Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([Cl:13])[CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Br[CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]([O:20]CC)=[O:19].Cl>O.C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:17]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:18]([OH:20])=[O:19])=[C:8]([Cl:13])[CH:7]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccc(O)c(Cl)c1
Reactant: CCCCCCC(Br)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC(Oc1ccc(C(C)(C)CC)cc1Cl)C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 37.2 g of 4-t-amyl-2-chlorophenol, 200 ml of toluene, and 20.4 g of sodium hydroxide was heated to 80° C., and 40.3 g of ethyl 2-bromooctanoate was added dropwise thereto over a period of one hour, followed by reacting the mixture at that temperature for 3 hours. After cooling the mixture with water, 300 ml of water was added thereto, and 40 ml of concentrated hydrochloric acid was dropwise added. The organic layer was separated, washed twice with water, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 55 g of an oily substance.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: N[C@@H](Cc1ccccc1)C(=O)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
115 mg (0.200 mmol) of diastereomer B of (2R*,4S *)-2-benzyl-1-((S)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine are reacted with 30 mg (0.801 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR54## is obtained as white foam. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.20, FD-MS: M+ =478.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: OB(O)c1cc(Br)cc(Br)c1
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 3,5-dibromophenylboronic acid (2.58 g, 9.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.42 g, 13.8 mmol), K2CO3 (2.54 g, 18.4 mmol) and Pd(PPh3)2Cl2 (129 mg, 0.18 mmol) in THF (12 mL) and H2O (6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (2.3 g; 76% yield) as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C1COCC1>[C:20]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: Cc1ccc(O)cc1C(F)(F)F
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 4-methyl-3-(trifluoromethyl)phenol (5 g) and triethylamine (4.75 mL) in THF (40 mL) was added acetic anhydride (3.48 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (6.04 g).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=1.O>CN(C)C=O>[F:12][C:13]([F:24])([F:25])[O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:21]=2)=[CH:17][CH:16]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: NC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Oc1ccc(-c2coc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
2-Bromo-1-(4-hydroxyphenyl)ethanone (0.39 g) and 4-trifluoromethoxybenzamide (0.39 g) were dissolved in N,N-dimethylformamide (10 ml) and stirred at 140° C. for 2 hours. After cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25). The result was concentrated to dryness under reduced pressure to afford the title compound as a pale yellow solid (70 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6](=[O:10])[N:7]([CH3:9])[CH:8]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:28](Br)=[N:27][C:26]([Br:30])=[CH:25][N:24]=1)(=[O:21])=[O:20]>>[Br:30][C:26]1[N:27]=[C:28]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6](=[O:10])[N:7]([CH3:9])[CH:8]=2)[C:23]([NH:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=2[Cl:11])(=[O:21])=[O:20])=[N:24][CH:25]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl
Reactant: Cn1cc(CO)ccc1=O
Product: Cn1cc(COc2nc(Br)cnc2NS(=O)(=O)c2cccc(Cl)c2Cl)ccc1=O

Procedure:
Prepared by the method of Example 31 using 5-hydroxymethyl-1-methyl-1H-pyridin-2-one (0.1 g) and 2,3-dichloro-N-(3,5-dibromo-2-pyrazinyl)benzenesulphonamide (0.16 g). Yield 0.035 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:37]1([C:43]2([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:29][CH2:30][N:46]3[CH2:45][CH2:44][C:43]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:49]([NH2:51])=[O:50])[CH2:48][CH2:47]3)[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)CN2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)CN2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-phenacyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.22 g, 0.4 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.20 g, 0.8 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1.[N-:32]=[N+:33]=[N-:34].[Na+].O>CS(C)=O>[N:32]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH:14]([O:24][CH:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:11]=[CH:12][CH:13]=1)=[N+:33]=[N-:34]
Reactant: CN1CCC(OC(c2cccc(OCCCCCCl)c2)c2nc3ccccc3s2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(OC(c2cccc(OCCCCCN=[N+]=[N-])c2)c2nc3ccccc3s2)CC1
Temperature: 70 °C

Procedure:
A mixture of 2-[[3-(5-chloropentyloxy)phenyl](1-methyl-piperidin-4-yloxy)-methyl]benzothiazole (200 mg) and sodium azide (85 mg) in dimethylsulfoxide (3 mL) is heated overnight at 70° C., then cooled back to room temperature. Water is added and the product is extracted with ethyl acetate. Pooled extracts are washed with water, then brine, dried over magnesium sulfate and concentrated under reduced pressure to give 2-[[3-(5-azidopentyloxy)phenyl](1-methyl-piperidin-4-yloxy)methyl]benzothiazole used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O:21][C:22]1[C:23](=[O:38])[O:24][CH:25]([CH2:35][CH2:36]O)[C:26]=1[O:27]CC1C=CC=CC=1)C1C=CC=CC=1>CCOCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:3][C:2]([O:1][CH2:36][CH2:35][CH:25]2[O:24][C:23](=[O:38])[C:22]([OH:21])=[C:26]2[OH:27])=[CH:7][CH:6]=1
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: O=C1OC(CCOc2ccc(-c3ccccc3)cc2)C(O)=C1O
Yield: 32 %

Procedure:
Mitsunoble coupling of 0.20 g (1.2 mmol) of 4-hydroxy-1,1'-biphenyl with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 100 mg (32% yield) of 5-[2-((1,1'-biphenyl)-4-oxy)ethyl]-3,4-dihydroxy-2(5H)-furanone as a white powder after trituration with ether and hexanes: 1H NMR (acetone-d6) δ 7.71-7.02 (m, 9H), 4.97 (dd, J=4.9, 8.7 Hz, 1H), 4.25 (dd, J=2.6, 4.7 Hz, 2H), 2.58-2.41 (m, 1H), 2.10-1.92 (m, 1H). Anal Calcd for C18H16O5 +1H2O: C, 67.49; H, 5.66. Found: C, 67.34; H, 5.42.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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.O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1
Reactant: Ic1ccccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2ccccn2)cn1
Temperature: 96 °C

Procedure:
To a reaction tube were added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (220 mg, 1.00 mmol), 2-iodopyridine (205 mg, 1.00 mmol), Pd(PPh3)4 (57.7 mg, 0.05 mmol) and K3PO4 (424 mg, 2.00 mmol). The tube was subjected to vacuum and back filled with argon. Dioxane (3.0 ml) and water (0.3 ml) were added and the mixture was heated at 96° C. overnight. After cooled to room temperature, the reaction mixture was filtered through celite (washed with ethyl acetate) and concentrated by evaporation. The residue was redistributed between ethyl acetate (40 ml) and 0.1 N HCl solution (40 mL). The acidic aqueous phase was further extracted with ethyl acetate (40 ml×2) and treated with Na2CO3 to have pH around 9 and concentrated by evaporation of water. The solid residue was extracted with refluxing ethyl acetate (40 ml) to give 2,3′-bipyridin-6′-amine (124-1) which is used for reaction without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C>ClCCl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:14]
Reactant: Clc1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(CCCCCCCBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 74 h

Procedure:
To a stirring suspension of aluminium chloride (33.6 g) in dry dichloromethane (474 ml) was added 8-bromo-n-octanoyl chloride (67.8 g) over 10 min. Chlorobenzene (123 ml) was then added over 10 min and the mixture allowed to stir at 25° C. for 74 h and stood for 64 h. The mixture was poured into ice/water (540 ml) and diethyl ether (1.3 L). The organic layer was removed and was washed with water (540 ml), saturated sodium hydrogen carbonate (540 ml), water (400 ml) and brine (400 ml) and dried over magnesium sulfate. Removal of the organic layer under reduced pressure and chromatography of the residue on silica gel using 5% ethyl acetate in hexane gave 8-bromo-1-(4-chlorophenyl)octan-1-one (35.5 g). 1H-NMR (CDCl3) δ 1.2-1.6 (6H, m), 1.6-1.95 (4H, m), 2.95 (2H, t), 3,42 (2H, t), 7.43 (2H, m) and 7.90 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1ccc(F)cc1

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (1.95 g, 7.79 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography (1% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(4-fluoro-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ 7.12 (m, 2H), 6.97 (m, 2H), 5.75 (m, 1H), 3.83 (m, 1H), 3.60 (m, 1H), 2.71 (m, 2H), 2.36-2.24 (m, 3H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), −0.05 (d, 3H), −0.2 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:27]5[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:23][C:22]=5[C:21]([C:32]5[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=5)=[N:20]4)[CH2:12][CH2:11]3)=[C:8]([C:42](O)=[O:43])[S:7][C:6]=2[CH:45]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:79]([CH2:81][NH2:82])[OH:80]>CN(C=O)C>[OH:80][CH2:79][CH2:81][NH:82][C:42]([C:8]1[S:7][C:6]2[CH:45]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]2[C:27]3[CH2:26][CH2:25][N:24]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:23][C:22]=3[C:21]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=3)=[N:20]2)[CH2:14][CH2:15]1)=[O:43]
Reactant: NCCO
Reactant: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)O)sc4cc(F)ccc34)CC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CCCN2CCC(c3c(C(=O)NCCO)sc4cc(F)ccc34)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A stirred solution of 20 mg (0.03 mmol) of 6-fluoro-3-(1-{3-[5-methanesulfonyl-3-(4-trifluoromethyl-phenyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1-yl]-propyl}-piperidin-4-yl)-benzo[b]thiophene-2-carboxylic acid in 0.3 mL of dry DMF was treated with 14 mg (0.036 mmol) of HBTU and 8 μL (0.045 mmol) of DIEA. The solution was stirred for 5 min before the addition of 0.01 mL (0.15 mmol) of ethanol amine. The reaction was stirred at room temperature for 30 min then partitioned between EtOAc (30 mL) and saturated NaHCO3 (20 mL). The aqueous layer was further extracted with EtOAc (2×20 mL). The combined organic layers were then washed with brine, dried over Na2SO4, and concentrated. Purification by column chromatography (silica, 5-10% of 2 N NH3 in MeOH/CH2Cl2) yielded 16 mg (76%) of a white solid. MS (electrospray): exact mass calculated for C33H37F4N5O4S2: 707.22; m/z found, 708.2 [M+H]+. 1H NMR (CDCl3, 400 MHz): 7.97 (br s, 1H), 7.73 and 7.66 (A and B of AB quartet, J=8.41 Hz, 4H), 7.49 (dd, J=8.41, 2.35 Hz, 1H), 7.15 (dt, J=8.61, 2.54 Hz, 1H), 6.41 (t, J=5.67 Hz, 1H), 4.56 (s, 2H), 4.16 (t, J=7.04 Hz, 2H), 3.84 (dd, J=5.28, 4.70 Hz, 2H), 3.70 (t, J=5.67 Hz, 2H), 3.62 (m, 2H), 3.58 (br s, 1H), 3.05 (br m, 2H), 2.97 (t, J=5.67 Hz, 2H), 2.91 (s, 3H), 2.40 (br m, 4H), 2.13 (br m, 4H), 1.84 (br d, J=12.32 Hz, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([NH:30][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4ccccc4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and aniline (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-((phenylamino)methyl)-phenyl)-7-(4-methyl-phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 115) (0.1 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7](=[O:18])[C:6](=[O:19])[NH:5]2.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:20]([O-:22])=[O:21])[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:7](=[O:18])[C:6](=[O:19])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2n(C2CCCCC2)c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2n(C2CCCCC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
26.3 g (94 mmol) of 6-Chloro-1-cyclohexyl-2,3(1H,4H)-quinoxalinedione were dissolved in 275 ml of concentrated sulfuric acid and then, at 0° C., 9.5 g (94 mmol) of potassium nitrate were added a little at a time. The mixture was then stirred at 0° C. for 30 min and at 25° C. for 2 h and poured into ice-water. The precipitate was filtered off with suction to yield 29.5 g (97%) of the product.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([OH:24])=[C:19]([Cl:25])[CH:18]=1>>[Cl:23][C:21]1[CH:22]=[C:17]([NH2:16])[CH:18]=[C:19]([Cl:25])[C:20]=1[O:24][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Product: Nc1cc(Cl)c(Oc2nc3ccc(OC(F)(F)F)cc3s2)c(Cl)c1

Procedure:
3,5-Dichloro-4-(6-trifluoromethoxy-benzothiazol-2-yloxy)-phenylamine was synthesized (76%) from 2-chloro-6-trifluoromethoxybenzothiazole (413) and 4-amino-2,6-dichlorophenol (Aldrich) in a similar manner as described in Example 417. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J=1.6 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.44 (ddd, J=8.8, 1.6, 0.8 Hz, 1H), 6.74 (s, 2H), 5.87 (s, 2H). MS (EI): m/z 395 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22](S(C)(=O)=O)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[NH:43]1[CH:47]=[CH:46][N:45]=[C:44]1[CH2:48][NH2:49]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([C:18]3[C:19]4[CH:31]=[CH:30][C:29](=[O:32])[N:28]([C:33]5[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=5[F:40])[C:20]=4[N:21]=[C:22]([NH:49][CH2:48][C:44]4[NH:43][CH:47]=[CH:46][N:45]=4)[N:23]=3)[CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ncc[nH]1
Reactant: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from 6-chloro-N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-3-pyridinecarboxamide and (1H-imidazol-2-ylmethyl)amine dihydrochloride: LC-MS m/z 599 (M+H)+, 1.92 min (ret time).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O)(=[O:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[CH:2][C:1]([CH:4]1[C:9]([OH:10])=[C:8]([C:11](=[O:13])[CH3:12])[C:7](=[O:14])[O:6][C:5]1=[O:15])=[O:3])(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cccc(C=O)c1
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc(C=CC(=O)C2C(=O)OC(=O)C(C(C)=O)=C2O)c1

Procedure:
Similarly, 4.2 g. (0.02 m.) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 3.2 g. (0.02 m.) of m-acetamidobenzaldehyde, 200 ml. of chloroform and 0.5 ml. of piperidine is azeotroped for four hours and the reaction mixture is filtered to yield 3-(m-acetamidocinnamoyl)-5-acetyl-4-hydroxy-2H-pyran-2,6(3H)-dione, m.p. 222°-224° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:36]=[CH:35][C:14]([O:15][C:16]2[C:21]([C:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=3)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:25]1[CH2:24][CH:23]=[C:22]([C:21]2[C:16]([O:15][C:14]3[CH:35]=[CH:36][C:11]([NH:10][C:2]4[S:1][C:5]5[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=5[N:3]=4)=[CH:12][CH:13]=3)=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCNC1

Procedure:
Tert-butyl 4-(2-(4-(benzo[d]thiazol-2-ylamino)phenoxy)pyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (501.9 mg) was taken up in DCM and TFA was added. Upon completion, the solvent was evaporated. The residue was taken up in DCM and loaded onto an Agilent SCX cartridge. The impurities were washed from the cartridge with DCM and MeOH. N-(4-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-2-yloxy)phenyl)benzo[d]thiazol-2-amine was filtered from cartridge using 2.0M ammonia in MeOH. MS (ESI, pos. ion) m/z: 401.0 (M+1). IC50 (uM) +++++.