Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31][C:32]3C=CC=C4C(=O)NCC[C:38]=2[C:37]=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.N1CCCC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][N:31]5[CH2:32][CH2:37][CH2:38][CH2:30]5)=[CH:17][CH:18]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Solvent: C1CCNC1
Product: O=C1NCCc2c(-c3ccc(CN4CCCC4)cc3)[nH]c3cc(F)cc1c23

Procedure:
In a manner similar to that described for Compound PPP, 4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl) benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 from 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with pyrrolidine (115 mg, 1.62 mmol) to yield 8-fluoro-2-(4-pyrrolidin-1-ylmethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3 -cd]indol-6-one, 16 mg (14%) as a yellow solid: m.p. 264-265° C. (dec), 1H NMR (300 MHz, d6-DMSO) 1.72 (m, 4H), 2.49 (m, 4H), 3.04 (m, 2H), 3.39 (m, 2H), 3.64 (br s, 2H), 7.31 (dd, J=9.3, 2.4 Hz, 1H), 7.43 (m, 3H), 7.58 (d, J=8.1 Hz, 2H), 8.2 (br t, 1H), 11.66 (br s, 1H). HRMS (MALDI MH+) Calcd for C22H22N3OF: 362.1825. Found: 364.1810. Anal. (C22H22N3OF.0.5 H2O) C, H, N.
Reaction SMILES: [Na].CCO.[C:5]([NH:8][CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1>O1CCOCC1>[C:5]([NH:8][C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[C:24]([CH2:30][CH3:31])[CH:23]=1)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:7])[CH3:6]
Reactant: CCc1ccc(CBr)cc1CC
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(CC)c(CC)c1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere 8.14 g (354 mmol) of sodium was added in batches to 200 mL abs. EtOH and stirred until fully dissolved. 76.9 g (354 mmol) diethyl 2-acetylaminomalonate was then added to this solution, whereupon the sodium salt formed was precipitated. After the addition of 150 mL 1,4-dioxane a solution of 80 g (352 mmol) of 4-bromomethyl-1,2-diethyl-benzene in 500 mL of 1,4-dioxane was added dropwise to this suspension. The reaction solution was kept at 50° C. for 2 hours and then stirred for 16 hours at RT. The solvent was distilled off i. vac., the oily residue was combined with water, while the product was obtained in the form of white crystals. These were suction filtered, washed with water and reacted without any further purification.
Reaction SMILES: N1(CC[C@@H](NC2C=CC(S(N)(=O)=O)=CC=2S(C(F)(F)[F:33])(=O)=O)CSC2C=CC=CC=2)CCOCC1.[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43](Cl)(=[O:45])=[O:44].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[S:43]([F:33])(=[O:45])=[O:44]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c(S(=O)(=O)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=S(=O)(F)c1ccccc1F

Procedure:
Scheme 2 shows two routes used to make 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). One route involves reacting commercially available 2-fluorobenzenesulfonyl chloride (11) with TBAF (tetra-n-butylammonium fluoride) to provide 2-fluorobenzenesulfonyl fluoride (12). The reaction is typically performed below room temperature in a solvent such as but not limited to tetrahydrofuran. 2-Fluorobenzenesulfonyl fluoride (12) can be converted to 1-fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) by reaction with Ruppert's reagent (CH3SiCF3) catalyzed by (((CH3)2N)3S)+(F2Si(CH3)3)−, also known as TASF. The reaction is typically performed at about room temperature in a solvent such as but not limited to tetrahydrofuran, dichloromethane, toluene, dimethoxyethane, or mixtures thereof. 1-Fluoro-2-((trifluoromethyl)sulfonyl)benzene (13) can be reacted with chlorosulfonic acid to provide 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14). The reaction is typically performed at an elevated temperature before cooling for the addition of SO2Cl2, used to quench the chlorosulfonic acid. 4-Fluoro-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (15) can be prepared from 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonyl chloride (14) by reacting the latter with aqueous ammonium hydroxide. The reaction is typically performed in a solvent such as acetonitrile, tetrahydrofuran, ethyl acetate, isopropyl alcohol, isopropyl acetate, dimethoxyethane, dichloromethane, toluene, or mixtures thereof. (1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propylamine (16), prepared as described in U.S. Pat. No. 7,390,799 B2, can be reacted with 4-fluoro-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (15) in the presence of a base such as but not limited to triethylamine, to provide 4-(((1R)-3-morpholin-4-yl-1-((phenylthio)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide (17). The reaction is typically performed at elevated temperatures in a solvent such as but not limited to ethyl acetate.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH2:15]([O:14][C:12]([C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][N:6]2[CH:8]=1)([CH3:18])[CH3:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: C1CNCCN1
Product: CCOC(=O)C(C)(C)c1cn2nc(N3CCNCC3)ccc2n1
Yield: 100 %

Procedure:
Using ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate (2.00 g) and piperazine (19.7 g), and by a reaction at 100° C. in the same manner as in Example 196 (1), 1-[2-(1-ethoxycarbonyl-1-methylethyl)-6-imidazo[1,2-b]pyridazinyl]piperazine (2.37 g) was obtained as an oil.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[N:7][CH:6]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)nc3)CC2)c(C)c1
Yield: 62.2 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (749 mg) described in Preparation Example 20 and oxazolidin-2-one (174 mg), the title compound (473 mg) was obtained.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:18][C:19]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>C(O)(=O)C>[C:29]([C:27]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([NH:18][CH2:1][CH3:2])[CH:28]=1)#[N:30]
Reactant: COC(=O)c1ccc(C#N)cc1N
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1cc(C#N)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Acetaldehyde (90%)(10 mL) and sodium triacetoxyborohydride (7.71 g, 36.4 mmol) were added to an acetic acid solution (10 mL) of methyl 2-amino-4-cyanobenzoate (3.04 g, 17.3 mmol) under ice cooling. The mixture was stirred at the same temperature for an hour and at room temperature for 2 hours. Ice water was added to the reaction mixture, the mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with water and then saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crystals obtained were washed with diisopropyl ether-hexane to give the title compound (800 mg, 23%). The residue was applied to silica gel column chromatography (hexane/ethyl acetate=50:1 and then 30:1). The crystals obtained were washed with hexane to give the title compound (920 mg, 26%).
Reaction SMILES: N(C(OC(C)C)=O)=NC(O[CH:6](C)[CH3:7])=O.[O:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)C>C1COCC1>[O:25]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:15])[N:17]1[N:26]([CH2:6][CH3:7])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: CC(C)(C)OC(=O)NN1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Yield: 90 %

Procedure:
Diisopropyl azodicarboxylate (2.92 mL, 15.00 mmol) was added in one portion to a solution of tert-butyl 1,3-dioxoisoindolin-2-ylcarbamate (2.62 g, 10 mmol, prepared following the procedure described by Nicolas Brosse et al. in Eur. J. Org. Chem. 4757-4764, 2003), triphenylphosphine (3.93 g, 15.00 mmol) and ethanol (0.691 g, 15.00 mmol) in THF (20 mL) at 0° C. and the reaction solution was stirred at room temperature for 1 h (monitored by TLC until completion). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes) to provide tert-butyl 1,3-dioxoisoindolin-2-yl(ethyl)carbamate (2.6 g, 90% yield) as a white solid which was used as it in the next step
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9](C(OCC2C=CC=CC=2)=O)[C:10]2[C:15]([C:16]=1[NH:17][C:18]([NH:20][C:21]1[C:25]([C:26](OC)=[O:27])=[CH:24][S:23][CH:22]=1)=[O:19])=[CH:14][C:13]([C:30]([F:33])([F:32])[F:31])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C(OCC)(=O)C>CO>[C:1]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[N:17]1[C:26](=[O:27])[C:25]3=[CH:24][S:23][CH:22]=[C:21]3[NH:20][C:18]1=[O:19])=[CH:14][C:13]([C:30]([F:33])([F:31])[F:32])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cscc1NC(=O)Nc1c(C(=O)OC(C)(C)C)n(C(=O)OCc2ccccc2)c2ccc(C(F)(F)F)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)c1[nH]c2ccc(C(F)(F)F)cc2c1-n1c(=O)[nH]c2cscc2c1=O
Temperature: 100 °C
Yield: 86.9 %

Procedure:
To a solution of 1-benzyloxycarbonyl-3-[3-(4-methoxycarbonylthiophen-3-yl)-ureido]-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5G (5.29 g, 8.57 mmol) in anhydrous methanol (50 mL) was added a 0.5 M solution of sodium methoxide (25 mL, 12.5 mmol). The reaction mixture was heated in a microwave reactor at 100° C. for 10 minutes. Ethyl acetate (500 mL) was added and the organic layer was washed with 1 N hydrochloric acid and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by flash column chromatography to provide 3-(2,4-dioxo-1,2-dihydro-4H-thieno[3,4-d]pyrimidin-3-yl)-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 5H (3.36 g, 7.45 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]23[CH2:16][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:9]3)[CH:7]=1.[CH3:34][O:35][C:36]1[N:37]=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C=O)C>[C:25]([NH:24][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:42]([C:39]3[CH:38]=[N:37][C:36]([O:35][CH3:34])=[CH:41][N:40]=3)=[O:43])[CH:3]=[CH:4][C:5]=2[F:33])[N:9]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: Nc1ccc(F)c([C@]23CN(c4ncc(F)cn4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CN(c5ncc(F)cn5)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
N-[(4aR,7aS)-7a-(5-Amino-2-fluoro-phenyl)-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (0.361 g, 0.77 mmol, isomer 1) is dissolved in a mixture of dichloromethane (4 mL) and DMF (0.5 mL). 5-Methoxypyrazine-2-carboxylic acid (240 mg, 1.55 mmol), 1-hydroxybenzotriazole (210 mg, 1.55 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.55 mmol) are added to the mixture and the mixture is stirred overnight at room temperature. The reaction solution is added directly onto a 12 g silica gel loading column and purified using a 40 g silica gel column and eluting with a 0-100% ethyl acetate/hexanes gradient. The product is dissolved in ethyl acetate (200 mL), washed with 1 N NaOH (2×50 mL), and with brine (1×50 mL). The silica gel purification is repeated as described above to give the title compound (350 mg, 74%). ES/MS (m/e): 603 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=[CH2:6])[C@H:3]1[C:7]([OH:9])=[O:8].[CH2:11]([N:14]1[CH:18]=[CH:17][C:16]([CH2:19]O)=[C:15]1[C:21]([F:24])([F:23])[F:22])[C:12]#[CH:13]>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=[CH2:6])[C@H:3]1[C:7]([O:9][CH2:19][C:16]1[CH:17]=[CH:18][N:14]([CH2:11][C:12]#[CH:13])[C:15]=1[C:21]([F:24])([F:23])[F:22])=[O:8]
Reactant: C#CCn1ccc(CO)c1C(F)(F)F
Reactant: C=C[C@H]1[C@@H](C(=O)O)C1(C)C
Solvent: Cc1ccccc1
Product: C#CCn1ccc(COC(=O)[C@@H]2[C@H](C=C)C2(C)C)c1C(F)(F)F
Yield: 99.9 %

Procedure:
Using the procedure of Example 1, 610 mg of (1R,cis) 2,2-dimethyl-3-ethenyl-cyclopropane carboxylic acid and with 800 mg of 1-(2-propynyl)-2-trifluromethyl-3-pyrrole-methanol were reacted to obtain 1.28 g of [2-trifluoromethyl-1-(2-propynyl)-1H-pyrrol-3-yl]-methyl (1R,cis) 2,2-dimethyl-3-ethenyl-cyclopropane carboxylate with a specific rotation of [α]D =+9° (0.2% toluene)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=O)[CH:10]=[CH:11][C:12]=1[Cl:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([OH:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15]2[NH:1][CH2:2][CH2:3][CH2:4][OH:5])[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: O=C1Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: OCCCNC1=Nc2ccccc2C1(O)c1ccc(Cl)c(Cl)c1

Procedure:
Reaction of 3-aminopropanol with 3-(3,4-dichlorophenyl)-3-hydroxy-3H-indol-2-one in presence of toluene-p-sulphonic acid by a procedure analogous to that of Example 1 gives 3-(3,4-dichlorophenyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[CH:4][CH:3]=1.C1COCC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@@H:9]2[CH2:11][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: O=C([C@H]1C[C@@H]1c1ccc(Br)cc1)N1CCCC1
Solvent: C1CCOC1
Product: Brc1ccc([C@H]2C[C@@H]2CN2CCCC2)cc1

Procedure:
Following the general procedure, reaction of 6f (3.95 g assayed, 13.42 mmol) with 1 M BH3 in THF (40.3 mL, 40.3 mmol) afforded 7f in an assay yield of 3.15 g (11.25 mmol, 84% assay yield, 100% peak area). A sample was concentrated in vacuo to an oil to provide the standard.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1.[Cl-].[NH4+].C[N:34](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[S:3][C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])=[C:5]([C:7]2[S:23][C:10]3[C:11]4[CH:19]=[CH:18][C:17]([C:20]([NH2:34])=[O:21])=[CH:16][C:12]=4[O:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)[N:6]=1
Reactant: Nc1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(-c2ccccc2Cl)s1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2c(c1)OCCc1cc(-c3nc(N)sc3-c3ccccc3Cl)sc1-2

Procedure:
Following Example 47, 2-(2-amino-5-(2-chlorophenyl)thiazol-4-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid and ammonium chloride were coupled with HATU and DIPEA in DMF to give 268.
Reaction SMILES: N[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:11]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:19].N([O-])=O.[Na+]>O>[Cl:19][C:2]1[CH:7]=[CH:8][C:9]2[S:10][C:11]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=3[CH:6]=[CH:5][C:4]=2[CH:3]=1
Reactant: Cl
Reactant: N#Cc1ccc2c(c1)SC=Cc1c(N)cccc1-2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc2c(c1)Sc1ccc(Cl)cc1C=C2
Reaction time: 0.5 h

Procedure:
1 G. 8-amino-3-cyanodibenzothiepin is suspended in 16 cc. concentrated hydrochloric acid and 5 cc. of water. The suspension is maintained at a temperature between 0° and 5° C. and 300 mg. sodium nitrite in 2 cc. of cold water is added slowly. The reaction mixture is stirred for 1/2 hour. A mixture of 400 mg. cuprous chloride and 700 mg. cupric chloride dihydrate is then added slowly. After the evolution of nitrogen has subsided, the reaction mixture is stirred at room temperature for 20 minutes, water added and the reaction mixture extracted with chloroform, dried over sodium sulfate and evaporated to dryness to yield 995 mg. (92%) of the pure chloro derivative, m.p. 207°-210° C.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[O:14]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:1]12([C:11]([O:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:22]=3)=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCc1cccc(Oc2ccccc2)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(OCc1cccc(Oc2ccccc2)c1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 66 h
Yield: 98.7 %

Procedure:
1 g (5.03 mmol) of tricyclo[3.3.1.13,7 ]decane-1-carbonyl chloride, 1.01 g (5.04 mmol) of 3-phenoxybenzyl alcohol and 0.08 g (10.07 mmol) of anhydrous pyridine were dissolved in 30 ml of anhydrous benzene. The mixture was stirred at room temperature for 66 hours. Then the reaction was terminated. The resulting pyridine hydrochloride was removed by filtration and the filtrate was thoroughly washed with 1N hydrochloric acid, 5% sodium carbonate and then saturated saline solution, and dried over sodium sulfate. The solvent was removed to obtain 1.8 g of an oily material. Purification by column chromatography on silica gel employing a developer consisting of n-hexane and benzene (1:1) gave 1.69 g (yield 93%) of a colorless oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[C:10]2[CH:18]=[CH:17][N:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1>>[C:2]1([NH:1][C:13]2[N:14]=[CH:9][C:10]3[CH:18]=[CH:17][N:16]=[CH:15][C:11]=3[N:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2cnccc12
Reactant: Nc1ccccc1
Product: c1ccc(Nc2ncc3ccncc3n2)cc1
Yield: 22 %

Procedure:
Using a procedure analogous to that described in Example 5, this product was prepared in 22% yield from aniline (1.8 eq.) and 4-chloropyrido[3,4-d]pyrimidine (1 eq.). MP 161° C.; LC-MS: 223 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:57])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:31](=[O:56])[C@H:32]2[CH2:36][C@H:35]([NH:37][C:38](=[O:48])[CH2:39][NH:40]C(OC(C)(C)C)=O)[CH2:34][N:33]2C(OC(C)(C)C)=O)[CH:2]=1>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:57])[C@@H:13]2[CH2:17][C@@H:16]([NH:18][C:19](=[O:30])[C@H:20]([OH:29])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:15][N:14]2[C:31](=[O:56])[C@H:32]2[CH2:36][C@H:35]([NH:37][C:38](=[O:48])[CH2:39][NH2:40])[CH2:34][NH:33]2)[CH:2]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Solvent: CO
Product: NCC(=O)N[C@@H]1CN[C@@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)C1
Reaction time: 2 h
Yield: 108.4 %

Procedure:
A solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylglycylamino)-D-prolyl-trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (G, 120 mg) at 0° C., and methanol (3 mL) was added to dissolve until insoluble materials. After stirring for 2 hr, the reaction mixture was evaporated and coevaporated with 1,4-dioxane and ether in vacuo to give solid. The solids were washed with ether to afford the title compound (97 mg) as a colorless solid: 1H NMR (400 MHz, D2O) δ 1.86-2.03 (m, 2H), 2.24-2.45 (m, 3H), 2.59-2.63 (m, 2H), 3.32 (m, 1H), 3.40-3.45 (m, 1H), 3.60-3.70 (m, 3H), 3.92-4.07 (m, 2H), 4.35-4.42 (m, 2H), 4.61-4.79 (m, 4H), 7.06-7.24 (m, 5H), 7.76 (t, 1H), 7.90 (t, 1H), 8.03 (d, 1H), 8.05(d, 1H), 8.86(s,1H), and 9.21 (s, 1H); mass spectrum (FAB+) m/e 588 (M+1); Anal. Calcd. For C31H37N7O5.3HCl.2H2O: C, 50.79; H, 6.05; N, 13.37. Found: C, 51.09; H, 6.07; N, 12.97.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C@H:7]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9](=[O:17])[C@@H:8]2[CH2:18][CH2:19][C@@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[OH:21])=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C@@H:20]([OH:21])[CH2:19][CH2:18][C@@H:8]2[C@@H:7]([C:5]3[S:6][C:2]([C:33]4[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=4)=[CH:3][CH:4]=3)[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]2=[O:17])=[CH:23][CH:24]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(Br)s2)N1c1ccccc1
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3ccc(O)cc3)s2)N1c1ccccc1
Yield: 56.5 %

Procedure:
(3R,4S)-4-(5-Bromo-2-thienyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-1-phenylazetidin-2-one (69.8 mg, 0.152 mmol) was coupled with 4-hydroxyphenyl boronic acid (25.2 mg, 0.183 mmol) under standard Suzuki conditions illustrated by Example 42. Purification by chromatography (12 g silica gel, 15% to 100% ethyl acetate-hexane) afforded (3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[5-(4-hydroxyphenyl)-2-thienyl]-1-phenylazetidin-2-one (40.7 mg, 56% yield) as a clear foam; Rf 0.39 (1:1 ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.64-7.60 (m, 4H), 7.56-7.48 (m, 5H), 7.33-7.27 (m, 2H), 7.25-7.20 (m, 2H), 7.07 (d, J=8.6 Hz, 2H), 6.81 (br s, 1H), 5.14 (d, J=2.3 Hz, 1H), 5.00-4.95 (m, 1H), 3.57-3.50 (m, 1H), 2.29-2.11 (m, 4H) ppm; MS [M+H]+ 474.0.