Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)=[CH:4][CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>CN(C)C=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>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][C:5]1[CH:13]=[CH:14][C:2]([C:20]2[CH:21]=[CH:22][C:17]([CH:15]=[O:16])=[CH:18][CH:19]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(-c2ccc(OC3CCCCO3)cc2)cc1
Temperature: 95 °C
Yield: 45.2 %

Procedure:
2-(4-Bromophenoxy)tetrahydropyran (3.0 g) was dissolved in N,N-dimethylformamide (30 ml). 4-Formylphenylboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium (0) (1.35 g) and tripotassium phosphate (4.95 g) were added thereto, and the resulting mixture was heated at 90 to 100° C. under a nitrogen atmosphere for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture and filtered through Celite. The filtrate was separated into layers. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a white powder (1.49 g).
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([OH:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:37][C:38]#[CH:39].[H-].[Na+]>O>[F:1][CH:2]([F:30])[O:3][CH:4]=[C:5]([C:20]1[CH:29]=[CH:28][C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH2:39][C:38]#[CH:37])[CH:12]=1)=[O:7]
Reactant: C#CCCl
Reactant: COc1ccc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(CCNC(=O)C(=COC(F)F)c2ccc3c(c2)CCCC3)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.6 %

Procedure:
417 mg (1.00 mmol) of 3-difluoromethoxy-N-[2-(3-hydroxy-4-methoxyphenyl)ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide, 5 ml of anhydrous N,N-dimethylformamide, 74 mg (1.00 mmol) of 3-chloropropyne and 50 mg (1.25 mmol) of 60% sodium hydride were mixed and stirred at room temperature for 3 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 162 mg of 3-difluoromethoxy-N-[2-{4-methoxy-3-(2-propynyloxy)phenyl}ethyl]-2-(5,6,7,8-tetrahydronaphthalen-2-yl)acrylamide (the present compound 1299).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.Cl.[O:12]1[C:18]2[CH:19]=[CH:20][C:21]([C:23]3[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=3)=[CH:22][C:17]=2[CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C)C=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:15]2[CH2:16][C:17]3[CH:22]=[C:21]([C:23]4[S:27][C:26]([NH:28][C:29](=[O:31])[CH3:30])=[N:25][CH:24]=4)[CH:20]=[CH:19][C:18]=3[O:12][CH2:13][CH2:14]2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ncc(-c2ccc3c(c2)CNCCO3)s1
Reactant: CC1CCN(C(=O)Cl)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)Nc1ncc(-c2ccc3c(c2)CN(C(=O)N2CCC(C)CC2)CCO3)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64150.9 %

Procedure:
4-Methylpiperidine-1-carbonyl chloride (reagent preparation 37) (103 mg, 0.64 mmol) was added to a mixture of N-[5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1,3-thiazol-2-yl]acetamide hydrochloride, (173 mg, 0.53 mmol) and potassium carbonate (374 mg, 2.7 mmol) in N,N-dimethylformamide (2 mL). The resulting mixture was stirred at room temperature for 18 hours, then methanol (2 mL) was added and concentrated. The residue was diluted with ethyl ether (40 mL), a solid was collected by filtration, and washed with ether and water to give N-(5-{4-[(4-methylpiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}-1,3-thiazol-2-yl)acetamide (140 mg, 0.34 mol, 63% yield), 1H NMR (400 MHz, DMSO-d6): 7.58 (s, 1H), 7.35 to 7.32 (m, 2H), 6.91 (d, 1H), 4.36 (s, 2H), 4.12 (br, 2H), 3.54 to 3.47 (m, 4H), 2.71 to 2.65 (m, 2H), 2.00 (s, 3H), 1.60 to 1.43 (m, 3H), 1.16 to 1.067 (m, 2H), 0.92 (d, 3H); MS (EI) for C21H26N4O3S: 415 (MH+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:17][C@H:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:18][C@H:16]2[CH2:17][C@@H:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:15]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C([C@H]1C[C@@H](O)C1)N1CCCN(C2CCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutanol (50 mg, 0.19 mmol) in DCM (2 ml) at RT was added triethylamine (77 mg, 0.7 mmol) and toluene-4-sulfonyl chloride (108 mg, 0.57 mmol). The mixture was stirred at RT for 1 h and then at 35° C. for 2 h. After cooling to RT and dilution with DCM the mixture was washed with 1:1 H2O/saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (73 mg, 91%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:22])([F:21])[C:9]([NH:11][CH2:12][CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].CN1CCOCC1>C(OCC)(=O)C>[CH2:5]([O:4][C:2](=[O:3])[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][CH2:12][NH:11][C:9](=[O:10])[C:8]([F:7])([F:21])[F:22])[CH3:6]
Reactant: O=C(NCCNc1ccccc1)C(F)(F)F
Reactant: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N(CCNC(=O)C(F)(F)F)c1ccccc1
Reaction time: 17 h

Procedure:
Ethyl chloroformate [541-41-3] (1.4 mL, 14.7 mmol) was added to an ambient temperature solution of 2,2,2-trifluoro-N-(2-phenylamino-ethyl)-acetamide (3.4 g, 14.6 mmol) and N-methyl morpholine [109-02-4] (2.0 mL, 17.7 mmol) in ethyl acetate (145 mL) and stirred under N2 blanket for 17 h. The reaction suspension was then washed with dilute aqueous hydrochloric acid, brine, dried (MgSO4), evaporated and carried on to the next synthetic step without further isolation.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]2[C:15]=1C=C[C:18](=[O:32])[NH:19]2)[O:6][Si](C(C)(C)C)(C)C)=[N+:2]=[N-:3].C(OC1C=CC([C@@H](O)CBr)=CC=1NC=O)C1C=CC=CC=1>>[N:1]([CH2:4][C@@H:5]([C:14]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:19][CH:18]=[O:32])[CH:15]=1)[OH:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Agent: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Product: [N-]=[N+]=NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 1, using Intermediate 10 as a substrate. ES/MS calcd. C16H17N4O3+ 313.1. Found m/z=313 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>C1COCC1>[F:1][C:2]1[C:9]([O:10][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[C:6]([I:11])[C:3]=1[C:4]#[N:5]
Reactant: COCCl
Reactant: N#Cc1c(I)ccc(O)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(I)c(C#N)c1F
Reaction time: 0.08 h
Yield: 72 %

Procedure:
A 0° C. solution of Example 68A (250 mg, 0.95 mmol) in THF (5 mL) at room temperature was treated with NaH (25 mg, 95%, 1.05 mmol), stirred for 5 minutes, treated with chloromethyl methyl ether (0.108 mL, 1.4 mmol), stirred overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% ethyl acetate/hexanes to provide 0.21 g of the desired product. R1=0.4 (10% ethyl acetate/hexanes).
Reaction SMILES: C1(CC([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=3[O:31][CH3:32])=[CH:12][CH:11]=2)=O)CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(OCC)(=O)C>[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=2[O:31][CH3:32])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(Cc2cccc3ccc(N)cc23)c(OC)c1
Yield: 90.9 %

Procedure:
A mixture of methyl 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoate (15.00 g), anhydrous p-toluenesulfonic acid (11.97 g), and methanol (dried over 3A molecular sieves) (70 ml) was refluxed for 42 hours. After cooling, the mixture was added to ethyl acetate (250 ml), washed (saturated sodium bicarbonate, brine), dried (MgSO4) and evaporated. The solid obtained was recrystallized from 1:12 methanol:methylene chloride and petroleum ether to give methyl 4-(7-aminonaphth-1-ylmethyl)-3-methoxybenzoate (10.15 g, 91%) as a light tan solid; mp 138°-40° C., MS(CI), m/e=322(M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[C:14]([Br:24])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCc1ccnc(N)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A solution of crude (2-amino-pyridin-4-ylmethyl)-carbamic acid tertbutyl ester (17.55 g) in DMF (50 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (12.6 g, 70.7 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (800 mL) and washed with water (2×100 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/DCM/TBME 100:10:1→TBME 100%) to yield the title compound (13.95 g, 46.2 mmol, 50% for 2 steps) as a pale yellow solid. MS: 303 [M+1]+ HPLC: AtRet=1.10; TLC: RF 0.18 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]1[CH3:31].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:19][CH2:20][CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]2[CH3:31])[N:3]=1
Reactant: CN1c2ccccc2CCC1CN
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CN1c2ccccc2CCC1CNc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-(aminomethyl)-1,2,3,4-tetrahydro-1-methyl-quinoline hydrochloride and DBU in DME. ES-MS m/e (%): 361 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(O)ccc1[N+](=O)[O-]
Reactant: ClCCCBr
Product: COC(=O)c1cc(OCCCCl)ccc1[N+](=O)[O-]
Yield: 94 %

Procedure:
Methyl 5-hydroxy-2-nitrobenzoate (4.37 g, 22.17 mmol, prepared as previously described), and 1-bromo-3-chloropropane (6.58 mL, 66.5 mmol) were reacted using the procedure described in Example 40A Step 3 to give methyl 5-(3-chloropropoxy)-2-nitrobenzoate (5.70 g, 20.8 mmol, 94%). 1H NMR (300 MHz, DMSO-d6) δ 8.14 (d, 1H), 7.33 (d, 1H), 7.30 (dd, 1H), 4.27 (dt, 2H), 3.86 (s, 3H), 3.68 (t, 2H), 2.21 (t, 2H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]1[CH:11]([CH3:20])[CH:12](OS(C)(=O)=O)[CH2:13][CH2:14][C:8]1=[C:7]2[CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.CCOC(C)=O>[N:28]([CH:12]1[CH:11]([CH3:20])[N:9]2[C:10]3[C:6]([C:7]([CH2:21][C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23])=[C:8]2[CH2:14][CH2:13]1)=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])=[N+:29]=[N-:30]
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(OS(C)(=O)=O)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)C(C)C(N=[N+]=[N-])CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Propyl {4-fluoro-6-methyl-7-[(methylsulfonyl)oxy]-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl}acetate was dissolved in DMF (1 M) and treated with NaN3 (2.0 eq.), warmed to 80° C. and stirred overnight. The reaction mixture was diluted with EtOAc and extracted with sat'd NH4Cl, water, dried (Na2SO4) and concentrated. Chromatography on SiO2 (0-100% EtOAc/hexanes) gave propyl (7-azido-4-fluoro-6-methyl-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate: 1H NMR (600 MHz, CDCl3) δ 7.30 (d, J=7.9 Hz, 1 H), 6.96-6.99 (m, 1 H), 6.80 (dd, J=12.6, 7.6 Hz, 1 H), 4.87 (dd, J=13.2, 6.5 Hz, 1 H), 4.10 (d, J=7.0 Hz, 1 H), 4.02 (t, J=6.2 Hz, 2 H), 3.61 (m, 2 H), 3.01 (m, 2 H), 2.10-2.20 (m, 2 H), 1.57-1.63 (m, 2 H), 1.43 (d, J=6.8 Hz, 3 H), 0.87 (t, J=7.3 Hz, 3 H); MS (EI) calc'd for C18H22FN4O2 [M+1]+345.2, found 345.1.
Reaction SMILES: C(OC(=O)[C@H](O[C:8]1C=C(Cl)N=C(SCC2C=CC=C(F)C=2F)[N:9]=1)C)C.C([O:28][C:29](=O)[C@H:30]([O:32][C:33]1[CH:38]=[C:37]([NH:39][S:40]([N:43]2[CH2:46][CH2:45][CH2:44]2)(=[O:42])=[O:41])[N:36]=[C:35]([S:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=2[F:56])[N:34]=1)[CH3:31])C.CN>C(O)C>[N:43]1([S:40]([NH:39][C:37]2[N:36]=[C:35]([S:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=3[F:56])[N:34]=[C:33]([O:32][C@H:30]([CH3:31])[C:29]([NH:9][CH3:8])=[O:28])[CH:38]=2)(=[O:41])=[O:42])[CH2:44][CH2:45][CH2:46]1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CCOC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Agent: CN
Solvent: CCO
Product: CNC(=O)[C@@H](C)Oc1cc(NS(=O)(=O)N2CCC2)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 166 h

Procedure:
To a solution of 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester (the product of example 23) (100 mg) in ethanol (1.5 mL) was added 8M methylamine in ethanol. The resulting mixture was stirred in a sealed tube at ambient temperature for 166 h. The solvent was evaporated under reduced pressure. Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) to give the title compound as a white solid. Yield: 60 mg MS: APCI (+ve) 474 [M+H+]
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=O)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([F:21])[CH:15]=3)=[CH:12][C:11]([C:22]([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=[O:24])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: Cc1cc(F)cc(-c2cc(C(=O)N3CNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 106A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 5 mg (6% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C1C=CC=CC=1.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:31])[CH3:34]
Reactant: CCOC(=O)Cl
Reactant: CCCCCCCC(=O)c1ccc(O)c(C(=O)O)c1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)c1ccc(OC(=O)OCC)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
4.89 g (18.50 mmol) of 2-hydroxy-5-octanoylbenzoic acid and 9 ml (70.30 mmol) of N,N-dimethylaniline are dissolved in 30 ml of toluene. The medium is cooled to 0° C., and 1.77 ml (18.50 mmol) of ethyl chloroformate are then added dropwise. After stirring for 2 hours at room temperature, the mixture is washed with aqueous 0.5N hydrochloric acid solution and then with water. The organic phase is dried over magnesium sulfate, filtered and concentrated. 5.59 g of 2-ethoxycarbonyloxy-5-octanoylbenzoic acid are obtained in the form of a white solid in a yield of 89%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[S:10][C:11]=1[O:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=1)[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=2)[CH2:20][N:21]2[C:22](=[O:31])[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]2=[O:30])=[O:16])[S:10][C:11]=1[O:12][CH3:13]
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: COc1sc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-(methyloxy)-2-thiophenecarboxylic acid (210 mg, 0.77 mmol) [prepared according to the procedure of Example 188], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (294 mg, 0.764 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (442 mg, 0.94 mmol) in chloroform (7.6 mL). DIEA (670 μL, 3.84 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (238 mg, 0.43 mmol, 56%): LC-MS (ES) m/z=603 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[C:25]1([C:31]2[N:32]([CH2:43][C:44](Cl)=[O:45])[C:33](=[O:42])[O:34][C:35]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[C:44](=[O:45])[C@H:43]([N:32]2[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])[C@@H:7]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Reactant: COC(=O)C=NCc1ccc(OC)cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@@H](n2c(-c3ccccc3)c(-c3ccccc3)oc2=O)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Methyl N-(2,4-dimethoxybenzyl)iminoacetate (1.43 g) is dissolved in 13 ml of dry methylene chloride and 1 ml of triethylamine and cooled in an ice bath. A solution of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride (2.0 g, 6.4 mmole) in 10 ml of methylene chloride is added over a 10 minute period. After one hour, the mixture is washed with water and 5% aqueous sodium bicarbonate then dried and evaporated to give a red oil which is chromatographed on silica gel to give methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.I[CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH:15]([CH3:17])[CH3:16])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc2cc(F)cc(OC(C)C)c2n1
Temperature: 70 °C
Yield: 89.6 %

Procedure:
To 6-fluoro-2-methylquinolin-8-ol (1.0 g, 5.6 mmol) in acetone (20 mL) were added 2-iodopropane (1.9 g, 11 mmol) and K2CO3 (2.3 g, 17 mmol). The reaction was heated to 70° C. for 20 hours in a sealed tube and then cooled. Water was added and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried with MgSO4, filtered and concentrated under reduced pressure to yield 6-fluoro-8-isopropoxy-2-methylquinoline (1.1 g, 89% yield) as a dark oil.