Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=[O:12].[Cl:24][C:25](Cl)([Cl:30])[C:26]([F:29])([F:28])[F:27]>[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[C:25]([Cl:30])([Cl:24])[C:26]([F:29])([F:28])[F:27]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: OC(COCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(Cl)(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 63.4 %

Procedure:
To a mixture of 2.01 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde, 1.31 g of zinc dust and 10 ml of N,N-dimethylformamide was added 4.12 g of 1,1,1-trichlorotrifluoroethane. After stirring at room temperature for 1.5 hours, the reaction mixture was filtered. The filtrate was poured into 20 ml of diluted hydrochloric acid and extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 1.76 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(3,3-dichloro-4,4,4-trifluoro-2-hydroxybutyloxy)butyloxy)benzene (yield, 63%), nD24.2 1.5188.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][CH:16]2[OH:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:24][CH2:25][CH:21]([N:18]3[CH2:19][CH2:20][C@H:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[C@H:16]([OH:35])[CH2:17]3)[C:22]2=[O:34])=[CH:28][CH:29]=1
Reactant: [H][H]
Reactant: O=C1C(N2CCC(c3ccc(OCc4ccccc4)cc3)C(O)C2)CCN1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C1C(N2CC[C@H](c3ccc(O)cc3)[C@H](O)C2)CCN1Cc1ccc(F)cc1
Yield: 101.2 %

Procedure:
A mixture of 3-(4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)-pyrrolidin-2-one (D2 from step E, 85 mg, 0.18 mmol), methanol (5 mL), and 38 mg 10% Pd/C was stirred in a pressure vessel overnight under 125 psi hydrogen pressure. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness to yield 70 mg of racemic 1-(4-fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one. LCMS (method J) RT=0.63 (52% AP), 0.66 (31% AP) min, m/z 385.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27-7.28 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (d, J=8.4, 2H), 6.45 (d, J=8.4, 2H), 4.39 (d, J=15, 1H), 4.32 (d, J=15, 1H), 3.74-3.76 (m, 1H), 3.66 (m, 1H), 3.47 (m, 1H), 3.10-3.18 (m, 2H), 3.01 (m, 1H), 2.85-2.88 (m, 1H), 2.76 (m, 1H), 2.30-2.40 (m, 1H), 2.06-2.11 (m, 2H), 1.80-1.95 (m, 1H), 1.46 (d, J=12, 1H). The complete relative stereochemistry was not determined.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].CN(C=O)C.[OH:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20]>C(OCC)C>[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH:23]=[C:24]([O:26][S:27]([C:30]([F:33])([F:31])[F:32])(=[O:29])=[O:28])[CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH3:9]
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
With cooling with ice, potassium carbonate (152 mg, 1.10 mmol) and iodoethane (0.088 mL, 1.10 mmol) were added to a DMF solution (2.0 mL) of methyl 3-hydroxy-5-trifluoromethane-sulfonyloxybenzoate (300 mg, 1.00 mmol), and stirred at room temperature for 14 hours. The reaction mixture was diluted with diethyl ether (30 mL), then washed with water and aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[N:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=1)=[C:2]=[O:3].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1>C(Cl)Cl>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:8]1[CH:7]=[C:6]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])[N:5]=[C:4]([NH:1][C:2](=[O:3])[N:23]([CH3:22])[C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:33])[F:34])=[CH:26][CH:25]=2)[N:9]=1
Reactant: CNc1ccc(OC(F)(F)F)cc1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Solvent: ClCCl
Product: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(OC(F)(F)F)cc1
Reaction time: 18 h
Yield: 38.6 %

Procedure:
To a solution of 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (400 mg, 1.26 mmol) in CH2Cl2 (1 mL) was added a solution of N-methyl-4-(trifluoromethoxy)aniline (285 mg, 1.50 mmol) in CH2Cl2 (2 mL). The resulting solution was stirred 18 h and then concentrated. The resulting residue was purified by column chromatography (silica, hexanes/EtOAc) to afford 7 as a white solid (247 mg, 38% yield): m.p. 100-102° C.; 1H NMR (CDCl3) δ 7.39 (app s, 4H), 5.96 (s, 1H), 6.82 (bs, 1H), 4.77-4.69 (q, 4H, J=8.5 Hz); ESI/MS 509 (M+H), 507 (M−H).
Reaction SMILES: [Na].[CH2:2]([CH:5]1[S:9][C:8](=[O:10])[NH:7][C:6]1=[O:11])[CH2:3][CH3:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>CN(C)C=O>[CH2:2]([CH:5]1[S:9][C:8](=[O:10])[N:7]([CH2:16][CH2:15][CH2:14][CH2:13][Br:12])[C:6]1=[O:11])[CH2:3][CH3:4]
Reactant: BrCCCCBr
Reactant: CCCC1SC(=O)NC1=O
Agent: [Na]
Solvent: CN(C)C=O
Product: CCCC1SC(=O)N(CCCCBr)C1=O
Yield: 67 %

Procedure:
The sodium salt of 5-(propyl)-2,4-thiazolidinedione (1.59 g., 0.0088 mole) in 80 ml. of dry dimethylformamide is slowly added to 1,4-dibromobutane (5.68 g., 0.026 mole) in 20 ml. of dry dimethylformamide according to the procedure of Example 1(b) affords a 67% yield of 5-(propyl)-3-(4-bromobutyl)-2,4-thiazolidinedione, b.p. 117°-120° C. at 0.02 mmHg.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24](O)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30].S(Cl)(Cl)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[NH:21][CH:20]=[C:19]([C:22]#[N:23])[N:18]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:24]([N:34]3[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]3)([CH3:26])[CH3:25])[N:9]=2)=[CH:4][CH2:3]1
Reactant: CCN1CCNCC1
Reactant: CC1(C)CC=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCN1CCN(C(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)n2)CC1

Procedure:
The title compound is prepared from 5-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-amide (as prepared in the previous step), N-ethylpiperizine, and thionyl chloride in DCM solvent according to the procedure in Example 14, step (e).
Reaction SMILES: [NH2:1][N:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:3]1=O.C(O[C:17](=[NH:30])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:19]=1)C>C(OCC)C>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([C:17]2[N:30]=[C:3]3[C:4]4[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=4[CH2:6][CH2:7][CH2:8][N:2]3[N:1]=2)=[CH:23][CH:22]=1
Reactant: CCOC(=N)c1ccc(-c2ccccc2)cc1
Reactant: NN1CCCc2ccccc2C1=O
Solvent: CCOCC
Product: c1ccc(-c2ccc(-c3nc4n(n3)CCCc3ccccc3-4)cc2)cc1
Yield: 63 %

Procedure:
This compound was prepared according to the procedure of Example 3 starting from 2-amino-4,5-dihydro-2-benzazepine-1(2H,3H)-one and 4-phenyl-benzimidic acid ethyl ester. Yield 63%. M.p. 135°-37° C. (from diethyl ether).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:23]([O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCCl.ClCCl>[CH2:1]([NH:8][C@H:36]1[CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][C@H:31]1[O:30][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(OCc2ccccc2)C1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.6 %

Procedure:
Benzylamine (1.47 g, 13.7 mmol) and sodium (triacetoxy)borohydride (5.30 g, 25 mmol) were added to a solution of tert-butyl 3-(benzyloxy)-4-oxopiperidine-1-carboxylate obtained in Example (90b) (3.81 g, 12.5 mmol) in 1,2-dichloroethane (40 mL), and the mixture was stirred at room temperature for 40 minutes. The reaction solution was diluted with dichloromethane, washed with a 1 N aqueous sodium hydroxide solution and brine, and dried over magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=4/1, 1/1, 1/3, 0/1) to obtain 4.34 g of the title compound as a colorless solid (91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:34](OC(N1CCC2(CCNC2)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:34][C:10]2([CH2:14][CH2:13][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2)C1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)C2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a pale yellow oil (96 mg, 67%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(CC(=O)O)cc1OCC2

Procedure:
Methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and lithium hydroxide were reacted to give 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid. M/z 354.1, calc. 353.15
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:22])=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)N2CCOCC2)s1
Yield: 83 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using morpholine instead of 4-aminotetrahydropyran, to the title compound (83 mg, 83%) which was obtained as a yellow solid after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=401.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)(=[O:27])=[O:26])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
To a solution of (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester (296 mg, 1.25 mmol) in CH2Cl2 at 0° C. was added pyridine-3-sulfonyl chloride hydrochloride (279 mg, 1.31 mmol) followed by Et3N (0.36 mL, 2.6 mmol). The reaction was stirred at room temperature for 24 h and was quenched with a 1:1 solution of water and saturated aqueous NaHCO3. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (1:1 hexanes:EtOAc) provided the title compound as a white solid (369.5 mg). 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.75 (m, 1H), 8.09 (d, 1H), 7.44 (m, 1H), 7.15 (m, 1H), 6.76 (m, 3H), 5.23 (bs, 1H), 4.44 (s, 2H), 4.16 (d, 2H), 1.47 (s, 9H); MS 379 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Br:10])[CH:5]=[C:4]([F:11])[C:3]=1[NH:12][C:13](=[O:15])[CH3:14].[H-].[Na+].Br[CH2:19]/[CH:20]=[CH:21]/[C:22]([O:24][CH2:25][CH3:26])=[O:23].O>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Br:10])[CH:5]=[C:4]([F:11])[C:3]=1[N:12]([CH2:19]/[CH:20]=[CH:21]\[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13](=[O:15])[CH3:14]
Reactant: COc1c(Br)cc(F)c(NC(C)=O)c1Br
Reactant: CCOC(=O)/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\CN(C(C)=O)c1c(F)cc(Br)c(OC)c1Br
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To the solution of 8-6 (1.3 g, 3.82 mmol) in THF (20 mL) at room temperature was added NaH (100 mg, 4.2 mmol, dispersed in mineral oil, 60%). The mixture was stirred for 30 min until no gas was released. (E)-ethyl 4-brombut-2-enoate (0.88 g, 4.58 mmol) in THF (5 mL) was added. The mixture was stirred overnight at room temperature. TLC showed that the reaction was completed. Water was added to the reaction mixture and extracted with ethyl acetate (50 mL×3). The combined organic layers were combined and were concentrated in vacuo. The residue was purified by flash chromatography (silica gel, elution with ethyl acetate/petroleum=1:8 to 1:2) to afford 8-7 (1.6 g, 92.4%) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13]CC1C=CC=CC=1)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(/C=C/C(=O)O)cn1
Yield: 60.9 %

Procedure:
A solution of 2-amino-5-bromopyridine (2.25 g, 13.0 mmole), benzyl acrylate (3.2 g, 19.7 mmole), Pd(OAc)2 (0.31 g, 1.4 mmole), tri-ortho-tolylphosphine (0.73 g, 2.4 mmole), and diisopropylethylamine (3.5 mL, 20.0 mmole) in propionitrile (50 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica gel (3% MeOH/CH2Cl2) gave the title compound (1.3 g, 39%): MS (ES) m/e 255 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([F:29])[C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[C:22]([F:29])=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=463.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:40]=[CH:39][C:22]4[O:23][CH:24]([CH2:27]OS(C5C=CC(C)=CC=5)(=O)=O)[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:41])[C:9]1=[O:42].[CH3:43][NH:44][CH3:45]>CN1C(=O)CCC1.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:18][C:19]3[CH:40]=[CH:39][C:22]4[O:23][CH:24]([CH2:27][N:44]([CH3:45])[CH3:43])[CH2:25][O:26][C:21]=4[CH:20]=3)=[N:14][CH:15]=2)[N:10]([CH3:41])[C:9]1=[O:42]
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3cc(Nc4ncc5c(n4)N(C)C(=O)N(c4ccccc4Br)C5)ccc3O2)cc1
Reactant: CNC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: CN(C)CC1COc2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3ccccc3Br)C4)ccc2O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
90 mg of the tosylate from example 4 in 8 ml NMP were treated with 0.62 ml 2 M dimethylamine in THF and stirred at room temperature for 3 d. The mixture was heated to 50° C. for 4 hrs, then to 65° C. for another 2 hrs. Stirring was continued at 45° C. over night. Separation by HPLC-MS yielded crude product contaminated by NMP, which was further purified by dissolving in CHCl3 and washing with water.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([CH2:23][PH:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)CC)C>C(#N)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([O:26][P:24]([CH2:23][P:18]([O:17][CH2:15][CH3:16])([O:19][CH2:20][CH3:21])=[O:22])([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH2:6][C:5]2([CH3:14])[CH3:13])=[O:25])[CH3:28]
Reactant: CC1(C)CC(=O)Oc2ccc(Br)cc21
Reactant: CCO[PH](=O)CP(=O)(OCC)OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(=O)(CP(=O)(OCC)c1ccc2c(c1)C(C)(C)CC(=O)O2)OCC
Temperature: 100 °C
Yield: 73.9 %

Procedure:
A mixture of 6-bromo-4,4-dimethylchroman-2-one (3.5 g, 9.7 mmol), diethyl(ethoxyphosphinyl)methylphosphonate (1.7 g, 9.7 mmol), triethylamine (4.1 mL, 29 mmol) and Pd(PPh3)4 (0.56 g, 0.48 mmol) in acetonitrile (20 mL) was heated to 100° C. for 18 hr. The reaction mixture was cooled and diluted with acetonitrile (50 mL) followed by washing with aqueous HCl (10%), water and saturated aqueous NaCl. The organic phase was dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (0-10% methanol in CH2Cl2) on a Biotage™ flash chromatography system, resulting in 120 as pale yellow oil (3.0 g, 73%): 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J=7.2, 3H), 1.30-1.37 (m, 6H), 1.40 (s, 6H), 2.61 (dd, J=1.7, 17.2, 20.7, 2H), 2.66 (s, 2H), 3.95-4.08 (m, 2H), 4.11-4.21 (m, 4H), 7.16 (dd, J=3.1, 8.3, 2H), 7.73 (dd, J=3.1, 8.3, 2H): 31P (162 MHz, CDCl3) δ 20.07 (d, J=7.7, 1 P), 33.74 (d, J=7.7, 1 P).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])[CH2:19][CH3:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:26]=[CH:27][C:22]([C:18]([CH3:17])([CH3:21])[CH2:19][CH3:20])=[CH:23][CH:24]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CCC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CCC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 123 mg of 4-(1,1-dimethyl-propyl)-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.59 (t, 3H, J=7.2 Hz), 1.23 (s, 6H), 1.61 (q, 2H, J=7.2 Hz), 7.28 (d, 1H, J=2.8 Hz), 7.36 (m, 2H), 7.53 (m, 3H), 7.67-7.74 (m, 3H), 8.84 (m, 2H), 10.14 (s, 1H). MS: m/z 443.9 (M++1).
Reaction SMILES: Cl[CH2:2][CH:3]=O.[CH3:5][O:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10][CH:9]=1>C(O)C>[CH3:5][O:6][C:7]([C:8]1[CH:13]=[CH:12][C:11]2[N:10]([CH:2]=[CH:3][N:14]=2)[CH:9]=1)=[O:15]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=CCCl
Solvent: CCO
Product: COC(=O)c1ccc2nccn2c1

Procedure:
To a solution of 50% aq. chloroacetaldehyde (1.1 eq, 36 mmol, 4.6 ml) in ethanol (120 ml) is added 6-amino-nicotinic acid methyl ester (1 eq, 33 mmol, 5 g) at room temperature. The reaction mixture is heated at reflux for 18 hours. The solvent is removed in vacuo and the crude product is dissolved in water (400 ml). The aqueous solution is treated with sodium bicarbonate to pH=8 and extracted with DCM (3×250 ml). The organic layer is dried (MgSO4) and evaporated to give the title compound as a beige solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:16]>CN(C)C=O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([CH2:14][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2([CH3:12])[CH3:1])=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC1(C)CCc2ccccc2N1
Solvent: CN(C)C=O
Product: CC1(C)CCc2ccccc2N1CC(=O)c1ccc(F)cc1
Yield: 85.2 %

Procedure:
A stirred mixture of 2,2-dimethyl-1,2,3,4-tetrahydroquinoline (4.69 g) and 2-bromo-4'-fluoroacetophenone (3.17 g) in dry N,N-dimethylformamide (6 ml) was heated at 70°-80° C. for 5 hours under nitrogen. The reaction mixture was poured was triturated with diethyl ether to give pale yellow crystals. The crystals were collected and washed with methanol to give N-(4-fluorobenzoylmethyl)-2,2-dimethyl-1,2,3,4-tetrahydroquinoline (3.7 g).