Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.N1C2C(=CC=CC=2)CCC1.N1C2C(=CC=CC=2)C(CC(N)=O)=C1.COC(=O)C=O>>[C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Agent: COC(=O)C=O
Agent: NC(=O)Cc1c[nH]c2ccccc12
Agent: c1ccc2c(c1)CCCN2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12

Procedure:
Preferred embodiments of the invention include mixtures of compounds of formulas IVa and IVb, including racemic mixtures. In another preferred embodiment, the compounds of formula IVa and IVb are the separate enantiomers of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. In this embodiment the preparation of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione is prepared as a mixture beginning with the starting materials 1,2,3,4-tetrahydroquinoline and indole-3-acetamide. The 1,2,3,4-tetrahydroquinoline is converted into 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester as described in Example 1, steps 1-5. The 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester is reacted with indole-3-acetamide as described in Example 1, step 6, to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrole-2,5-dione. The mixture of (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione is then prepared by catalytic hydrogenation as described in Example 2 using Procedure B.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([Cl:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Clc1cccc(Br)c1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromochlorobenzene (1.76 mL, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 2.06 g (91%) of the product 4-(3-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[N:3]=1.[H][H]>[Ni].CO>[NH2:8][C:7]1[C:6]([Cl:11])=[N:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[Cl:1]
Reactant: CC(=O)Nc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(=O)Nc1nc(Cl)c(N)c(Cl)n1
Yield: 50.4 %

Procedure:
N1-(4,6-Dichloro-5-nitro-2-pyrimidinyl)acetamide (100 g, 0.40 mol) and Raney nickel (100 g, wet) were suspended in methanol (1.5 L) and stirred vigorously for 5 hours in a hydrogen atmosphere, at ordinary temperature and at normal pressure. After the nickel was filtered off, the filtrate was concentrated. The residue was crystallized from methanol/ethyl acetate, and the crystals were collected by filtration and washed with ethyl acetate, to give the title compound (44.6 g, 51%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[C:13]([N+:25]([O-])=O)[CH:12]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH4+].[Cl-]>[Fe]>[NH2:25][C:13]1[CH:12]=[C:11]([O:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])[CH:16]=[CH:15][C:14]=1[S:17][C:18]1[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=1
Reactant: CC(Oc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(Oc1ccc(Sc2ccc(O)cc2)c(N)c1)c1cccc(Br)c1
Yield: 70.9 %

Procedure:
The product from Example 228c (5.4 g, 12.2 mmol) was reacted with Fe and NH4Cl as described in Example 10E to give the title compound (3.6 g, 76%).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][C:10](I)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C-:14]#[N:15].[Li+].O1CCOCCOCCOCC1>C1C=CC=CC=1.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>[Cl:1][C:2]1[N:12]=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5]
Reactant: [C-]#N
Reactant: CN(C)C(=O)c1cc(I)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCO1
Agent: [Li+]
Solvent: c1ccccc1
Product: CN(C)C(=O)c1cc(C#N)cnc1Cl
Temperature: 40 °C
Yield: 54.4 %

Procedure:
A mixture of 2-chloro-5-iodo-N,N-dimethylnicotinamide (1.54 g, 5 mmol), prepared as in Example 14, and lithium cyanide (0.5M in DMF, 20 mL, 10 mmol) was distilled at reduced pressure. The residue was suspended in 1,4,7,10-tetraoxacyclo-dodecane (0.2 mL, 1.25 mmol) in 50 mL of benzene and the mixture was distilled under nitrogen until a forefraction of approximately 5 mL had collected. The suspension was allowed to cool and then tetrakis(triphenylphosphine)palladium(0) (2.44 g, 2.1 mmol) was added. The mixture was stirred at 40° C. under nitrogen for 1 week, allowed to cool to room temperature and partitioned between aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with diethyl ether and the extract was washed with brine, dried (Na2 SO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (5:1) to give 2-chloro-5-cyano-N,N-dimethylnicotinamide (0.57 g, 2.72 mmol), m.p. 148°-153° C.
Reaction SMILES: Cl[C:2]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[O:3].[CH3:11][N:12]([C:21]([S:23][CH3:24])=[NH:22])[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>ClCCl>[CH3:11][N:12]([C:21](=[N:22][C:2](=[O:3])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[S:23][CH3:24])[N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CSC(=N)N(C)N=Cc1ccccc1
Reactant: COC(=O)CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCC(=O)N=C(SC)N(C)N=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 920.2 %

Procedure:
Methyl 4-(chloroformyl)butyrate (31.2 g) was added dropwise during 1 h at 20° to a stirred solution of methyl 1-methyl-2-(phenylmethylene)hydrazine carboximidothioate (3.60 g) and triethylamine (20.0 g) in dichloromethane (100 ml). The pale yellow suspension was stirred at 20° C. for 16 h. A further portion of methyl 4-(chloroformyl)butyrate (6.2 g) and triethylamine (4.0 g) was added and stirring continued for a further 1 h. Water (100 ml) was added, the organic layer separated and washed successively with saturated aqueous sodium bicarbonate and water, dried, and evaporated to give a brown solid (53.6 g). This solid was recrystallised from ether to give the title compound (30.9 g) as a pale yellow solid m.p. 69°-70°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([C:39](Cl)=[O:40])=[N:34]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:39]([C:35]2[CH:36]=[C:37]([CH3:38])[N:33]([CH3:32])[N:34]=2)=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: Cc1cc(C(=O)Cl)nn1C
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Product: COc1cc2c(Oc3ccc(NC(=O)c4cc(C)n(C)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q5 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. MS (ES) C29H32FN5O5 requires: 549. Found: 550 (M+H)+.
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:25])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=O)=[C:9](Cl)[N:8]=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:27][NH:28][NH2:29]>N1C=CC=CC=1>[N:1]1([C:5]2[N:6]=[CH:7][N:8]=[C:9]3[N:28]([CH3:27])[N:29]=[C:11]([C:13]4[CH:14]=[N:15][N:16]([CH3:25])[C:17]=4[C:18]4[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=4)[C:10]=23)[CH2:4][CH2:3][CH2:2]1
Reactant: CNN
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CCC3)cnn2C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(-c3nn(C)c4ncnc(N5CCC5)c34)cnn2C)cc1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(azetidin-1-yl)-6-chloropyrimidin-5-yl][1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C6) (from Step 6, ≦0.576 mmol) in pyridine (5.0 mL) was added methylhydrazine (0.302 mL, 5.74 mmol), and the reaction was stirred at 85° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified via silica gel chromatography (Gradient: 0 to 30% methanol in dichloromethane) to provide the title product as a colorless oil. Yield: 200 mg, 0.556 mmol, 97% over two steps. LCMS m/z 360.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.21-2.30 (m, 2H), 2.34 (br s, 3H), 3.75-4.04 (br m, 4H), 3.91 (s, 3H), 3.99 (s, 3H), 7.20 (br AB quartet, JAB=8.1 Hz, ΔνAB=33 Hz, 4H), 7.67 (s, 1H), 8.32 (s, 1H).
Reaction SMILES: [CH3:1][P:2](Cl)([CH3:4])=[O:3].[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][P:2]([CH3:4])(=[O:3])[O:13][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OCc1ccccc1
Reactant: CP(C)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CP(C)(=O)OCc1ccccc1

Procedure:
To a cooled (0°) solution of dimethylphosphinyl chloride (3.4 g., 0.03 moles) in dichloromethane (50 ml.) is added dropwise (over a period of 20 minutes), with stirring, a solution of benzyl alcohol (3.2 g., 0.03 moles) and triethylamine (3.4 g., 0.03 moles) in dichloromethane (30 ml.). After stirring at 0° for one hour, and at ambient temperature overnight, the mixture is filtered and the filtrate is concentrated in vacuo. The residue (5 g., 90%) becomes semi-solid at room temperature. It is recrystallized from pentane (450 ml.) with a recovery of dimethylphosphinic acid, phenylmethyl ester, yield 3.6 g. (65%) m.p. 41°-45°. A second recrystallization of 0.5 g. from pentane (75 ml.) gives a recovery of 0.26 g. of product, m.p. 46°-47°.
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])C.[F:42][C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:36]([CH2:35][CH2:34][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][C:43]([F:42])=[CH:44][CH:45]=3)[CH:25]=[C:26]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:41])=[O:3])([OH:38])=[O:37]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(C(=O)N(C)C)c2)c1CCC(=O)OCC
Product: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 41 %

Procedure:
The title compound was prepared according to the general procedure described in Steps 3 and 4 of Method F starting from 4-[3-[6-(3-bromo-5-dimethylcarbamoyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester and 4-fluorophenylboronic acid. LC/MS indicated a purity of 100% as measured by UV 214 nM. Yield: 41% (after two steps)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:38]([O:40][C:41]([CH3:43])=[CH2:42])=[O:39]>N1C=CC=CC=1>[CH2:26]([O:25][C:24]1[CH:23]=[CH:22][N:21]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[C:20](=[O:35])[C:19]=1[C:17]([NH:16][C:12]1[C:11]([F:36])=[CH:10][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:38](=[O:39])[O:40][C:41]([CH3:43])=[CH2:42])[CH:7]=2)=[C:14]([F:15])[CH:13]=1)=[O:18])[CH3:27]
Reactant: C=C(C)OC(=O)Cl
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(N)c2)cc1F
Solvent: c1ccncc1
Product: C=C(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OCC)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
N-(4-((2-Aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.12 g, 0.24 mmol) was dissolved in pyridine (2 mL), treated with isopropenyl chloroformate (0.030 mL, 0.27 mmol), and stirred at RT overnight. The solution was concentrated to obtain crude prop-1-en-2-yl (4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)pyridin-2-yl)carbamate which was used for the next reaction (assuming 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].B.[Na].C(O)(=O)C>O1CCCC1.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH2:7][OH:8]
Reactant: Cc1ccc(Br)cc1C=O
Agent: B
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(Br)cc1CO
Temperature: 17.5 °C
Reaction time: 4 h
Yield: 103.2 %

Procedure:
161.2 g (810 mmol) of 5-bromo-2-methylbenzaldehyde was dissolved in 1.5 L of tetrahydrofuran and 150 ml of water, and to the resulted solution was dropped, at 15 to 20° C., a solution prepared by dissolving 10.0 g (264 mmol) of sodium boron hydride in 100 ml of a 0.1 wt % sodium hydroxide aqueous solution. After completion of dropping, the mixture was stirred at 15 to 20° C. for 4 hours. To the reaction solution was dropped 12.0 g of glacial acetic acid at 20° C. or lower, then, this was poured into ice water. The reaction solution was extracted with t-butyl methyl ether, the organic layer was washed with water, further washed twice with a saturated sodium bicarbonate solution, then, washed with saturated saline, and dried over anhydrous magnesium sulfate, then, concentrated to obtain 168 g of 5-bromo-2-methylbenzyl alcohol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.CC(C)([O-])C.[Na+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1.[CH3:72][O:73][C:74]1[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[CH:79][C:75]=1[CH2:76][NH:77][CH3:78]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:72][O:73][C:74]1[CH:82]=[C:81]([O:83][CH3:84])[CH:80]=[CH:79][C:75]=1[CH2:76][N:77]([CH3:78])[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Reactant: CNCc1ccc(OC)cc1OC
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(CN(C)c2ccc(S(=O)(=O)Nc3nccs3)c(F)c2)c(OC)c1
Temperature: 100 °C

Procedure:
Into a vial was added the [B] 4-bromo-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (170 mg, 0.00050 mol), sodium tert-butoxide (117 mg, 0.00121 mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (18 mg, 0.000030 mol), Tris(dibenzylideneacetone)dipalladium(0) (9.3 mg, 0.000010 mol) and 1,4-dioxane (1.58 mL, 0.0202 mol). Argon was bubbled for 15 minutes. Into the reaction was added the [2,4-dimethoxy-benzyl)-methyl-amine (110 mg, 0.00061 mol) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature then filtered over Celite. The filtrate was concentrated to give the crude compound as a yellow solid that was used in the next step without purification.
Reaction SMILES: [NH2:1][CH:2]([C:11]([OH:13])=[O:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[ClH:14].[CH2:15](O)[CH3:16]>>[ClH:14].[NH2:1][CH:2]([CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:11]([O:13][CH2:15][CH3:16])=[O:12]
Reactant: NC(CCc1ccccc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(N)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of d,l-homophenylalanine (5 g., 27.9 mmole) in absolute ethanol (60 ml.) was cooled to 0° (ice bath) and saturated with hydrochloric acid gas. The mixture was allowed to warm to room temperature and stirred overnight. A stream of nitrogen was then passed through the solution to remove the bulk of the hydrochloric acid and the mixture was evaporated to dryness. The solid residue was triturated with ether, filtered and dried to give (±)-α-aminobenzenebutanoic acid, ethyl ester, monohydrochloride as a fluffy white solid; m.p. 129°-130°. Rf (acetic acid/methanol/dichloromethane; 1:1:8)=0.63.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:45])([F:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([C:34]([F:33])([F:44])[F:45])=[CH:36][CH:37]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(C(=O)c3ccc(C(F)(F)F)cc3)C2)c1
Yield: 87 %

Procedure:
To a solution of compound 33b, 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester) (51 mg, 0.11 mmol) in CH3CN (5 ml) was added 4-(Trifluoromethyl)benzoyl chloride (35.6 mg, 0.17 mmol) and diisopropylethylamine (40 μl, 0.23 mmol). The reaction was microwaved at 130° C. for 10 minutes, was diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product, (62 mg, 87%). Calcd for C34H35F6NO3 (M+H) 619.64, Found 620.4.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.Cl.[CH3:23][O:24][NH2:25].C(OCC)(=O)C>O.O1CCCC1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:25][O:24][CH3:23])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CON
Reactant: CCCCCCCCOc1ccc(C(=O)C(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=NOC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A solution of 4-octyloxyphenylglyoxylic acid (0.935 g) in a mixture of water (9 ml) and tetrahydrofuran (18 ml) was adjusted to pH 3.5-4 with 1N hydrochloric acid, and methoxyamine hydrochloride (0.337 g) was added thereto at room temperature. The mixture was stirred for 2 hours at room temperature maintaining pH 3.5-4 with 1N hydrochloric acid. The reaction mixture was added to ethyl acetate. The organic layer was separated and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 2-(4-octyloxyphenyl)-2-methoxyiminoacetic acid (0.57 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[CH3:9][C:10]([C:20]1[CH:25]=[CH:24][N:23]2[C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:27][N:28]=[C:22]2[N:21]=1)([O:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:11]>>[Br:8][C:4]1[N:3]=[C:2]([C:26]2[N:23]3[CH:24]=[CH:25][C:20]([C:10]([CH3:9])([O:12][Si:13]([CH2:14][CH3:15])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:11])=[N:21][C:22]3=[N:28][CH:27]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)O[Si](CC)(CC)CC)ccn12
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3cccc(Br)n3)cnc2n1

Procedure:
2,6-Dibromopyridine was coupled with 7-(1-methyl-1-triethylsilanyloxyethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine by the method of Example 1 to afford 3-(6-bromopyridin-2-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine as an orange oil: δH (360 MHz, CDCl3) 0.69 (6H, q, J 8), 0.99 (9H, q, J 8), 1.69 (6H, s), 7.34 (1H, d, J 7), 7.54-7.62 (2H, m), 7.69 (1H, d, J 8), 8.29 (1H, s), 10.00 (1H, d, J 7).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:21])[C@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:28])(=O)=O.O>ClCCl>[NH2:13][C@H:10]([CH2:11][O:12][CH3:28])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC[C@@H](N)C(=O)NCc1ccccc1
Temperature: -10 °C
Reaction time: 4 h

Procedure:
Accordingly to a solution of the compound tert-butyl [(R)-2-(benzylamino)-1-(hydroxymethyl)-2-oxoethyl]carbamate of Formula-XXI in dichloromethane, charged the phase transfer catalyst and cooled the reaction mass to −10° C. and charged dilute solution of sodium hydroxide. Maintaining the temperature at −10° C.-0° C. charged dimethyl sulfate and maintained the reaction under stirring for 3-5 hours. Charged water at the end of the reaction, stirred, separated the organic layer and extracted the aqueous layer with the dichloromethane. Combined the organic layer and acidified with concentrated hydrochloric acid. Charged water to the clear solution and stirred. Separated the aqueous layer and extracted the organic layer further with water. Combined the entire aqueous layer and adjusted the pH to 12 with aqueous sodium hydroxide solution. Extracted the aqueous layer with dichloromethane and separated the organic layer. Extracted the aqueous layer further with dichloromethane to ensure the complete extraction of the desired product. The organic layer is washed and concentrated to isolate the compound (2R)-2-amino-N-benzyl-3-methoxypropanamide of Formula-VIII.