28]
Reactant: O=C(O)c1ccc(C[C@@]2(C(=O)O)CCCN2C(=O)Nc2cc(Cl)cc(Cl)c2)cc1
Solvent: O=S(Cl)Cl
Product: O=C(O)c1ccc(CC23CCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.6 %

Procedure:
A mixture of N-[N-(3,5-dichlorophenyl)carbamoyl]-2-(4-carboxybenzyl)proline (0.080 g) and SOCl2 (2.0 mL) was heated at 100° C. for 1 hour. The solution was evaporated. The residue was dissolved in toluene, evaporated and dried under vacuum. The residue was dissolved in a mixture of THF/H2O (4/0.4 mL) and the solution was stirred for 18 hours. It was diluted with EtOAc and water. The organic layer was separated, washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/1) afforded the titled compound (48 mg). MS (m/z) 441 (M++Na).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=O)(C)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[C:43]([F:45])[CH:44]=1>>[F:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][C:23]2[N:22]=[C:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]4[CH2:12][CH2:13][NH:8][C@@H:9]([CH2:28][C:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[NH:31][CH:30]=5)[CH2:10]4)[CH:16]=3)[CH:26]=[CH:25][N:24]=2)[CH:42]=[C:43]([F:45])[CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC1Cc1c[nH]c2ccccc12
Reactant: NCCc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(CCNc2nccc(-c3cccc(CN4CCN[C@@H](Cc5c[nH]c6ccccc56)C4)c3)n2)c1

Procedure:
Intermediate 109 was coupled with 2-(3,5-difluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 540. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.59 (s, 1H), 8.34 (d, 1H), 8.29 (d, 1H), 7.84 (d, 1H), 7.60 (m, 3H), 7.33 (d, 1H), 7.26 (s, 1H), 6.98 (m, 4H), 6.72 (s, 1H), 4.63 (s, 2H), 4.16 (m, 1H), 4.04 (s, 2H), 3.49 (m, 4H), 3.26 (m, 4H), 3.05 (t, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[F:9][C:10]1[CH:11]=[C:12]([N+:17]([O-:19])=[O:18])[CH:13]=[CH:14][C:15]=1F>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:1][C:15]1[CH:14]=[CH:13][C:12]([N+:17]([O-:19])=[O:18])=[CH:11][C:10]=1[F:9]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OCc1ccccn1
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(F)c1
Yield: 57.7 %

Procedure:
An analogous reaction to that described in example 42b, but starting with 2-(hydroxymethyl)pyridine (3.50 g, 36 mmol) and 3,4-difluoronitrobenzene (5.00 g, 31.4 mmol), yielded 2-((2-pyridyl)methoxy)-5-nitrofluorobenzene (4.50 g, 58% yield) as a yellow solid. d) An analogous reaction to that described in example 42c, but starting with 2-((2-pyridyl)methoxy)-5-nitrofluorobenzene (4.5 g, 18.1 mmol), yielded 3-fluoro-4-((2-pyridyl)methoxy)aniline (1.86 g, 47% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:21])[CH:7]=[C:8]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH2:20])[CH:9]=2)[N:4]=1.[C:22](C1NC=CN=1)(C1NC=CN=1)=[O:23]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([CH3:21])[CH:7]=[C:8]([N:13]3[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[NH:20][C:22]3=[O:23])[CH:9]=2)[N:4]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COc1ccc2cc(Nc3ccccc3N)cc(C)c2n1
Product: COc1ccc2cc(-n3c(=O)[nH]c4ccccc43)cc(C)c2n1

Procedure:
This compound, m.p. 280°, was prepared similarly to Example 16 using 2-methoxy-6-[(N-2-aminophenyl)-amino]-8-methylquinoline, and carbonyl diimidazole as starting materials. The product was characterised spectroscopically and used directly in Example 3 without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]O)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:30])(=O)=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:14])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][Cl:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COC/C=C\CO
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)COC/C=C\CCl

Procedure:
To a solution of 420 mg of 2-[4-hydroxy-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester in 10 ml of N,N-dimethylformamide, 1.00 g of 2,4,6-collidine and 350 mg of lithium chloride were added. While stirring under ice cooling, 0.64 ml of methanesulfonyl chloride was added dropwise, followed by stirring at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate after adding iced water, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of the desired compound as a colorless oily substance.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:32](Br)[CH:33]=[CH2:34].O>CN(C=O)C>[CH2:34]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH:23]([CH3:25])[CH3:24])[CH:33]=[CH2:32]
Reactant: C=CCBr
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C(C)C)CO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C(C)C
Temperature: 50 °C
Yield: 90.5 %

Procedure:
A suspension of (3R)-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.010 g, 0.028 mmol) and K2CO3 (0.019 g, 0.140 mmol) in DMF (1.0 mL) was treated with allyl bromide (0.024 mL, 0.280 mmol) and heated at 50° C. for 16 h. The reaction mixture was poured into 25 mL water and extracted with EtOAc (2×25 mL). The extracts were washed with 25 mL each water and brine, dried over MgSO4, filtered and concentrated to a yellow oil. Column chromatography (5–10% EtOAc in hexane gradient) gave 0.010 g (91%) of (3R)-4-allyl-3,4-dihydro-8-isopropoxy-3-isopropyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a yellow oil. This material (0.006 g, 0.015 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (1.0 mL) heated at 70° C. for 1 h to afford 0.004 g (80%) of Compound 126, a yellow solid. Rf 0.6 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 11.82 (broad s, 1H), 7.12 (d, 1H, J=8.9), 7.11 (s, 1H), 6.93 (d, 1H, J=8.9), 5.92–5.81 (m, 1H), 5.27–5.17 (m, 2H), 4.48 (d, 1H, J=10.9), 3.99 (dd, ABX, 1H, J=16.4, 5.8), 3.84 (dd, ABX, 1H, J=16.4, 5.8), 3.77 (dd, ABX, 1H, J=10.9, 2.8), 2.96–2.93 (m, 1H), 1.94–1.84 (m, 1H), 0.98 (d, 3H, J=6.7), 0.96 (d, 3H, J=6.7).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9]C)[CH:8]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([O:24]C)[CH:17]=1)=[O:15]>>[OH:22][C:20]1[CH:21]=[C:16]([C:14]2[O:15][C:5]3[C:6](=[C:7]([OH:9])[CH:8]=[C:3]([OH:2])[CH:4]=3)[CH:13]=2)[CH:17]=[C:18]([OH:24])[CH:19]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Product: Oc1cc(O)cc(-c2cc3c(O)cc(O)cc3o2)c1
Yield: 74 %

Procedure:
This compound was prepared using Method A from 3,5-dimethoxyphenol and 2-bromo-1-(3,5-dimethoxyphenyl)ethanone: Yield 74% following procedures A.2 and A.5; m.p. 244° C. (dec.); IR 3349, 2920, 1610, 1442, 1252, 1134 cm−1; 1H-NMR (500 MHz, δ ppm, DMSO-d6) 9.78 (s, 1H), 9.33 (s, 2H), 9.32 (s, 1H), 7.01 (s, 1H), 6.62 (d, J=2.0, 2H), 6.39 (s, 1H), 6.19-6.15 (m, 2H); 13C-NMR (126 MHz, δ ppm, CD3OD) 160.0, 158.6, 157.9, 154.5, 152.4, 134.1, 112.9, 103.9, 103.4, 99.8, 98.8, 90.8.