Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[NH:5][CH3:6])[CH3:2].[Al](CC)(CC)CC.CO[C:20](=[O:42])[C:21]1[CH:26]=[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:37])[F:36])=[CH:31][C:32]=2[C:33]#[N:34])[C:24]([Cl:39])=[CH:23][C:22]=1[O:40][CH3:41]>ClCCCl.N#N>[Cl:39][C:24]1[C:25]([C:27]2[CH:28]=[N:29][C:30]([C:35]([F:38])([F:36])[F:37])=[CH:31][C:32]=2[C:33]#[N:34])=[CH:26][C:21]([C:20]([N:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:1][CH3:2])[CH3:6])=[O:42])=[C:22]([O:40][CH3:41])[CH:23]=1
Reactant: COC(=O)c1cc(-c2cnc(C(F)(F)F)cc2C#N)c(Cl)cc1OC
Reactant: CNc1ccccc1OC
Agent: CC[Al](CC)CC
Agent: N#N
Solvent: ClCCCl
Product: COc1cc(Cl)c(-c2cnc(C(F)(F)F)cc2C#N)cc1C(=O)N(C)c1ccccc1OC
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
To a mixture of 2-methoxyl-N-methylaniline (27.7 mg, 0.2 mmol) and Et3Al (196 μL, 1.9 M in toluene, 0.2 mmol) in 1,2-dichloroethane (1 mL) which was preheated at 50° C. for 10 min under N2 atmosphere, was added 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-benzoic acid methyl ester (50 mg, 0.14 mmol). The mixture was sealed in N2 atmosphere and heated at 80° C. for 16 hrs. Upon cooling to rt, the mixture was quenched with 2 N HCl (5 mL) and diluted with 1,2-dichloroethane. The organic layer was separated and concentrated. The residue was purified via reverse phase preparative LCMS to yield 4-chloro-5-(4-cyano-6-trifluoromethyl-pyridin-3-yl)-2-methoxy-N-(2-methoxy-phenyl)-N-methyl-benzamide 38-1 (4.9 mg). MS [M+H]+475.9; tR=5.91 min (method 3)
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:20])=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:7]2[C:12]=1[CH:11]=[C:10](Cl)[CH2:9][CH2:8]2)(=[O:3])[CH3:2]>[Pd]>[C:1]([C:4]1[C:5]([Cl:20])=[C:6]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:7]2[C:12]=1[CH2:11][CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2
Agent: [Pd]
Product: CC(=O)c1c(Cl)c(-c2cccnc2)n2c1CCCC2
Yield: 3.3 %

Procedure:
1-Acetyl-2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine is prepared as described in Example 39, from 1.7 g of 1-acetyl-2,7-dichloro-3-(3-pyridyl)-5,6-dihydroindolizine and from 0.09 g of 10% palladium on charcoal. 0.05 g of 1-acetyl-2-chloro-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine are thus obtained in the form of whitish crystalline solid melting at 115° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][P:13]([O:20][CH2:21][C:22]1[CH:76]=[CH:75][C:25]([C:26]([O:28][C:29]2[C:33]([O:34][C:35](=[O:56])[C:36]3[CH:41]=[CH:40][C:39]([CH2:42][O:43][P:44]([O:51]C(C)(C)C)([O:46]C(C)(C)C)=[O:45])=[CH:38][CH:37]=3)=[C:32]([C:57](=[O:61])[N:58]([CH3:60])[CH3:59])[N:31]([C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[C:30]=2[C:70](=[O:74])[N:71]([CH3:73])[CH3:72])=[O:27])=[CH:24][CH:23]=1)([O:15]C(C)(C)C)=[O:14])(C)(C)C>C(Cl)Cl>[P:44]([O:43][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:35]([O:34][C:33]2[C:29]([O:28][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([CH2:21][O:20][P:13]([OH:15])([OH:14])=[O:12])=[CH:76][CH:75]=3)=[C:30]([C:70](=[O:74])[N:71]([CH3:73])[CH3:72])[N:31]([C:62]3[CH:63]=[CH:64][C:65]([O:68][CH3:69])=[CH:66][CH:67]=3)[C:32]=2[C:57](=[O:61])[N:58]([CH3:60])[CH3:59])=[O:56])=[CH:41][CH:40]=1)([OH:51])([OH:46])=[O:45]
Reactant: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)c3ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc3)c(OC(=O)c3ccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)cc3)c2C(=O)N(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-n2c(C(=O)N(C)C)c(OC(=O)c3ccc(COP(=O)(O)O)cc3)c(OC(=O)c3ccc(COP(=O)(O)O)cc3)c2C(=O)N(C)C)cc1
Reaction time: 72 h

Procedure:
TFA (16 mL, 208 mmol) was added dropwise to a solution of 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(4-(((di-tert-butoxyphosphoryl)oxy)methyl)benzoate) (64) (88 mg, 0.09 mmol) in DCM (64 mL) the mixture was left to stand for 72 h, and then concentrated in vacuo to afford 2,5-bis(dimethylcarbamoyl)-1-(4-methoxyphenyl)-1H-pyrrole-3,4-diyl bis(4-((phosphonooxy)methyl)benzoate) (UL1-124) as a yellow oil: m/z 776 (M+H)+ (ES+); 774 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 8.00-7.98 (m, 4H), 7.54-7.52 (m, 4H), 7.20-7.18 (m, 2H), 7.00-6.98 (m, 2H), 4.98-4.96 (d, 4H), 3.79 (s, 3H), 2.89 (s, 6H), 2.74 (s, 6H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1>CN(C=O)C>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:14]2[N:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=2)=[CH:4][CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cc(-n2ncc3ccc(I)cc32)ncn1
Temperature: 60 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
To a solution of 6-iodoindazole (500 mg, 2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion, 131.12 mg, 3.28 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 10 minutes before addition of 6-chloropyrimidin-4-amine (477.78 mg, 3.69 mmol) and stirring at 60° C. for 17 hr and then transferred to a pressure tube and heated at 70° C. for a further 6 hr. The reaction mixture was cooled and quenched by the addition of water (10 ml) and EtOAc (a few drops) was added. The resultant precipitate was collected by suction filtration and then thoroughly dried under high vacuum to give the title intermediate (248 mg): LC-MS: m/z=+338.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:23][CH:22]=1.[Cl-].C[Al+]C.CO>C1(C)C=CC=CC=1>[O:31]=[C:30]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])[CH2:29][CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: COC(=O)CCCc1ccncc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(CCCc1ccncc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Yield: 82.4 %

Procedure:
To a solution of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1) (1.5 g, 5 mmol), prepared as described above in Example 1, and methyl 4-(4-pyridyl)butanoate (48) (2.4 g, 13 mmol), prepared as described above in Example 48, in toluene (250 mL) was added dimethylaluminumchloride (20.0 mmol). The resulting yellow solution was refluxed under a N2 atmosphere for 16 hours. The reaction mixture was allowed to cool to room temperature, followed by the addition of methanol (7 mL). The reaction mixture was extracted with sodium hydroxide (1M, 2×200 mL), and the aqueous extracts were combined and extracted with ethyl acetate (3×200 mL). The organic solutions were combined, dried (Na2SO4) and evaporated to yield 1.8 g of crude product as a thick oil.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]([NH:13]C(=O)C)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:18][CH:17]=1
Reactant: CC(=O)Nc1ccc(C(=O)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C(=O)c2ccccc2)cc1

Procedure:
p-Benzoylacetanilide (2.8 g.) and 100 ml. of 1N hydrochloric acid are refluxed for six hours. After cooling, the solution is made alkaline by the addition of 2N sodium hydroxide solution and extracted with ether to give 4-aminobenzophenone, which is recrystallized from methanol.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]([CH:29]([N:32]([CH2:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)[C:33](=[O:41])[C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]>>[ClH:1].[CH3:8][O:9][C:10]([C:12]1[CH:13]=[CH:14][N:15]2[C:20]=1[C:19](=[O:21])[N:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]([CH:29]([N:32]([CH2:42][CH2:43][CH2:44][NH2:45])[C:33](=[O:41])[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1)[CH2:30][CH3:31])=[N:16]2)=[O:11]
Reactant: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(c1nn2ccc(C(=O)OC)c2c(=O)n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
Anhydrous HCl in dioxane (4 M, 0.20 ml, 0.80 mmol) was added to 3-benzyl-2-{1-[(3-tert-butoxycarbonylamino-propyl)-(4-methyl-benzoyl)-amino]-propyl}-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-5-carboxylic acid methyl ester (0.003 g, 0.004 mmol) and the reaction mixture was stirred at 0° C. for 4 h. The reaction mixture was concentrated in vacuo, dissolved in aqueous CH3CN and lyophilized to afford the title compound (0.0021 g, 72%) as a white solid: MS (ESI+) 516 (M++H); HRMS (ESI+) calculated: 516.2611 (M++H), found: 516.2591 (M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.C[O:27][C:28]([C:30]1[S:31][C:32]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)=[CH:33][C:34]=1[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:28]([C:30]3[S:31][C:32]([C:41]4[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=4)=[CH:33][C:34]=3[C:35]#[C:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:27])=[CH:15][C:14]=2[O:20][CH3:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)c2sc(-c3ccc(Cl)cc3)cc2C#C[Si](C)(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
Dissolve 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (320 mg, 1.09 mmol) in toluene (11 mL) and add 2 M trimethylaluminum (0.65 mL, 1.30 mmol, solution in toluene). Stir the solution at RT for 1 h and then add 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (380 mg, 1.09 mmol). Stir the solution at 50° C. overnight, then carefully quench with saturated Rochelle's salt solution. Stir the mixture for 1 h and then extract with CH2Cl2 (3×30 mL). Combine the organic solutions, dry, filter, and concentrate the filtrate. Purify the crude material by flash chromatography, using 8% MeOH (2 N NH3) in CH2Cl2 as eluent, to give 425 mg (64%) of the title compound as a white solid. LC-MS/ES m/z (35Cl) 555.0 [M−t-butyl+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(OC(C)(C)C)=O.[ClH:45].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:45].[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)[C@@H](N)Cc1ccccc1

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-phenylalanineamide (1,082 mg, 1.11 mmols) was dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at room temperature for 1 hour. One-hundred milliliters of diethyl ether were added thereto, and the resulting mixture was filtered. The thus-obtained powder was recrystallized from a mixture of chloroform, methanol and ethyl acetate at a ratio of 4:1:4 to produce 450 mg (0.859 mmols) of the final compound in a yield of 77%.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C1(C)C=CC=CC=1>[C:1]([CH2:2][CH:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][CH3:21])=[O:18])#[N:10]
Reactant: N#CC=Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)C(CC#N)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
[(S,S)-N-methanesulfonyl-1,2-diphenylethylenediamine]-(hexamethylbenzene)ruthenium (5.5 mg, 0.01 mmol, S/C=50), cinnamonitrile (65 μl, 0.5 mmol), diethyl malonate (76 μl, 0.5 mmol) and toluene (0.5 ml) were added into Schlenk (20 ml) under an argon atmosphere, and stirred at 30° C. for 48 hours. 1HNMR determination of the solution showed that the yield of the product was 46%. The reaction solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2), and the optical purity was measured by HPLC (CHIRALPACK AS manufactured by Daicel Co., Ltd., hexane:2-propanol=90:10, flow rate 0.5 ml/min, detection by 210 nm), resulting to 56% ee.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]4[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4ccc(C(F)(F)F)cc4)cc32)N=C1N
Temperature: 120 °C
Yield: 12.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg, 0.01 mmol) in a 10 mL flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(trifluoromethyl)phenylboronic acid (20 mg, 0.104 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative HPLC twice to give pure 2′-amino-1′-methyl-2-phenyl-6-(4-(trifluoro methyl)phenyl)spiro[chroman-4,4′-imidazol]-5′(1′H)-one (2.87 mg, 12%). 1H-NMR (MeOD): 2.46 (m, 1H), 2.60 (m, 1H), 3.32 (s, 3H), 5.25 & 5.85 (m, 1H), 7.14 (m, 1H), 7.37-7.54 (m, 6H), 7.66-7.78 (m, 5H).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16].C(Br)C=C.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:9][O:10][C:11](=[O:25])[CH:12]([CH2:8][CH:6]=[CH2:7])[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)CC(CC(=O)O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78° C.) solution of LDA (7.1 mL, 2.0 M, 14.2 mmol) in 50 mL THF was added a solution of 3-(3-fluoro-phenyl)-pentanedioic acid monomethyl ester (2-4) (1.58 g, 6.58 mmol) in 10 mL THF gradually. The mixture was stirred for 40 min, treated with allyl bromide (1.71 mL, 19.7 mmol) at -78° C. and stirred overnight while it was warmed to room temperature. It was then concentrated and diluted with 20 mL CH2Cl2 and 15 mL EtOH. To the resulting solution was added EDAC (1.88 g, 9.87 mmol) and DMAP (25 mg, 0.02 mmol). After stirring for 5 hr, the reaction was quenched with 20 mL 10% NaHCO3 and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide 2-5 as an oil, which was further purified using flash silica chromatography (Hexane/EtOAc, 4:1).
Reaction SMILES: [CH3:1]C([O-])(C)C.[Na+].[CH3:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][OH:15].CI>C1COCC1.CC(OC)(C)C>[CH3:1][O:15][CH2:14][CH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH3:7]
Reactant: CC(C)(C)[O-]
Reactant: Cc1sccc1CCO
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: COCCc1ccsc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of NaOtBu (3.00 g, 31.3 mmol) in THF (25 mL) was added the above prepared 2-(2-methyl-thiophen-3-yl)-ethanol (3.56 g, 25 mmol) and then methyl iodide (2.34 mL, 37.5 mmol). After stirring at rt for 1 h the reaction mixture was diluted with TBME (150 mL) and washed with 0.5M HCl (50 mL), 0.1M Na2S2O3 (50 mL) and 10% brine. The aqueous layers were extracted with TBME (50 mL) and the combined organic layers were dried (Na2SO4) and evaporated affording 3.78 g (96.7%, GC 96.0%) crude product as a yellow oil which was used without purification in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:12]([OH:21])(=[O:20])[CH:13]([CH:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14].C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[OH:19][C:17]([CH:15]([CH:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])=[O:18].[NH2:1][C@@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O=Cc1ccccc1O
Solvent: CC(=O)O
Product: N[C@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of 0.1 mole (15.5 g) of L-histidine, 0.1 mole (15.1 g) of (+) tartaric acid and 0.05 mole (5.2 ml) of salicylaldehyde in 95 ml of acetic acid was stirred mechanically for two hours at 80°-100° C. The mixture was cooled to 25° C. and the formed salt was filtered. The crude D-histidine bitartrate (a very light yellow solid) was obtained in 97% yield. The volume of recovered acetic acid containing salicylaldehyde was 85 ml (89.5% recovery). The crude D-His-(+)TA was stirred and heated in 45 ml water at 80°-90° C. for 35 minutes, cooled to 30° C. and filtered. Drying in air gave 26.7 g (87.5%) of pure D-His-(+)TA. [α]18D =+13.04[C=1.35, H2O].
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[S:7](=[O:15])(=[O:14])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:32]([O:34][CH2:35][CH3:36])=[CH2:33].CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1>[CH2:32]([O:34][CH:35]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:6]1[C:5]([CH2:3][OH:4])=[CH:10][C:9]2[CH:11]=[CH:12][S:13][C:8]=2[S:7]1(=[O:14])=[O:15])[CH3:36])[CH3:33]
Reactant: COC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCCCO
Reactant: C=COCC
Agent: CC(C)C[AlH]CC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: C1CCOC1
Product: CCOC(C)OCCCCN1C(CO)=Cc2ccsc2S1(=O)=O
Reaction time: 0.25 h

Procedure:
To a solution of the product from Step B (1.01 g, 3.19 mmol) and p-toluenesulfonic acid (0.05 g) in anhydrous THF (30 mL) at 0° C. was added ethyl vinyl ether (0.5 mL, 5.23 mmol) and stirred for 15 min. To this solution was added via syringe DIBAL-H (1M solution in hexanes, 12 mmol); this mixture was stirred for 20 min at which point a solution of potassium sodium tartrate (8.0 g in 30 mL water) was added over 5 min. The resulting mixture was stirred overnight and extracted with ethyl acetate (2×50 mL). The combined extracts were dried (MgSO4) and evaporated to give an oil.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:19][CH:20]([CH2:23][CH3:24])[CH2:21][NH2:22]>>[CH3:6][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[CH:9][CH:8]=1)([CH3:1])[C:3]([NH:22][CH2:21][CH:20]([CH3:19])[CH2:23][CH3:24])=[O:5]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncnc2)cc1
Reactant: CCC(C)CN
Product: CCC(C)CNC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1
Yield: 58 %

Procedure:
Prepared in a similar manner to Example 20 from 2-methyl-2-(4-(pyrimidin-5-yl)phenyl)propanoic acid (example 25a) and 2-methylbutan-1-amine. Yield: 58%. 1H NMR (400 MHz, dMSO): δ 0.72-0.74 (d, 3H), 0.79-0.84 (m, 3H) 0.97-1.00 (m, 1H), 1.24-1.27 (m, 1H), 1.47 (m, 1H), 1.48 (s, 6H), 2.81-2.87 (m, 1H), 2.93-2.98 (m, 1H), 7.37-7.39 (t, 1H), 7.44-7.47 (d, 2H), 7.76-7.79 (d, 2H), 9.13 (s, 1H), 9.18 (s, 1H); MS+H (312.1).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[C:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37](O)=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:42]=[CH:41][C:24]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31](/[C:35](/[CH3:40])=[CH:36]/[C:37]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:38])=[CH:32][CH:33]=3)[CH:28]=[CH:27]2)=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
177 mg of compound 37 was obtained in a similar manner to those described in the Examples 1 and 2 using 513 mg of ethyl 4-(2-aminophenoxy)butyrate and 400 mg of 3-[1-(4-tert-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)([CH3:15])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].I[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=1[CH3:32].N1C=CC=CC=1C(O)=O>CS(C)=O.[Cl-].[Na+].O.[Cu]I>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=3[CH3:32])=[CH:20][CH:21]=2)([CH3:15])[CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCN1CCOC(C)(c2ccc(O)cc2)C1
Reactant: Cc1cccc(I)c1C
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(Oc2ccc(C3(C)CN(CCC(=O)OC(C)(C)C)CCO3)cc2)c1C
Temperature: 90 °C
Yield: 93.1 %

Procedure:
To a degassed solution of 3-[2-(4-hydroxy-phenyl)-2-methyl-morpholin-4-yl]-propionic acid tert-butyl ester (1.07 g; 3.33 mmol), and 3-iodo-o-xylene (0.97 g; 4.16 mmol) in DMSO (20 mL) was added picolinic acid (82 mg; 0.67 mmol), CuI (63.4 mg; 0.33 mmol) and powdered (1.41 g; 6.66 mmol). The resulting mixture was heated for 24 h, at 90° C. After cooling to room temperature, brine was added and the mixture extracted with CH2Cl2. The combined layers were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,3-dimethyl-phenoxy)-phenyl]-2-methyl-morpholin-4-yl}-propionic acid tert-butyl ester (1.32 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25](O)=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].Cl.[O:29]([NH2:31])[CH3:30]>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[C:21]([S:23][CH3:24])[N:20]=[C:19]([C:25]([NH:31][O:29][CH3:30])=[O:26])[CH:18]=3)[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CON
Reactant: CSc1nc(C(=O)O)cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)n1
Agent: Cl
Product: CONC(=O)c1cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)nc(SC)n1

Procedure:
Title compound was synthesized by an analogous method to Example 8 by coupling 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(methylthio)pyrimidine-4-carboxylic acid (Example 35) with methoxylamine hydrochloride (commercially available).