Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:4]=2[N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:6](=[O:9])[CH2:7][N:8]=1.COCCOC.C([O-])([O-])=O.[Na+].[Na+].[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>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.CCOC(C)=O.CCCCCCC.CCOC(C)=O>[Cl:23][C:21]1[CH:20]=[CH:19][C:4]2[N:5]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:6](=[O:9])[CH2:7][N:8]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([O:37][CH3:36])=[CH:39][CH:40]=3)[C:3]=2[CH:22]=1
Reactant: COc1ccc(CN2C(=O)CN=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCCCCCC
Product: COc1ccc(CN2C(=O)CN=C(c3ccc(OC)cc3)c3cc(Cl)ccc32)cc1
Temperature: 85 °C
Reaction time: 0.08 h
Yield: 33.3 %

Procedure:
In a 1 L 3 neck RBF equipped with magnetic stir bar, condenser, thermocouple, and N2 inlet, crude (E)-5,7-dichloro-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (54 g) was dissolved into 360 mL of DME. To this was added a solution of Na2CO3 (23 g, 0.15 mol, in 250 mL of H2O) followed by the addition of 4-methoxyphenyl boronic acid (22.7 g, 0.15 mol) and Pd(PPh3)4 (1.4 g, 1.2 mmol). The reaction mixture was heated in a 85° C. oil bath for 2 h and then cooled (RT). To this was added 200 mL of EtOAc and the mixture stirred for 5 min. Organic layer was separated and washed with 200 mL H2O and then brine. Organic layer was concentrated to dryness to give 68 g of crude product. This was subjected to column chromatography using 550 g of silica gel and 25/75 to 60/40 EtOAc/heptane. Fractions containing pure product were combined to give 21 g of pure product and other fractions containing a small amount of impurity (by TLC) gave another 20 g of product, albeit less pure. However NMR of both lots was identical. Total of 41 g of product was obtained. Yield 72% over two steps. 1H NMR (300 MHz, CDCl3) δ 3.7 (s, 3H), 3.80 (d, 1H), 3.85 (s, 3H), 4.57 (d, 1H), 4.85 (d, 1H), 5.57 (d, 1H), 6.63 (d, 2H), 6.85-6.95 (m, 4H), 7.16 (d, 1H), 7.3-7.44 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:13]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:3]=[C:4]([N:11]=[C:12]2[S:16][CH2:15][C:14]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[N:13]2[CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: BrC1CCCC1
Reactant: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]
Product: Cc1cc(N=C2SCC3(CCCC3)N2C2CCCC2)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(3-methyl-4-nitrophenylimino)-1-cyclopentyl-3-thia-1-azaspiro [4.4]nonane.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>>[OH:33][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(O)c1ccccn1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#CC(C)(O)c3ccccn3)cc1-2
Yield: 17 %

Procedure:
10-bromo-N3-methyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide was reacted with 2-(pyridin-2-yl)but-3-yn-2-ol via General Procedure E to yield 14 mg (17%) of (±)-10-[3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[O:44]=[C:45]1[CH2:49][CH2:48][CH2:47][N:46]1[C:50]1[CH:51]=[C:52]([CH:56]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:58]=1)[C:53](O)=[O:54].[CH:65]12[CH2:71][CH:68]([CH2:69][CH2:70]1)[CH2:67][CH:66]2[NH:72][C:73](=[O:88])[C@H:74]([CH3:87])[CH2:75][C@H:76]([OH:86])[C@@H:77]([NH2:85])[CH2:78][C:79]1[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=1>>[CH2:78]([C@H:77]([NH:85][C:53](=[O:54])[C:52]1[CH:51]=[C:50]([N:46]2[CH2:47][CH2:48][CH2:49][C:45]2=[O:44])[CH:58]=[C:57]([N:59]2[CH2:63][CH2:62][CH2:61][C:60]2=[O:64])[CH:56]=1)[C@@H:76]([OH:86])[CH2:75][C@H:74]([C:73](=[O:88])[NH:72][CH:66]1[CH2:67][CH:68]2[CH2:71][CH:65]1[CH2:70][CH2:69]2)[CH3:87])[C:79]1[CH:80]=[CH:81][CH:82]=[CH:83][CH:84]=1
Reactant: O=C(O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(N2CCCC2=O)cc(N2CCCC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6, from 3,5-bis-(2-oxopyrrolidin-1-yl)benzoic acid (D8) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@H:9]([C:26]([C@@:28]1(C)CO1)=O)[CH2:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1.[CH:32]([S:34](C=C)(=[O:36])=[O:35])=C.CON(C)C(=O)[C@@H](NC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CC1C=CC(CNC(=O)OC(C)(C)C)=CC=1>>[CH3:32][S:34](/[CH:28]=[CH:26]/[C@@H:9]([NH2:8])[CH2:10][C:11]1[CH:25]=[CH:24][C:14]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)C(=O)[C@@]2(C)CO2)cc1
Reactant: C=CS(=O)(=O)C=C
Agent: CON(C)C(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)/C=C/S(C)(=O)=O)cc1

Procedure:
Retro-synthetically, the modified oligopeptides can be prepared from tripeptide hydrazide N3Phe-Leu-Leu-NHNH2 and the properly protected warhead amines in an (epimerization free) azide coupling. The synthesis of P1-benzyl amine containing vinyl sulfone and epoxyketone warheads leading to inhibitors 4a and 4b is shown in Scheme 3. The synthetic scheme commenced with the introduction of the aminomethylene substituent on L-phenylalanine 8, by performing an electrophilic aromatic substitution with N-(hydroxymethyl)trichloroacetamide under acidic conditions. In this reaction both the ortho and the para substituted isomers were formed, which could be separated by column chromatography. The desired para substituted isomer was obtained in 35% yield. After Cbz-protection of the α-amine, compound 9 was obtained. Basic removal of the trichloroacetamide group followed by Boc protection of the formed amine gave 10, which was coupled to N,O-dimethylhydroxylamine to give Weinreb-amide 11. Upon a reaction with 2-lithiumpropene the α′,β′-unsaturated ketone 12 was obtained. Stereoselective reduction to the allylic alcohol 13 and subsequent asymmetric epoxidation and Dess-Martin oxidation resulted in epoxyketone 14. This compound was α-amine deprotected by hydrogenation, which finalized the synthesis of compound 15. The vinylsulfone analogue was created by α-amine deprotection of compound II, followed by tritylation (16). Reduction of the Weinreb-amide, followed by a Horner-Wadworth-Emmons reaction and de-tritylation finally resulted in compound 18.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([CH2:13][OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1.[OH:17][C:18]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)[C:19]([O:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([NH:28][CH3:29])[CH2:24][CH2:23]1)=[O:20].C(N(CC)CC)C.C1COCC1>C(#N)C>[OH:17][C:18]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[C:19]([O:21][C@H:22]1[CH2:23][CH2:24][C@H:25]([N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]([O:15][CH3:16])[C:9]([CH2:13][OH:14])=[CH:10][C:11]=2[Cl:12])[CH3:29])[CH2:26][CH2:27]1)=[O:20]
Reactant: COc1cc(OCCCBr)c(Cl)cc1CO
Reactant: CN[C@H]1CC[C@H](OC(=O)C(O)(c2cccs2)c2cccs2)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OCCCN(C)[C@H]2CC[C@H](OC(=O)C(O)(c3cccs3)c3cccs3)CC2)c(Cl)cc1CO
Reaction time: 24 h

Procedure:
A mixture of [4-(3-bromopropoxy)-5-chloro-2-methoxyphenyl]methanol (intermediate 55; 386 mg; 1.25 mmol), trans-4-(methylamino)cyclohexyl hydroxy(di-2-thienyl)acetate (intermediate 5; 438 mg, 1.25 mmol) and triethylamine 0.345 ml; 2.49 mmol) in 12 ml acetonitrile and 8.7 ml THF was stirred at 70° C. for 16 hr. An additional amount of intermediate 5 (219 mg; 0.62% mmol) was added and the heating prosecuted for 24 hr. The solvent was evaporated in vacuum and the residue purified by preparative reversed-phase HPLC (hexane/EtOAc from 0 to 40%), affording the title compound (80%) as a light yellow oil.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[NH2:1][C@@H:4]1[CH2:28][CH2:27][C@@:26]2([CH3:29])[C:6](=[CH:7][CH2:8][C@@H:9]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:30])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[C@H:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:5]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N=[N+]=[N-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 30 h
Yield: 88.1 %

Procedure:
3α-Azidocholest-5-ene (4.62 mmol, 1.9 g) was dissolved in 154 mL of anhydrous diethyl ether. Lithium aluminum hydride (46.2 mmol, 1.75 g) was then added in one portion. After 30 hours, the reaction mixture was cooled to 0° C. 1.75 mL of deionized water was then added dropwise. After stirring for five minutes, 1.75 mL of 15% aqueous NaOH was added dropwise. After stirring for another five minutes, 5.25 mL of deionized water was added dropwise. The reaction was then stirred until all the salts turned white. Immediately afterwards, the reaction was filtered, dried (Na2SO4), and concentrated to afford 3α-Aminocholest-5-ene (1.57 g, 93%) as a white solid. mp 104-106° C.; IR (thin film) 3367, 3343, 2931, 1557 cm−1; 1H NMR (300 MHz, CDCl3) d 5.37-5.34 (m, 1H), 3.15 (t, 1H, J=3.2 Hz), 2.61-2.54 (m, 1H), 2.04-1.74 (m, 6H), 1.63-1.03 (m, 21H), 1.00 (s, 3H), 0.91 (d, 3H, J=6.5 Hz), 0.86 (d, 6H, J=6.6 Hz), 0.67 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[O:11][CH2:12][CH2:13][C:9]=2[C:8]2[C:7](=[O:14])[CH2:6][CH2:5][C:4]=2[C:3]=1Br.C([O-])(=O)C.[Na+].[H][H]>[Pd].CO>[CH2:13]1[CH2:12][O:11][C:10]2[CH:2]=[CH:3][C:4]3[CH2:5][CH2:6][C:7](=[O:14])[C:8]=3[C:9]1=2
Reactant: [H][H]
Reactant: O=C1CCc2c(Br)c(Br)c3c(c21)CCO3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCc2ccc3c(c21)CCO3
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4,5-Dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (280 kg, 843 mol), anhydrous sodium acetate (173 kg, 2109 mol), methanol (6384 L) were mixed, and the reaction system was replaced with nitrogen. Then, to the reaction mixture was added 10% Pd/C (30.8 kg, as dry weight), and pressurized with hydrogen to 0.29 to 0.49 MPa, and catalytically reduced at about 40° C. for 8 hrs with stirring at such a stirring rate that the gas-liquid overall mass transfer coefficient KLa(1/hr) is about 15. The catalyst was filtered, and the filtrate was concentrated under reduced pressure, and further water was added to the residue, followed by concentrating under reduced pressure to substitute the solvent, cooling and stirring for 1 hr to mature. The crystallization solution was filtered to give wet crystals of title compound (amount 127 kg as dry weight, yield 86.6%). The content of dimer in the wet crystals was less than 0.1% by weight. (2) Purification Step
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2.CN(C)CCC=C1C2C=CC=CC=2C=CC2C=CC=CC1=2>>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[C:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]1=2
Reactant: CN(C)CCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21
Agent: CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Product: CNCCC=C1c2ccccc2CCc2ccc(S(C)(=O)=O)cc21

Procedure:
By substituting 10,11-dihydro-5-(3-dimethylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (β-isomer) for the 5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene of Example 6, and following substantially the procedure of Example 6, Steps A and B., 10,11-dihydro-5-(3-methylaminopropylidene)-3-methylsulfonyl-5H-dibenzo[a,d]cycloheptene (β-isomer) is obtained in the form of a yellow oil. The product is converted to the hydrochloride that melts at 232.5°-234.5° C. after recrystallization from isopropyl alcohol.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[C:9]([S:21](Cl)(=[O:23])=[O:22])=[CH:10][C:11]2[CH2:12][CH2:13][C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.C(N(CC)CC)C>O>[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:20])[C:15]2([CH3:19])[CH3:18])=[CH:10][C:9]=1[S:21]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1S(=O)(=O)Cl)CCC(=O)C2(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1S(=O)(=O)N1CCCC1)CCC(=O)C2(C)C
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 75 %

Procedure:
The THF (4 ml) solution of 3-methoxy-5,5-dimethyl-6-oxo-5,6,7,8-tetrahydro-naphthalen-2-sulfonyl chloride (Compound CC1, 295 mg, 0.974 mmol) was cooled to 0° C., and the tetrafuran (1 ml) solution combining pyrrolidine (121 μl, 1.5 eq.) and triethylamine (272 μl, 2 eq.) was added dropwise thereto over 2 min. The mixture was stirred at 0° C. until Compound CC-1 disappears. The reaction solution was added with distilled water and extracted with ethyl acetate. The organic layer was washed with 10% aqueous solution of disodium ethylenediamine tetraacetic acid. The organic layer was washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (246 mg, 75%).
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([NH:15][CH:16]1[CH2:22][S:21][CH:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:19][N:18]([CH2:29][C:30]([OH:32])=[O:31])[C:17]1=[O:33])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CSC(c2ccccc2)CN(CC(=O)O)C1=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1CC(c2ccccc2)SCC(NC(CCc2ccccc2)C(=O)O)C1=O

Procedure:
50 mg of α-{6-[1-ethoxycarbonyl-3-phenylpropylamino]-5-oxo-2-phenylperhydro-1,4-thiazepin-4-yl}acetic acid (prepared as described in Example 11 above) was hydrolyzed with aqueous sodium hydroxide in the manner described in Example 5, giving the title compound as a powder in a yield of 40 mg.
Reaction SMILES: [NH2:1][C@:2]1([C:14](OC)=[O:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1.[BH4-].[Na+]>CO>[NH2:1][C@:2]1([CH2:14][OH:15])[CH2:6][CH2:5][C@@H:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH2:3]1
Reactant: COC(=O)[C@@]1(N)CC[C@@H](c2ccc(Br)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N[C@]1(CO)CC[C@@H](c2ccc(Br)cc2)C1
Reaction time: 2 h
Yield: 90.8 %

Procedure:
(1R,3R)-Methyl 1-amino-3-(4-bromophenyl)cyclopentanecarboxylate (1-2, 3.88 g, 13.01 mmol) was dissolved in MeOH (65.1 ml) and sodium borohydride (1.477 g, 39.0 mmol) was added portionwise. Additional sodium borohydride was added (0.5 equiv every 1 h) portionwise until the reaction was determined to be complete by HPLC analysis. The reaction was found to be complete after 2 hours. The reaction mixture was quenched with water and diluted with ethyl acetate. The aqueous layer was back extracted three times with EtOAc. The organic layers were combined, washed with saturated NaCl, dried over MgSO4, filtered and concentrated to afford ((1R,3R)-1-amino-3-(4-bromophenyl)cyclopentyl)methanol (3.19 g, 11.81 mmol). HPLC ret time=0.68 min; LC/MS M+1=272: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.4 Hz, 2H), 3.49 (s, 2H), 3.32-3.41 (m, 1H), 2.19-2.25 (m, 1H), 1.98-2.07 (m, 1H), 1.90-1.95 (m, 1H), 1.66-1.74 (m, 2H), 1.52-1.60 (m, 1H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:8][C:6]1[CH:7]=[C:2]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-n2cccn2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 106.8 %

Procedure:
To a solution of 5-fluoro-2-nitrotoluene (1.27 g, 8.20 mmol) and pyrazole (1.3 g, 19.3 mmol) in dimethylformamide (32 mL) was added potassium carbonate (1.3 g, 9.7 mmol), and the mixture was heated to 100° C. overnight. The reaction was cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with 10% aqueous lithium chloride, water and saturated sodium chloride, then dried over sodium sulfate and concentrated on a rotary evaporator to give 1-(3-methyl-4-nitrophenyl)-1H-pyrazole (1.78 g, 100%). This material was dissolved in ethanol (50 mL) and, after addition of 5% palladium on carbon (100 mg), the reaction was stirred under a balloon of hydrogen overnight. The mixture was filtered through Celite and washed with ethanol. The solvent was removed on a rotary evaporator to give 2-methyl-4-(1H-pyrazol-1-yl)aniline. A portion of this material (52 mg, 0.30 mmol) was added to a solution of 4-(4-phenylquinazolin-2-ylamino)benzoyl chloride (110 mg, 0.30 mmol) and Hunig's base (157 μL, 0.90 mmol) in tetrahydrofuran (2 mL) and the reaction was allowed to stir at rt overnight. The mixture was concentrated on a rotary evaporator and purified by flash column chromatography to give N-[2-methyl-4-(1H-pyrazol-1-yl)phenyl]-4-[(4-phenylquinazolin-2-yl)amino]benzamide (90 mg, 60%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 9.80 (s, 1H), 8.50 (d, 1H), 8.20 (d, 2H), 8.02 (d, 2H), 7.86 (m, 3H), 7.80 (m, 3H), 7.75 (d, 1H), 7.70 (dd, 1H), 7.64 (t, 3H), 7.50 (d, 1H), 7.42 (m, 1H), 6.58 (t, 1H), 2.30 (s, 3H). MS (EI) for C31H24N6O: 497.4 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([F:9])[CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:23])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11].[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH:26]=[CH:25]1>>[F:9][CH:6]1[CH2:5][N:4]([C:10]([C:12]2[N:13]=[C:14]([CH3:23])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:11])[CH:3]([CH2:2][NH:1][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH:25]=[CH:26][C:27]=23)=[O:34])[CH2:8][CH2:7]1
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Reactant: O=C(O)c1cccc2occc12
Product: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)c2cccc3occc23)c(-c2ccccc2)s1

Procedure:
N-((5-Fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methyl)benzofuran-4-carboxamide was prepared by following general procedure A using (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone and benzofuran-4-carboxylic acid. MS (ESI) 478 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][C@H:13]([F:15])[CH2:12][N:11]([C:16](OCC2C=CC=CC=2)=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.CCN(C(C)C)C(C)C.ClC1[CH:43]=[CH:42][N:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45]>[Pd].CCOC(C)=O>[F:15][C@@H:13]1[CH2:12][N:11]([C:16]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])[CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](F)CN(C(=O)OCc2ccccc2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](F)CN(c2ccncc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
To a solution of (3S,5S)-benzyl 3-(tert-butoxycarbonylamino)-5-fluoropiperidine-1-carboxylate (1 eq) in 5 methanol and 5 mL of EtOAc was added 10% Pd/C (0.1 eq). The resulting suspension was stirred at H2 atmosphere for 4 hours. The crude solids were filtered through a pad of Celite on a paper lined Buchner funnel, washed with MeOH, then concentrated in vacuo. The residue was dissolved in 5 mL of isopropanol and DIPEA (1.8 eq) and 4-chloro-3-nitropyridine (1.5 eq) were added. The reaction mixture was stirred at 65° C. for 3 hours, at which point the reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was diluted with 120 mL of EtOAc, washed with brine, then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (EtOAc:hexanes=1:1) to give tert-butyl(3S,5S)-5-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate (78%). LC/MS (m/z): 341.1 (MH+), Rt=0.57 min. HPLC: Rt: 2.01 min.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17](O)=[O:18].N>CC(=O)OCC>[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:17]([NH2:3])=[O:18]
Reactant: Cc1cc(Br)cc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C(N)=O)c1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
CDI (42.2 g, 260.4 mmol) was cautiously added to a solution of 3-bromo-5-methylbenzoic acid (16.0 g, 74.4 mmol) in EA (300 mL), and then the mixture was kept at reflux for 3 h. After cooling to room temperature, NH3 (g) was passed though the mixture for 1 h. It was filtered and the organic layer was washed with HCl (10%, 100 mL) and water (100 mL). The organic phase was dried over Na2SO4 and concentrated in vacuum to obtain 15.0 g of 3-bromo-5-methylbenzamide as white crystals (yield: 94%). 1H NMR (400 MHz, CDCl3) δ 7.73-7.72 (m, 1H), 7.56-7.55 (m, 1H), 7.50-7.49 (m 1H), 2.39 (s, 3H).