Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH3:13])[CH:3]=1)#[N:15]
Reactant: CCc1cc(Br)ccc1C(=O)OC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCc1cc(C#N)ccc1C(=O)OC
Temperature: 100 °C
Yield: 40 %

Procedure:
Charged methyl 4-bromo-2-ethylbenzoate (1.9 g, 7.85 mmol), Zn(CN)2 (1.48 g, 12.56 mmol), Pd(PPh3)4 (1.0 g, 0.94 mmol) and DMF (30 mL) to a flask, the system was then purged with nitrogen and heated at 100° C. for 6 h. The reaction mixture was then filtered. The filtrate was extracted with ethyl acetate and concentrated the organic phase for flash column chromatograph to give 0.6 g of the title compound (40%). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.99 (2H, q, J=7.6 Hz), 3.92 (3H, s), 7.52-7.54 (1H, m), 7.57 (1H, s), 7.90 (1H, d, J=8.0 Hz).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[O:9]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:9]([C:16]1[CH:17]=[CH:18][C:19]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1nccnc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nccnc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 96.9 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.268 g) was added to a suspension of 3-chloropyrazin-2-amine (1.00 g), 4-phenoxyphenylboronic acid (2.15 g) and sodium carbonate (1.64 g) in DME (37.5 mL) and water (7.5 mL) and the mixture was stirred at 80° C. under N2 for 4 hr. The reaction mixture was added with water and EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (1.97 g) as a white solid.
Reaction SMILES: [F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(Cl)(=O)=[O:35])=CC=1.C[O-].[Na+].OO>CO>[F:1][P-:2]([F:7])([F:6])([F:5])([F:4])[F:3].[C:8]1([CH3:27])[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S+:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:35]
Reactant: Cc1ccccc1[S+](c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: OO
Solvent: CO
Product: Cc1ccccc1[S+](=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 19.7 %

Procedure:
(Tolyl)diphenylsulphonium hexafluorophosphate (1.08 g, 2.57 mol) and p-toluenesulphonyl chloride (2.38 g, 12.5 mmol) are dissolved with stirring in methanol (40 ml) with cooling in ice water. Sodium methoxide (1.67 g, 31 mmol) and hydrogen peroxide (30% in water, 3.5 g, 31 mmol) are added over 25 mins. After 1 hour the reaction mixture is filtered and evaporated in vacuo. Water is added and the resulting solid is collected and washed with water and ether to give (tolyl)diphenylsulphoxonium hexafluorophosphate (1.08 g, 96% ) with spectra identical to those of authentic material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][OH:27])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P(CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCO)C2)CC1
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCN(CCOc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
N-(3,4-Dichlorophenyl)-4-{[(3S)-1-(2-hydroxyethyl)piperidin-3-yl]methyl}piperazine-1-carboxamide (250 mg, 0.62 mmols) and phenol (58.35 mg, 0.62 mmols) were stirred at room temperature under an atmosphere of argon before addition of P(Bu)3 (0.30 ml, 1.24 mmols) and 1,1-azodicarbonyl dipiperidine (312 mg, 1.24 mmols). This reaction mixture was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was washed using brine and the organic layer dried (MgSO4) filtered then concentrated in vacuo onto silica gel (1 g). The resulting solid was subjected to chromatography on silica gel (20 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (65.4 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:14]2[C:15](=[O:42])[N:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C@H:26]([NH:31]C(=O)OCC4C=CC=CC=4)[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[CH2:17][C:13]2=[CH:12][N:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[C].[Pd]>[NH2:31][C@H:26]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([N:21]1[CH2:22][CH2:23][CH:18]([N:16]2[CH2:17][C:13]3=[CH:12][N:11]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[N:14]3[C:15]2=[O:42])[CH2:19][CH2:20]1)=[O:25]
Reactant: CC(C)(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[C@@H](N)C(=O)N1CCC(N2Cc3cnc(CO[Si](C)(C)C(C)(C)C)n3C2=O)CC1
Yield: 96.7 %

Procedure:
Benzyl(1R)-1-((4-(5-(((tert-butyldimethylsilyl)oxy)methyl)-3-oxo-1H-imidazo[1,5-c]imidazol-2(3H)-yl)-1-piperidinyl)carbonyl)-2,2-dimethylpropylcarbamate (0.44 g) obtained in Example 83j) and 10% palladium carbon (44 mg) were suspended in methanol (10 ml), and mixed under hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered using Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound as a colorless solid (0.33 g, 96%).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[O:17][CH3:18].B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl>C(OCC)(=O)C.C(OCC)(=O)C.C(Cl)(Cl)Cl.O>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[CH:6][C:5](=[O:7])[CH2:4][C:1](=[O:3])[CH3:2])=[CH:11][C:10]=1[O:17][CH3:18]
Reactant: CC(=O)CC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=CC(=O)CC(C)=O)ccc1O
Reaction time: 12 h
Yield: 40 %

Procedure:
Boric anhydride (16.32 g, 237.2 mmoles) and acetylacetone are stirred at room temperature under nitrogen for 12 hours. 4-Hydroxy-3-methoxybenzaldehyde (18.06 g, 118.8 mmoles) and tributyl borate (364 g, 3.16 moles) are combined with the acetyl acetone/boric anhydride complex in 100 ml of ethyl acetate. The reaction is stirred at room temperature for one hour, at which time n-butylamine (4.34 g, 59.4 mmoles) is added in 4 equal portions over 8 hours. The reaction is allowed to stir for 12 hours. 300 ml of water containing 20 ml of concentrated hydrochloric acid is added to the reaction and stirred for 2 hours. The solid which forms is removed by filtration through celite, and the layers of filtrate are separated. The ethyl acetate layer is washed with 2×100 ml of saturated sodium bicarbonate, followed by 100 ml of brine. Drying over magnesium sulfate followed by evaporation of the solvent gives a red solid. Chromatography in 5% ethyl acetate/chloroform gives 11.06 g (40%) of a yellow solid. mp=146°-147° C. Analysis for C13H14O4 requires C-66.65, H-6.04. Found C-66.88, H-6.18.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:21]([O-])([OH:23])=[O:22].[OH-].[K+]>C(O)(=O)C>[N+:21]([C:9]1[CH:8]=[CH:7][C:6]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(CCCc2ccncc2)cc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(CCCc2ccncc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Into a solution consisting of 10.3 ml of pure acetic acid and 18.6 ml of 98% sulfuric acid, cooled to 5° C., are introduced slowly, drop by drop, 25 g of 4-(3-phenylpropyl) pyridine. When this addition has been completed, the solution obtained is cooled to -15° C. and a sulfonitric mixture consisting of 9 ml of nitric acid and 18.6 ml of 98% sulfuric acid is added drop by drop. During the whole of the addition the temperature of the reaction medium is maintained below +10° C. The addition is completed in one hour. The yellow solution obtained is poured into 600 g of a water+ice mixture. The pH is adjusted to 11 by the addition of an aqueous potassium hydroxide solution and the mixture is extracted twice with 200 ml of ether. The ethereal phases are collected and washed with water, dried over magnesium sulfate and concentrated. 29.7 g of 4-[3-(4-nitrophenyl)propyl]pyridine are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.[CH2:12]([C@H:14]1[O:16][CH2:15]1)Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:16]1[CH2:15][C@@H:14]1[CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: ClC[C@@H]1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H]3CO3)ccc2s1
Reaction time: 8 h

Procedure:
A mixture of 2-methylbenzothiazol-5-ol, a compound of formula (1) (6.0 g, 36 mmol), (S)-(+)-epichlorohydrin, a compound of formula (2) (20 ml, 182 mmol), and potassium carbonate (20 g, 144 mmol) in acetone (100 ml), was heated to reflux and allowed to stir overnight. The solution was allowed to cool and filtered through Celite 512. The filtrate was evaporated (in vacuo), to yield an oil. The oil was chromatographed on silica gel, eluting with 20% ethyl acetate/hexanes, to yield 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole as a white solid (6.2 g, 28 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[O:15][C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:39])[CH3:38])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: CC(=O)Cl
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc3cccc(-c4ccc(NC(C)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.075 g (0.1927 mmol) [7-(4-amino-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 11), 0.027 ml triethylamine and 0.016 g (0.199 mmol) acetyl chloride in 4 ml dichloromethane is stirred for 1 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford the title compound as orange crystals. Rt=2.16 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 434 (M+1)+; m.p. 265-270° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]#[N:27].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([NH:27][CH2:26][C:25]#[N:24])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](O[C@@H](c1ccc(Br)cc1)c1cccs1)C(=O)O
Reactant: N#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](O[C@@H](c1ccc(Br)cc1)c1cccs1)C(=O)NCC#N
Reaction time: 3 h

Procedure:
To a solution of (2S)-2-{[(S)-(4-bromophenyl)(thien-2-yl)methyl]oxy}-4-methylpentanoic acid from step 2, (273 mg, 0.71 mmol) in DMF (3.5 mL) was added aminoacetonitrile HCL salt (66 mg, 0.71 mmol), triethylamine (359 μL, 3.55 mmol) and HATU (270 mg, 0.71 mmol). The mixture was aged for 3 hours under a nitrogen atmosphere and was then poured into a saturated aqueous solution of NaHCO3. The resulting mixture was extracted 3 times with ethyl acetate. The organic extracts were washed with brine, dried and evaporated to a solid. The crude product was chromatographed on silica gel using 35% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [N:1]1([C:7]2[C:8]([CH2:13][NH2:14])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:15][C:16]1[C:17]([CH:23]=O)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:15][C:16]1[C:17]([CH2:23][NH:14][CH2:13][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1
Reactant: NCc1ncccc1N1CCOCC1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1cnc(CNCc2ncccc2N2CCOCC2)c(C)c1

Procedure:
Using General Procedure B: Reaction of C-(3-morpholin-4-yl-pyridin-2-yl)-methylamine, 3.5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (3,5-dimethyl-pyridin-2-ylmethyl)-(3-morpholin-4-yl-pyridin-2-ylmethyl)-amine as a colorless oil. 1H NMR (CDCl3) δ 2.27 (s, 3H), 2.30 (s, 3H), 2.92-2.95 (m, 4H), 3.79-3.82 (m, 4H), 3.95 (s, 2H), 4.03 (s, 2H), 7.14 (dd, 1H, J=4.5, 8.1 Hz), 7.23 (s, 1H), 7.33 (dd, 1H, J=1.2, 8.1 Hz), 8.22 (s, 1H), 8.31 (dd, 1H, J=1.2, 4.5 Hz). Further reaction of (3,5-dimethyl-pyridin-2-ylmethyl)-(3-morpholin-4-yl-pyridin-2-ylmethyl)-amine, 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde and NaBH(OAc)3 following General Procedure B gave a colorless oil. Deprotection with NH2NH2.H2O, following General Procedure E, gave a colorless oil. Subsequent conversion to the HBr salt gave COMPOUND 201 as a pale yellow solid. 1H NMR (D2O) δ 1.58-1.70 (m, 4H), 2.42 (s, 3H), 2.44 (s, 3H), 2.78-2.84 (m, 2H), 2.94-3.02 (m, 2H), 3.04 (s, br., 4H), 3.96 (s, br., 4H), 4.24 (s, 2H), 4.28 (s, 2H), 7.80-7.88 (m, 1H), 8.07-8.15 (m, 2H), 8.8.36-8.42 (m, 2H); 13C NMR (D2O) δ 17.21, 17.49, 23.06, 25.05, 39.66, 51.91, 52.65, 54.34, 55.96, 66.81, 126.80, 135.15, 136.40, 137.34, 137.78, 137.91, 147.61, 148.92, 149.75. ES-MS m/z 384 (M+H). Anal. Calcd. for C22H33N5O.3.3HBr.1.5H2O.0.3C4H10O: C, 39.82; H, 6.09; N, 10.01; Br, 37.68. Found: C, 39.83; H, 6.20; N, 10.08; Br, 37.59.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](OC(C)(C)C)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[C:42]([NH:49][C@H:50](C(O)=O)[CH:51]([CH3:53])[CH3:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1.C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:34])[C@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[NH:11][C:12](=[O:26])[C@H:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[NH:14][C:15](=[O:16])[C@H:50]([CH:51]([CH3:53])[CH3:52])[NH:49][C:42]([O:44][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
A 500 mL round bottom flask was charged with 46.52 g (99 mmol) N-tert-Butyloxycarbonyl-L-leucinyl-L-phenylalanine benzyl ester, 340 mL anhydrous methylene chloride (CH2Cl2), and 51 mL trifluoroacetic acid (TFA). The mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours, and then concentrated in vacuo. The residue was azetroped twice with toluene, and carried on. The same 500 mL round bottom flask containing the crude TFA salt was placed under a nitrogen atmosphere and charged with 21.5 g (99 mmol) Boc-L-valine, 13.4 g (99 mmol) HOBT, and 270 mL anhydrous THF. The solution was cooled in an ice/acetone bath and 21.4 g (104 mmol) DCC was added in one portion. The mixture was stirred in the cold for 1 hour, and then warmed to room temperature and stirred overnight. The precipitated DCU was filtered off, and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and washed once with water, once with a 10% solution of citric acid, once with saturated NaHCO3, and once with brine. The organic layer was then dried over Na2SO4, filtered, and concentrated in vacuo. The resultant solid was precipitated from ethanol with H2O to provide 41.96 g (75%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4](OCC)=[O:5].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:4](=[O:5])[C:3]1[CH:9]=[CH:10][CH:11]=[N:12][C:2]=1[CH3:1]
Reactant: CCOC(=O)c1cccnc1C
Reactant: CN
Product: CNC(=O)c1cccnc1C

Procedure:
200 g. (1.21 mol) of ethyl 2-methylnicotinate (Compound XI) and 1 l. of 40% aqueous methylamine were heated at 40° C. for 4 hours. The reaction mixture was stripped at reduced pressure to obtain the crude product (197.8 g.) as a thick oil which was distilled at 121°-133° C./0.18 mm. Hg. to give the product (175.8 g.), m.p. 69°-72° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([S:50](Cl)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[C:44]1([S:50]([NH:8][C@@H:9]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@@H:11]([CH2:20][N:21]3[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=4)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]3)[CH2:10]2)(=[O:52])=[O:51])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@H](NS(=O)(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(R)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 34 in Step A and phenylsulfonyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH3:10])[C:12]2[S:11][CH2:17][C:15](=[O:16])[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCNc1cccc(F)c1
Reactant: O=C1CSC(=S)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C1=NC(=O)CS1)c1cccc(F)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 76.6 %

Procedure:
To a solution of (3-fluorophenyl)-ethylamine (3.06 g, 22 mmol) and rhodanine (2.66 g, 20 mmol) in acetonitrile (70 mL) was added DIEA (7.66 mL, 44 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (5.97 g, 22 mmol) was added in two portions. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (250 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (25 mL) at hot condition and stored in the refrigerator overnight. Then, the solids were collected by filtration and washed with ethyl acetate. After drying in air, 3.65 g (76.6% yield) of 2-[(3-fluorophenyl)-ethylamino]-thiazol-4-one was isolated as a white amorphous solid: HRES(+) m/e calcd for C11H11FN2OS (M+H)+239.0649, found 239.0647.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.96 (s, —CO2H); 7.48 (d-like, 1 arom. H); 7.40 (m, 2 arom. H); 7.18 (m, 1 arom. H); 5.86 (m, —CH═CH2); 5.15, 5.08 (2 d-like, CH═CH2); 4.03 (t, J=6.6, OCH2—CH2—CH2═CH2); 2.47 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 167.07 (—C═O); 158.44; 134.79; 132.18; 129.70; 121.55; 119.31; 117.04; 114.54; 66.84; 32.90.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[CH3:1][C:2]1[N:3]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:4]2[C:9]([C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1[nH]c2ccccc2c1Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.1 %

Procedure:
2-Methyl-3-(4-nitrobenzyl)-1H-indole (4.0 g, 15 mmol) was weighed, and dissolved in 30 mL DMF. Cesium carbonate (9.77 g, 30 mmol) was added, and stirred at room temperature for 15 min. Ethyl bromoacetate (2.755 g, 16.5 mmol) was added, and reacted at room temperature for 3 h. Upon completion of the reaction, it was filtered. The filtrate was added into water, and extracted with ethyl acetate. The extract was washed with water, and a saturated solution of sodium chloride, rotate evaporated to dryness, chromatographed on a silica gel column (petroleum ether) to obtain a yellow solid 2.7 g, at a yield of 51.1%.