Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[OH-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.Cl.[Cl-].[Ti+3].[Cl-].[Cl-]>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Agent: [Ti+3]
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Product: Nc1ccccc1-c1ccccc1
Reaction time: 0.25 h

Procedure:
40 mmol of an aniline derivative (III) were suspended or dissolved in a mixture of 20 ml of water, 8 ml of 10% by weight aqueous hydrochloric acid and 8 ml of a 1M solution of titanium(III) chloride in 16 ml of 10% by weight aqueous hydrochloric acid (48 mmol of HCl). To this suspension or solution were added, at room temperature, 2 mmol of the tetrafluoroborate salt of a diazonium compound (II) in small portions as a solid over a period of 10 minutes. Once the mixture thus formed had been stirred for a further 15 minutes, a solution of 4.0 g of sodium hydroxide and 4.0 g of sodium sulfite in 40 ml of water was added. The reaction mixture was extracted three times with diethyl ether and the combined organic phases were then washed with saturated sodium chloride solution and dried over sodium sulfate. After the crude product had been concentrated under reduced pressure and purified by column chromatography, the 2-aminobiphenyl was obtained as a light brown oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[F:30][C:31]1([F:39])[CH2:34][N:33]([CH:35]2[CH2:38][NH:37][CH2:36]2)[CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:30][C:31]1([F:39])[CH2:34][N:33]([CH:35]2[CH2:38][N:37]([CH2:18][C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)[CH2:36]2)[CH2:32]1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: FC1(F)CN(C2CNC2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CC(F)(F)C4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 79.6 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.0725 g, 0.18 mmol), 3,3-difluoro-[1,3′]biazetidinyl (0.033 g, 0.22 mmol) and 4 Å molecular sieves (0.2 g) in DCE (5 mL). The reaction mixture was stirred for 7 h at room temperature. Sodium triacetoxyborohydride (0.079 g, 0.37 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:EtOAc, gradient 0:100 to 40:60) to give 562 as a yellow solid (0.075 g, 78%). LCMS (Method I): RT=2.66 min, [M+H]+ 524.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.27-7.20 (m, 2 H), 4.50-3.96 (m, 4 H), 3.88 (s, 2 H), 3.86-3.67 (m, 7 H), 3.71-3.55 (m, 4 H), 3.48-3.39 (m, 1 H), 3.37-3.35 (m, 2 H), 3.26 (q, J=7.5 Hz, 2 H), 3.06 (dd, J=7.5, 5.3 Hz, 2 H), 1.33 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.S(OC)(O[CH3:14])(=O)=O>C(O)=O>[CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[CH3:14][N:3]1[C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: COS(=O)(=O)OC
Agent: Cc1ncc([N+](=O)[O-])[nH]1
Solvent: O=CO
Product: Cc1ncc([N+](=O)[O-])n1C
Temperature: 80 °C

Procedure:
600 parts of formic acid (85%), 225 parts of 2-methyl-5-nitroimidazole and 250 parts of dimethyl sulfate are heated in a stirred vessel for 4 hours under reflux (80° C.). The formic acid is then distilled off in vacuo. The residue which remains is dissolved in 400 parts of water neutralized to pH 1.8 with aqueous ammonia solution and cooled to from 0° to +5° C. The unreacted 2-methyl-5-nitroimidazole is deposited and is centrifuged off. The mixture is then adjusted to pH 10 with aqueous ammonia solution and 1,2-dimethyl-5-nitroimidazole is separated at 10° C. 75 parts of 2-methyl-5-nitroimidazole and 145 parts of 1,2-dimethyl-5-nitroimidazole of the melting point 137° to 140° C. are obtained. The yield based on reacted 2-methyl-5-nitroimidazole is 87% of theory.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH2:9][C:10]3([CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36]>O1CCCC1.CCOCC>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]\[C:35]([OH:37])=[O:36].[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1
Reactant: N#CN1CCC2(CC1)CN(c1ccccc1F)c1cc(Cl)ccc12
Agent: O=C(O)/C=C\C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: Fc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A solution of 3.4 g of 6-chloro-1'-cyano-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine], Example 26, in 50 ml of tetrahydrofuran is added dropwise to a refluxing slurry of 1.0 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. After total addition the mixture is stirred at reflux for 2.5 hours before being treated with water and alkali. The resulting oily product, in ether, is converted to its maleic acid salt which is recrystallized from an ethyl alcohol-ether mixture to provide off-white granules, mp 174.5°-175.5° C. of 6-chloro-1-(2-fluorophenyl)spiro[indoline-3,4'-piperidine] maleate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:45][C:46]([OH:50])([C:48]#[CH:49])[CH3:47]>[Pd].COCCOC.O.[Cu]I.C(OCC)(=O)C>[OH:50][C:46]([CH3:47])([C:48]#[CH:49])[CH2:45][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]=[N:6][CH:7]=1
Reactant: C#CC(C)(C)O
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cncc(Br)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C#CC(C)(O)Cc1cncc(C2CCCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A mixture of 5-bromo-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine (1 g, 3.06 mmol), 10% palladium on charcoal (80 mg, 0.077 mmol), copper(I)iodide (58 mg, 0.30 mmol), triphenylphosphine (80 mg, 0.30 mmol) and potassium carbonate (1.06 g, 7.65 mmol) in DME (5 mL) and water (5 mL) was stirred at 25° C. After 0.75 h 2-methyl-3-butyn-2-ol (0.74 mL, 7.65 mmol) was added and the reaction flask was heated at 80° C. for 18 h. Water (30 mL) and ethyl acetate (30 mL) were added to the cooled mixture and this was filtered through celite. The organic phase was separated and the aqueous layer extracted with ethyl acetate (3×20 mL) and the combined ethyl acetate extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate:hexane (1:3 to 1:1) as eluants to afford 5-(2-hydroxy-2-methyl-3-butynyl)-3-(1-tert-butyloxycarbonyl-2-pyrrolidinyl)pyridine as an oil (772 mg, 76%). LRMS (EI) m/e 231 (M+ +H--CO2 and isobutylene), 230 (M+ --CO2 and isobutylene), 229 (M+ --CO2 tBu); 1H NMR (CDCl3, 300 MHz): δ 8.56 (b-s, 1H), 8.37 (b-d, J=1.5 Hz, 1H), 7.53 (m, 1H), 4.93 (b-m, 0.5H), 4.76 (b-m, 0.5H), 3.5-3.7 (b-m, 2H), 2.36 (m, 1H), 1.75-2.0 (b-m, 3H), 1.72 (b-s, 1H), 1.63 (s, 6H), 1.45 (b-s, 3H), 1.21 (b-s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=O)([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][CH2:23][C:18]12[CH2:22][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16][CH2:17]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=O)(CCC3)C4)nc2n(CCC)c1=O
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CNCCN(C)C)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde (40 mg) taken in 5 ml of CH2Cl2.N1,N1-Dimethyl-ethane-1,2-diamine (40 mg), Na(OAc)3BH (100 mg), 2 drops of Acetic acid were added and stirred at rt overnight. Next day the reaction mixture was diluted with ethyl acetate, washed with sat. NAHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure. The crude product was purified by Preparative HPLC. Mass (ES+ 459)
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH2:11])=O)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]#[N:11])[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(C(N)=O)n1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cccc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To an ice cold solution of 6-methoxy-pyridine-2-carboxylic acid amide (300 mg, 1.97 mmol) in THF (3 mL) were added triethylamine (1.25 mL, 8.68 mmol) and dropwise added TFAA (0.61 mL, 4.34 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The volatiles were concentrated in vacuo and the liquid residue was added dropwise to a vigorously stirred, ice cold, pH 7 phosphate buffer solution (5 mL). After 15 min of further stirring the yellowish solid was filtered and air dried for 1 h to yield 250 mg (95%) of 6-methoxy-pyridine-2-carbonitrile as yellowish solid, m/z 135.4 [M+1]+.
Reaction SMILES: O1CCOCC1.Cl.[NH2:8][C:9]1[CH:10]=[C:11]([CH:43]=[CH:44][C:45]=1[OH:46])[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([CH2:19][NH:20][C:21](=[O:42])[CH2:22][NH:23][C:24](=[O:41])[C:25]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:26]=2[NH:33]C(OC(C)(C)C)=O)[CH2:15][CH2:14]1>CO>[NH2:33][C:26]1[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=1[C:24]([NH:23][CH2:22][C:21]([NH:20][CH2:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:11]2[CH:43]=[CH:44][C:45]([OH:46])=[C:9]([NH2:8])[CH:10]=2)[CH2:18][CH2:17]1)=[O:42])=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(O)c(N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M dioxane solution of HCl (0.50 mL) was added to a methanol (1 mL) solution of 1-(3-amino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (20.0 mg, 0.035 mmol), and the resulting mixture was stirred at room temperature overnight and concentrated. The obtained residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated to thereby afford 4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]-1-(3-amino-4-hydroxybenzyl)piperidine (Compd. No. 2141) (17.6 mg, quantitative). The purity was determined by RPLC/MS (85%). ESI/MS m/e 448.3 (M++H, C22H27F2N5O3).
Reaction SMILES: C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][OH:78])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(Cl)Cl.S(=O)(=O)(O)O>C(O)C>[CH2:22]([O:29][C@@H:30]1[C@@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:34]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@@H:33]([CH2:52][O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[O:32][C@H:31]1[O:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[O:78])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OCCCCCCCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: ClCCl
Product: O=CCCCCCCCCCCCCCCCO[C@@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 76 %

Procedure:
PDC oxidation of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanol. Under an atmosphere of nitrogen, pyridinium dichromate (320 mg, 0.851 mmol) was added to a dry methylene chloride solution (6 mL) of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanol (455 mg, 0.583 mmol). The resulting brown slurry was stirred at room temperature under nitrogen. TLC analysis (visualization by UV and char with 10% sulfuric acid in ethanol) of the reaction mixture indicated complete consumption of the starting material and the formation of a new compound after 17 h. The reaction mixture was treated with ether (10 mL), filtered through silica gel and Celite with an ether wash (25 mL) and concentrated to an off-white oil. Chromatographic purification (silica gel, 10% ethyl acetate in hexanes) afforded 345 mg (0.443 mmol, 76%) of 16-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyloxy)-n-hexadecanal as a clear oil. Rf=0.72 (silica gel, 30% ethyl acetate in hexanes); 1H NMR (CDCl3, 300 MHz) δ: 9.75 (t, J=1.5 Hz, 1H), 7.30 (m, 20H), 4.95 (d, J=11.7 Hz, 2H), 4.75 (m, 2H), 4.63 (d, J=11.7 Hz, 1H), 4.43 (d, J=4.5 Hz, 2H), 4.36 (d, J=7.8 Hz, 1H), 3.65 (m, 2H), 3.82 (dt, J=8.7, 1.5 Hz, 1H), 3.56 (m, 6H), 2.40 (dt, J=7.5, 1.5 Hz, 2H), 1.60 (m, 4H), 1.26 (m, 24H); MS (FAB+): 801.3 (M+Na, 14), 785.3 ((M+Li)+, 29), 253.1 (10), 181.1 (100), 160.0 (16), 136.0 (21), 123.0 (12).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:17]([NH:25][C:26]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C(=O)C>[C:17]([NH:25][C:26]1[CH:38]=[C:37]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:36]=[CH:35][C:27]=1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
38 mg of 2-methylphenylboronic acid, 49 mg of sodium carbonate and 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of tert-butyl 2-(benzamido)-4-bromobenzoate, and stirred at 110° C. for 20 hours. After the reaction mixture was cooled to room temperature, 6 mg of polymer supported bis(acetato)triphenylphosphine palladium(II) was added and stirred at 110° C. for 22 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 10% citric acid aqueous solution were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 2-(benzamido)-4-(2-methylphenyl)benzoate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[S:48]([CH3:51])(=[O:50])=[O:49])[C:40]2=[O:52])[C:36](O)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(C[C@H](N2CC3C(=C(S(C)(=O)=O)C=CC=3)C2=O)C(O)=O)CCCCC1.[NH2:78][C:79]1[S:80][CH:81]=[CH:82][N:83]=1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>C(OCC)(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][C:45]=3[S:48]([CH3:51])(=[O:49])=[O:50])[C:40]2=[O:52])[C:36]([NH:78][C:79]2[S:80][CH:81]=[CH:82][N:83]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CS(=O)(=O)c1cccc2c1CN([C@@H](CC1CCCCC1)C(=O)O)C2=O
Reactant: Nc1nccs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CS(=O)(=O)c1cccc2c1C(=O)N([C@@H](CC1CCCCC1)C(=O)O)C2
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cccc2c1CN([C@@H](CC1CCCCC1)C(=O)Nc1nccs1)C2=O

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid and regio-isomeric (S)-3-cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (112 mg; 0.31 mmol) and 2-aminothiazole (54 mg; 0.52 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40M; eluent: ethyl acetate/methylene chloride: gradient 15%-50% ethyl acetate) provided 51 mg (S)-3-Cyclohexyl-2-(4-methylsulfonyl-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C21H25N3O4S2 (M+−2) 445.1130, found 445.1125 and 39 mg of (S)-3-Cyclohexyl-2-(7-methylsulfonyl-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide: EI-HRMS m/e calcd for C21H25N3O4S2 (M+) 447.1286, found 447.1280.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Yield: 6774.2 %

Procedure:
To a solution of 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26, 1.35 g, 3.1 mmol) in ethyl acetate (30 mL) was added 5% palladium on carbon (wet). The resulting suspension was subjected to an atmosphere of hydrogen (40 psi) for 15 h. The catalyst was then removed by filtration through celite. The filtrate was concentrated to provide 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (748 mg, 210 mmol, 68% yield) as an orange viscous syrup. MS (EI) for C20H25N3O3: 356 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:51][CH:52]1[C@H:56]2[C@H:57](OC3CCCCO3)[N:58](C(OC(C)(C)C)=O)[C:59]3[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]1[C@H:24]2[C@H:25](OC3CCCCO3)[N:26](C(OC(C)(C)C)=O)[C:27]3[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:18]([O:19][CH:20]1[C@@H:24]2[CH:25]=[N:26][C:27]3[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[CH:31][C:28]=3[C:29](=[O:30])[N:23]2[CH2:22][CH2:21]1)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:51][CH:52]1[C@@H:56]2[CH:57]=[N:58][C:59]3[CH:66]=[C:65]([O:67][CH3:68])[CH:64]=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][CH2:53]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCCCCCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 85 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8i (217 mg, 0.20 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9i (113 mg, 0.17 mmol, 87%) as a solid: [α]20D=+401° (c=0.19, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.26-1.52 (m, 14H, 14-H, 14′-H, 15-H, 15′-H, 16-H, 16′-H, 17-H), 1.84-1.92 (m, 4H, 13-H, 13′-H), 2.01-2.11 (m, 4H, 2-H, 2′-H), 2.27-2.36 (m, 4H, 1-H, 1′-H), 3.55-3.64 (m, 2H, 3-H, 3′-H), 3.70-3.76 (m, 2H, 11a-H, 11a′-H), 3.78-3.87 (m, 2H, 3-H, 3′-H), 3.92 (s, 6H, 7-OMe, 7′-OMe), 4.02-4.20 (m, 4H, 12-H, 12′-H), 6.81 (s, 2H, 9-H, 9′-H), 7.52 (s, 2H, 6-H, 6′-H), 7.67 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.9, 29.0, 29.3, 29.5, 29.6, 46.6, 53.7, 56.0, 69.1, 109.6, 112.5, 120.2, 140.5, 147.1, 151.6, 162.2, 164.6; IR (neat): 3325, 2928, 1600, 1507, 1448, 1261, 1217, 1023 cm−1; MS (FAB) m/z (relative intensity) 709 ([M+2×MeOH]+., 14), 677 ([M+MeOH]+., 20), 645 (M+., 100).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:17]=[CH:16][C:8]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][CH:6]=1.Cl[C:19]1[N:24]=[C:23]([C:25](=[C:28]2[NH:32][C:31]([CH2:33][CH3:34])=[CH:30][S:29]2)[C:26]#[N:27])[CH:22]=[CH:21][N:20]=1>C(#N)C>[CH2:33]([C:31]1[NH:32][C:28](=[C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][N:10]4[CH2:15][CH2:14][O:13][CH2:12][CH2:11]4)=[CH:16][CH:17]=3)[N:24]=2)[C:26]#[N:27])[S:29][CH:30]=1)[CH3:34]
Reactant: OCc1ccc(CN2CCOCC2)cc1
Reactant: CCC1=CSC(=C(C#N)c2ccnc(Cl)n2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCC1=CSC(=C(C#N)c2ccnc(OCc3ccc(CN4CCOCC4)cc3)n2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (99 mg, 2.27 mmol) in ACN (4 mL) was added a solution of N-(4-hydroxymethylbenzyl)morpholine 313 mg, 1.51 mmol) in ACN (4 mL). The mixture was stirred 1 h at rt. Then (2-chloropyrimidin-4-yl)(4-ethyl-1,3-thiazol-2(3H)-ylidene)acetonitrile (200 mg, 0.76 mmol) was added portion wise. The resulting mixture was heated up at 80° C. for 5 h. After cooling down to rt the ACN was evaporated. EtOAc (5 mL) was added to the residue. After one night at 4° C., the yellow solid was filtered off affording the title compound as a free base (HPLC (max plot) 73.9%). The solid was taken up in DCM and excess TFA then ether were added. The precipitate formed was filtered off, washed with ether (3×) then dried under reduced pressure at 40° C. overnight, affording 409 mg of the title compound as a diTFA salt (Yellow powder, Y=81.1%)