Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][C:26]=3[Cl:27])[CH2:17][NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:27][C:26]1[CH:25]=[CH:24][C:16]([CH2:17][NH:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])=[CH:15][C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([CH:30]3[CH2:32][CH2:31]3)=[O:34])=[C:3]([O:28][CH3:29])[CH:4]=2)[N:9]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1NC(=O)C1CC1
Yield: 25.9 %

Procedure:
The title compound was prepared by following the procedure as described for step-2 of Intermediate-30 by using N-(3-(1-(4-amino-3-methoxyphenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4-chlorobenzyl)cyclopropanecarboxamide (Intermediate-37, 0.050 g, 0.120 mmol), cyclopropylcarbonyl chloride (0.018 g, 0.180 mmol), DIPEA (2.0 mL) and THF (5 mL) to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 0.77 (s, 4H), 1.60 (m, 1H), 2.08 (m, 1H), 3.88 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.45 (m, 2H), 7.62 (s, 2H), 7.96 (d, J=8.4 Hz, 1H), 8.69 (m, 1H), 9.49 (s, 1H), 12.54 (s, 1H); MS (m/z): 482.10 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:28]([O:35][C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][C:46](O)=[O:47])=[CH:41][CH:40]=1)=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)(=O)C.O.O1CCCC1.C(N(CC)CC)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:46](=[O:47])[CH2:45][C:42]1[CH:41]=[CH:40][C:39]([NH:38][C:36](=[O:37])[O:35][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:44][CH:43]=1
Reactant: O=C(O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Reaction time: 20 h

Procedure:
N,N-Dimethylethylenediamine (0.64 ml), WSC (1.31 g), HOBt (1.05 g), and triethylamine (2.4 ml) were added to a tetrahydrofuran (50 ml) solution of 2-[4-[[(benzyloxy)carbonyl]amino]phenyl]acetic acid (1.5 g) obtained in Reference Example 90. After stirring for 20 hours, the reaction mixture was poured into water, and extraction was conducted using ethyl acetate. The organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, dried and then concentrated. The residue was recrystallized from ethyl acetate-hexane, to give the titled compound (1.72 g).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[CH3:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[C:39]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[N:38]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:36][C:37]1[N:38]=[C:39]([N:46]2[CH:50]=[CH:49][N:48]=[N:47]2)[C:40]([C:41]([N:17]2[CH2:16][CH2:15][C@@H:14]3[C@@H:19]([N:12]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=4)[CH2:13]3)[CH2:18]2)=[O:42])=[CH:44][CH:45]=1
Reactant: Cc1ccc(C(=O)O)c(-n2ccnn2)n1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4ccc(C)nc4-n4ccnn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 6-methyl-2-(1H-1,2,3-triazol-1-yl)nicotinic acid (Intermediate 51) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C21H21F3N8O, 458.45; m/z found 459.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18](SC)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.CCN(C(C)C)C(C)C>>[CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11](/[CH:14]=[C:15]3/[C:16](=[O:22])[N:17]=[C:18]([NH:34][CH2:33][C:29]4[CH:28]=[C:27]([C:26]([F:36])([F:25])[F:35])[CH:32]=[CH:31][N:30]=4)[S:19]/3)[CH:12]=2)[N:7]=[CH:6][C:5]=1[C:23]#[N:24])[CH3:2]
Reactant: CCOc1c(C#N)cnc2ccc(/C=C3\SC(SC)=NC3=O)cc12
Reactant: NCc1cc(C(F)(F)F)ccn1
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(C#N)cnc2ccc(/C=C3\SC(NCc4cc(C(F)(F)F)ccn4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 14h was used, starting from 4-ethoxy-6-[2-methylsulfanyl-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile (example 14g), 4-trifluoromethyl-pyridin-2-ylmethylamine and DIEA to give 4-ethoxy-6-[4-oxo-2-[(4-trifluoromethyl-pyridin-2-ylmethyl)-amino]-4H-thiazol-(5Z)-ylidenemethyl]-quinoline-3-carbonitrile. LC-MS m/e 484 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9]([O:16][C:17](Cl)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1.N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([NH:8][C:17](=[O:18])[O:16][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cccnc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Nc1ncccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-diaminopyridine in tetrahydrofuran/pyridine (10/1) at 0° C. benzylchloroformate was added dropwise. The suspension was stirred at room temperature and after 2 hours partitioned between water and EtOAc. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over sodium sulfate and the filtrate concentrated to dryness under reduced pressure. To the residue was added Et2O-MeOH and the solid was filtered.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH2:34][N:35]2[CH2:51][CH2:50][C:38]3([O:43][CH2:42][CH2:41][N:40]([C:44](=[O:49])[C:45]([F:48])([F:47])[F:46])[CH2:39]3)[CH2:37][CH2:36]2)[S:32][CH:33]=1)(C(C)(C)C)(C)C>C1COCC1>[F:48][C:45]([F:46])([F:47])[C:44]([N:40]1[CH2:39][C:38]2([CH2:37][CH2:36][N:35]([CH2:34][C:31]3[S:32][CH:33]=[C:29]([CH2:28][CH2:27][OH:26])[CH:30]=3)[CH2:51][CH2:50]2)[O:43][CH2:42][CH2:41]1)=[O:49]
Reactant: CC(C)(C)[Si](C)(C)OCCc1csc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(N1CCOC2(CCN(Cc3cc(CCO)cs3)CC2)C1)C(F)(F)F
Reaction time: 1 h

Procedure:
TBAF (1M in THF, 2.96 mL) was added to a stirred solution of 1-(9-((4-(2-(tert-butyldimethylsilyloxy)ethyl)thiophen-2-yl)methyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)-2,2,2-trifluoroethanone (Example 43, step a) (1.500 g, 2.96 mmol) in THF (5 mL). After 1 h, the solution was evaporated to gum. Purification by silica gel chromatography eluting with ethyl acetate:triethylamine, 10:1 gave the subtitled compound as a gum. Yield 0.25 g.
Reaction SMILES: [C:1]([CH2:3][C:4]1[O:5][C:6](=[O:17])[C:7]2[C:13]([OH:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:8]=2[CH:9]=1)#[N:2].N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C1(C)C=CC=CC=1>CN(C)C=O>[Si:23]([O:14][C:13]1[C:7]2[C:6](=[O:17])[O:5][C:4]([CH2:3][C:1]#[N:2])=[CH:9][C:8]=2[CH:10]=[C:11]([O:15][CH3:16])[CH:12]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O)c2c(=O)oc(CC#N)cc2c1
Agent: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(O[Si](C)(C)C(C)(C)C)c2c(=O)oc(CC#N)cc2c1
Reaction time: 2 h
Yield: 93.4 %

Procedure:
2.70 g (11.68 mmol) of the 3-cyanomethyl-8-hydroxy-6-methoxy-1-oxo-1H-2-benzopyran obtained in Example 3 was suspended in 25 ml of dimethylformamide. 1.59 g (23.4 mmol) of imidazole and 2.82 g (18.7 mmol) of tert-butyldimethylsilyl chloride were successively added thereto under cooling with ice, and the resulting mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was mixed with toluene, washed once with 50 ml of a 10% aqueous solution of sodium chloride, and washed twice with 50 ml portions of a 20% aqueous solution of sodium chloride. The toluene layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried in vacuo. The resulting residue was recrystallized from 20 ml of ethanol to obtain 3.77 g of the title compound in a 93% yield.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[C:9]#[N:10].[Cl-].[Cl:12][C:13](Cl)=[N+:14]([CH3:16])[CH3:15]>ClCCl>[C:9]([C:3]1[C:4]([CH2:7][CH3:8])=[N:5][S:6][C:2]=1[N:1]=[C:13]([Cl:12])[N:14]([CH3:16])[CH3:15])#[N:10]
Reactant: C[N+](C)=C(Cl)Cl
Reactant: CCc1nsc(N)c1C#N
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1nsc(N=C(Cl)N(C)C)c1C#N
Yield: 16.6 %

Procedure:
In the manner of Example VI, 7.6 g of 5-amino-4 -cyano-3-ethylisothiazole and 8.1 g of N-(dichloromethylene) -N,N-dimethylammonium chloride were allowed to react in 100 ml of dichloromethane. The volatile materials were evaporated under reduced pressure. The residue was recrystallized twice from cyclohexane to give 2.0 g of N'-(4-cyano-3-ethyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 95°-97°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C@@H:14]([CH3:19])[CH2:15][C:16]([OH:18])=O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)(=O)C(C)(C)C.C([Li])CCC.[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[NH:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O1CCNC1=O>O1CCCC1>[C:32]1([C@H:38]2[CH2:42][O:41][C:40](=[O:43])[N:39]2[C:16](=[O:18])[CH2:15][C@@H:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:19])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: C[C@@H](CC(=O)O)c1ccccc1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Triethylamine (1.3 mL, 9.1 mmol) was added to (S)-3-phenylbutyric acid (1.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (60 mL) at −78° C. followed by the dropwise addition of pivaloyl chloride (0.83 ml, 6.7 mmol) to give a white solid. The reaction was allowed to warm to room temperature for 10 minutes then cooled back down to −78° C. In a separate flask, n-butyllithium (4.6 mL, 11.6 mmol, 2.5 M F in hexanes) was added to (S)-(+)-4-phenyl-2-oxazolidinone (2.0 g, 12.2 mmol) in anhydrous tetrahydrofuran at −78° C. and allowed to stir for 10 minutes. The lithiated oxazolidinone was transfered via cannula to the mixed anhydride at −78° C. and stirring continued for 2 hours. The reaction was quenched with water (25 mL) and extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over sodium sulfate. The crude product was purified by chromatography over silica gel eluted with 2:3 ethyl acetate/hexanes and the resulting solid was recrystallized from ethyl acetate/hexanes to afford (S)-4-phenyl-3-((S)-3-phenyl-butyryl)-oxazolidin-2-one (1.63 g, 88% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:21])([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[AlH4-].[Li+].[OH-].[Na+]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][OH:15])([CH3:21])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1(C)CCN(Cc2ccccc2)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOCC
Product: CC1(CO)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 1-benzyl-4-methylpiperidine-4-carboxylate (4.7 g, 18 mmol) in diethyl ether (47 mL) was cooled at 0° C. and to this was added lithium tetrahydroaluminate (990 mg, 25 mmol) portion-wise. The reaction mixture was warmed to ambient temperature and stirred vigorously for 1 hour. The mixture was then cooled to 0° C. and a 1N solution of sodium hydroxide (6 mL) was added dropwise to the reaction mixture producing a white precipitate. The mixture was filtered and the solids were washed with ethyl acetate (100 mL). The combined filtrate was separated and the aqueous portion was extracted with ethyl acetate (2×50 mL). The combined organic portions were dried over sodium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 80 g, ISCO, 45-100% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (2.7 g, 67%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=2)[N:17]=[C:16]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:15]=1[CH:31]([CH3:33])[CH3:32].Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([C:14]3[C:23]4[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:15]=3[CH:31]([CH3:33])[CH3:32])[CH2:9][C:8]([CH3:12])([CH3:11])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CC1(C)CNc2cc(Br)cnc21
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: CC(C)c1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (94 mg, 0.416 mmol), 4-chloro-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline (125 mg, 0.416 mmol) and 4.0M solution of HCl in 1,4-dioxane (0.10 mL, 0.416 mmol) in NMP (0.6 mL) and heating in the microwave for 5 h at 150° C. After purification 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-isopropyl-2-(pyridin-2-yl)quinoline was obtained as a colorless film. Mass Spectrum (ESI) m/e=491 [(M+1) (79Br)] and 493 [(M+1) (81Br)].
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32].[N:41]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:44]=[C:43]([CH:51]=O)[CH:42]=1>O1CCCC1>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:31])[CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:43]1[CH:42]=[N:41][C:50]2[C:45]([CH:44]=1)=[CH:46][CH:47]=[CH:48][CH:49]=2
Reactant: COC(=O)C(NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: O=Cc1cnc2ccccc2c1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 134; 120 mg, 0.24 mmol) in tetrahydrofuran (5 mL) at −20° C. After 10 min, quinoline-3-carboxaldehyde (39.3 mg, 0.25 mmol) was added and the solution was stirred at room temperature for 16 h. The solvent was evaporated and ethyl acetate (10 mL) was added. The solution was washed with saturated sodium bicarbonate solution (5 mL) and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered, evaporated and chromatographed over silica gel (50% ethyl acetate/hexanes) to give rac.-(Z)-2-[[2-chloro-4-[1-hydroxy-3-(3-hydroxyphenyl)propan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (93 mg, 75% yield) as an off-white solid.
Reaction SMILES: N1[C:6]2[CH:7]=[CH:8]S[C:5]=2[C:4](=O)NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)[CH2:22][CH2:23][O:24][CH2:25][Cl:26]>>[CH2:23]([O:24][CH2:25][Cl:26])[C:22]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=c1[nH]c(=O)c2sccc2[nH]1
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using thieno[3,2-d]pyrimidine-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 87%) as a pale yellow powder.
Reaction SMILES: BrC1C=CC=C2C=1CC(=[O:11])C2.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1[CH2:15][C:16]([F:23])([F:22])[CH2:17]2.C(N(S(F)(F)F)CC)C.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(OO)(=O)C>[Pd]>[F:22][C:16]1([F:23])[CH2:15][C:14]2[C:13]([OH:11])=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: FC1(F)Cc2cccc(Br)c2C1
Reactant: O=C1Cc2cccc(Br)c2C1
Agent: [Pd]
Agent: CC(=O)OO
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Product: Oc1cccc2c1CC(F)(F)C2

Procedure:
4-Bromo-1,3-dihydro-2H-inden-2-one was converted to 4-bromo-2,2-difluoroindane with (diethylamino)sulfur trifluoride. Palladium-catalyzed reaction with bis(pinacolato)diboron, followed by oxidation with peracetic acid, afforded 2,2-difluoroindan-4-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]3=[N:17][N:18]([CH3:21])[C:19]([CH3:20])=[C:13]3[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:53][CH2:52][N:51]3[C:44](=[CH:45][C:46]4[CH2:47][C:48]([CH3:55])([CH3:54])[CH2:49][C:50]=43)[C:43]2=[O:56])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]3=[N:17][N:18]([CH3:21])[C:19]([CH3:20])=[C:13]3[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]
Reactant: Cc1c2cc(Nc3cc(Br)cn(C)c3=O)ncc2nn1C
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4c(C)n(C)nc4cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 326b (160 mg, 0.46 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (300 mg, 0.69 mmol), K3PO4 (195 mg, 0.92 mmol), sodium acetate (75 mg, 0.92 mmol), 1,1′-bis(diphenylphosphino) ferrocenedichloropalladium(II) (42 mg, 0.046 mmol), acetonitrile (10 mL), and water (6 drops). The system was subjected to three cycles of vacuum/nitrogen flush and heated at 100° C. under N2 protection for 1.5 h. LCMS Analysis showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by gel-silica column chromatography eluting with 60:1 dichloromethane/methanol to afford 326c (130 mg, 45%) as a black solid. MS-ESI: [M+H]+ 621.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH3:18]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(Cl)cc1
Yield: 88 %

Procedure:
A solution of (4-chloro-phenyl)-acetic acid (6.29 g, 0.03 mol) in ethanol (38.4 mL) was treated with a catalytic amount of sulfuric acid. The reaction mixture was refluxed for 12 h. The reaction was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded (4-chloro-phenyl)-acetic acid ethyl ester (6.45 g, 88%) as a pale yellow solid: mp 39-41° C.; EI-HRMS m/e calcd for C10H11ClO2 (M+) 198.0448, found 198.0452.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: COCCOc1nc(C(=O)O)ccc1C1CC1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: COCCOc1nc(C(=O)N[C@@H](CC(C)C)C(N)=O)ccc1C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=350.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[CH3:20][CH:21]1[NH:23][CH2:22]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][N:23]2[CH2:22][CH:21]2[CH3:20])[N:8]=1
Reactant: CC1CN1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Product: COc1nc2cc([N+](=O)[O-])cc(CN3CC3C)c2nc1OC

Procedure:
200 mg (0.61 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 0.086 ml (2 equiv.) of propyleneimine and 0.295 ml (0.3 equiv.) of an aqueous 40% tetrabutylammonium hydroxide solution are stirred in 8 ml of dichloromethane for 20 hours at room temperature. The mixture is concentrated by evaporation and the residue is extracted with ethyl acetate and a 5% sodium carbonate solution. The combined organic phases are washed once with brine, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20].CO.C(Cl)CCl>O>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: ClCCCl
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
Typically, N-acetyl-D-phenylalanine is allowed to contact DL-phenylalanine methyl ester in a suitable solvent, e.g. methanol, ethylene chloride or water, to produce a crude crystalline salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester. That salt is separated from the filtrate, purified and decomposed with aqueous hydrochloric acid to afford N-acetyl-D-phenylalanine as a precipitate and L-phenylalanine methyl ester hydrochloride in solution. After filtering, the solvent in the filtrate is removed to afford the hydrochloride salt of L-phenylalanine methyl ester. Alternatively, the salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester is dissolved in aqueous potassium carbonate and extracted with ether. The D-amide remains in the aqueous phase and the L-ester is extracted into the organic phase. After phase separation, the ethereal solution is acidified with hydrochloric acid-isopropanol to precipitate the hydrochloride salt of L-phenylalanine methyl ester.