Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1>C(O)(C)C>[C:19](/[N:18]=[C:17](\[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)/[NH:5][C:4]1[CH:6]=[CH:7][C:8]([F:9])=[C:2]([F:1])[CH:3]=1)#[N:20]
Reactant: Nc1ccc(F)c(F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC(C)O
Product: N#C/N=C(/Nc1ccc(F)c(F)c1)Oc1ccccc1
Temperature: 25 °C
Yield: 86.4 %

Procedure:
To a solution of 3,4-difluoroaniline (646 mg, 5 mmol) in isopropanol (10 mL) was added diphenyl cyanocarbonimidate (1.19 g, 5 mmol) and the suspension was stirred at room temperature over night. The precipitate was filtered off, washed with isopropanol and dried under reduced pressure to yield the title compound as a white solid (1.18 g, 86%).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.O.[C:11](=[O:14])([O-])[O-:12].[K+].[K+]>C1COCC1>[C:3]([O:12][C:11]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)=[O:14])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C(O)C1CCCNC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of nipecotic acid, 2.0 g (16.0 mmol) in 20 mL of THF and 20 mL of water was added 4.7 g (33.6 mmol) of potassium carbonate and 3.5 g (16.0 mmol) of Boc-anhydride. The resulting solution was stirred overnight at ambient temperature then concentrated to dryness. The residue was dissolved in water, washed with ether and acidified to pH=2 with 5N HCl. The acidic aqueous layer was extracted with 20% isopropanol/chloroform. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to dryness to yield 3.2 g (86%) of the desired mixture of isomers as a white solid. MS (ion spray) 228.2 (M−1).
Reaction SMILES: [O:1]([C:8]1[C:9]2[NH:16][C:15]([C:17]([NH2:19])=O)=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P(Cl)(Cl)(Cl)=O>[O:1]([C:8]1[C:9]2[NH:16][C:15]([C:17]#[N:19])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1cc2ncnc(Oc3ccccc3)c2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (1.67 g) was suspended in phosphorus oxychloride (20 mL), and the suspension was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (25 mL). Water and aqueous ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=1/1. The organic layer washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10→67:33) to give the title compound (1.07 g) as a pale-yellow powder.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][CH:2]([NH:1][C:12]([NH:11][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccccc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with 2-amino-2-phenylethanol and 3-(4-isothiocyanatophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole and isolated as a white solid (1.36 g, quantitative): 1H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.38 (d, J=4.6 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 6.88-6.61 (m, 8H), 6.43 (d, J=7.9 Hz, 1H), 5.22-4.90 (m, 1H), 3.46-3.28 (m, 2H); ESIMS m/z 484 ([M+H]+).
Reaction SMILES: O[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1)=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH2:65])([CH3:53])([CH3:52])[CH3:51]>CN(C=O)C>[C:50]([O:54][C:55](=[O:66])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][NH:65][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH:16]2[NH:15][C:13](=[O:14])[NH:12][CH:11]2[CH2:10][S:9]1)([CH3:53])([CH3:51])[CH3:52]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[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: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCCC1SCC2NC(=O)NC21
Temperature: 21 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of biotin (0.59 g, 2.42 mmol, 1.5 eq), HBTU (0.79 g, 2.10 mmol, 1.3 eq) and DIEA (0.45 mL, 2.60 mmol, 1.6 eq) in DMF (15 mL) was stirred for 20 min at 21° C. before being added dropwise to a solution of tert-butyl-N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)carbamate (400 mg, 1.61 mmol, 1 eq) in DMF (10 mL). The reaction mixture was stirred for 2 h at 21° C., after which the DMF was removed in vacuo to give a yellow residue. The crude product was purified by column chromatography (gradient 2-10% MeOH/CH2Cl2) to yield the desired compound as a white solid (0.61 g, 1.29 mmol, 80% yield). m.p. 106-108° C.; [α]D20.0+23.0 (c 0.6, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.55 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 4.36 (dd, J=5.0, 7.5 Hz, 1H, NHC(O)NHCH), 3.62 (bs, 6H, OCH2), 3.59-3.55 (m, 2H, OCH2), 3.46 (m, 2H, NCH2), 3.31 (m, 2H, NCH2), 3.17 (dt, 3.0, 5.0 Hz, 1H, SCH), 2.92 (dd, J=5.0, 13.0 Hz, 1H, SCHH), 2.79 (d, J=13.0 Hz, 1H, SCHH), 2.27 (t, J=7.0 Hz, 2H, NHC(O)CH2CH2CH2), 1.71 (m, 4H, NHC(O)CH2CH2CH2CH2), 1.47 (br, 11H, C(CH3)3 & NHC(O)CH2CH2CH2CH2); 13C NMR (125 MHz, CDCl3) δ 173.69 (s), 163.92 (s), 155.99 (s), 79.14 (s), 70.03 (t), 69.69 (br t), 61.58 (d), 60.06 (d), 55.19 (d), 40.16 (t), 39.96 (t), 38.91 (t), 35.44 (t), 28.09 (q), 27.80 (t), 27.67 (t), 25.23 (t), * 2 t absent; IR (neat) 3307, 2933, 1691 cm−; HRMS (ES) calcd for C21H38N4O6NaS [M+Na]+ 497.2410, observed 497.2423.
Reaction SMILES: [C:1]([C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]([CH:21]2[C:30]3N=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)=[C:5]([CH2:33][OH:34])[CH:4]=1)#[N:2].[C:35]([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1.N#N>CN(C=O)C>[OH:34][CH2:33][C:5]1[CH:4]=[C:3]([CH:32]=[CH:31][C:6]=1[CH2:7][NH:8][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:35]=2)[CH2:24][CH2:23][CH2:22]1)[C:1]#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CN(C2CCCc3cccnc32)S(=O)(=O)c2ccccc2[N+](=O)[O-])c(CO)c1
Agent: N#N
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CNC2CCCc3ccccc32)c(CO)c1
Yield: 86 %

Procedure:
To a solution of N-(4-cyano-2-hydroxymethyl-benzyl)-2-nitro-N-(5,6,7,8-tetrahydro-quinolin-8-yl)-benzenesulfonamide (2.32 g, 4.85 mmol) dissolved in DMF (50 mL) was added K2CO3 (3.35 g, 24.3 mmol) and thiophenol (1.49 mL, 14.6 mmol). The solution was stirred at room temperature under a positive pressure of N2 for 3 hours. The mixture was concentrated in vacuo and redissolved in CH2Cl2 (50 mL). The mixture was filtered through a sintered glass funnel containing celite. The solution was concentrated in vacuo to afford a yellow solid. Purification via column chromatography on silica gel (hexane:EtOAc, 1:1, v/v) afforded 3-hydroxymethyl-4-[(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-methyl]-benzonitrile as a yellow solid (1.22 g, 86%). 1H NMR (CDCl3) δ 1.92 (m, 3H), 2.26 (m, 1H), 2.77 (m, 2H), 3.86 (m, 1H), 4.02 (d, 1H, J=13.3 Hz), 4.17 (d, 1H, J=12.3 Hz), 4.51 (d, 1H. J=12.3 Hz), 4.80 (d, 1H, J=11.4 Hz), 7.09 (dd, 1H, J=8.3, 5.3 Hz), 7.42 (d, 1H, J=6.6 Hz), 7.49 (d, 1H, J=7.9 Hz), 7.59 (m, 1H), 7.64 (s, 1H), 8.35 (d, 1H, J=4.8 Hz).
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:14](=[O:15])[CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[CH2:12][CH2:11][C:10](=[O:29])[N:9]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[CH2:30]([N:9]1[C:10](=[O:29])[CH2:11][CH2:12][CH:13]([NH:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][N:20]=2)=[O:18])[C:14](=[O:15])[N:8]1[CH2:7][C:6]([OH:37])=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1

Procedure:
{2-Benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid tert-butyl ester (7a) (115 mg, 0.23 mmol) was stirred in 20% of trifluoroacetic acid (TFA) in dichloromethane (2 mL) overnight. The solution was evaporated to afford {2-benzyl-6-[(isoquinoline-1-carbonyl)-amino]-3,7-dioxo-[1,2]diazepan-1-yl}-acetic acid (8a). 1H-NMR (500 MHz, CDCl3) δ 2.05-2.11 (m, 1H), 2,45-2.50 (m, 1H), 2.72-2.83 (m, 1H), 3.45-3.54 (m, 1H), 4.01-4.06 (d, 1H), 4.59-4.63 (d, 1H), 4.70-4.82 (m, 2H), 4.93-4.98 (d, 1H), 7.28-7.42 (m, 5H), 7.80-8.10 (m, 4H), 8.40-8.52 (m, 2H), 8.85 (d, 1H). The acid (8a) was dissolved in dichloromethane (2 mL) followed by addition of HOBT (77 mg, 0.57 mmol) and EDC (110 mg, 0.57 mmol) and stirred for 30 min. A solution of (2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester (9, anti diastereomer) (166 mg, 0.57 mmol) in dichloromethane/DMF (3/1 mL), charged with 1,3-dimethylbarbituric acid (DMBA) (90 mg, 0.57 mmol) and Pd(PPh3)4 (66 mg, 0.057 mmol) for 30 min, was added and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL×3), dried over Na2SO4, filtered and evaporated to give a pale yellow solid, that was purified by flash chromatography using dichloromethane/methanol (99.5/0.5 to 98.5/1.5) to afford 97.5 mg (67% yield) of the title compound. 1H-NMR (500 MHz, CDCl3) δ 2.03-2.13 (m, 1H), 2.40-2.43 (d, 1H), 2.55-2.60 (m, 1H), 2.83-2.92 (m, 1H), 3.04-3.10 (q, 1H), 3.28-3.38 (m, 1H), 4.08-4.11 (d, 1H), 4.20-4.24 (d, 1H), 4.38-4.41 (m, 1H), 4.67-4.70 (d, 1H), 4.78-4.87 (m, 2H), 4.91-5.02 (m, 2H), 5.36 (s, 1H), 6.05 (d, 1H), 7.20-7.38 (m, 10H), 7.68-7.78 (m, 2H), 7.80-7.88 (m, 2H), 8.48 (d, 1H), 8.70 (d, 1H), 9.49 (d, 1H). Analytical HPLC: 12.53 min. LC-MS (ES+): m/e=636 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:20](=[O:21])[C:9]2[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.[I-].[K+]>CN(C=O)C>[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][N:47]([CH2:2][CH2:3][CH2:4][CH:5]3[C:20](=[O:21])[C:9]4[C:10]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[F:19])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: O=C1c2c(-c3ccccc3F)noc2CCC1CCCCl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2c(-c3ccccc3F)noc2CCC1CCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 80 °C
Yield: 37.3 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-3-(2-fluorophenyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one (6.0 g) and DMF (100 ml) was added anhydrous potassium carbonate (1.4 g), diisopropylethylamine (5.1 ml), 1-(3-chlorophenyl) piperazine (4.9 g) and potassium iodide (0.3 g) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 18 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine twice, and dried (MgSO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel) afforded 3.4 g of 5-[3-(4-(3-chlorophenyl) -1-piperazinyl) propyl]-6,7-dihydro-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one as an oil. The hydrochloride was prepared in methanol with ethereal HCl. The precipitate was filtered and washed with anhydrous ether, m.p. 104°-106° C.
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([O:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([O:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2nc(OC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a mixed solution of 1 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 385 mg of ethyl 8-chloro-1-(3,5-difluoro-6-methoxypyridine-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture heated under reflux with stirring for 30 minutes. After adding 2 ml of distilled water, the solution was allowed to cool and stand. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 297 mg of the title compound as a colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=2[CH2:30][NH:31][CH2:32][CH3:33])[C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH3:2].[CH2:35]([N:42]=[C:43]=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:7]=[C:8]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][C:21]=2[CH2:30][N:31]([CH2:32][CH3:33])[C:43]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:44])[C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OCc1ccccc1
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)Cc1ccc(OCc2ccccc2)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (6-benzyloxy-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=1.CCN(C(C)C)C(C)C.[CH2:24]([NH:26][C:27]([N:29]1[N:33]=[CH:32][C:31]2([CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:30]1)=[NH:28])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10](=[O:12])(=[O:11])[N:28]=[C:27]([N:29]2[N:33]=[CH:32][C:31]3([CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30]2)[NH:26][CH2:24][CH3:25])[CH:5]=1
Reactant: CCNC(=N)N1CC2(C=N1)CCCC2
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=NS(=O)(=O)c1cccc(C(=O)OC)c1)N1CC2(C=N1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 4.07 g 3-chlorosulfonyl-benzoic acid methyl ester in 150 mL DCM were added 17.69 mL (6.0 equiv.) DiPEA and 4.00 g (1.0 equiv.) N-ethyl-2,3-diaza-spiro[4.4]non-3-ene-2-carboxamidine. The reaction mixture was stirred overnight at room temperature under N2 atmosphere, and extracted with water. The organic phase was dried over Na2SO4 and evaporated, and the residue was purified by automated flash chromatography (EtOAc/PA 1:1) to give 4.80 g (71%) of a yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=8 Hz, 3H), 1.62-1.86 (m, 8H), 3.42-3.53 (m, 2H), 3.87 (s, 2H), 3.95 (s, 3H), 6.83 (s, 1H), 6.83-6.95 (broad peak, 1H), 7.56 (t, J=8 Hz, 1H), 8.13-8.18 (m, 2H), 8.61 (s, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[C:13]([Cl:23])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:24])[CH:11]=2)[N:6]=1.ClCCl>C1(C)C=CC=CC=1>[Cl:23][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([I:24])[CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1
Reactant: C[O-]
Reactant: Cc1ccc(Cc2c(Cl)nc3ccc(I)cc3c2Cl)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(C)cc1
Temperature: 105 °C
Reaction time: 18 h

Procedure:
Sodium methoxide (3.2 g, 60 mmol) was added to a solution of 2,4-dichloro-6-iodo-3-(4-methylbenzyl)quinoline (4.3 g, 10 mmol, Intermediate 22: step b) in toluene (50 mL) with stirring. The mixture was heated to 105° C. After 18 hours, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added and then the mixture was filtered through Celite®. The filter cake was washed with dichloromethane. The filtrate was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexanes initially, grading to 20% ethyl acetate-hexanes to provide the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Br:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Brc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2Cc3cccc(Br)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 34.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 198 mg of 4-bromoisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 147 mg of the target compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:34])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[OH:33][C:29]1[CH:28]=[C:27]([CH2:26][CH2:25][C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([C:15]([NH:13][N:14]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=4)[NH:7][C:6]3=[O:11])=[O:16])=[CH:18][CH:19]=2)=[O:34])[CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)c1ccc(NC(=O)CCc2cccc(O)c2)cc1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(CCc1cccc(O)c1)Nc1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 63 %

Procedure:
Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added N-[4-(hydrazinocarbonyl)phenyl]-3-(3-hydroxyphenyl)propanamide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 45 mg of the title compound (63%) as a yellow solid in 92.4% purity by HPLC (Rt: 3.88, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=1[O:24][CH3:25]>>[NH2:1][C:2]1[C:3]([C:4]([C:18]2[C:17]([O:24][CH3:25])=[CH:16][CH:21]=[C:20]([F:22])[C:19]=2[F:23])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: COc1cc(F)c(F)cc1Br
Product: COc1ccc(F)c(F)c1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-4,5-difluoroanisole (Apollo) using the procedure described in Example 7. HRMS, observed: 298.0318, Calcd for M+: 298.0321.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Li+]>O1CCCC1>[CH2:22]([C@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:5](=[O:7])[CH2:4][CH:1]1[CH2:2][CH2:3]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CC1CC1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CC1CC1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
A cooled (−40° C.) solution of cyclopropylacetic acid (5.13 g, 51.250 mmol) in anhydrous tetrahydrofuran (150 mL) was subsequently treated with triethylamine (21.4 mL, 153.75 mmol) and trimethylacetyl chloride (6.9 mL, 56.375 mmol). After stirring at −40° C. for 1 h, the mixture was treated with (S)-4-benzyl-oxazolidin-2-one (9.99 g, 56.375 mmol) and lithium chloride (2.39 g, 56.375 mmol). The mixture was allowed to slowly warm to room temperature and after stirring at room temperature for 22 h, the reaction was partitioned between dichloromethane and half-saturated ammonium chloride. The aqueous layer was extracted with dichloromethane. The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 100 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to afford the title compound (11.63 g, 87%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 0.19-0.32 (m, 2H), 0.56-0.69 (m, 2H), 1.10-1.24 (m, 1H), 2.76-2.87 (m, 2H), 2.96 (dd, J=16.9, 6.9 Hz, 1H), 3.34 (dd, J=13.2, 3.3 Hz, 1H), 4.15-4.29 (m, 2H), 4.66-4.77 (m, 1H), 7.20-7.40 (m, 5H). LCMS (m/z) 282.1 [M+Na], Tr=2.78 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1.[NH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:21])=[CH:17][N:16]=2)=[C:11]([CH3:24])[N:10]=[N:9]1
Reactant: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Reactant: NN1CCOCC1
Product: Cc1nnn(-c2ccccc2F)c1COc1ccc(C(=O)NN2CCOCC2)cn1
Yield: 66 %

Procedure:
As described for example 67, 6-((1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (78 mg, 0.24 mmol), was converted, using 4-aminomorpholine instead of isopropylamine, to the title compound (65 mg, 66%) which was obtained as an off white foam. MS: m/e=413.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([OH:20])=O.S(Cl)(Cl)=O.C[N:26](C)C=O>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([NH2:26])=[O:20]
Reactant: COc1ccc2c(C(=O)O)c(Br)ccc2c1C(F)(F)F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(C(N)=O)c(Br)ccc2c1C(F)(F)F
Temperature: 60 °C
Reaction time: 0.58 h

Procedure:
A suspension of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid (2.0 g, 5.73 mmol, prepared by the process of Example 11, Step 2), thionyl chloride (11 mL) and dimethylformamide (40 μl, 0.095 eq) was heated with stirring at 60° C. under a dry N2 atmosphere for 35 minutes. The reaction mixture was cooled to room temperature and the thionyl chloride was removed. The solid residue was dissolved in THF (20 mL) and this solution was added dropwise to stirred, cold (0°-5° C.) ammonium hydroxide over a 5 minute period. After 15 minutes water (100 mL) was added and the suspension was filtered. The solid was washed with water and dried in vacuo to yield the title compound as a white solid in (1.80 g, 90%)