Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10](Cl)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[NH2:13][C:14]1[CH:18]=[C:17]([CH:19]2[CH2:21][CH2:20]2)[NH:16][N:15]=1.C(N(CC)CC)C>C(O)C>[Cl:1][CH:2]1[N:11]=[C:10]([NH:13][C:14]2[NH:15][N:16]=[C:17]([CH:19]3[CH2:21][CH2:20]3)[CH:18]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1
Reactant: ClC1=NC(Cl)NC2=C1CCCC2
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: ClC1N=C(Nc2cc(C3CC3)n[nH]2)C2=C(CCCC2)N1
Temperature: 120 °C

Procedure:
2,4-Dichloro-1,2,5,6,7,8-hexahydro-quinazoline (1 g, 4.93 mmol) and 3-amino-5-cyclopropylpyrazole (0.606 g, 4.93 mmol) in ethanol (8 ml) was treated with triethylamine (1.24 ml, 8.87 mmol) and the mixture heated at 120° C. for 3 days, cooled and filtered to give (0.72 g, 51%) as a colourless solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][CH:8]1[CH2:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[CH:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=[O:3])[CH3:2].[OH2:26].N1C=CC=CC=1.[Cl-:33].[Cl-].IC1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([NH:4][CH2:5][CH2:6][S:7]([C:8]1([Cl:33])[CH2:14][CH:13]2[N:10]([C:11](=[O:15])[CH2:12]2)[CH:9]1[C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:26])(=[O:3])[CH3:2]
Reactant: O
Reactant: [Cl-]
Reactant: CC(=O)NCCSC1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Ic1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NCCS(=O)C1(Cl)CC2CC(=O)N2C1C(=O)OCc1ccccc1

Procedure:
Benzyl 3-(2-acetamidoethylthio)-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (91) (0.050 g) was dissolved in chloroform (5 ml) and stirred at 0° under argon. It was treated with water (0.010 g) and pyridine (0.022 g) followed by iodobenzene dichloride (0.038 g). A period of 2 hours was allowed to elapse and the solution was concentrated and the product chromatographed on silica gel 60 (<230 mesh) eluting with chloroform/ethanol 9:1. This gave benzyl 3-(2-acetamidoethylsulphinyl)-3-chloro-7-oxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (62) (0.040 g); m.p. 89°-93°, νmax (CHCl3) 3450, 2980, 1780, 1745, 1670 and 1515 cm-1 ; τ(CDCl3) 2.70 (5H, s, phenyl), 3.70 (1H, br, NH) 4.88 (2H, s, benzyl CH2) 4.97 (1H, s, C2-H), 5.6-5.9 (1H, m, C5-H), 6.40 (2H, q J 5 Hz, NCH2), 6.6-7.0 (4H, m, SCH2 and C6-H2), 7.05 (1H, dd J 15 and 8 Hz, C4-H), 7.68 (1H, dd J 15 and 2 Hz, C4-H) and 8.07 (3H, s, COCH3); (Found: C, 52.1; H, 5.4; N, 6.9%. C18H21ClN2O5S requires C, 52.4; H, 5.1 and N, 6.8%).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].[N:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[CH:21][CH:20]=1)=[C:17]=[O:18].[Br-].[Li+]>ClC1C=CC=CC=1Cl>[O:18]=[C:17]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C:26]3=[O:31])=[CH:21][CH:20]=2)[CH2:3][C@H:2]([CH2:4][N:5]2[C:13](=[O:14])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:15])[O:1]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CO1
Reactant: O=C=Nc1ccc(N2CCOCC2=O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 160 °C
Yield: 88.66 %

Procedure:
(S)-2-(oxiran-2-ylmethyl)isoindoline-1,3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in o-dichlorobenzene (70 mL) respectively and heated to 160° C. Then lithium bromide (0.15 g, 1.74 mmol) was added, the mixture was reacted for 4 h, white solid was obtained by filtration (6.46 g, yield: 88.66%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[C:13]4=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1ncccc1-c1ccc(N2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(N4CCCC4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of 3-(4-(pyrrolidin-1-yl)phenyl)pyridin-2-amine (17.0 mg) in THF (dry) (5 mL) was added to a mixture of NaH (60%, 14.2 mg) and 2-chloroethanesulfonyl chloride (34.7 mg) in THF (dry) (5.00 mL) at room temperature. The mixture was stirred at 50° C. for 1 hr. Water and NH silica gel were added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (14.8 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[O:23][C:24]([CH2:33][CH2:34][C:35]([O:37]C)=[O:36])=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[CH:17][CH:16]=1.O.[OH-].[Li+].O1CCCC1.Cl>CO.O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[O:23][C:24]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)CCc1oc(Sc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Sc2nc(-c3ccccc3)c(CCC(=O)O)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
A mixture of methyl 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionate (250 mg), lithium hydroxide hydrate (61.4 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (1.5 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 3-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenylthio]-4-phenyl-5-oxazolyl]propionic acid (200 mg, yield 82%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 136–137° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[C:19]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][C:30](Cl)=[O:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C1COCC1.C(OCC)C>[C:19]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:24]=[CH:23][C:22]([S:25]([O:28][CH2:29][C:30]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:31])(=[O:26])=[O:27])=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)COS(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: O=C(COS(=O)(=O)c1ccc(-c2ccccc2)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of p-aminobenzoic acid (43 mg, 0.31 mmol) and NaOH (12.5 mg, 0.31 mmol) in water (3 ml) was stirred at room temperature for 10 min until all of the solid material had dissolved. Na2CO3 (27 mg, 0.258 mmol) was then added and the mixture cooled to 0° C. A suspension of sulfonyl chloride 18 (106 mg, 0.341 mmol) in THF (1 ml) was injected rapidly and the resulting solution allowed to warm to room temperature and stirred for 2 h. Then reaction mixture was poured into a separating funnel containing diethyl ether. The phases were separated and the aqueous phase washed with a further portion of diethyl ether. The aqueous phase was acidified to pH 1 by addition of 1N HCl solution and the product extracted into ethyl acetate. The ethyl acetate was washed twice with 1N HCl solution and the organic phase was dried (Na2SO4), filtered and the solvent removed in vacuo. The resulting solid was recrystallized from hexane/ethyl acetate affording acid 20 as an off white powder (81 mg, 64%). δH (400 MHz, DMSO) 4.79 (2H, s, CH2), 7.45-7.70 (9H, m, ArH), 7.86-8.03 (4H, m, ArH), 10.43 (1H, NH); δc (100.6 MHz, DMSO) 68.2, 119.4, 126.5, 127.9, 128.6, 129.2, 129.6, 129.8, 131.1, 134.3, 138.7, 142.7, 146.7, 164.4, 167.5; MS (ES+) 411.7 (100%, [M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH:5]2O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:6][CH2:5]2
Reactant: Cc1ccccc1C1CC(O)c2cc(Br)ccc2O1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C1CCc2cc(Br)ccc2O1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-bromo-2-o-tolyl-chroman-4-ol (11.9 g, 37.3 mmol) in dichloromethane (130 ml) at 0° C. triethylsilane (29.6 g, 255 mmol, 6.8 eq) and trifluoroacetic acid (75 ml, 27 eq) were added. The solution was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure and the residue separated between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layers washed with water and saturated aqueous solution of sodium hydrogencarbonate, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by column chromatography (silica gel; ethyl acetate/heptane gradient). 6-Bromo-2-o-tolyl-chroman was obtained as a pale yellow oil (7.10 g, 63%).
Reaction SMILES: C(P(C1C=CC=CC=1)CCP(CC1C(OC)=CC=CC=1)C1C=CC=CC=1)C1C(OC)=CC=CC=1.CO.[C:37]([NH:40][C:41](=[CH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:39])[CH3:38].[H][H]>C(O)(C)C>[C:37]([NH:40][C@H:41]([C:42]([OH:44])=[O:43])[CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: COc1ccccc1CP(CCP(Cc1ccccc1OC)c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(C)O
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 0.013 g. of [Rh(COD)Cl]2 (.026 m moles) and 0.024 g. 1,2-bis(o-anisylphenylphosphino) ethane prepared in Example 1 (0.051 m moles) in 5 ml. of methanol was made with stirring for 15 minutes at 25° C. With careful exclusion of air, 0.5 ml. of this solution was added to a slurry of 1.00 g. of α-acetamidocinnamic acid in 25 ml. of 88% i-propanol at 50° C. and the resulting mass was subjected to 3.5 atm. (abs. pressure) of hydrogen. The hydrogenation reaction was completed in 0.7 hours. N-acetyl-L-phenylalanine can be isolated from the reaction mass by crystallization. Analysis of the reaction mixture showed that an optical purity of 92.8% of the L isomer was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:8]4[N:13]=[C:12]([N:14]5[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]5)[CH:11]=[CH:10][CH:9]=4)=[CH:40][CH:39]=3)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC5(CC4)OCCO5)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the title compound from Example 1 Step B (251 mg, 0.67 mmol), the title compound from Example 10 Step C (248 mg, 1.00 mmol), and triphenylphosphine (349 mg, 1.33 mmol) in DCM (3 mL) was added diisopropyl azodicarboxylate (0.259 mL, 1.33 mmol). The resulting mixture was stirred at ambient temperature. After 5 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 608.06 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.23 (d, J=7.5 Hz, 2H), 7.12-7.06 (m, 2H), 5.12 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.98 (s, 4H), 2.60-2.54 (m, 1H), 1.87-1.65 (m, 8H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [N:1](OCCC(C)C)=O.[NH2:9][C:10]1[C:11]([NH:21][C@@H:22]2[CH2:26][C@H:25]([OH:27])[CH:24]=[CH:23]2)=[N:12][C:13]([S:17][CH2:18][CH2:19][CH3:20])=[N:14][C:15]=1[Cl:16]>C(#N)C>[Cl:16][C:15]1[C:10]2[N:9]=[N:1][N:21]([C@@H:22]3[CH2:26][C@H:25]([OH:27])[CH:24]=[CH:23]3)[C:11]=2[N:12]=[C:13]([S:17][CH2:18][CH2:19][CH3:20])[N:14]=1
Reactant: CC(C)CCON=O
Reactant: CCCSc1nc(Cl)c(N)c(N[C@H]2C=C[C@@H](O)C2)n1
Solvent: CC#N
Product: CCCSc1nc(Cl)c2nnn([C@H]3C=C[C@@H](O)C3)c2n1
Temperature: 70 °C

Procedure:
Isoamyl nitrite (1.08 ml) was added to a solution of the product of step b) (2.20 g) in acetonitrile (100 ml) and the solution heated at 70° C. for 1 hour. The cooled reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, ethyl acetate:isohexane 1:2 as eluant) to afford the subtitle compound (1.79 g).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].O>CS(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ccc2[N+](=O)[O-])CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
Triethylamine (4.2 ml) was added to a stirred solution of 2,4-dichloronitrobenzene (1.9 g) and 1-t-butoxycarbonyl-piperazine (2.2 g) in dimethylsulfoxide (18 ml) under N2. The resulting solution was stirred at 70° C. for 48 hours then cooled to room temperature. Water was added and the mixture extracted three times with ethyl acetate; the combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (cyclohexane:ethyl acetate 8:2) to afford 4-(5-chloro-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.6 g) as a foam. 1H NMR (400 MHz, CDCl3) 1.5 (s, 9H), 2.9 (br s, 4H), 3.5 (br s, 4H), 6.9 (d, J=10 Hz, 1H), 7.0 (s, 1H), 7.7 (d, J=10 Hz, 1H); MS (ES+) 242/244 (M+H+—CO2-isobutene), 286/288 (M+H+-isobutene).
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.CN.[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23](F)[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1>C(O)(=O)C.C(O)C>[NH2:9][C:10]1[C:11]([F:35])=[CH:12][C:13]([F:34])=[C:14]([N:16]2[C:25]3[C:20](=[C:21]([OH:29])[C:22]([F:28])=[C:23]([NH:1][CH3:2])[C:24]=3[CH3:26])[C:19](=[O:30])[C:18]([C:31]([OH:33])=[O:32])=[CH:17]2)[CH:15]=1
Reactant: Cc1c(F)c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c12
Reactant: c1ccncc1
Agent: CN
Solvent: CC(=O)O
Solvent: CCO
Product: CNc1c(F)c(O)c2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1C
Temperature: 30 °C
Reaction time: 48 h
Yield: 32.1 %

Procedure:
Pyridine (300 mg) and a 40% aqueous solution (300 mg) of methylamine were added to 1-(5-amino-2,4-difluorophenyl)-6,7-difluoro-5-hydroxy-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), and the mixture was stirred at 30° C. for 2 days. Acetic acid (1 drop) and ethanol (1 ml) were added to the reaction mixture, and the solvent was distilled off. Methanol was added to the residue, and solids were collected by filtration to obtain the title compound (33 mg) as a brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH3:21])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1[C:39](C)=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41].C(N1C=CC(N)=N1)C1C=CC=CC=1>C(Cl)Cl>[CH2:21]([N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[C:2]([Cl:1])[CH:3]=2)[CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[N:17]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:41]=1
Reactant: Cc1cccc(C)n1
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Agent: Nc1ccn(Cc2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccccc3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a solution containing 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 100 mg, 0.30 mmol) in methylene chloride (20 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (181 μL, 0.36 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (70 μL, 0.61 mmol) was added to the solution at 0° C. After 1 h, crude 1-benzyl-1H-pyrazol-3-ylamine (0.42 mmol based on theory) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-(1-benzyl-1H-pyrazol-3-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (101 mg, 69%) as a white solid: ESI-LRMS m/e calcd for C25H28ClN3O3S [M+] 485.2, found 486.4 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.05-1.18 (m, 2H, CH2), 1.40-1.91 (m, 8H, 4×CH2), 2.10-2.31 (m, 1H, CH), 3.23 (s, 3H, SO2CH3), 3.56 (t, J=7.6 Hz, 1H, CH), 5.12 (s, 2H, NCH2), 6.69 (d, J=2.3 Hz, 1H, Ar), 7.12 (dd, Jo=7.2, Jm=1.7 Hz. 2H, Ar), 7.26-7.33 (m, 4H, Ar), 7.43 (dd, Jo=8.2, Jm=1.6 Hz. 1H, Ar), 7.57 (d, Jm=1.6 Hz, 1H, Ar), 8.04 (d, Jo=8.2 Hz. 1H, Ar), 8.27 (brs, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:14])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[H-].[Na+].I[CH3:18].O>O1CCCC1>[CH3:18][NH:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: Nc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a solution of 8-nitroquinolin-7-amine (1.89 g, 10 mmol) in tetrahydrofuran (THF) (10 mL) was added sodium hydride (60% wt in mineral oil, 800 mg, 20 mmol). The mixture was stirred at room temperature for 30 minutes, then iodomethane (1.42 g, 10 mmol) was added. The mixture was stirred at room temperature for 5 h. Then water (10 mL) was added. The mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel column chromatography (eluting with PE/EtOAc v/v 2:1) to give N-methyl-8-nitroquinolin-7-amine as a yellow solid (1.6 g, yield 79%). ESI MS: m/z 204 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O1CCCC1.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C)C=O.CN1CCCC1=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:42][C:41]4[CH:43]=[CH:44][CH:45]=[C:39]([C:38]([F:37])([F:46])[F:47])[CH:40]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 9 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), oxalyl chloride (100 μL, 1.2 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), 3-(trifluoromethyl)aniline (80 mg, 0.48 mmol) and N-methylpyrrolidone (1.0 mL) as starting materials and in the same manner as in Example 335, the title compound (13 mg, 8.9%) was obtained as a pale-yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([OH:29])[CH:15]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH:24]([CH3:25])[CH3:26])[CH:21]([CH3:23])[CH3:22])=[O:19])=[C:16]([CH:15]=2)[O:29][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:30][CH:31]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 70 °C

Procedure:
A stirred solution of 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide (1.0 g, 2.36 mmol) in 10.0 mL of N,N-dimethylformamide is treated with 60% sodium hydride (100 mg, 2.59 mmol) and ethyl bromoacetate (290 μL, 2.59 mmol), and the mixture is heated at 70° C. overnight; the reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 40-50% ethyl acetate/hexane as the eluent to afford ethyl 5-[5-(4-cyanophenoxy )pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxyacetate as a colorless foam.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30](O)=[C:29]([Br:36])[CH:28]=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:23][O:24][C:25](=[O:37])[CH2:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:29]([Br:36])[CH:28]=1
Reactant: COC(=O)Cc1cc(Br)c(O)c(OC)c1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Br)c(O[Si](C)(C)C(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Trifluoromethanesulfonic acid t-butyldimethylsilyl ester (0.159 mL, 0.690 mmol) and triethylamine (0.120 mL, 0.863 mmol) were added to a solution of (3-bromo-4-hydroxy-5-methoxy-phenyl)-acetic acid methyl ester (158 mg, 0.574 mmol) in dichloromethane (4 mL), and the mixture was stirred at room temperature for one hour. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (203 mg, 91%).