Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8](O)[CH2:9][CH:10]([OH:12])[CH3:11])[C:4](=[O:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].CN([CH:25]=[O:26])C>>[C:15]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C@@H:9]([C@H:10]([OH:12])[CH3:11])[CH2:25][OH:26])[C:4](=[O:14])[N:3]=1)(=[O:17])[CH3:16]
Reactant: CN(C)C=O
Reactant: CC(O)CC(O)n1ccc(N)nc1=O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccn(C[C@H](CO)[C@@H](C)O)c(=O)n1
Reaction time: 72 h
Yield: 108 %

Procedure:
To a solution of 20 (0.5 g, 2.34 mmol) in 12 ml of anhydrous DMF was added dropwise with stirring 0.243 ml (2.57 mmol) of acetic anhydride. The reaction was kept at room temperature for 3 days and then concentrated. The oily residue was dried by co-evaporation with xylene and then in vacuo to afford 0.65 g (108%) of 21 (contaminated with some DMF) as a white solid, which was sufficiently pure to be used in the next step without additional purification. 1H NMR (DMSO-d6): δ 10.81 (s, 1H), 8.00 (d, J=7.2 Hz, 1H), 7.13 (d, J=7.2 Hz, 1H), 4.62 (d, J=5.1 Hz, 1H), 4.53 (t, J=4.8 Hz, 1H), 4.02 (m, 1H), 3.73 (m, 2H), 3.53 (m, 2H), 2.09 (s, 3H), 1.80 (m, 1H), 1.10 (d, J=6.3 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]CC1C=CC=CC=1)=[O:14]>CN(C=O)C.[Pd]>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([OH:15])=[O:14]
Reactant: Nc1c(C(=O)OCc2ccccc2)c(=O)[nH]c2ccccc12
Agent: [Pd]
Solvent: CN(C)C=O
Product: Nc1c(C(=O)O)c(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
Benzyl 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 66a) (0.6 g, 2.04 mmol) was dissolved in DMF (8 mL) and heated at 70° C. under a hydrogen balloon in the presence of 10% Pd/C (0.15 g) for 1 hour. The Pd/C was filtered out and washed with dichloromethane and the solvents were removed under vacuum. The residue was dissolved/suspended in NaOH (2M, 40 mL), stirred at room temperature for 30 minutes and the solution washed with dischloromethane. The aqueous layer was cooled to 0° C. and acidified to pH 1 with 2M HCl. The resultant precipitate was collected and washed with dichloromethane to give 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (0.050 g, 12%) as a light yellow solid. M.p.: >250° C. 1H NMR (400 MHz, DMSO-d6) δ7.32 (m, 1H), 7.39 (d, J=7.6 Hz, 1H), 7.69 (m, 1H), 8.27 (d, J=8.4 Hz, 1H), 8.86 (s, 1H), 9.87 (s, 1H), 11.95 (s, 1H). MS 205 (MH+).
Reaction SMILES: [CH3:1][C:2]([N:10]1[N:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:11]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Br[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>[Ni]>[CH3:29][O:28][C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:12]2[N:13]=[N:14][N:10]([C:2]([CH3:1])([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:3])[N:11]=2)=[CH:23][CH:24]=1)=[O:27]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2)n1
Agent: [Ni]
Product: COC(=O)c1ccc(-c2ccccc2-c2nnn(C(C)(C)c3ccccc3)n2)cc1

Procedure:
reacting the ortho-transmetalated 2-(1-methyl-1-phenylethyl)-5-phenyl-2H-tetrazole with methyl 4-bromobenzoate in the presence of phospinated nickel catalyst to give 2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-carboxylic acid methyl ester,
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][NH:27][CH2:26]1.C(#N)C.[CH2:35]([O:37][C:38]([C:40]1[C:49](=[O:50])[C:48]2[C:43](=[N:44][C:45](Cl)=[CH:46][CH:47]=2)[N:42]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)[CH:41]=1)=[O:39])[CH3:36]>[Ag].C(N(CC)CC)C>[CH3:23][O:24][C@@H:25]1[C@@H:29]([NH:30][CH3:31])[CH2:28][N:27]([C:45]2[N:44]=[C:43]3[C:48]([C:49](=[O:50])[C:40]([C:38]([O:37][CH2:35][CH3:36])=[O:39])=[CH:41][N:42]3[C:52]3[S:53][CH:54]=[CH:55][N:56]=3)=[CH:47][CH:46]=2)[CH2:26]1
Reactant: CCOC(=O)c1cn(-c2nccs2)c2nc(Cl)ccc2c1=O
Reactant: CN[C@H]1CNC[C@@H]1OC
Agent: [Ag]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2nccs2)c2nc(N3C[C@H](NC)[C@@H](OC)C3)ccc2c1=O
Yield: 97.6 %

Procedure:
To a glass reactor covered with silver foil and equipped with an overhead stirrer was added (3S,4S)-3-methoxy-4-methylaminopyrrolidine di-p-toluenesulfonic acid (1190 g) and acetonitrile (9.0 L), and the mixture stirred. The solution was cooled and triethylamine (TEA) (1560 mL) was added, maintaining the batch temperature below 5° C. Ethyl-7-chloro-1,4-dihydro-4-oxo-1-(2-thiazolyl)-1,8-naphthyridine-3-carboxylate (750 g) was added, the ice-bath was removed and the reaction temperature allowed to rise and then stirred an additional 48 hours. The reaction was filtered, the filter cake was washed with acetonitrile (3×800 mL), and dried in vacuo to afford 936 g of the title compound as a white solid (97.6%).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:3][CH:2]=1.[Cl:31][C:32]1[C:33]([OH:43])=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=[C:36]([Cl:38])[CH:37]=1.CCN(CC)CC>C(Cl)Cl>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]([CH2:9][C:10]2[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=2)[CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[S:39]([C:34]2[CH:35]=[C:36]([Cl:38])[CH:37]=[C:32]([Cl:31])[C:33]=2[OH:43])(=[O:40])=[O:41])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(-c3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1cccc(CN(Cc2ccc(-c3ccccc3)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)c1
Reaction time: 1.5 h
Yield: 73.7 %

Procedure:
To a solution of tert-butyl 3-((biphenyl-4-ylmethylamino)methyl)benzylcarbamate (2.42 g, 6.01 mmol) in CH2Cl2 (30.0 mL) was added a solution of 3,5-dichloro-2-hydroxybenzene-1-sulfonyl chloride (1.65 g, 6.31 mmol) in CH2Cl2 (8.0 mL) at ice bath temperature followed by Et3N (2.5 mL, 18.0 mmol). The reaction mixture was stirred at ice bath temperature for 1.5 h and concentrated in vacuo. The residue was purified by flash chromatography on SiO2 eluting with CH2Cl2 to 8% of ethyl acetate in CH2Cl2 to give the product as a white glassy solid (2.78 g, 72.5%). 1H NMR (CDCl3): δ 9.18 (bs, 1H), 7.59-7.38 (m, 9H), 7.28-7.21 (m, 4H), 7.06 (m, 2H), 4.48 (s, 2H), 4.43 (s, 2H), 4.25 (s, 2H), 1.49 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])[C:11]([OH:13])=O)[C:7](=[O:19])[CH:6]=1.[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]2)[CH2:27][O:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][C:25]1([CH3:37])[O:29][C@H:28]([CH2:30][N:31]2[CH:35]=[CH:34][C:33]([NH:36][C:11](=[O:13])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=4[Cl:1])=[CH:6][C:7]3=[O:19])[CH2:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[N:32]2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: CCC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.4 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid (337 mg, 1 mmol), 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 276 mg, 1.4 mmol) in N,N-dimethylformamide (7 mL) was treated with N,N-diisopropylethylamine (0.46 mL) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (664 mg, 1.5 mmol) and stirred at room temperature for 6 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and an aqueous ammonium chloride solution. The layers were separated and the organic layer washed with brine and dried with sodium sulfate. The mixture was filtered and the filterate concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica column 40 g, 20% to 80% ethyl acetate/hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (400 mg, 76%) as a pale yellow solid: HR-ES-MS (m/z) calculated for C26H33ClN4O5 [M+H]+ 517.2212, observed 517.2209. 1H NMR showed mixture of diastereomers (300 MHz, DMSO-d6) δ ppm 0.75-0.95 (m, 6H), 1.02-1.23 (m, 2H), 1.25 (s, 3H), 1.31 (s, 3H), 1.40-1.93 (m, 3H), 3.73 (dd, J=8.5, 5.7 Hz, 1H), 4.00 (dd, J=8.3, 6.5 Hz, 1H), 4.04-4.28 (m, 3H), 4.35 (quin, J=5.7 Hz, 1H), 4.60 (dd, J=18.4, 14.5 Hz, 1H), 4.80 (2×s, 1H), 4.86-4.96 (m, 1H), 6.42-6.46 (m, 1H), 7.37 (t, J=7.5 Hz, 1H), 7.42-7.57 (m, 2H), 7.60 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 10.76-10.84 (m, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([C:17]1[C:18]([OH:39])=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][C:24](=[O:27])[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:22]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.ClC(Cl)(Cl)C(=N)O[C@H:44]1[C@@H:49]2[O:50][C:51](=[O:53])[O:52][C@@H:48]2[C@@H:47]([O:54][CH3:55])[C:46]([CH3:57])([CH3:56])[O:45]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:10]([C:17]1[C:18]([O:39][C@H:44]2[C@@H:49]3[O:50][C:51](=[O:53])[O:52][C@@H:48]3[C@@H:47]([O:54][CH3:55])[C:46]([CH3:57])([CH3:56])[O:45]2)=[CH:19][CH:20]=[C:21]2[C:26]=1[O:25][C:24](=[O:27])[C:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:22]2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Nc1cc2ccc(O)c(Cc3ccccc3)c2oc1=O)OCc1ccccc1
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](Oc2ccc3cc(NC(=O)OCc4ccccc4)c(=O)oc3c2Cc2ccccc2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.2 %

Procedure:
Boron trifluoride etherate (7.80 μL, 0.062 mmol) was added to 23e (80.0 mg, 0.21 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3 aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (299 mg, 0.83 mmol) in anhydrous CH2Cl2 (5.20 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 40:1 CH2Cl2:Acetone) to give 25e as a colorless foam (47.0 mg, 39%): 1H MMR (CDCl3, 500 MHz) 8.22 (s, 1H), 7.46 (s, 1H), 7.35-7.27 (m, 5H), 7.17-7.06 (m, 5H), 6.86 (d, J=10 Hz, 1H), 6.01 (d, J=10 Hz, 1H), 5.65 (d, J=1.6 Hz, 1H), 5.23 (s, 2H), 5.16 (s, 2H), 4.77-4.70 (m, 1H), 4.10 (s, 1H), 3.50 (s, 3H), 3.28 (s, 1H), 3.16 (d, J=7.4 Hz, LH), 1.25 (s, 3H), 1.18 (s, 3H); 13C NMR (CDCl3, 125 MHz) 155.1, 153.2 (2C), 153.1, 148.6 (2C), 139.6 (2C), 128.7, 128.6 (2C), 128.4 (2C), 128.3 (2C), 128.3 (2C), 126.5, 126.2, 123.1, 122.4, 121.7, 117.6, 114.9, 111.5, 94.7, 82.8, 67.6, 60.6 (2C), 29.7, 27.6, 21.9; IR (film) νmax 2926, 2854, 2359, 2341, 1811, 1709, 1607, 1522, 1456, 1381, 1366, 1259, 1209, 1171, 1078, 1049, 968, 766, 700 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C33H31NO10, 602.2026. found, 602.2053.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22][CH:21]1[C:27](O)=[O:28])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH:23]([C:25]#[N:26])[CH2:22][CH:21]1[C:27](=[O:28])[NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5])=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C#N)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl salt (664 mg, 2.65 mmol) was dissolved in DMF (10 mL) and to this solution was added 4-Cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester crude from the previous step, diisopropyl ethylamine (0.93 mL, 5.3 mmol), followed by HATU (1 g, 2.65 mmol). Reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was dissolved in ethyl acetate and washed with dilute sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 2-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (1.05 g, yield 91%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:54])[C@H:10]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:37])[CH3:36])[NH:14][C:15](=[O:34])[C@H:16]([CH3:33])[NH:17][C:18](=[O:32])[C@H:19]([CH2:28][CH2:29][S:30][CH3:31])[NH:20][C:21](OC(C)(C)C)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:55]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[C@H:56](C(OC1C=CC([N+]([O-])=O)=CC=1)=O)[CH2:57][CH2:58][C:59](=[O:61])[NH2:60].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(OC(N[C@H](C(N[C@H](C(O)=O)CCSC)=O)CCC(=O)N)=O)(C)(C)C>>[CH2:1]([O:8][C:9](=[O:54])[C@H:10]([CH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[NH:11][C:12](=[O:38])[C@H:13]([CH:35]([CH3:36])[CH3:37])[NH:14][C:15](=[O:34])[C@H:16]([CH3:33])[NH:17][C:18](=[O:32])[C@H:19]([CH2:28][CH2:29][S:30][CH3:31])[NH:20][C:21](=[O:22])[C@H:56]([CH2:57][CH2:58][C:59](=[O:61])[NH2:60])[NH:55][C:74]([O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[O:75])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C

Procedure:
The Boc group was removed from a sample of compound XXII (2.5 g, 3.3 mmole) as described in previous paragraphs. The trifluoroacetate salt washed with ether and dried; the white solid (RfC, 0.76) showed on tlc a slight impurity at the origin (presumably the t-butylsulfonium salt). This material was acylated with Boc-L-Gln-ONp (1.4 g, 3.8 mmole, Bachem) in the presence of DIEA (1.3 ml, 8 mmole) and HOBt (0.58 ml, 3.8 mmole). Next day the product was isolated as described for XII and then purified by precipitation from a solution in DMF with H2O. The product was washed with H2O and dried: 28 g (93%), m.p. 238°-241° C. [α]D23 -27.7° (c 0.8, DMF); RfK, 0.43; RfL, 0.50.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])=[C:2]=[S:3].[NH2:11][C@H:12]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH3:30][CH:29]([CH3:31])[C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][C@@H:12]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:11][C:2]([NH:1][C:4]3[C:5]([CH3:10])=[CH:6][CH:7]=[CH:8][CH:9]=3)=[S:3])[CH2:20][CH2:19]2)[CH:22]=1)=[O:32]
Reactant: Cc1ccccc1N=C=S
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: Cc1ccccc1NC(=S)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure P and Scheme AB using 1-isothiocyanato-2-methylbenzene and N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide: ESMS m/e: 529.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9](Cl)[C:10]([F:16])=[C:11]([Cl:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C(N)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([Cl:15])[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)c(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: NCc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(Cl)c(F)cc2c1=O
Yield: 83.9 %

Procedure:
58.3 g of ethyl 1-cyclopropyl-5,7-dichloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylate (0161 mol), 15.4 ml of benzyl amine, and 37.0 g of anhydrous K2CO3 in 220 ml of acetonitrile were stirred at 100-110° C. for 1 hour. The reaction was monitored by TLC. After the solvent was evaporated, the residue was re-crystallized from ethanol to give 58.3 g of ethyl 1-cyclopropyl-7-chloro-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.135 mol) in 83.7% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Br:11][C:12]1[CH:13]=[N:14][C:15](Cl)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>C(O)CC(C)C.BrC1C=NC(Cl)=C(C=1)C(NC1C=CC=CC=1)=O>[Br:11][C:12]1[CH:13]=[N:14][C:15]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[C:16]([CH:26]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: COc1ccc(N)cc1F
Reactant: O=C(Nc1ccccc1)c1cc(Br)cnc1Cl
Solvent: CC(C)CCO
Product: COc1ccc(Nc2ncc(Br)cc2C(=O)Nc2ccccc2)cc1F
Temperature: 200 °C
Yield: 373.9 %

Procedure:
5-bromo-2-chloro-N-phenylnicotinamide (224 mg, 719 μmol) and 3-fluoro-4-methoxybenzenamine (316.7 mg, 2244 μmol) were suspended in isoamyl alcohol (1.5 ml) in a reaction microwave vessel which was sealed. This vessel was heated in the Biotage Initiator microwave at 200° C. for 20 minutes, with 45 seconds of stirring beforehand, and then cooled to room temperature. This process was repeated using 5-bromo-2-chloro-N-phenylnicotinamide (810 mg, 2.60 mmol) and 3-fluoro-4-methoxybenzenamine (1.092 g, 7.74 mmol), and isoamyl alcohol (7.5 ml), and then repeated a third time with 5-bromo-2-chloro-N-phenylnicotinamide (1.643 g, 5.28 mmol), 3-fluoro-4-methoxybenzenamine (2.285 g, 16 mmol), and isoamyl alcohol (10 ml). These three sets of reaction were combined, concentrated, treated with Et2O, and filtered. The solid was washed with Et2O, and the filtrate was concentrated and purified on a silica gel filter (˜3 inches, DCM) to afford the desired 5-bromo-2-(3-fluoro-4-methoxyphenylamino)-N-phenylnicotinamide (3.49 g, 8.39 mmol, 75% yield). MS (ESI pos. ion) m/z: 416 (MH+, 79Br), 418 (MH+, 81Br). Calc'd exact mass for C19H15BrFN3O2: 415 (79Br), 417 (81Br).
Reaction SMILES: [CH2:1]([S:4](Cl)(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:8][C:9]1[C:10]([F:19])=[C:11]([C:15]([F:18])=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13].C(N([CH2:25][CH3:26])CC)C>C(Cl)Cl>[F:19][C:10]1[C:9]([N:8]([S:4]([CH2:1][CH2:25][CH3:26])(=[O:6])=[O:5])[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])=[CH:17][CH:16]=[C:15]([F:18])[C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ccc(F)c(C(=O)O)c1F
Reactant: CCN(CC)CC
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCS(=O)(=O)N(c1ccc(F)c(C(=O)O)c1F)S(=O)(=O)CCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Propane-1-sulfonyl chloride (1.225 mL, 10.92 mmol) was added to a mixture of 3-amino-2,6-difluorobenzoic acid (0.573 g, 3.310 mmol), triethylamine (2.030 mL, 14.56 mmol) and CH2Cl2 (17 mL, 0.2M) cooled to 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was then partitioned between saturated NaHCO3 (100 mL) and ethyl acetate (75 mL). The aqueous layer was washed with ethyl acetate (50 mL) and then acidified with concentrated HCl to a pH of about 1. The acidified aqueous layer was extracted with ethyl acetate (2×50 mL), and the combined ethyl acetate extracts were dried (Na2SO4), filtered and concentrated. The resulting residue was triturated with hexanes to afford 2,6-difluoro-3-(N-(propylsulfonyl)propyl-sulfonamido)benzoic acid as a solid (0.948 g, 74% yield). 1H NMR (400 MHz, d6-DMSO) δ 7.90-7.84 (m, 1H), 7.39-7.34 (m, 1H), 3.73-3.58 (m, 4H), 1.88-1.74 (m, 4H), 1.01 (t, J=7.5 Hz, 6H). m/z (APCI-neg) M-(SO2Pr)=278.1.
Reaction SMILES: C(N(CC)[C:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[NH:15][CH:14]=[C:13]2[CH2:17][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])=[O:5])C.[OH-:30].[K+]>O.C(O)C>[C:23]([O:22][C:21]([NH:20][C@H:18]([CH3:19])[CH2:17][C:13]1[C:12]2[C:16](=[C:8]([O:7][CH2:6][C:4]([OH:30])=[O:5])[CH:9]=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:27])([CH3:24])([CH3:26])[CH3:25]
Reactant: [OH-]
Reactant: CCN(CC)C(=O)COc1cccc2c(C[C@@H](C)NC(=O)OC(C)(C)C)c[nH]c12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)O)cccc12)NC(=O)OC(C)(C)C
Yield: 99 %

Procedure:
A solution of tert-butyl (R)-[2-(7-diethylcarbamoylmethoxy-1H-indol-3-yl)-1-methylethyl]carbamate (0.35 g, 0.87 mmol) and potassium hydroxide (0.39 g, 7 mmol) in water (4 mL) and ethanol (6 mL) is stirred at 60° C. for 8 hours. After cooling, the mixture is concentrated and acidified by addition of water (30 mL) and acetic acid. The resultant is extracted with chloroform, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give the desired (R)-[3-(2-(tert-butoxycarbonylamino)propyl)-1H-indol-7-yloxy]acetic acid (0.30 g, yield: 100%).
Reaction SMILES: Cl[C:2]1[C:3]([NH2:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[NH2:18]>CN1C(=O)CCC1>[CH3:23][O:22][C:20]1[CH:19]=[C:17]([NH:18][C:2]2[C:3]([NH2:12])=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:11]=2)[CH:16]=[C:15]([O:14][CH3:13])[CH:21]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Nc1nc2ccccc2nc1Cl
Solvent: CN1CCCC1=O
Product: COc1cc(Nc2nc3ccccc3nc2N)cc(OC)c1
Temperature: 145 °C
Yield: 60 %

Procedure:
3-chloroquinoxalin-2-amine (1.8 g, 10 mmol) and 3,5-dimethoxyaniline (4.6 g, 30 mmol, commercially available from Aldrich) are taken up in NMP (4.5 ml) and heated to 145° C. in the sealed tube for 3 h under N2. When TLC confirms the total consumption of the starting material, the reaction is cooled to rt and treated with EtOAc (4 ml). The first crop of solid is filtered followed by the 2nd crop. The first is recrystallised from CHCl3: EtOAc and the 2nd crop is washed with EtOAc, to afford 1.8 g (60%) of pure title compound. LC/MS: (ES+): 297.1, (ES−): 295.1.
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].C(N(CC)CC)C.[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][C:29](=[O:31])[CH3:30])[C:22](Cl)=[O:23])(=[O:17])[CH3:16]>ClCCl>[C:15]([O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][C:29](=[O:31])[CH3:30])[C:22]([NH:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7])=[O:23])(=[O:17])[CH3:16]
Reactant: NN1CCNC1=O
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C(=O)NN2CCNC2=O)cc1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
1-Amino-2-imidazolidinone (2.61 g, 0.026 mol) was dissolved in 200 ml of dichloromethane. The solution was cooled to 0° C. and 4.1 ml of triethylamine was added, followed by 7.5 g of 3,4-bis(acetyloxy)benzoyl chloride (0.029 mol). The mixture was stirred at 0° C. for 1 hour and at room temperature for an additional hour. The precipitate was filtered off to yield 8.3 g of 1-[[3,4-bis(acetyloxy)benzoyl]amino]-2-imidazolidinone.