Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:2][CH2:3][CH3:4].[CH:18]([NH:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:20])[CH3:19].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([N:21]([CH:18]([CH3:20])[CH3:19])[NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(F)cc1CCC(=O)O
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1ccc(F)cc1CCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 4.4 %

Procedure:
A solution of 3-(2-butoxy-5-fluoro-phenyl)-propionic acid (300 mg, 1.37 mmoles) and benzoic acid N′-isopropyl-hydrazide (203 mg, 1.14 mmoles) in DMF (3 mL) was treated with diisopropylethylamine (0.50 mL, 2.85 mmoles), and PyBroP (800 mg, 1.71 mmoles) at room temperature for 16 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (20 mg, 5%). LC-MS m/e 401.28 (M+H+)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.[BH4-].[Na+]>CO.O>[OH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=2)=[CH:9][CH:10]=1)[CH3:15]
Reactant: CC(=O)c1ccc(C2=CCC(C)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1CC=C(c2ccc(C(C)O)cc2)CC1
Reaction time: 4 h

Procedure:
8.8 g of para-(4-methyl-1-cyclohexenyl)-acetophenone are stirred portionwise into a solution, cooled to 0°C, of 1.8 g of sodium borohydride in 80 ml of methanol and 15 ml of water. Stirring is continued at 5°-10°C for an hour and a half and at room temperature for 4 hours, 200 ml of water are added, and the batch then extracted with 3 × 100 ml of methylene chloride. The methylene chloride residue is recrystallized from petroleum ether and yields 1-hydroxy-1-[para-(4-methyl-1-cyclohexenyl)-phenyl]-ethane of melting point 65°-67°C.
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: C=CS(=O)(=O)C=C
Reactant: CC(C)(C)OC(=O)NCc1ccc(C[C@H](N)C(=O)[C@@]2(C)CO2)cc1
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: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][N:21]=1.CCN=C=NCCCN(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([O:16][CH2:17][CH3:18])[CH:4]=3)[CH2:8][CH2:9]2)=[O:25])=[CH:22][N:21]=1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: Nc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(N)nc3)CC2)ccc1Cl
Temperature: 60 °C
Yield: 30.9 %

Procedure:
1-(4-Chloro-3-ethoxy-benzyl)piperidin-4-ylamine (0.33 g, 1.0 mmol), 6-amino-nicotinic acid (0.17 g, 1.0 mmol) and EDCI (0.28 g, 1.2 mmol) were mixed with DMF (5 ml) and heated to 60° C. for 24 h, after which time the reaction was allowed to cool, poured into dilute NaHCO3 and extracted with EtOAc. The combined organic was dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (DCM:MeOH 9:1-4:1) affording the title product (0.12 g, 24%).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].C[N:38](C=O)C.N>C(O)C>[C:1]([N:3]=[C:4]([NH2:38])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CN(C)C=O
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: N
Solvent: CCO
Product: Cn1cc(C2=C(c3cn(CCCNC(N)=NC#N)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
100 mg of the product of Example 50 were heated with 30 ml of ethanol, 2 ml of DMF and 40 ml of a saturated solution of ammonia in ethanol at 100° C. for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 1% methanol in dichloromethane to give 10 mg of 3-[1-[3-(2-cyanoguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p. 168°-170° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](Cl)=[O:15])[CH2:9]1.[NH2:23][C@@H:24]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:23][C@@H:24]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])=[O:15])[CH2:9]1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Crude (R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carbonyl chloride (60 mg, 0.184 mmol), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylcarbamate (69 mg, 0.23 mmol, 1.25 equiv) and triethylamine (64 μL, 0.46 mmol, 2.5 equiv) were combined in CH2Cl2 (1 mL) at rt and left on the shaker overnight. After concentration, the product was isolated by prep HPLC to afford 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)-(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexyl-propylcarbamate (85.3 mg, 79%). LC-MS (3 min) tR=2.44 min, m/z 590 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.Cl[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C[N-]C.CCOCC.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1[nH]c2c(Br)cccc2c1CCCOc1cccc2ccccc12
Agent: C[N-]C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1c(CCCOc2cccc3ccccc23)c2cccc(Br)c2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 7-bromo-3-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (2.39 g, prepared in a similar manner as described herein) in N, N-dimethylamide (20 mL) was added 1-(chloromethyl)-4-methoxybenzene (1.0 g) and Cs2CO3 (5.16 g). The mixture was stirred overnight at room temperature. The mixture was diluted with ether (300 mL) and water (200 mL). The aqueous layer was extracted with ether. The combined extracts were washed with water (×3), brine and dried over Na2SO4. Concentration gave Example 581A.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]#[N:18])=[N:9]1.C(O)(=O)C.[NH4+:27].[Cl-:28]>CO>[Cl-:28].[F:4][C:5]1[CH:22]=[CH:21][CH:20]=[CH:19][C:6]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([NH2:27])=[NH2+:18])=[N:9]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ccccc12
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=[NH2+])c1nn(Cc2ccccc2F)c2ccccc12
Temperature: 40 °C
Reaction time: 22 h

Procedure:
A sodium methoxide solution, which had been prepared from 190 mg (8.26 mmol) of NaOMe and 30 ml of abs. methanol, was added to a solution of 20.0 g (97.7 mmol) of 1-(2-fluorobenzyl)-3-cyanoindazole (from Example IX) in 200 ml of methanol, and the mixture was stirred at 40° C. for 22 h. After addition of 0.46 ml of acetic acid and 4.30 g of NH4Cl, the mixture was stirred at 40° C. for another 24 h and subsequently concentrated to dryness using a rotary evaporator. The residue was taken up in acetone and the remaining precipitate was filtered off with suction, giving, after drying under high vacuum, the product in the form of a light-beige powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:14][C:3]1[CH:4]=[C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1cc(N2CCCC2=O)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Yield: 51.3 %

Procedure:
A stirred mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (D46, 50 g, 0.20 mole) and 4-boronobenzoic acid (32 g, 0.20 mole) in 1,2-dimethoxyethane (500 ml) was treated with a solution of Na2CO3 (94 g, 0.88 mole) in water (500 ml), then de-gassed by bubbling argon through for 0.25 hrs. Tetrakis (triphenylphosphine)palladium (O) (5 g) was added and the mixture heated under reflux for 22 hours, then allowed to cool and concentrated in vacuo to approx. 50% volume. The aqueous residue was diluted with water to approx. 1000 ml, washed with ethyl acetate, then acidified with conc. HCl acid. The precipitate was filtered off, washed with water, dried and recrystallised from ethanol to afford the title compound as a cream solid (30.3 g, 52%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH3:20][O:21][C:22]([NH:24][C:25](=NC(OC)=O)SC)=[O:23].CC(O)=O>CO.[Pd]>[CH3:1][N:2]1[C:3]2[CH:4]=[C:5]([O:6][C:7]3[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=3)[CH:14]=[CH:15][C:16]=2[N:17]=[C:25]1[NH:24][C:22](=[O:23])[O:21][CH3:20]
Reactant: CNc1cc(Oc2ccc(N)cc2)ccc1[N+](=O)[O-]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2ccc(Oc3ccc(N)cc3)cc2n1C
Temperature: 85 °C
Reaction time: 5.5 h
Yield: 84.7 %

Procedure:
After hydrogenation of 4-(3-methylamino-4-nitrophenoxy)aniline (Intermediate 8G-519.2 mg, 2.0 mmol) with 5% Pd—C in MeOH (20 mL), 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (1.03 g, 5.0 mmol) and AcOH (2.0 mL) was added then stirred at 85° C. for 5.5 hrs. After cooling, the mixture was added 2N HClaq. (25 mL) then stirred at 65° C. for 2 hrs. The mixture was passed through celite pad to remove catalyst and the solvent was removed by evaporation. The residue was extracted with ethyl acetate. The organic layer was washed with NH4OH(aq). and brine, dried over Na2SO4 then evaporated. Sequence purification on SiO2 column chromatography gave the title compound (529.1 mg, 85%): MS m/e 313 (M+1).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21
Solvent: c1ccncc1
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the title compound of Example 13 (1.0 g) in pyridine (15 mL) under nitrogen at approximately 5° C. (ice water bath) was added dropwise via syringe methanesulfonyl chloride (0.28 mL). The ice bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The reaction was then evaporated under vacuum, and the residue was treated with 1 M HCl. The insoluble product was collected by filtration, washed twice with 1 M HCl, and then with water. The solid was suspended in methanol, heated to reflux on a steam bath, cooled to room temperature, and the product was collected by filtration. Recrystallization from acetonitrile yielded the title compound as a pinkish solid. Mp: 211°-212° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11](C)[CH:10]=[CH:9][C:8]=1[CH2:14]O.C[Si](C)(C)[Br:18]>C(Cl)(Cl)Cl>[Br:18][CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: C[Si](C)(C)Br
Reactant: COCCCOc1cc(C)ccc1CO
Solvent: ClC(Cl)Cl
Product: COCCCOc1ccccc1CBr
Temperature: 25 °C
Yield: 110.3 %

Procedure:
To a solution of the title C compound, [2-(3-methoxy-propoxy)-4-methyl-phenyl]-methanol (300 mg, 1.4 mmol) in 5 mL of chloroform is added trimethylbromosilane (0.28 mL, 2.1 mmol), with stirring at room temperature. After 2 h the solvent is evaporated off and the crude residue is purified by flash column chromatography on silica gel (hexane/EtOAc 1/1) to afford the title compound as a colorless oil (0.4 g). Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 4.70 min.
Reaction SMILES: [S:1]([N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19][OH:20].C(N(CC)CC)C.[Cl-].ClC1N(C)C=C[N+]=1C>C(Cl)Cl>[S:1]([N:11]([CH2:13][C:14]([N:17]1[CH2:23][CH2:22][CH2:21][C@H:18]1[CH2:19][OH:20])=[O:16])[CH3:12])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: OC[C@@H]1CCCN1
Agent: Cn1cc[n+](C)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N2CCC[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
N-tosylsarcosine (60 g, 247 mmol) and L-prolinol (24.9 g, 247 mmol) are dissolved in methylene chloride (800 ml), and triethylamine (102.5 ml, 741 mmol) is added thereto. To this mixture is added dropwise, over a period of one hour under water-cooling, a solution of 2-chloro-1,3-dimethylimidazolium chloride (DMC) (62.6 g, 371 mmol) in methylene chloride. The mixture is further stirred for 2 hours at room temperature and then the reaction liquid is washed successively with water (1 l, a saturated aqueous solution of sodium hydrogen carbonate (1 l, 1N hydrochloric acid (1 l) and water (1 l). The organic layer is dried over anhydrous magnesium sulfate and filtered, and the filtrate is concentrated to dryness under reduced pressure to give N-tosylsarcosyl-L-prolinol (82.1 g, 102%).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[C:20]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:14]=[CH:13][CH:12]=1)=[O:10])[NH:2]2.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[N:26]=1>>[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[C:20]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:14]=[CH:13][CH:12]=3)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:30])[N:26]=1
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2c1OCCO2
Reactant: Nc1nc(-c2ccccc2C(=O)O)cs1
Product: Nc1nc(-c2ccccc2C(=O)N2[C@H](CNC(=O)c3cccc4c3OCCO4)C[C@@H]3C[C@@H]32)cs1

Procedure:
prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-(2-amino-thiazol-4-yl)-benzoic acid. LC-MS (basic): tR=1.24 min; [M+H]+=477.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14]([C:16]1[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3Cl)[CH:17]=1)=[O:15])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[NH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([NH2:37])=[CH:32][CH:31]=2>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14]([C:16]1[S:24][C:23]3[C:18](=[N:19][CH:20]=[CH:21][C:22]=3[NH:37][C:33]3[CH:34]=[C:35]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:27])=[CH:36]4)[CH:17]=1)=[O:15])[CH2:12]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3cc4nccc(Cl)c4s3)CC21
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)N5CC6C(C5)C6NC(=O)OC(C)(C)C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from {3-[7-chloro-thieno[3,2-b]pyridine-2-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamic acid tert-butyl ester and 2-methyl-1H-indol-5-ylamine by a procedure analogous to Example 1C. MS: 504 (MH+); HPLC Rf: 5.31 min.; HPLC purity 95%.
Reaction SMILES: CO[CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1.B(Br)(Br)[Br:19]>>[Br:19][CH2:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]2[O:9][C:10]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:11][C:7]=2[CH:6]=1
Reactant: BrB(Br)Br
Reactant: COCCc1ccc2oc(S(N)(=O)=O)cc2c1
Product: NS(=O)(=O)c1cc2cc(CCBr)ccc2o1

Procedure:
This material is prepared by treatment of 5-(2-methoxyethyl)-2-sulfamoylbenzo[b]furan with boron tribromide.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([O:10][C:11](=[O:24])[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][O:19]C(=O)C)[CH3:16])=[O:13])([CH3:9])[CH3:8])(=O)C>C(Cl)Cl.C(NC(C)C)(C)C>[C:12]([O:14][C:15]([CH3:23])([CH2:17][CH2:18][OH:19])[CH3:16])(=[O:13])[C:11]([O:10][C:7]([CH3:9])([CH2:6][CH2:5][OH:4])[CH3:8])=[O:24]
Reactant: CC(=O)OCCC(C)(C)OC(=O)C(=O)OC(C)(C)CCOC(C)=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(C)(CCO)OC(=O)C(=O)OC(C)(C)CCO

Procedure:
The cleavable diol is made in the following manner. To a solution of compound (73) in methylene chloride, diisopropylamine is added and the solution is stirred until reaction is complete. A standard aqueous workup is done and the diol should remain in the organic phase. Evaporate the solvent and collect bis(4-hydroxy-2-methylbutan-2-yl) oxalate (74).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.IC1NC2C=CC=C3C(=O)NCCC=1C=23.[Br:36]C1C=CC(B(O)O)=CC=1>>[Br:36][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(Br)cc1
Agent: O=C1NCCc2c(I)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(Br)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, 2-iodo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one (85 mg, 0.28 mmol; see Example NN below) and 4-bromophenylboronic acid (62 mg, 0.31 mmol) were coupled to yield 2-(4-bromophenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 19 mg (20%), as a white solid. mp 160° C. (dec.); 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.23 (app t, 1H, J=7.5 Hz), 7.56 (dd, 1H, J=8.1, 0.9 Hz), 7.60 (d, 2H, J=8.7 Hz), 7.69 (dd, 1H, J=7.5, 0.6 Hz), 7.73 (d, 2H, J=8.4 Hz), 8.09 (br t, 1H), 11.64 (br s, 1H); MS (FAB, MH+) 341/343; Anal. (C17H13BrN2O.0.6 H2O) C, H, N.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.C(=O)([O-])[O-].[K+].[K+].[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[N:1]=[C:8]([Cl:9])[N:7]=[C:5]([Cl:6])[N:4]=2)=[CH:19][CH:18]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.8 %

Procedure:
To a mixture of cyanuric chloride (5.15 g, 27.9 mmol), potassium carbonate (3.98 g, 28.8 mmol) and 18-crown-6 (158 mg, 0.60 mmol) in toluene (40 ml), cooled in an ice bath, was added a solution of 4-chloroaniline (3.61 g, 28.3 mmol) in toluene (20 ml) over 15 minutes. After stirring at room temperature for 20 hours, the mixture was treated with ethyl acetate (60 ml) and filtered through a pad of celite under suction. The filtrate was concentrated under vacuum and recrystallized (chloroform) to give (4-chlorophenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (4.06 g, 53% yield) as a white solid. 1H NMR (d6-DMSO) δ 11.23 (1 H, s), 7.62 (2 H, d, J=9 Hz), 7.47 (2 H, d, J=9 Hz). 3C NMR (d6-DMSO) δ 169.5, 168.5, 163.6, 135.7, 128.6, 122.5, ESMS m/z 273 (M−H)−.