Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[S:23][CH2:24][CH:25]2[CH2:27][O:26]2)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[CH:17]3[CH:12]([CH:13]=[CH:14][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:16]3)[NH:11][C:10](=[O:22])[C:9]=2[S:23][CH:24]=[CH:25][CH2:27][OH:26])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1=C(SCC2CO2)C(=O)NC2C=CC(C(F)(F)F)=CC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1=C(SC=CCO)C(=O)NC2C=CC(C(F)(F)F)=CC12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
4-(5-Chloro-2-methoxy-phenyl)-3-(3-hydroxy-propenylsulfanyl)-6-trifluoromethyl-4a,8a-dihydro-1H-quinolin-2-one (Ig) was prepared by a base-mediated epoxide rearrangement process. To a solution of VIII (0.2 g, 0.45 mmol) in dry THF (4 mL) at −78° C. under nitrogen was added a THF solution of lithium diisopropylamide (LDA, used as supplied by Aldrich, 1.5 Molar, 0.6 mL). The mixture was stirred at −78° C. for a further 10 min. before it was allowed to warm to room temperature and stirring was continued for another 30 min. It was quenched with saturated solution of NH4Cl, organic residues were extracted into ethyl acetate. The organic layers were combined and dried over MgSO4. Evaporation of solvent gave 0.18 g (90% yield) of the desired product as pale yellow solid, mp 148–150° C. Calcd. for C20H15Cl1F3N1O3S1: C, 54.34; H, 3.42; N, 3.17; F, 12.90; Cl, 8.02. Found: C, 54.34; H, 3.66, N, 2.93; F, 12.80; Cl, 7.95. 1H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.84 (d, J=10.2 Hz, 1H), 7.58–7.54 (m, 2H), 7.30–7.23 (m, 2H), 7.08 (s, 1H), 6.28 (d, J=15.3 Hz, 1H), 5.58 (dt, J=15.3, 5.4 Hz, 1H), 4.74 (t, J=5.7 Hz, 1H), 3.84 (t, J=6.0 Hz, 2H), 3.69 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]2[CH2:14][C@H:9]1[CH2:10][N:11]2[C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=O)(C)(C)C.[ClH:26]>C(O)=O.CO>[ClH:26].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: O=C(c1cc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of (S,S)-5-(1H-indole-2-carbonyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (124 mg, 0.36 mmol) in formic acid was added 5.0 N HCl (75 μL, 1.82 mmol). After 1 h at rt, the solution was diluted with MeOH (30 mL) and concentrated to give a purple solid (87 mg, 99%). MS (ESI): mass calcd. for C14H15N3O, 241.12; m/z found, 242.3 [M+H]+. 1H NMR (MeOD): 7.67-7.63 (m, 1H), 7.49-7.44 (m, 1H), 7.28-7.22 (m, 1H), 7.12-7.05 (m, 1H), 7.01-6.97 (m, 1H), 5.49 (s, 1H), 5.41-5.02 (m, 1H), 4.58 (s, 1H), 4.28-3.39 (m, 4H), 3.33-3.29 (m, 1H), 2.32-2.21 (m, 1H), 2.13-2.04 (m, 1H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](F)[C:10]([F:22])=[C:11]([N:15]4[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[NH3:28]>>[NH2:28][C:9]1[C:10]([F:22])=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[CH2:16]2)[C:12]([F:14])=[C:13]2[C:8]=1[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5][N:4]2[CH:1]1[CH2:3][CH2:2]1
Reactant: CC1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Reactant: N
Product: CC1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CCN1
Temperature: 100 °C

Procedure:
A mixture of 1-cyclopropyl-5,6,8-trifluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (150 mg) and 28% aqueous ammonia (15 ml) was heated at 100° C. for 48 hours in a sealed tube. The reaction mixture was evaporated to dryness under reduced pressure and water was added to the residue. The mixture was extracted with chloroform. After drying, the extract was evaporated and the residue was recrystallized from chloroform-ethanol to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (93 mg), m.p. 251°-253° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:7]=1.[C:17]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([N:27]2[C:39]3[CH:38]=[C:37]([OH:40])[CH:36]=[CH:35][C:34]=3[C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:22]=1)([CH3:20])([CH3:19])[CH3:18].N1C=CC=CC=1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.[Cu]I>[C:8]([C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:5]=1)[O:40][C:37]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([C:23]3[CH:22]=[C:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:26]=[CH:25][N:24]=3)[C:39]=2[CH:38]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccnc(-n2c3ccccc3c3ccc(O)cc32)c1
Reactant: CC(C)(C)c1cc(Br)cc(-n2ccnc2)c1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(Oc2ccc3c4ccccc4n(-c4cc(C(C)(C)C)ccn4)c3c2)cc(-n2ccnc2)c1
Temperature: 100 °C
Reaction time: 96 h
Yield: 80.5 %

Procedure:
A mixture of 1-(3-bromo-5-tert-butylphenyl)-1H-imidazole 7 (0.98 g, 3.50 mmol, 1.0 eq), 9-(4-tert-butylpyridin-2-yl)-9H-carbazol-2-ol 10 (1.11 g, 3.50 mmol, 1.0 eq), CuI (0.10 g, 0.53 mmol, 0.15 eq), picolinic acid (0.13 g, 1.05 mmol, 0.30 eq) and K3PO4 (1.78 g, 8.40 mmol, 2.4 eq) in DMSO (7 mL) was stirred at a temperature of 100° C. for four days under a nitrogen atmosphere, then cooled to ambient temperature. The solid was filtered off and washed with plenty of ethyl acetate. The filtrate was washed with water three times and then dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane/ethyl acetate as an eluent to obtain the desired product as a brown sticky liquid (1.45 g in 81% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[C:3]=1[C:4]#[N:5].[CH3:14][N:15]=[C:16]=[O:17]>C1C=CC=CC=1>[C:4]([C:3]1[C:6]([O:12][CH3:13])=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[NH:1][C:16]([NH:15][CH3:14])=[O:17])#[N:5]
Reactant: CN=C=O
Reactant: COc1ccc(N)c(C#N)c1OC
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(OC)c(OC)c1C#N
Yield: 35.6 %

Procedure:
To 2-amino-5,6-dimethoxybenzonitrile (3.4 g, 19.0 mmol) dissolved in 50 ml of benzene, was added 30 mmol of methylisocyanate in benzene. The resultant mixture was refluxed for 0.75 hours and the tan precipitate which formed was collected by filtration. Recrystallization of the crude product from 2-propanol gave 1.59 g (34%) of the analytical urea, mp 236°-237.5°.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([F:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:28]1[C:29]([CH3:31])=[CH:30][C:26]([O:25][C:15]2[C:16]([F:24])=[CH:17][C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:14]=2[Cl:13])=[N:27]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(F)cc(C(F)(F)F)cc2Cl)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
Triethylamine (2.02 g, 20.0 mmol) and ethyl isocyanate (1.42 g, 20.0 mmol) were added to an ethyl acetate (50 mL) solution of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (5.33 g, 18.0 mmol), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2 mol/L hydrochloric acid, followed by extraction with ethyl acetate (50 mL×3 times). The organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, the desiccant was removed by filtering and the solvent was distilled off the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane= 1/10) to give a white solid of N-ethyl-3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (5.37 g, yield: 81.6%). Melting point: 84˜86° C., 1H-NMR (Acetone-d6, Acetone, ppm): δ1.10 (t, J=7.2 Hz, 3H), 2.55 (d, J=0.9 Hz, 3H), 3.26 (dq, J=6.1 and 7.2 Hz, 2H), 5.98 (q, J=0.9 Hz, 1H), 7.39˜7.48 (brt, J=6.1 Hz, 1H), 7.75 (ddq, J=2.1 and JHF=0.7 and 9.7 Hz, 1H), 7.82 (dq, 1H, J=2.1 and JHF=0.7 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].[C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25]O)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:19]([O:18][C:16]([N:23]1[CH2:29][CH2:28][CH2:27][C@H:24]1[CH2:25][O:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1C(=O)OC
Yield: 102.5 %

Procedure:
To a stirred solution of dimethyl 4-hydroxyphthalate (3.00 g, 14.27 mmol), N-Boc-prolinol (2.87 g, 14.26 mmol), Ph3P (4.49 g, 17.12 mmol) in THF (50 mL) was added DIAD (3.40 mL, 17.27 mmol) at 0° C. Then the resulting mixture was heated under reflux overnight. The resulting mixture was evaporated and the residue was purified by column chromatography on silica-gel with n-hexane-EtOAc (3:1, v/v) as eluent to give 5.75 g (q.y.) dimethyl (S)-4-[1-(tert-butoxycarbonyl)-2-pyrrolidinyl methoxy]phthalate as an oil. 1H-NMR (CDCl3) δ1.47 (s, 9 H), 1.86-2.05 (m, 4 H), 3.36-3.40 (m, 2 H), 3.87 (m, 3 H), 3.91 (s, 3 H), 3.96-4.19 (m, 3 H), 7.03-7.24 (m, 2 H), 7.80 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][C:5]1=[O:14])(=[O:3])[CH3:2].[N:15]1[CH:20]=[CH:19][C:18]([C:21](O)=[O:22])=[CH:17][CH:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(O)(=O)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6](=[C:21]([OH:22])[C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[C:5]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=O)Cc2ccc(Cl)cc21
Reactant: O=C(O)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1C(=O)C(=C(O)c2ccncc2)c2ccc(Cl)cc21

Procedure:
6.3 g of 1-acetyl-6-chloro-2-indolinone, 4.06 g pyridine-4-carboxylic acid, 10.6 g TBTU and 21 ml triethylamine are stirred in 60 ml of DMF for 15 hours at ambient temperature. The mixture is combined with water, then adjusted to pH 5 by the addition of 10% acetic acid. The precipitate is suction filtered, washed with water and taken up in ethyl acetate. The solution obtained is dried with sodium sulphate and evaporated almost to dryness. The precipitate obtained is suction filtered and dried at 100° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10](=[O:32])[NH:11][CH2:12][CH2:13][N:14]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:15]([NH2:24])=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C1COCC1>C1COCC1.O>[C:25]([N:14]([CH2:13][CH2:12][NH:11][C:10]([C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=1)=[O:32])[C:15]([NH2:24])=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: COC(=O)c1ccc(C(=O)NCCN(C(=O)OC(C)(C)C)C(N)=NC(=O)OC(C)(C)C)s1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N=C(N)N(CCNC(=O)c1ccc(C(=O)O)s1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
With continued reference to Scheme K, To Compound XXVII: 5-(2-(N,N′-Bis-(BOC)-guanidino)-ethylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (2.2 g, 4.66 mmol) in 50% THF/H2O (50 ml) was added 1.5 eq. of LiOH (294 mg, 6.99 mmol) and the reaction mixture was left to stir at room temperature for 3 hours. 10% citric acid solution was added until acidic pH and THF was evaporated. The aqueous solution was then extracted with CH2Cl2 (3×70 ml). The organic phases were combined and washed with a solution of Brine, dried over MgSO4 and evaporated to give the desired product in 84% yield. 1H NMR (CD3OD, 400 MHz) δ 1.34-1.66 (m, 21H), 3.49-3.67 (m, 4H), 7.61-7.70 (dd, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:43]1=[O:58]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][CH2:46][CH2:45][N:44]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([O:56][CH3:57])[CH:51]=2)[C:43]1=[O:58])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1cccc(CN2CCCC[C@H](N)C2=O)c1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCCN(Cc4cccc(OC)c4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((S)-1-(3-methoxybenzyl)-2-oxoazepan-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (7.0 mg, 0.012 mmol) and Intermediate 43 (3.1 mg, 0.012 mmol) to give a white solid (7.1 mg, 70% yield). Anal. Calcd. for C45H56N4O7S m/z 796.7. found: 797.7 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 7.25-7.19 (m, 5H), 7.19-7.11 (m, 8H), 6.85-6.72 (m, 3H), 5.33 (t, J=4.67 Hz, 1H), 5.12 (d, J=6.60 Hz, 1H), 5.04-4.95 (m, 1H), 4.63-4.43 (m, 3H), 3.78 (s, 3H), 3.67 (s, 3H), 3.46 (dd, J=15.12, 11.82 Hz, 1H), 3.24-3.12 (m, 3H), 2.86-2.70 (m, 5H), 2.46-2.37 (m, 3H), 2.02 (d, J=4.95 Hz, 1H), 1.84-1.49 (m, 11H), 1.28-1.23 (m, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:43]12[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH:44]1[NH2:53])[CH2:50]2>C(#N)C>[CH:43]12[CH2:52][CH:47]3[CH2:48][CH:49]([CH2:51][CH:45]([CH2:46]3)[CH:44]1[NH:53][C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])=[O:3])[CH2:50]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)NC1C2CC3CC(C2)CC1C3
Yield: 6.6 %

Procedure:
Using the procedure described previously, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (113 mg, 0.30 mmol), triethylamine (168 uL, 1.20 mmol, 4 eq) in acetonitrile (1.5 mL, was cooled to 0° C. and treated with isobutyl chloroformate (43 uL, 0.33 mmol, 1.1 eq) followed by the hydrochloride salt of 2-adamantylamine (113.2 mg, 0.60 mmol, 2 eq). After TLC indicated the reaction was complete, the mixture was purified by HPLC to provide 10 mg (6.5%) of L-isoleucine, N-[1-(adamantan-2-ylcarbamoylmethyl)-L-prolyl] benzylamide.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][CH2:7][N:8]([C:11]([CH:13]3[CH2:18][O:17][CH2:16][CH2:15][O:14]3)=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.O1CCOCC1C=O.Cl[C:30]1[N:35]=[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])[C:33]([Cl:49])=[CH:32][N:31]=1>>[Cl:49][C:33]1[C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[S:43]([N:46]([CH3:48])[CH3:47])(=[O:45])=[O:44])=[N:35][C:30]([NH:1][C:2]2[CH:20]=[CH:19][C:5]3[CH2:6][CH2:7][N:8]([C:11]([CH:13]4[CH2:18][O:17][CH2:16][CH2:15][O:14]4)=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:31][CH:32]=1
Reactant: Nc1ccc2c(c1)CCN(C(=O)C1COCCO1)CC2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: O=CC1COCCO1
Product: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(C(=O)C2COCCO2)CC3)ncc1Cl

Procedure:
(7-Amino-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone, prepared in a similar manner as 7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1,4-dioxinan-2-yl-methanone of Example 633b, was reacted with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide, in a similar manner as Example 601b, to yield desired product 2-{5-Chloro-2-[3-([1,4]dioxane-2-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N,N-dimethyl-benzenesulfonamide as a lyophylate (25%); 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 9.33 (s, 1H), 8.49 (bs, 1H), 8.29 (s, 1H), 7.84 (d, J=7.97 Hz, 1H), 7.71 (m, 1H), 7.41-7.32 (m, 3H), 7.07-7.01 (m, 1H), 4.39 (m, 1H), 3.78-3.49 (m, 10H), 2.87-2.77 (m, 2H), 2.65 (s, 6H); MS (m/e) 587.15 (M+H).
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[CH3:22][O:23][C:24](=[O:59])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH:35]1[CH:40]([C:41]2[O:42][CH2:43][CH:44]([C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:45]=2)[CH:39]2[O:58][CH:36]1[CH2:37][CH2:38]2>ClCCl.[Cu](Br)Br>[CH3:22][O:23][C:24](=[O:59])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH:35]1[CH:40]([C:41]2[O:42][CH:43]=[C:44]([C:46](=[O:57])[NH:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[N:45]=2)[CH:39]2[O:58][CH:36]1[CH2:37][CH2:38]2
Reactant: CCCCCCCCCNC(=O)C1COC(C2C3CCC(O3)C2Cc2cc(F)ccc2CCC(=O)OC)=N1
Agent: Br[Cu]Br
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCCCCCCCNC(=O)c1coc(C2C3CCC(O3)C2Cc2cc(F)ccc2CCC(=O)OC)n1
Reaction time: 0.25 h

Procedure:
To a suspension of Copper bromide (6.27 g, 28.08 mmol) in dichloromethane (90 mL), under nitrogen atmosphere and in a water bath, was added HMTA (3.94 g, 28.08 mmol) followed by DBU (4.17 mL, 28.08 mmol) and the resulting mixture was stirred for 15 minutes. Then, a solution of (3-{4-Fluoro-2-[3-(4-nonylcarbamoyl-4,5-dihydro-oxazol-2-yl)-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl]-phenyl}-propionic acid methyl ester (3.72 g, 7.02 mmol) in dichloromethane (40 ml) was added and the resulting mixture was stirred at room temperature for 16 h.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH2:17]([O:24][P:25]([CH2:34][C@H:35]([OH:45])[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]([NH2:43])[CH:40]([CH3:42])[CH3:41])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][P:25]([CH2:34][C@H:35]([OH:45])[CH2:36][NH:37][C:38](=[O:44])[C@@H:39]([NH:43][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:40]([CH3:42])[CH3:41])([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1

Procedure:
The title compound was prepared substantially in a similar manner as in Step 1 of Example 10 using N-Cbz-glycine and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound thus obtained was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.20-7.15 (m, 10H), 5.17 (s, 2H), 5.02 (m, 2H), 4.19 (d, 1H), 4.09 (m, 1H), 3.80 (s, 2H), 3.23-3.15 (m, 2H), 2.08 (m, 1H), 2.01-1.90 (m, 2H), 1.88-1.78 (m, 6H), 1.70-1.59 (m, 2H), 1.30-1.11 (m, 2H), 1.03 (m, 1H), 0.95-0.88 (m, 8H). 31P NMR (CD3OD, 300 MHz): δ 60.61, 59.94. LCMS m/z: [M+H]+=616.26.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]=[C:13]=[S:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[C:32]([CH3:37])[C:31]=1[CH3:38].C1(C)C=CC=CC=1>C(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH3:28])[N:23]=[CH:22][CH:21]=[C:20]2[O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:13]([NH:12][C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[S:14])=[C:32]([CH3:37])[C:31]=1[CH3:38]
Reactant: O=C(N=C=S)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc([N+](=O)[O-])cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
Commercially available 4-nitro-1-benzenecarbonyl isothiocyanate (30 mg) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (62 mg, yield 75%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[CH:4][C:3]=1[F:24].[NH:25]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:26]1>>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:24])=[C:2]([N:25]3[CH2:29][CH2:28][CH:27]([C:30]4[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=4)[CH2:26]3)[N:11]=2)[C:6](=[O:23])[C:7]([C:20]([OH:22])=[O:21])=[CH:8]1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reactant: c1cc(C2CCNC2)ccn1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 56 %

Procedure:
Starting from 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid (0.51 g, 1.5 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1, provided the title compound (0.39 g, 56%) as an off white solid, mp 253°-255° C. (dec).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([C:26]#[C:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][N:29]=1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:31]2[CH:32]=[C:33]([F:34])[C:28]([C:27]#[CH:26])=[N:29][CH:30]=2)=[CH:36][CH:37]=1
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ncc(-c2ccc(Cl)cc2)cc1F
Reaction time: 2 h

Procedure:
1.14 g (3.61 mmol) of TBAF was added at RT to a solution of 1.25 g (3.61 mmol) of 2-[(tert-butyldimethylsilanyl)ethynyl]-5-(4-chlorophenyl)-3-fluoropyridine in 30 mL of DCM and the mixture was stirred for 2 hours. The organic phase was washed with water, dried over sodium sulfate, and evaporated down in vacuo. The residue was stirred with PE, the precipitate was filtered off, washed with PE, and dried in the air. Yield: 0.72 g (86% of theoretical); C13H7ClFN (M=231.653); calc.: molpeak (M+H)+: 232/234 (Cl); found: molpeak (M+H)+: 232/234 (Cl); HPLC-MS: 5.81 minutes (method B).