Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]2[CH3:28])[C:5]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]([CH2:19][C:20]#[N:21])[C:6]=2[N:7]=1.B(O)O.[C:32]([O-:35])(=O)C.[K+].[C:37](#[N:39])[CH3:38]>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>[C:20]([CH2:19][C@@H:8]1[C:6]2[N:7]=[C:2]([C:8]3[CH:19]=[CH:20][C:37]([NH:39][C:32]([NH:3][CH2:4][CH3:5])=[O:35])=[CH:38][CH:6]=3)[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:5]=2[CH2:11][CH2:10][N:9]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])#[N:21]
Reactant: CC#N
Reactant: CC(=O)[O-]
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CCN(C(=O)OC(C)(C)C)C2CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [K+]
Solvent: O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(C(=O)OC(C)(C)C)[C@@H]3CC#N)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Step 2—Synthesis of compounds xp1 and xp2: Tert-butyl 2-chloro-8-(cyanomethyl)-4-((S)-3-methylmorpholino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate (0.494 g, 0.00121 mol), [4-Ethylureido)phenyl]boronic acid, pinacol ester (0.471 g, 0.00162 mol), Tetrakis(triphenylphosphine)palladium(0) (0.1019 g, 8.818E-5 mol) Sodium carbonate (0.205 g, 0.00193 mol) and Potassium acetate (0.205 g, 0.00209 mol) were combined, nitrogen purged three times, added dry Acetonitrile (10.0 mL, 0.191 mol) followed by deoxygenated Water (6.00 mL, 0.333 mol), heated at 90° C. and stirred overnight. The reaction mixture was cooled to room temperature and stirred for 2 days. The reaction mixture was diluted with water, extracted three times with 10% MeOH in dichloromethane, dried over Magnesium sulfate, filtered, concentrated, chromatographed through silica gel (40 g, 0-100% EtOAc in heptane), purified by HPLC, and the diastereomers were separated out by SFC.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19](Cl)(=O)C.[CH2:23]([N:25]1[C:37]2[CH:36]=[CH:35][C:34]([NH2:38])=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24]>>[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([NH:38][C:34]1[CH:35]=[CH:36][C:37]2[N:25]([CH2:23][CH3:24])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:18])(=[O:7])[CH3:19]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(=O)Cl
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=NOC)CN3C(C)=O)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, acetyl chloride, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 69% purity by LC/MS. MS(ESI+): m/z=393.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[C:30]2[C:37]#[N:38]>>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([C:30]=1[C:37]#[N:38])=[CH:28][C:27]([O:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][C:13]([C:17]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:18])=[C:14]([CH3:16])[N:15]=4)[S:10][C:3]=13)=[CH:35][CH:34]=2
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCN(C)CC1
Reactant: Cc1[nH]c2ccc(O)cc2c1C#N
Product: Cc1nc(-c2cc3nccc(Oc4ccc5[nH]c(C)c(C#N)c5c4)c3s2)sc1C(=O)N1CCN(C)CC1
Yield: 41 %

Procedure:
The title compound (61 mg, 41%) was prepared from [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone and 5-Hydroxy-2-methyl-1 H-indole-3-carbonitrile by a procedure analogous to Example 16 using and in a 41% yield. C27H25N6O2S2: APCI m/z 529.4 (pos.); 1H NMR (CD3OD): δ 8.72 (d, 1H, J=6.6 Hz), 8.17 (s, 1H), 7.60 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 7.07 (d, 1H, J=6.6 Hz), 3.65–3.15 (bm, 8H), 2.96 (s, 3H), 2.63 (s, 3H), 2.52 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Na+].[CH3:25]I>>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[C:16]3[CH2:19][CH2:20][CH2:21][C:15]=3[N:14]([CH3:22])[C:13]2=[O:23])=[CH:7][C:3]=1[C:4]([O:6][CH3:25])=[O:5]
Reactant: CI
Reactant: Cn1c2c(c(=O)n(-c3cc(C(=O)[O-])c(Cl)cc3F)c1=O)CCC2
Agent: [Na+]
Product: COC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(F)cc1Cl

Procedure:
using sodium 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and methyl iodide there is obtained methyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 138°-141° C.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)=[O:28])[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:17][CH2:16][CH2:15][CH2:14]1>C1COCC1>[CH:13]1([O:18][C:19]2[CH:20]=[C:21]([C:27]([C:29]3[O:30][CH:31]=[CH:32][CH:33]=3)([OH:28])[CH2:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(C(=O)c2ccco2)cc1OC1CCCC1
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)(Cc2ccncc2)c2ccco2)cc1OC1CCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
n-Butyllithium (1.6M solution in hexanes; 4.2 ml, 6.64 mmol) was added to a solution of a 4-methylpyridine (0.62 g, 0.65 ml, 6.64 mmol) in THF (25 ml) at -70° C. After 0.5 h, a solution of the crude ketone (1.9 g, ca. 6.6 mmol) in THF (5 ml) was added, stirred for 1 h at -70° C., then at RT for 0.25 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (3×50 ml). The extract was dried (MgSO4), concentrated in vacuo, and the residual red oil subjected to chromatography (SiO2 ; EtOAc/hexane, 3:2) to afford the title compound (1.23 g, 49%) as a pale yellow oil; δH (CDCl3) 1.5-1.9 (8H, br m, (CH2)4), 2.84 (1H, br s, OH), 3.30 (1H, d, J 13.2 Hz, CHAHB pyridine), 3,59 (1H, d, J, 13.2 Hz, CHAHB pyridine), 3.82 (3H, s, OMe), 4.65 (1H, br m OCH), 6.24 (1H, dd, J 3.3, 0.7 Hz, furan H3), 6.35 (1H, dd, J 3.3, 1.8 Hz, furan H4), 6.75-6.85 (3H, m, C6H3), 6.85 (2H, dd, J 4.5, 1.6 Hz, pyridine H3, H5), 7.43 (1H, dd, J 1.8, 0.7 Hz, furan H5), and 8.33 (2H, dd, J 4.5, 1.6 Hz, pyridine H2, H6); m/z (ESI) 402 (M+ +23, 20%), 380 (M+ +1, 35), 287 (100), 95 (28), and 94 (97).
Reaction SMILES: CC1C(=O)OC(=O)C=1CC=C.[CH3:12][C:13]1[C:14](=[O:34])[N:15]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:33])([F:32])[F:31])[CH:23]=2)[C:16](=[O:21])[C:17]=1[CH2:18][CH:19]=C>>[CH:18]([C:17]1[C:16](=[O:21])[N:15]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([C:30]([F:31])([F:33])[F:32])[CH:23]=2)[C:14](=[O:34])[C:13]=1[CH3:12])=[CH2:19]
Reactant: C=CCC1=C(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: C=CCC1=C(C)C(=O)OC1=O
Product: C=CC1=C(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O

Procedure:
The reaction of 1.8 g of the compound, produced under 8a, analogously to the instructions described under 7b and 7c yielded 1.1 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl.[CH3:24][N:25]([CH2:27][CH:28]([OH:38])[CH2:29][O:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1)[CH3:26]>CN1C(=O)CCC1>[CH3:26][N:25]([CH2:27][CH:28]([OH:38])[CH2:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([NH:35][C:2]2[N:7]=[C:6]([N:8]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:36][CH:37]=1)[CH3:24]
Reactant: Clc1nccc(N(CCc2ccccc2)c2ccccc2)n1
Reactant: CN(C)CC(O)COc1ccc(N)cc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: CN(C)CC(O)COc1ccc(Nc2nccc(N(CCc3ccccc3)c3ccccc3)n2)cc1
Temperature: 120 °C
Yield: 35.7 %

Procedure:
2-Chloro-4-(N-(2-phenylethyl)anilino)pyrimidine (Reference Example E-3; 270 mg, 0.87 mmol) was dissolved in NMP (2 ml), 4-[3-(N,N-dimethyl)amino-2-hydroxypropoxy]aniline hydrochloride (Reference Example D-1; 222 mg, 0.90 mmol) was added and the mixture heated at 120° C. for 12 hours. The solvent was evaporated, the residue was resolubilized in methanol/ammonia 6M and evaporated again to dryness. The resulting solid was purified by flash chromatography using increasingly polar solvent mixtures starting with DCM and ending with DCM/methanol with 10% ammonia (87.5/12.5). Evaporation of the solvent gave a foam which was triturated in ether to give the title product as a white solid (150 mg, 36%). NMR: (400 MHz, 353K) 2.30 (s, 6H), 2.50 (m, 2H), 2.90 (m, 2H), 3.80 (m, 1H), 3.85 (m, 1H), 3.95 (br s, 1H), 4.10 (m, 2H), 5.00 (br s, 1H), 5.50 (d, 1H), 6.70 (d, 2H), 7.15 (m, 3H), 7.25(m, 4H), 7.35 (t, 1H), 7.50 (t, 2H), 7.60 (d, 2H), 7.80 (d, 1H), 8.85 (s, 1H), M.S.: (ES+) 484 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][O:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)=[C:4]([C:26]([F:29])([F:27])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: O=C1S/C(=C\c2ccc3c(ccn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCOCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-3-(2-morpholin-4-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 243) and 4-(2-chloroethyl)morpholine hydrochloride following General Procedure H.
Reaction SMILES: [CH2:1]([C@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:9][C@H:10]([OH:37])[C@@H:11]([NH:19]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NCC)C>CN(C=O)C>[NH2:19][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@@H:10]([OH:37])[CH2:9][C@@H:8]([NH:38][C:39]([C@@H:41]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 594.5 %

Procedure:
A solution of the product of Example 3C (0.130 g, 0.192 mmol) in DMF (6 mL) was treated with diethylamine (1.5 mL), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with a gradient starting with ethyl acetate and ending with methanol to give the title compound (0.52 g, 60% yield).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10]1>O1CCOCC1.C(OCC)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=C1CCCC(=O)O1
Reactant: CCN1CCNCC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 19 h
Yield: 65 %

Procedure:
1.5 g of 1-ethylpiperazine and 1.5 g of glutaric anhydride in solution in 5 cm3 of dioxane are added, under argon, to 10 cm3 of dioxane. The stirring is continued at 25° C. for 19 hours. The solvents are evaporated under reduced pressure (2.7 kPa) to give a brown oil which is stirred in ethyl ether. The solid obtained is filtered, rinsed with diethyl ether and then dried at 20° C. (90 Pa) to give 1.95 g of 5-(4-ethylpiperazin-1-yl)-5-oxopentanoic acid in the form of a hygroscopic pink solid which is used as it is.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[C:11]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH:7][CH:11]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCCCCCCCCCCC1
Reactant: NCCN(CCN)CCN
Product: NCCN(CCN)CCNC1CCCCCCCCCCCCCC1

Procedure:
Following the general procedure of Example 33, but starting with tris-(2-aminoethyl)amine and cyclopentadecanone, the title compound is produced; IR (liquid film) 3361, 3287, 2928, 2857, 2810, 1460, 1350, 1282, 1116, 1043, 893, 843, 711. (PLA2)
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][C:14](O)=[O:15])=[C:7]([C:17](=[O:29])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:6]=1.Cl.[NH2:31]O.C>O>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([CH2:18][C:17]([C:7]2[CH:6]=[C:5]([O:4][CH3:3])[C:10]([O:11][CH3:12])=[CH:9][C:8]=2[CH2:13][C:14](=[N:31][OH:1])[OH:15])=[O:29])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: COc1ccc(CC(=O)c2cc(OC)c(OC)cc2CC(=O)O)cc1OC
Reactant: NO
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC(=O)c2cc(OC)c(OC)cc2CC(O)=NO)cc1OC

Procedure:
Aqueous sodium hydroxide (20 ml. of 5.15N) added to a suspension of 4,5-dimethoxy-2-[(3,4-dimethoxyphenyl)acetyl]phenylacetic acid (10.0 g., 0.0267 mole) and hydroxylamine hydrochloride (4.9 g., 0.07 mole) in 50 ml. of water provides a clear solution which is heated for 1 hr. at 90° C. The solution is stirred with decolorizing charcoal, filtered, acidified to a pH of 3 with concentrated hydrochloric acid, and then chilled to provide an amber gum which is separated by decanting the supernatent liquid. Triturating the gum with ethyl acetate affords 2-(3,4-dimethoxyphenylacetyl)-4,5-dimethoxyphenylacetic acid oxime, m.p. 134°-138° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(O)C.O>[Si:29]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]2[CH:20]=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=2)=[CH:3][CH:4]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2ccnc(Cl)n2)cc1
Temperature: 150 °C
Reaction time: 15 h

Procedure:
4-Aminophenol (8.8 g, 80.6 mmol) and triethylamine (18.6 mL, 133.4 mmol) are added to a solution of 2,4-dichloropyrimidine (10.0 g, 67.1 mmol) in ethanol (150 mL). The reaction mixture is heated at 150° C. for 14 hours in a sealed flask. The batch is then cooled to ambient temperature and the solvent is evaporated off in vacuo. Dichloromethane (200 mL) is added to the residue, and then imidazole (9.1 g, 133.7 mmol) and tert-butyl(dimethyl)silyl chloride (12.1 g, 80.3 mmol) are added. The mixture is stirred for 15 hours at ambient temperature. The reaction mixture is diluted with water (200 mL). The phases are separated and the organic phase is washed with brine (1×100 mL). It is then dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain a solid. The latter is triturated in heptane, filtered off and rinsed with heptane to yield the expected compound in the form of a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.BrC1C=C(Cl)C=CC=1O[CH2:18][C:19]([F:22])([F:21])[F:20].FC(F)(F)COS(C(F)(F)F)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:4][CH:3]=1
Reactant: FC(F)(F)COc1ccc(Cl)cc1Br
Reactant: Oc1ccc(Br)cc1
Agent: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: FC(F)(F)COc1ccc(Br)cc1
Yield: 40 %

Procedure:
Following the method described in Example 89 for the synthesis of 2-bromo-4-chloro-1-(2,2,2-trifluoro-ethoxy)-benzene 4-bromo-phenol and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester gave 1-bromo-4-(2,2,2-trifluoro-ethoxy)-benzene (40% yield). 1H NMR (acetone-d6) δ 4.68 (q, 2H, J=8.5 Hz, CH2), 7.04 (d, 2H, J=9.1 Hz, Ar), 7.49 (d, 2H, J=9.1 Hz, Ar).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1>CN(C)C=O>[CH:13]1([CH2:16][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Oc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CC2)c2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A solution of 5.00 gm (37.6 mMol) 4-hydroxyindole in dimethylformamide was added dropwise over 30 minutes to a solution of 1.65 gm (41.3 mMol) sodium hydride (60% suspension in mineral oil) in 25 mL dimethylformamide at 0° C. The resulting black solution was stirred at room temperature for 2 hours and then a solution of 3.6 mL (37.6 mMol) cyclopropylmethyl bromide in 10 mL dimethylformamide was added dropwise. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was then quenched by the addition of 100 mL water and the resulting mixture extracted well with ethyl acetate. The organic phases were combined, washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10% ethyl acetate in hexane. Fractions shown to contain product were combined and concentrated under reduced pressure to provide 4.48 gm (64%) of the title compound as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.C[Si](C)(C)[O-:15].[K+].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[C:9]([NH2:10])=[O:15])=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1ccc(Br)cc1
Reactant: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanenitrile (3.29 g) in toluene (33 mL) was added potassium trimethylsilanolate (8.37 g) portionwise. After being stirred at reflux temperature for 5 h, the reaction mixture was cooled to room temperature. Water(17 mL) was added to the mixture dropwise. Filtration gave the product (3.28 g, 92%). 1HNMR (CDCl3) 400 MHz δ: 7.49 (d, J=8.7 Hz, 2H), 7.28 (d, J=8.7 Hz, 2H), 5.52-4.93 (m, 2H), 1.57 (s, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].CNN>C(O)C>[Si:5]([O:6][CH2:7][CH2:8][CH2:9][NH2:10])([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCCN1C(=O)c2ccccc2C1=O
Agent: CNN
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCCN
Temperature: 75 °C
Yield: 36 %

Procedure:
To a solution of N-(3-hydroxypropyl)phthalimide (5.25 g, 24.36 mmol) in DMF (20 mL) was added imidazole (16.6 g, 240 mmol) and tert-butyldimethylsilyl chloride (19 g, 120 mmol). The reaction was stirred at room temperature for 18 hours before the volatiles were removed in vacuo and a portion of the crude product was subjected to column chromatography (SiO2, 1:1 DCM/hexanes) to give 2-[3-(tert-butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione as a clear oil (5 g). 2-[3-(tert-Butyldimethyl-silanyloxy)propyl]isoindole-1,3-dione (5 g, 26.4 mmol) was dissolved in ethanol (50 ml) and methyl hydrazine (2.94 ml, 55.4 mmol) added. The reaction was heated to 75° C. for 8 hours before concentration in vacuo. The crude residue was triturated with a mixture of diethyl ether (150 mL) and hexanes (50 mL) and the resultant solid removed by filtration. The solvents were removed in vacuo to give the title compound as a pale yellow oil (1.8 g, 61%). δH (DMSO-d6) 4.58 (2H, br s), 3.63-3.58 (2H, m), 2.67-2.62 (2H, m), 1.60-1.55 (2H, m), 0.83 (9H, d, J=1.1 Hz), 0.00 (6H, d, J=1.2 Hz). LCMS (ES+) RT 1.77 minutes, 190 (M+H)+.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])N>>[Br:11][C:12]1[CH:13]=[C:14]([N:1]([C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[C:3]2[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=2[OH:10])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Product: O=C1CCCC(O)=C1N(C1=C(O)CCCC1=O)c1ccc(F)c(Br)c1

Procedure:
Following the procedure described in the Example 1, using 2-diazo-cyclohexane-1,3-dione and 3-bromo-4-fluoroaniline as starting materials to yield the title compound as a white solid.
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C:33]([O:35]C)=[O:34])[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:16][C:15]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([NH:9][CH2:10][C@@H:11]([C:33]([OH:35])=[O:34])[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:16][C:15]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A solution of 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (10.7 g, 21.0 mmol) in tetrahydrofuran/methanol (3:1; 80 mL) was added to a stirred solution of lithium hydroxide monhydrate (2.65 g, 63.0 mmol) in water (40 mL) at room temperature. The reaction was stirred at room temperature overnight and then concentrated to remove methanol and tetrahydrofuran. Water (150 mL) was added and the mixture was cooled to between 0 and −5° C. The mixture was acidified to pH 3 with concentrated HCl and stirred for 10 min. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine (7.1 g). The drying agent was extracted with ethyl acetate/methanol (50:3; 2×106 mL) to give a further quantity of the product (3.3 g). Overall yield:10.4 g (quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:10]2[CH2:11][CH:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)([CH2:13]3)[CH2:9]2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccc(F)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 15.8 g. of p-fluorobenzoyl chloride are reacted. Ether extraction of the reaction product gives a white solid, mp 130°-132° C.