Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:5][N:4]([C:6]2[C:7]([F:29])=[CH:8][C:9]3[C:10]([CH:28]=2)=[N:11][C:12]2[N:13]([CH:25]4[CH2:27][CH2:26]4)[CH:14]=[C:15]([C:20]([O:22]CC)=[O:21])[C:16](=[O:19])[C:17]=2[CH:18]=3)[C@H:3]1[CH3:30].[OH-].[K+]>O>[NH2:1][C@@H:2]1[CH2:5][N:4]([C:6]2[C:7]([F:29])=[CH:8][C:9]3[C:10]([CH:28]=2)=[N:11][C:12]2[N:13]([CH:25]4[CH2:26][CH2:27]4)[CH:14]=[C:15]([C:20]([OH:22])=[O:21])[C:16](=[O:19])[C:17]=2[CH:18]=3)[C@H:3]1[CH3:30]
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4C[C@@H](N)[C@@H]4C)c(F)cc3cc2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@H]1[C@H](N)CN1c1cc2nc3c(cc2cc1F)c(=O)c(C(=O)O)cn3C1CC1
Temperature: 95 °C
Yield: 79 %

Procedure:
A suspension of 1.4 g of 8-(trans-3-amino-2-methyl-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 15 cm3 of water and 6.8 cm3 of N aqueous potassium hydroxide is heated to approximately 95° C. for 3 hours. After cooling to approximately 60° C., some very slight insoluble matter is removed by filtration; at the same temperature, 6.8 cm3 of N methanesulphonic acid are added to the filtrate. The insoluble matter formed is drained at approximately 20° C. and washed with 3 times 50 cm3 of water and twice 25 cm3 of ethanol. After recrystallization in 30 cm3 of dimethylformamide, one obtains 1.03 g of 8-(trans-3-amino-2-methyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid in the form of a yellow solid, which decomposes at 268°-270° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[N:9][C:10](=[O:13])[C:11]=2[CH3:12])=[CH:3][CH:2]=1.[C:14]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC([O-])=O>O1CCCC1>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[NH:9][N:8]=2)=[CH:5][CH:6]=1
Reactant: CC1=C(c2ccncc2)N=NC1=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)[O-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1[nH]nc(-c2ccncc2)c1C
Temperature: 2 °C

Procedure:
1.5 mg of 3-(4-pyridyl)-4-methyl-5-pyrazolone, 2.3 g of triphenylphosphine and 0.27 g of methanol were placed in 30 ml of tetrahydrofuran. The mixture was cooled on an ice bath to 2° C. and 1.6 g of ethyl azodicarboxylate dissolved in 9 ml of tetrahydrofuran was added dropwise.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][NH:6][C:5]1=[O:14].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[CH2:15]([N:6]1[CH2:7][CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([CH3:3])[C:5]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CNC(=O)C1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C1CN(Cc2ccccc2)C(=O)C1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a suspension of sodium hydride (2.30 g) in absolute dioxane (100 ml) was added dropwise ethyl 3-methyl-2-oxo-4-pyrrolidinecarboxylate (13.68 g) with stirring at room temperature. After stirring for 30 minutes, to a reaction mixture was added benzylbromide (16.42 g) during 20 minutes, then stirred for 2 hours and allowed to stand overnight at room temperature. The reaction mixture was poured into ice-water (100 ml) and extracted with chloroform, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by vacuum distillation to give ethyl 1-benzyl-3-methyl-2-oxo-4-pyrrolidinecarboxylate (16.86 g), bp 155°-185° C./2 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([O:15]C)=O)[NH:8]2)[CH3:2]>C(N)CCC>[CH2:7]([NH:8][C:13]([CH:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][CH2:1][CH3:2])[NH:8]1)=[O:15])[CH2:6][CH2:5][CH3:4]
Reactant: CCOc1cccc2c1CC(C(=O)OC)N2
Solvent: CCCCN
Product: CCCCNC(=O)C1Cc2c(cccc2OCC)N1

Procedure:
Methyl 4-ethoxyindoline-2(R/S)-carboxylate (0.84 g, 3.8 mmol) was dissolved in butylamine (40 ml), under nitrogen, and the solution was then stirred at reflux for three hours. After cooling the mixture, the remaining butylamine was removed under vacuum. The crude product was purified by chromatography on a column of silica gel, using a 5/5 petroleum ether/ethyl acetate mixture as eluent. A yellow solid was obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16])=O)=[CH:8][C:7]([CH3:22])=[CH:6][CH:5]=2.[CH3:23][N:24]([CH3:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=1.C(OC(=O)C)(=O)C>>[CH3:32][N:31]([CH3:33])[C:27]1[CH:26]=[C:25]([N:24]([CH3:34])[CH3:23])[CH:30]=[CH:29][C:28]=1[C:11]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:22])[CH:8]=3)[NH:3][C:2]=2[CH3:1])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1ccc2[nH]c(C)c(C(=O)c3ccccc3C(=O)O)c2c1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2[nH]c(C)c(C3(c4ccc(N(C)C)cc4N(C)C)OC(=O)c4ccccc43)c2c1
Yield: 76.4 %

Procedure:
A mixture of 2.0 g (0.007 mole) of 2-[(2,5-dimethyl-3-indolyl)carbonyl]benzoic acid from part A above, 1.1 g (0.007 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine and seven ml of acetic anhydride was interacted in a manner similar to that described in Example 3, part E above, to obtain 2.35 g of 3-[2,4-bis(dimethylamino)phenyl]-3-(2,5-dimethyl-3-indolyl)phthalide (Formula III: R0 =R1 =R2 =R3 =R6 =H; R=R5 =CH3 ; R4 =N(CH3)2 ; Y1 =CH3), a light purple solid melting over the range of 100°-125° C. The infrared showed a characteristic absorption maximum at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on acid clay or phenolic resin developed an intense violet-colored image.
Reaction SMILES: [C]=O.FC(F)(F)S(O[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2)(=O)=O.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C([SiH](CCCCCCCC)CCCCCCCC)CCCCCCC.CN([CH:89]=[O:90])C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:89]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=[CH:12]2)=[O:90]
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2cc(C=O)ccc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 36 %

Procedure:
Carbon monoxide (CO) gas was slowly bubbled through a solution of methyl 6-(((trifluoromethyl)sulfonyl)oxy)-1-naphthoate (334 mg, 1.0 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), 1,3-bis-(diphenylphosphino)propane (40 mg, 0.10 mmol) and triethylamine (0.28 mL, 2.0 mmol) an DMF (8.3 mL). After 15 min, trioctylsilane (0.90 mL, 2.0 mmol) was added as bubbling continued. The mixture was heated at 70° C., continuing to bubble CO into the solution. After 6 h at 70 the bubbling CO was replaced with a balloon of CO and the reaction mixture was stirred overnight. After 18 h at 70° C., the reaction was cooled to room temperature, diluted with EtOAc (150 mL) and washed with water (3×50 mL) and brine (50 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified on 40 g silica gel (100% hexanes→25% EtOAc/hexanes, gradient) to afford 78 mg (36%) of methyl 6-formyl-1-naphthoate.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:14][CH:13]([OH:15])[CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9])=[O:5].[SH:16][CH2:17][CH2:18]C(N1CCC[C@H]1C(O)=O)=O>>[CH2:17]([S:16][S:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:14][CH:13]([OH:15])[CH2:12][CH2:11][CH:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:18]
Reactant: O=C(O)C1CCC(O)CN1C(=O)CCS
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CCS
Product: CCSSCCC(=O)N1CC(O)CCC1C(=O)O

Procedure:
By substituting 1-(3-mercaptopropanoyl)-5-hydroxy-L-pipecolic acid for the 3-mercaptopropanoyl-L-proline in the procedure of Example 97, 1-[3-(ethyldithio)propanoyl]-5-hydroxy-L-pipecolic acid is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](=[S:28])[NH2:8])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: NC(=S)c1cc(C(F)(F)F)c(Cl)c(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 158 %

Procedure:
4-Chloro-3,5-bis(trifluoromethyl)benzamide (1.2 g, 1.0 eq.) was dissolved in toluene (20 mL) and Lawesson's reagent (3.32 g, 2.0 eq.) was added. The reaction mixture was stirred at 90° C. for 8 h then filtered. The filtrate was poured into water. The compound was extracted with EtOAc (3×100 mL). The combined organic layers was washed with brine (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 2 g of 4-chloro-3,5-bis(trifluoromethyl)benzothioamide (95% yield), which was used in the next step with no further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](O)(=[O:20])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([CH3:27])[CH:3]=1.[CH2:28]([NH2:30])[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([S:18](=[O:19])(=[O:20])[NH:30][CH2:28][CH3:29])=[C:13]3[N:12]=[CH:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:4]([CH3:27])[CH:3]=1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)O)cnn2c1Nc1ccc(Cl)cc1C
Reactant: CCN
Product: CCNS(=O)(=O)c1cnn2c(Nc3ccc(Cl)cc3C)c(C(=O)OCC)cnc12
Yield: 94.9 %

Procedure:
Using 7-(4-chloro-2-methylphenylamino)-6-(ethoxycarbonyl)pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (1.00 g, 2.43 mmol) obtained in step 2 and ethylamine (2.0 mol/L THF solution; 4.9 mL, 9.74 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (1.01 g, 95%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH:22](Br)[CH:23]=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]2[N:3]3[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]3=[N:1][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(C(Br)C=O)CC1
Reactant: Nc1ccc(Br)cn1
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccc(Br)cn23)CC1

Procedure:
The title compound was prepared from 2-amino-5-bromopyridine and 1-(t-butoxycarbonyl)-4-(1-bromo-2-oxoethyl)-piperidine (from Example 292, Step C) according to the general procedure described in Example 235, Step A.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].O=[C:12]([CH2:18][CH3:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:18]([C:12]1[O:3][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:1][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[CH3:19]
Reactant: CCC(=O)CC(=O)OC
Reactant: O=C(CBr)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1oc(-c2ccccc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
To a solution of phenacyl bromide (10 g) and methyl 3-oxopentanoate (6.5 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (7.5 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (1.9 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (6.7 g, 58%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.[O:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.COC[C@@H](O)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][C@H:16]([CH3:17])[CH2:15][O:14][CH3:18])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: C1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COC[C@H](C)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6-fluoro-2-methylquinolin-8-ol (0.50 g, 2.8 mmol) in tetrahydrofuran (2.4 mL, 2.8 mmol) was added triphenylphosphine (2.6 g, 9.9 mmol), diisopropyl azodicarboxylate (0.91 mg, 4.5 mmol), and (S)-1-methoxypropan-2-ol (0.33 mg, 3.7 mmol) and the resultant mixture allowed to stir at ambient temperature for 24 hours. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (2×20 mL). The combined organic extracts dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by normal phase chromatography on silica gel (0-2% methanol/dichloromethane) afforded the title compound which was taken on to the subsequent step without further purification, assuming theoretical yield (0.70 g, 100%) was obtained, despite being contaminated with residual triphenylphosphine oxide.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].C(C(CCCCCCCCCCCC)CO)CCCCCCCCC>>[CH2:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: OCCCCCCCCCCCCCCCO
Agent: CCCCCCCCCCCCC(CO)CCCCCCCCCC
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 240.5 %

Procedure:
A 54 g portion of the hydrogenated product obtained in Reference Example 2 and 0.2 g of magnesium oxide were put into the same apparatus of Inventive Example 1 and the reaction was carried out under conditions of 230 to 260° C. and 1.3 kPa to 130 Pa to obtain 15.2 g of a colorless liquid distillate 3 hours thereafter. This distillate contained 2.2 g of cyclopentadecanolide (yield 94%), 0.93 g of 1,15-pentadecanediol (recovery ratio 96%) and 11.3 g of 2-decyl-1-tetradecanol. The reaction residue was a light yellow liquid having a viscosity of 85 mPa·s, and 28.4 g of di-2-decyl-1-tetradecyl pentadecandioate was recovered from the residue (recovery ratio 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10]/[CH:11]=[N:12]/[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:19][Mg]Br.C1COCC1>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH:11]([NH:12][S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH3:19])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/CCc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CCc1ccc(Cl)c(Cl)c1)N[S@@](=O)C(C)(C)C
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of Intermediate 16B (4.00 g, 13.1 mmol) in DCM (50 mL) was added slowly a solution of methylmagnesium bromide in toluene and THF (13.99 mL, 1.400 M, 19.59 mmol) and the reaction mixture was heated to reflux for 2.5 h. The reaction mixture was allowed to cool to rt and, diluted with DCM, washed with saturated NH4Cl, and the organic portion dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50% over 30 min, column 330 g, flow rate 100 mL/min) to give Intermediate 16C (2.80 g, 8.69 mmol, 67.0% yield) as a white solid. HPLC/MS (Method D) RT=1.12 min, [M+1]+ 322.1; Chiral HPLC (Method L) RT=4.55 min, PA=100%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a white solid (240 mg, 46%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=3[S:11][CH:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][O:17][C:14]1[CH:15]=[CH:16][C:9]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[CH:12][S:11][C:10]=2[CH:13]=1
Reactant: BrCCCCBr
Reactant: Oc1ccc2c(-c3ccc(Br)cc3)csc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)csc2c1
Temperature: 45 °C
Reaction time: 10 h
Yield: 93.6 %

Procedure:
2.0 g (6.55 mmol) 3-(4-Bromo-phenyl)-benzo[b]thiophen-6-ol in 25 ml acetone were treated with 5.89 g (42.6 mmol, 6.5 eq) K2CO3 and 2.0 ml (16.38 mmol, 2.5 eq) 1,4-dibromobutane. The reaction mixture was stirred at 45° C. for 10 h, filtered and evaporated. The excess of dibromide was removed in vacuo to yield 2.7 g crude 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[b]thiophene, MS: 439 (M).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:21]([I:22])=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O.O.C(OCC)(=O)C>[I:22][C:21]1[C:4]([O:3][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(I)cc2CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(I)c(OCc3ccccc3)cc2CC1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 576 mg, 14.4 mmol) was added to a stirred solution of 1,1-dimethylethyl 7-hydroxy-8-iodo-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (D41) (4.67 g, 12 mmol) in dimethylformamide (30 ml). After 15 minutes, benzyl bromide (2.04 g, 1.4 ml, 12 mmol) was added and the mixture stirred for 2 hours. The mixture was diluted with water and ethyl acetate, the organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a mixture of ethyl acetate:hexanes (1:10) to afford the title product (D44).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[CH:2].C(N(CC)CC)C.[Cl:17][CH:18]([Cl:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH:18]([Cl:22])[C:19]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[C:1]#[CH:2])=[O:20]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C#Cc1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccccc1NC(=O)C(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Ethynylaniline (1.0 g, 8.53 mmol) was dissolved in anhydrous dichloromethane (20 mL) with triethylamine (1.6 mL, 11.0 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (0.875 mL, 8.53 mmol) in anhydrous dichloromethane (20 mL) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound as a beige solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:17]([O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]([NH2:7])[CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:15][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCN(CC)CC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.6 %

Procedure:
A solution of 171 mg (0.4 mmol) [2-(4-benzyloxy-phenyl)-1-(diethylamino-methyl)-ethyl]-carbamic acid tert-butyl ester in 2 mL dichloromethane was treated with 0.5 mL 2,2,2-triflouroacetic acid and the resulting solution stirred 3 hours at 25° C. The mixture was concentrated at reduced pressure to a viscous amber oil to which was added 30 mL saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with three 20 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure and the residue purified by column chromatography using ethyl acetate containing 1% methanol as eluent. There was obtained 112 mg (90%) of (S)-3-(4-benzyloxy-phenyl)-N1,N1-diethyl-propane-1,2-diamine as a clear, colorless oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20]/[C:21](=[N:24]/[H])/[NH:22][OH:23])=[CH:16][CH:15]=1.[O:26]=[C:27]1[C:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][N:28]1[CH2:45][C:46](O)=O>ClC(Cl)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[N:24]=[C:46]([CH2:45][N:28]3[CH2:29][CH2:30][CH2:31][C:32]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:26])[O:23][N:22]=2)=[CH:16][CH:15]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(/Cc1ccc(Cl)cc1)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(Cc3ccc(Cl)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.160 g, 0.837 mmol), (Z)-2-(4-chlorophenyl)-N-hydroxyacetimidamide (0.103 g, 0.558 mmol) and 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.173 g, 0.558 mmol; Example 68E) were stirred together in dichloroethane at room temperature for 2 hours, then heated to 85° C. for 16 hours. The reaction was cooled and concentrated. The residue was dissolved in dichloromethane (3 mL) and washed with water (1 mL). The organic layer was concentrated and the residue was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 7.38-7.15 (m, 14H), 4.82 (s, 2H), 4.06 (s, 2H), 3.53 (t, J=6.5, 2H), 2.73-2.58 (m, 2H), 1.95-1.76 (m, 2H); MS (ESI+) m/z 458.1 (M+H)+.