Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[N:17]=2)=[O:14])[N:10]=[CH:9]1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:23]2[CH2:27][C@H:26]([CH2:28][NH:29][C:30](=[O:32])[CH3:31])[O:25][C:24]2=[O:33])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:34](=[O:36])[CH3:35])[N:17]=2)=[O:14])[N:10]=[CH:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Nc4cccc(N)n4)c3)c(F)c2)C(=O)O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cnc(C(=O)Nc4cccc(NC(C)=O)n4)c3)c(F)c2)C(=O)O1
Reaction time: 60 h

Procedure:
N-[(5S)-3-(3-Fluoro-4-(4-(6-aminopyridin-2-ylaminocarbonyl)imidazol-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (70 mg, 0.15 mM) was dissolved in pyridine (3 ml) and treated with acetic anhydride (0.5 ml). After standing 60 hours at ambient temperature, solvent was evaporated, and the residue triturated with water (10 ml). Filtration gave the title product (47 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(#N)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])[CH2:23][CH2:22]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Yield: 99.6 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (1.719 g, 8.468 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.58 g, 8.468 mmol), triethylamine (3.54 mL, 25.4 mmol) in acetonitrile (6 mL) is heated at 86 C for 2 h. After it is evaporated, the residue is dissolved in methylene chloride, and washed with saturated sodium bicarbonate solution. The organic layer is evaporated to yield 2.6 g (99%) of the title compound as a pale-yellow solid. NMR (CDCl3) showed it is pure.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24]>C1COCC1>[Br:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C@H:2]([CH2:7][OH:8])[C@@H:3]([CH3:4])[CH2:5][CH3:6])(=[O:25])=[O:24]
Reactant: CC[C@H](C)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccccc1Br
Reaction time: 12 h

Procedure:
To a solution of (S) isoleucinol (23 mg, 0.2 mmol) in THF (3 mL) was added triethylamine (46 μL, 0.24 mmol) and 2-bromobenzenesulfonyl chloride (51 mg, 0.2 mmol). The solution was stirred for 8 to 16 hours, then concentrated. The residue was dissolved in MeOH (1.5 mL) and purified by semi-preparative RP-HPLC using the following conditions:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.C1C2C(=CC=CC=2)C(C(O)=O)C(C(O)=O)C1C(O)=O>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C(O)C1Cc2ccccc2C(C(=O)O)C1C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 285.5 %

Procedure:
Using the procedure described in Example 5, a solution of L-proline-L-isoleucine benzylamide (162 mg, 0.51 mmol), and triethylamine (355 uL, 5.0 eq), THF (2 mL), was treated with 212 mg (2.0 eq) of 1-chloro-2-(1,2,3,4-tetrahydro-napththalen-2-yl)-2-oxoethane (prepared from 1,2,3,4-tetrahydro-2-napththoic acid using the procedure described in Example 1) to provide 191 mg (77%) of L-isoleucine, N-[1-(2-(1,2,3,4-tetrahydro-napththalen-2-yl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][OH:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[Cl:10][C:11]1[C:12]([O:9][CH2:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][C:14]([F:24])=[C:15]([CH:23]=1)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: C[C@H]1CC[C@H](CO)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OC[C@H]2CC[C@H](C)CC2)cc1F
Temperature: 70 °C

Procedure:
To a solution of trans-(4-methylcyclohexyl)methanol (3.00 g, 23.4 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (6.43 g, 25.90 mmol) in anhydrous dimethylsulfoxide (40 mL) was added cesium carbonate (16.11 g, 49.44 mmol). The mixture was heated at 70° C. for 96 hours, and then cooled to ambient temperature; diluted with water (300 mL) and extracted with ethyl acetate (4×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL); dried over anhydrous sodium sulfate; filtered and concentrated in vacuo. The residue was purified by column chromatography (0% to 10% ethyl acetate in hexanes gradient) to give the title compound (6.48 g 78%): 1H NMR (300 MHz, CDCl3) δ 7.87 (d, J=7.7 Hz, 1H), 6.61 (d, J=12.3 Hz, 1H), 3.82 (d, J=6.2 Hz, 2H), 1.91-1.73 (m, 8H), 1.56 (s, 9H), 1.17-0.96 (m, 5H).
Reaction SMILES: C(N(CC)CC)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([OH:39])=O)=[CH:32][CH:31]=1.[CH:40]1[C:48]2[C:47]3[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][C:46]=3[O:45][C:44]=2[CH:43]=[CH:42][C:41]=1[NH2:54]>ClCCl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:54][C:41]2[CH:42]=[CH:43][C:44]3[O:45][C:46]4[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:47]=4[C:48]=3[CH:40]=2)=[O:39])=[CH:34][CH:35]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
Triethylamine (0.52 mL, 3.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.37 g, 1.9 mmol), N-hydroxybenzotriazole (0.26 g, 1.9 mmol) and 4-fluorophenylacetic acid (0.27 g, 1.8 mmol) were added sequentially to a solution of 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at ambient temperature and then concentrated. The crude material was dissolved in ethyl acetate and washed with 1 N NaOH and water, dried (MgSO4) and concentrated to give 2-(4-fluorophenyl)-N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)acetamide (0.47 g). MS (ESI) m/z 338 ([M+H]+).
Reaction SMILES: Cl[CH2:2][N:3]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].Cl.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.CCOCC>ClCCl>[CH2:9]([N:3]([CH2:2][N:22]1[CH:23]=[C:18]([Cl:17])[CH:19]=[N:20][C:21]1=[O:24])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)N(CCl)Cc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)N(Cc1ccccc1)Cn1cc(Cl)cnc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
N-Chloromethyl-N-ethoxycarbonylbenzylamine (see German Offenlegungsschrift No. 2,119,518) (10 mmol) in dichloromethane (20 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one hydrochloride (20 mmol) in dichloromethane (80 ml). The reaction mixture was stirred at room temperature for 2 hours, extracted with water, the solution dried (MgSO4) and evaporated. The residual crude product (yield 80%, 2.57 g) was triturated with ether to leave the title compound in 53% yield (1.70 g), m.p. 143° C. 1H NMR (CDCl3): δ1.31 and 4.22 (EtO), 4.73 (CH2Ph), 5.23 (CH2N), 7.20 (Ph), 8.03 and 8.38 (H-4, H-6, J 4 Hz). IR(KBr): 1670 cm-1 (CO), 1720 (CO-carbamate).
Reaction SMILES: C([O:5][C:6](=[O:44])[C@@H:7]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:33]=[CH:32][C:31]3[CH2:30][CH2:29][CH2:28][NH:27][C:26]=3[N:25]=2)[CH2:20][CH2:19]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:38]1([S:35]([NH:34][C@@H:7]([CH2:8][N:9]2[CH:17]=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][C:14]=3[N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:33]=[CH:32][C:31]4[CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:25]=3)[CH2:20][CH2:19]2)[C:6]([OH:44])=[O:5])(=[O:36])=[O:37])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H](Cn1cnc2c(N3CCC(c4ccc5c(n4)NCCC5)CC3)ncnc21)NS(=O)(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
38 mg of the compound of step b) were dissolved in 1.5 ml of dichloromethane, and 1.5 ml of trifluoroacetic acid were added. After stirring for 5 hours at ambient temperature additional 0.1 ml of trifluoroacetic acid were added and stirring was continued for further 1.5 hours. The solvents were removed in vacuo, the residue was dissolved in acetic acid and again the solvent was removed in vacuo. The remaining resin was triturated with diethylether and the product isolated by filtration. Yield: 29 mg. MS (ES+): m/e=563.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:32][CH2:33][CH:28]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH2:29][CH2:30]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(c2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-phenylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=447.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]1[C:11]([O:32][CH3:33])=[CH:12][C:13]([O:30][CH3:31])=[C:14](/[CH:16]=[CH:17]/[C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])[CH:15]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:38]([O:37][C:35]([NH:29][S:26]([C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])/[CH:17]=[CH:16]/[C:14]2[CH:15]=[C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:11]([O:32][CH3:33])=[CH:12][C:13]=2[O:30][CH3:31])=[CH:25][CH:24]=1)(=[O:28])=[O:27])=[O:36])[CH3:39]
Reactant: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)NS(=O)(=O)c1ccc(C(=O)/C=C/c2cc(-c3cc4ccccc4[nH]3)c(OC)cc2OC)cc1
Yield: 0.9 %

Procedure:
To a solution of 4-{3E-[5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide (Ex-35E, 3.0 g, 6.5 mmol) in 250 mL of acetone were added ethyl chloroformate (0.93 g, 8.6 mmol) and K2CO3 (2.3 g, 16.7 mmol). The mixture was heated to reflux overnight. The yellow precipitate-formed was filtered. The filtrate was acidified to pH=1 with 3N HCl and extracted with CH2Cl2. The organic phase was washed with water, dried over MgSO4, and concentrated. The residue was further purified by passing a short silica gel column eluted with EtOAc/hexenes (1:1) to give 30 mg of the title compound as a yellow solid, mp 165–175° C. 1H-NMR (300 MHz, CDCl3) δ 9.39 (br, 1H), 8.04–8.20 (m, 6H), 7.64 (d, J=7 Hz, 1H), 7.57 (d, J=15 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.12–7.07(m, 2H), 6.87 (s, 1H), 6.59 (s, 1H), 4.16 (q, J=7 Hz, 2H), 4.10 (s, 3H), 4.01 (s, 3H), 1.24 (t, J=7 Hz, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH:20]=[CH:19]2
Reactant: OCc1ccccc1S
Reactant: Clc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccccc1Sc1ccc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A mixture of 2-mercaptobenzyl alcohol (1.78 g, 12.7 mmol), 2,6-dichloroquinoline (2.48 g, 12.5 mmol) and potassium carbonate (1.73 g, 12.5 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature under nitrogen for 3 hours, then at 60° C. for 17 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5-10% ethyl acetate/dichloromethane, to give {2-[(6-chloroquinolin-2-yl)thio]phenyl}methanol (0.37 g, 9%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.84 (1H, d, J=8.7 Hz), 7.72-7.66 (4H, m), 7.55-7.51 (2H, m), 7.39-7.35 (1H, m), 7.19 (1H, dd, J=1.2, 8.7 Hz), 4.84 (2H, s), 3.78 (1H, s); m/z (ES+) 302, 304 [MH+].
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH2:41][CH2:42][CH2:43]O)[N:36]=[CH:35]3)=[O:22])[N:17]([CH3:19])[N:18]=1)([CH3:13])([CH3:12])[CH3:11].[CH:45]([N:48](C(C)C)[CH2:49]C)(C)C.CNC>C1COCC1>[C:10]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:31][C:32]2[CH:40]=[C:39]3[C:38](=[CH:34][CH:33]=2)[N:37]([CH2:41][CH2:42][CH2:43][N:48]([CH3:49])[CH3:45])[N:36]=[CH:35]3)=[O:22])[N:17]([CH3:19])[N:18]=1)([CH3:11])([CH3:12])[CH3:13]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1ccccc1Nc1ccc2c(cnn2CCCO)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CN(C)CCCn1ncc2cc(Nc3ccccc3CNC(=O)Nc3cc(C(C)(C)C)nn3C)ccc21
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Methanesulfonic anhydride (12 mg, 0.070 mmol) was added to a solution of alcohol (7s) (24 mg, 0.050 mmol) and diisopropylethylamine (20 mg, 0.15 mmol) at room temperature. The solution was stirred for 1 hour. Dimethylamine (2.0 M in THF, 0.25 mL, 0.50 mmol) was added and the reaction was stirred overnight. Additional dimethylamine was added (2.0 M in THF, 0.25 mL, 0.50 mmol) and the reaction was stirred an additional 2 days. The mixture was then partitioned between CHCl3 and water. The aqueous phase was extracted once with CHCl3. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel with 5% MeOH/CH2Cl2 containing 1% Et3N to provide the desired compound (8s-1) (11 mg, 43% yield) as a dark foam. 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.42 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.11 (m, 4H), 6.80-6.75 (m, 2H), 5.94 (s, 1H), 5.55 (m, 1H), 4.43 (d, J=6.6 Hz, 2H), 4.38 (t, J=10.5 Hz, 2H), 3.57 (s, 3H), 2.24 (t, J=10.5 Hz, 2H), 2.19 (s, 6H), 2.08-2.01 (m, 2H), 1.24 (s, 9H); MS (ESI+) m/z 503 (M+H)+; HPLC (5 to 95%) 2.59 min.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 43.4 %

Procedure:
Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 38) (195 mg, 0.53 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 mg (43%) of product as a colorless oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([O:12][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:22][CH3:23])=[O:21])[CH:15]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: CSc1nc2ccc(O)cc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(SC)oc3c2)ccn1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(methylthio)benzo[d]oxazol-6-ol (8.5 g, 46.7 mmol, 1 eq) in 80 mL of N,N-dimethylformamide was added 4-chloro-N-methylpyridine-2-carboxamide (16.0 g, 93.4 mmol, 2.0 eq) and cesium carbonate (45.7 g, 140.1 mmol, 3.0 eq). The reaction mixture was stirred at 75° C. for 6 hours. After the mixture was cooled to room temperature, the mixture was added 120 mL of water. After filtration, the solid was purified by silica gel column eluted with ethyl acetate and hexane to give the titled compound. MH+=316.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([O:25][CH3:26])=[C:20]([CH:24]=1)[C:21](Cl)=[O:22]>ClCCl.CN(C)C1C=CN=CC=1>[Br:7][C:4]1[S:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:16]([Cl:15])[CH:17]=[CH:18][C:19]=2[O:25][CH3:26])=[N:6][CH:5]=1
Reactant: Nc1ncc(Br)s1
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Br)s1
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 2-amino-5-bromothiazole (1220 mg, 6.81 mmol) in dichloromethane (10 ml) was added triethylamine (1.235 ml, 8.86 mmol) and 4-dimethylamino pyridine (83 mg, 0.681 mmol), followed by addition of 5-chloro-2-methoxybenzoyl chloride (1397 mg, 6.81 mmol) and stirred overnight. The reaction was concentrated and water was added to the residue. The mixture was sonicated and filtered to obtain the title compound as off-white solid (1.56 g, 66%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.88 (m, 3H) 7.23 (d, J=8.81 Hz, 1H) 7.58-7.67 (m, 3H) 12.32 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].C(O[C:13]([N:15](C)[C@@H:16]([CH3:53])[C:17]([NH:19][C@H:20]1[C:26]2([CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[O:25][C:24]2[CH:32]=[CH:33][CH:34]=[CH:35][C:23]=2[N:22]([CH2:36][C:37]2[C:46]([O:47][CH3:48])=[CH:45][CH:44]=[C:43]3[C:38]=2[CH:39]=[CH:40][C:41]([C:49]([OH:51])=[O:50])=[CH:42]3)[C:21]1=[O:52])=[O:18])=O)(C)(C)C>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:48][O:47][C:46]1[C:37]([CH2:36][N:22]2[C:21](=[O:52])[C@@H:20]([NH:19][C:17](=[O:18])[C@@H:16]([NH:15][CH3:13])[CH3:53])[C:26]3([CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[O:25][C:24]3[CH:32]=[CH:33][CH:34]=[CH:35][C:23]2=3)=[C:38]2[C:43](=[CH:44][CH:45]=1)[CH:42]=[C:41]([C:49]([OH:51])=[O:50])[CH:40]=[CH:39]2
Reactant: COc1ccc2cc(C(=O)O)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C2(CCOCC2)Oc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(OC)ccc3cc(C(=O)O)ccc23)c2ccccc2OC12CCOCC2
Reaction time: 1 h
Yield: 83.1 %

Procedure:
TFA (0.2 mL, 56.4 μmol, Eq: 1.00) was added to a solution of 5-(((S)-3-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-4-oxo-2′,3′,5′,6′-tetrahydro-3H-spiro[benzo[b][1,4]oxazepine-2,4′-pyran]-5 (4H)-yl)methyl)-6-methoxy-2-nap hthoic acid (36.5 mg, 56.4 μmol, Eq: 1.00) in DCM (1 mL). After 1 h, the mixture was concentrated, the residue dissolved in MeCN/H2O, and lyophilized to afford the title compound (31.0 mg, 83%) as an off-white solid. MS m/z 548.4 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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.ClC1C=CC(B(O)O)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 140 °C
Yield: 107.4 %

Procedure:
A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol), 4-chlorophenylboronic acid (1.72 g, 11 mmol) and Pd(Ph3P)4 (462 mg, 0.4 mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene (10 mL) was heated at 140° C. in a microwave oven for 30 min. Analysis by HPLC/MS indicated that the reaction was not complete. Additional 4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed by Pd(Ph3P)4 (116 mg, 0.1 mmol). The reaction mixture was again heated at 140° C. in a microwave oven for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanes to afford 2.6 g of the product (60% pure) as an off-white solid. This was crystallized in EtOAc-hexanes to obtain the pure title compound (0.9 g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]+=242.0.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:10][C:9]=1[OH:18])(=[O:7])[CH3:6].[Br:19]Br.Cl>ClCCl>[C:5]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)=[C:10]([Br:19])[C:9]=1[OH:18])(=[O:7])[CH3:6]
Reactant: BrBr
Reactant: CC(=O)c1cc2c(cc1O)CCCC2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(c(Br)c1O)CCCC2
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A mixture of aluminium chloride (8.15 g) and 7-acetyl-1,2,3,4-tetrahydro-6-hydroxynaphthalene (4.75 g) in dichloromethane (250 ml) was cooled to -10°. A solution of bromine (6.0 g) in dichloromethane (150 ml) was then added over 1 hour with constant stirring. The reaction mixture was allowed to warm to room temperature overnight, dilute HCl (400 ml) was added and the organic layer was separated, washed with water and dried (MgSO4). The solvent was filtered and the filtrate was evaporated to dryness leaving an oil which solidified on cooling to give 7-acetyl-5-bromo-1,2,3,4-tetrahydro-6-hydroxynaphthalene (5.3 g, 79%) mp 127°-130°.