Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]#[N:11].BrBr.BrC1C=CN=C(OC)C=1C#N.[I:25]I>>[I:25][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[C:3]=1[C:10]#[N:11]
Reactant: COc1nccc(Cl)c1C#N
Reactant: II
Agent: BrBr
Agent: COc1nccc(Br)c1C#N
Product: COc1nccc(I)c1C#N

Procedure:
Thus, 2-chloro-3-cyanopyridine (A18) provided 2-methoxy-3-cyanopyridine (A19) upon treatment with sodium methoxide in methanol. Lithiation of the 2-methoxy-3-cyanopyridine (A19) with LDA gave the intermediate carbanion derivative 4-lithio-2-methoxy-3-cyanopyridine (A21), which upon treatment with hexachloroethane provided the 4-chloro-2-methoxy-3-cyanopyridine (A20). Analogously, reaction with bromine provides the 4-bromo-2-methoxy-3-cyanopyridine (A22) and reaction with iodine provides the 4-iodo-2-methoxy-3-cyanopyridine (A23). All 4-halo-2-methoxy-3-cyanopyridines are highly valuable intermediates, especially for the synthesis of kinase inhibitors. Reduction of the 4-halo-2-methoxy-3-cyanopyridines, for example with DIBAL (diisobutylaluminum hydride) in solvents such as toluene, dichloromethane, or tetrahydrofuran at temperatures ranging from −80° C. to about 80° C., preferably at 20° C. provides after standard workup the 4-halo-2-methoxypyridine-3-carboxaldehydes. The 4-halo-2-methoxypyridine-3-carboxaldehydes are highly valuable synthetic intermediates. 4-chloro-2-methoxy-3-pyridinecarboxaldehyde (A9) was prepared in this manner.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[N:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: COc1ccc(CC2c3cc(Oc4nccc(C(F)(F)F)n4)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 2-chloro-4-trifluoromethyl-pyrimidine
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][C:14]1[O:18][N:17]=[C:16]([C:19](O)=[O:20])[CH:15]=1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:19]([C:16]3[CH:15]=[C:14]([CH3:13])[O:18][N:17]=3)=[O:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: Cc1cc(C(=O)O)no1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 5-methylisoxazole-3-carboxylic acid (221 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH2Cl2 (10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred at room temperature overnight and additional BOP-Cl (81 mg, 0.87 mmol) and 5-methylisoxazole-3-carboxylic acid (110 mg, 0.87 mmol) were added. The mixture was stirred for an additional 48 hours at room temperature. Next, 2M LiOH (3 mL) was added to the mixture and stirred for 1 hour. The organic solvent was removed in vacuo, and water:CH2Cl2 (11 mL; 10:1) were added to the aqueous residue. The solid formed was filtered, washed with additional water and dried to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide (210 mg, 71% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.12 (s, 1H), 10.22 (s, 1H), 8.33 9d, 1H), 7.58 (s, 1H), 2.45 (s, 3H); LCMS (APCI+) m/z 338.9, 340.9 (M+H)+, Retention time=3.16 minutes (Method 2).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([CH:19]=[C:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:27]=1.C(N(CC)CC)C>CS(C)=O.O>[CH3:1][C:2]1[CH:18]=[C:17]([CH:16]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:14])([F:15])[F:13])=[CH:8][N:7]=2)[CH:3]=1)[CH:19]=[C:20]1[CH2:25][CH2:24][N:23]([C:33]([NH:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:34])[CH2:22][CH2:21]1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: Cc1cc(C=C2CCNCC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C=C2CCN(C(=O)Nc3cccnc3)CC2)cc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.6 %

Procedure:
To a solution of 2-(3-methyl-5-(piperidin-4-ylidenemethyl)phenoxy)-5-(trifluoromethyl)pyridine (445 mg, 1.276 mmol) in DMSO (3 mL) was added phenyl pyridin-3-ylcarbamate (273 mg, 1.276 mmol) followed by triethylamine (0.53 mL, 3.83 mmol). The resulting mixture was stirred at RT for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (30% acetone-70% hexane) to give the pure title compound (0.350 g, 58% yield). 1H NMR (500 MHz, CDCl3): δ 8.45 (m, 2H), 8.27 (s, 1H), 8.01 (m, 1H), 7.90 (m, 1H), 7.02 (m, 1H), 6.92 (s, 1H), 6.84 (d, J=20 Hz, 2H), 6.47 (s, 1H), 6.38 (s, 1H), 3.16 (s, 2H), 3.52 (s, 2H), 2.61 (s, 2H), 2.47 (s, 2H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 165.87, 154.81, 153.01, 145.50, 143.77, 141.29, 139.84, 138.79, 137.99, 136.71, 127.58, 126.93, 124.77, 123.58, 122.62, 121.62, 120.13, 118.82, 111.38, 45.72, 44.70, 35.78, 29.20, 21.45; m/z (469.5, M+H+); HPLC: 98.5%.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8]C.[CH:23]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(C)=CN=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH:21]2[CH2:22][CH2:23]2)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: Cc1cnc(C2CC2)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3-cyclopropyl-6-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.95–1.08, 1.69–1.78, 2.49, 3.04, 3.24, 4.78, 5.39, 5.58, 7.24–7.33; MS (ESI+) for C17H18BrN3O m/z 360 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].Cl.[CH3:30][NH:31][CH3:32]>CC(C)=O.C1(C)C=CC=CC=1>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]([O:12][CH:13]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][C:17]([C:18]([N:31]([CH3:32])[CH3:30])=[O:19])=[CH:21][CH:22]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2]
Reactant: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)O)cc1)C(=O)NCC#N
Reactant: CNC
Agent: Cl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](OC(c1ccccc1)c1ccc(C(=O)N(C)C)cc1)C(=O)NCC#N

Procedure:
Using the same coupling procedure as described for example 47, 4-[[((1S)-1-{[(cyanomethyl)amino]carbonyl}-3-methylbutyl)oxy](phenyl)methyl]benzoic acid (51 mg, 0.134 mmol) was reacted with dimethylamine hydrochloride (11 mg, 0.134 mmol, 1 eg) to give the title compound as an oil after chromatography with 25% acetone/toluene.
Reaction SMILES: [C:1]1([C@H:7]2[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH:20]([CH2:23]S(OC)(=O)=O)[CH2:19][CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-:29].[Na+].O.C(OCC)(=O)C>CC(C)=O>[I:29][CH2:23][CH:20]1[CH2:21][CH2:22][C:9]2([O:8][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10]2)[CH2:18][CH2:19]1
Reactant: COS(=O)(=O)CC1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: ICC1CCC2(CC1)O[C@@H](c1ccccc1)[C@H](c1ccccc1)O2
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a solution of methyl [(2S,3S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-8-yl]methanesulfonate (58.6 g) in acetone (800 mL) was added sodium iodide (52.3 g) at room temperature. The mixture was heated under reflux overnight and again cooled to room temperature. To the reaction mixture were added water and ethyl acetate. The organic layer was separated, sequentially washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:0-50:1-30:1-10:1) to obtain (2S,3S)-8-(iodomethyl)-2,3-diphenyl-1,4-dioxaspiro[4.5]decane (40.6 g) as a pale yellow oily substance.
Reaction SMILES: CON(C)[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5].[Li][CH3:25].[Li+].[Br-]>C1COCC1>[C:11]1([C:9]2[S:10][C:6]([C:4](=[O:5])[CH3:25])=[C:7]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [Li]C
Reactant: CON(C)C(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)c1sc(-c2ccccc2)nc1N1CCCCC1
Yield: 72 %

Procedure:
To a solution of the above-prepared 2-phenyl-4-piperidin-1-yl-thiazole-5-carboxylic acid methoxy-methyl-amide (0.754 mmol) in THF (5 mL) was added at 0° C. MeLi.LiBr (0.83 mmol). The reaction mixture was stirred until the reaction was complete, then quenched by the addition of saturated ammonium chloride and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give a brown oil. Silica gel chromatography provided the title compound (72%) as a yellowish oil. 1H NMR (CDCl3): δ 1.6-1.8 (m, 6H), 2.45 (s, 3H), 3.5 (m, 4H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH:13]2[CH2:15][CH2:14]2)[OH:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Br[Mg]C1CC1
Product: COC(=O)c1ccc(C(O)C2CC2)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and Cyclopropyl magnesium bromide following the general method exemplified in Preparation 1.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:31])[CH2:16][P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CI.[C:34](=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:31])[CH2:16][P:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18])[CH2:10][C:11]([O:13][CH3:34])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CC(=O)O)CC(=O)CP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(c1ccccc1)c1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To 0.92 g (2 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoic acid prepared above, 0.28 g of methyl iodide, 0.28 g of potassium carbonate and 10 ml of acetone were added, and then the mixture was stirred for 8 hours at room temperature. After 16 ml of water was added to the solution, the solution was extracted with two portions of 20 ml of ethyl acetate. The ethyl acetate portions were combined and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation in vacuo to give 0.81 g of methyl (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoate as a colorless oil (optical purity: 98% ee; yield: 85% based on the amount of (R)-3-t-butyldimethylsilyloxy-6-diphenylphosphinoyl-5-oxohexanoic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.48 g, 1.66 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.83 g, 1.66 mmol), and N,N-diisopropylethylamine (0.32 g, 2.49 mmol) in acetonitrile (10 mL). Heat to reflux. After 48 hours, cool and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.36 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][NH:14]2)=[CH:10][CH:9]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20].[CH3:35]C1C=CC(OC2C=C3C(=CC=2)NC=C3)=CC=1.BrC1C=C2C(=CC=1)NC=C2.C1C(O)=CC=C(C)C=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:35][N:31]3[CH2:32][CH2:33][CH:28]([C:24]4[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:34])[CH3:17])[CH:27]=[CH:26][CH:25]=4)[CH2:29][CH2:30]3)=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(Oc2ccc3[nH]ccc3c2)cc1
Reactant: Fc1ccccc1-c1ccc2cc[nH]c2c1
Agent: Brc1ccc2[nH]ccc2c1
Agent: Cc1ccc(O)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3c[nH]c4cc(-c5ccccc5F)ccc34)CC2)c1

Procedure:
Prepared by Procedure D and Scheme N using 6-(2-fluorophenyl)-1H-indole and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 470.2 (M+H)+. 5-(4-METHYLPHENOXY)-1H-INDOLE: Prepared by Procedure J and Scheme U using 5-bromo-1H-indole and p-cresol: ESMS m/e: 224.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13])[C:16]([O:15][CH3:14])=[O:23]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1c(C(=O)O)oc2ccccc12
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1oc2ccccc2c1C

Procedure:
Prepared in a similar manner to example 4 using 3-methylbenzofuran-2-carboxylic acid and D-leucine methyl ester. MS (M+H, 304).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][CH:14]([OH:16])[CH3:15].[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24](F)[CH:25]=1)[C:21]#[N:22].O>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:16][CH:14]([CH3:15])[CH2:13][O:12][CH3:11])[CH:25]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: COCC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)Oc1cc(Br)cc(C#N)c1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
NaHMDS (148 mmol; 27.2 g) was charged to a 1000 ml round-bottomed flask (4 necks, thermometer, pressure-equalising dropping funnel, stopper, nitrogen inlet, magnetically stirred, oven dried, nitrogen purged), followed by DMF (300 ml). The mixture was stirred for 5 minutes then 1-methoxy-2-propanol (1.50 equiv; 148 mmol; 14.3 ml; 13.4 g) was added dropwise over a 10-minute period. The reaction temperature increased to 25° C. The mixture was cooled using a cold-water bath to 23° C., then 3-bromo-5-fluorobenzonitrile (1.00 equiv; 99.0 mmol; 20.0 g) in DMF (90 ml) was added over a 5 minutes period (cold water bath still present). The mixture warmed to 27° C. during addition, turning from yellow to brown. A line wash of DMF (10 ml) was added. The mixture was stirred at ambient temperature for 30 minutes, then quenched by addition of HCl solution (2M, aqueous, 200 ml), the dark brown reaction mixture turning pale yellow. The mixture was poured into water (400 ml) and extracted with EtOAc (3×400 ml). The combined organic extracts were washed with water (3×400 ml) and dried over MgSO4, filtered and the solvent removed in vacuo affording 3-bromo-5-(2-methoxy-1-methylethoxy)benzonitrile as an orange oil (25.38 g, 95%). 1H NMR (400 MHz, CDCl3) δ: 7.32 (s, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 4.58-4.55 (m, 1H), 3.59-3.48 (m, 2H), 3.41 (s, 3H), 1.33-1.31 (d, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])#[N:33]>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([C:32]#[N:33])[CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2cccc(-c3cccc4c3/C(=C/c3ccc[nH]3)C(=O)N4)c2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.7 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (40 mg, 0.118 mmol) (from Example 5 supra) and Et3N (33 μL , 0.237 mmol) in 3 mL of chloroform was treated with 3-cyanobenzoyl chloride (22 mg, 0.130 mmol) (Aldrich), and the resulting reaction mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo to remove chloroform. The yellow residue was suspended in distilled water, and the resulting solid was collected by suction filtration to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-3-cyanobenzamide (yield: 41 mg, 81%) as a yellow solid (mp 250-251° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:5][C@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[N:8]=1)[CH3:2].[NH2:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:21]([C:20]1[CH:19]=[CH:18][C:17]([NH:16][C@@H:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C@H:7]2[NH:8][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:30][CH:29]=1)(=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: CCOC1=N[C@@H]2Cc3ccccc3[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1ccc(C(=O)c2ccccc2)cc1
Temperature: 80 °C
Yield: 76 %

Procedure:
A solution of (±) cis-2-ethoxy-3a,8b-dihydro-4H-indeno[2,1-d]oxazole (2.50 g, 0.012 mol) in dry toluene (40 ml) was treated with 4-aminobenzophenone (2.43 g, 0.012 mol) and a catalytic amount of p-toluenesulfonic acid (0.25 ml of an anhydrous 0.1M solution of p-toluenesulfonic acid in benzene). The mixture was heated under nitrogen at 80° C. overnight. The reaction was worked up as described in Preparation 5. Purification on a silica gel column using a graded eluant of 5-40% ethyl acetate in petroleum ether 40/60 afforded the title compound as a yellow foam (3.65 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C:10](CO)([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH:12]2[C:10]([S:24]([CH3:23])(=[O:26])=[O:25])([CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC12CC1CN(Cc1ccccc1)C2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)C12CC1CN(Cc1ccccc1)C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyl-1-hydroxymethyl-3-azabicyclo[3.1.0]hexane in ethyl acetate were added triethylamine (2.15 gm, 0.02125 mole) and methane sulphonylchloride (1.947 gm, 0.017 mole). The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by the addition of saturated NaHCO3. The separated organic layer was washed with water, brine, dried and evaporated to give the crude product, which was used as such for further reaction.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:40][CH3:41])=[C:11](\[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17](C1CCCCO1)[N:16]=[CH:15]2>C(O)C.C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1/[C:10](/[CH2:40][CH3:41])=[C:11](\[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1)/[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Cl)cc2Cl)c2ccc3[nH]ncc3c2)cc1
Temperature: 70 °C
Yield: 92.7 %

Procedure:
A solution of HCl (5.0 mL, 2.0 M in diethyl ether) was added to a solution of (E)-ethyl 3-(4-((E)-2-(2,4-dichlorophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (3.0 g, 5.2 mmol) in ethyl alcohol (25 mL) at room temperature. The resulting mixture was heated at 70° C. for 2 h. Upon completion, the mixture was cooled down to room temperature and concentrated to give a pale yellow solid. This crude material was dissolved in DCM and washed with water (50 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to give the title compound (2.37 g) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 8.11 (s, 1H), 7.69 (s, 1H), 7.58-7.52 (m, 2H), 7.48 (d, 1H), 7.43 (d, 2H), 7.36-7.32 (m, 2H), 7.19 (dd, 1H), 6.97 (d, 2H), 6.49 (d, 1H), 4.15 (q, 2H), 2.39 (q, 2H), 1.22 (t, 3H), 0.90 (t, 3H); LCMS: 491 (M+H)+.