Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH:21]=[CH:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][N:24]=1)[C:15]([OH:17])=[O:16].C(N(CC)CC)C.[N+:39](C1C=CC=C2C(OC(=O)C=12)=O)([O-:41])=[O:40]>C1(C)C(C)=CC=CC=1>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](/[CH:22]=[CH:21]/[C:20]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[N+:39]([O-:41])=[O:40])[C:4]2=[O:11])=[N:24]1
Reactant: O=C(O)c1ccc(C=Cc2n[nH]c3ccccc23)c(N2C(=O)c3ccccc3C2=O)c1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)c(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)c1
Temperature: 140 °C

Procedure:
To 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (1.7 g, 6.2 mmol) obtained in Step 2 of Example 276, xylene (55 mL), triethylamine (0.45 mL, 3.1 mmol), 3-nitrophthalic anhydride (1.4 g, 7.4 mmol), molecular sieves 3A (2.0 g) were added, followed by heating at 140° C. for 4 hours. Molecular sieves 3A was filtered off and the reaction mixture was acidified by hydrochloric acid (2 mol/L). The precipitated crystal was collected by filtration to obtain (E)-4-[2-(1H-indazol-3-yl)vinyl]-3-(4-nitro-1,3-dioxo-1,3-dihydroisoindol-2-yl)benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36](F)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]>C(#N)C>[C:17]([C:19]1([NH:22][C:23]([C@@H:25]2[CH2:29][C@@H:28]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:35][C:34]=3[C:40]([F:43])([F:42])[F:41])(=[O:32])=[O:31])[CH2:27][N:26]2[C:44]2[N:45]([CH:50]3[CH2:53][CH2:52][CH2:51]3)[N:46]=[C:47]([CH3:49])[CH:48]=2)=[O:24])[CH2:21][CH2:20]1)#[N:18]
Reactant: CN1CCNCC1
Reactant: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(F)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccc(N4CCN(C)CC4)cc3C(F)(F)F)C[C@H]2C(=O)NC2(C#N)CC2)n(C2CCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49 %

Procedure:
Methylpiperazine (10 ul, 116 umol; CAS Reg. No. 109-01-3) and DIEA (20 ul, 93 umol) were added to a solution of (2S,4R)-1-(2-cyclobutyl-5-methyl-2H-pyrazol-3-yl)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 46 umol; example 388 g) in acetonitrile (400 ul) under an argon atmosphere. The reaction mixture was stirred at ambient temperature for 72 h, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (14 mg, 23 umol; 49%) as colorless oil. MS (ESI): m/z=618.2 [M−H]−.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([OH:24])=O)=[CH:13][CH:12]=1.[CH3:25][CH:26]1[NH:30][CH2:29][C:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([OH:31])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[O:21][N:20]=[CH:19][C:18]=2[C:22]([N:30]2[CH:26]([CH3:25])[CH2:27][C:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([OH:31])[CH2:29]2)=[O:24])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cnoc1-c1ccc(F)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.04 mmol) was added to a solution of 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (8 mg, 0.04 mmol), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was left at rt for 2 h. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z: calcd for C21H19FN2O3: 366.1380, found 366.1391.
Reaction SMILES: Cl.[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:15]#[N:16])(=[O:4])[CH3:3].[CH2:17]([OH:19])[CH3:18]>C(OCC)C>[ClH:14].[C:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[CH2:7][CH:6]1[C:15](=[NH:16])[O:19][CH2:17][CH3:18])(=[O:4])[CH3:3]
Reactant: CCO
Reactant: CC(=O)N1c2ccc(Cl)cc2CC1C#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)C1Cc2cc(Cl)ccc2N1C(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
HCl (as a 2 M solution) was added slowly to intermediate (9) until gas evolution was noted. Then stopped adding the prepared HCl (2N in diethylether), and suspended HCl in diethylether (150 ml) and then ethanol (0.042 mole) was added. The mixture was cooled to 0° C. and HCl (gas) was added over an hour, with an oil precipitating out. The reaction was diluted to 1 l with diethylether. More oil precipitates, and no solid formed after sitting for 1 hour. The diethylether was decanted off. The residue was diluted (diethylether, 500 ml). The solid begins to form, and the mixture was stirred for 2 hours. The sample was filtered, rinsing with diethylether. The sample was placed under vacuum, yielding 6.41 g of ethyl 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carboximidate monohydrochloride (intermediate 10).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH3:22][S:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:28]([C:27]3[CH:30]=[CH:31][C:24]([S:23][CH3:22])=[CH:25][CH:26]=3)[OH:29])=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (2.74 g) in THF (40 mL) at −78° C. was added n-butyllithium (5.15 mL of a 2.5 M solution in hexanes) and the reaction stirred at −78° C. for 1 h. 4-Methylmercaptobenzaldehyde (1.43 mL) was then added and the reaction mixture was lowly warmed to room temperature. Water was added and the resulting precipitate was collected by filtration. Recyrstallisation from EtOAc/hexane yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol (2.53 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[CH2:5])C.[Br:25]NC(=O)CCC(N)=O>O1CCCC1.O>[Br:25][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:14][CH2:15][OH:16])=[CH:8][CH:7]=1)=[O:5]
Reactant: NC(=O)CCC(=O)NBr
Reactant: C=C(OCC)c1ccc(C[C@@H](CCO)NC(=O)OC(C)(C)C)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a cooled (0° C.) solution of 1,1-dimethylethyl [(1S)-1-({4-[1-(ethyloxy)ethenyl]phenyl}methyl)-3-hydroxypropyl]carbamate (15 g, 44 mmol) in tetrahydrofuran (450 mL) and water (150 mL) was added N-bromosuccinamide. The resulting solution was allowed to warm to room temperature and maintained for 90 minutes. The reaction was then concentrated and diluted with ethyl acetate (1 L). The resulting solution was washed with water (1 L) and brine (500 mL), dried (MgSO4) and concentrated to give 19.5 g (˜100%) of 1,1-dimethylethyl ((1S)-1-{[4-(bromoacetyl)phenyl]methyl}-3-hydroxypropyl)carbamate as a slightly yellow solid. ESMS [M+H]+: 386.2.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1>ClCCl>[Cl:3][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccnc2ccccc12
Solvent: ClCCl
Product: ClCc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 116.7 %

Procedure:
Thionyl chloride (12 mL, 170 mmol) was added dropwise for 15 minutes to a solution of 4-(hydroxymethyl)quinoline (Reference Compound No. 3-1, 13 g 82 mmol) in anhydrous dichloromethane (200 mL) under ice-cooling, and the mixture was stirred for 5 hours at room temperature. The solvent was evaporated under reduced pressure, and the resulting solid was filtered off with ethyl acetate, and washed to give 17 g of mixture containing the title Reference Compound, as a yellow-white solid.
Reaction SMILES: [ClH:1].[O:2]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH:25]C(OC(C)(C)C)=O)[CH2:19][N:18]2C(OC(C)(C)C)=O)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCOCC1>[ClH:1].[ClH:1].[O:2]([C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16](=[O:41])[C@@H:17]2[CH2:21][C@@H:20]([NH:22][C:23](=[O:33])[CH2:24][NH2:25])[CH2:19][NH:18]2)=[CH:13][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (8 mL) was added to a solution of trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-proline 4-phenoxyphenylamide (A, 249 mg) in 1,4-dioxane (8 mL) at room temperature. After stirring at room temperature for 1 hr, the reaction mixture was concentrated in vacuo. The residue was washed with ether to give the title compound (140 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 2.61 (t, J=6.35 Hz, 2 H), 3.49 (dd, J=4.88, 12.21 Hz, 1 H), 3.84 (t, J=6.35 Hz, 1H), 3.87 (s, 2 H), 4.64 (m, 1 H), 4.78 (m, 1H), 7.09 (m, 4 H), 7.23 (t, J=7.3 Hz, 1H), and 7.46 (m, 4 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][C:21](=[O:23])[CH3:22].Cl>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:22]1[O:10][C:5]2[C:4]([O:11][CH3:12])=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:23])[CH3:20]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2cc(C(C)=O)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
10.0 g of 5-bromo-2-hydroxy-3-methoxybenzaldehyde was dissolved in 39 ml of N,N-dimethylformamide, and the resulting solution was mixed with 11.9 g of anhydrous potassium carbonate and stirred at room temperature. 5.0 g of chloroacetone was added dropwise to the above reaction solution at the same temperature, followed by additional 1 hour of stirring at an elevated temperature of 80° C. The resulting reaction solution was diluted with ethyl acetate and adjusted to 2 with concentrated hydrochloric acid, and the resulting organic layer was collected. The organic layer was dried to distill off the solvent, and the resulting residue was purified by silica gel column chromatography, thereby obtaining 4.0 g of 2-acetyl-5-bromo-7-methoxybenzofuran.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@H:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)=[O:22]>O1CCOCC1.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>[Cl:19][CH:20]([Cl:36])[C:21]([NH:23][C@H:24]([CH2:34][F:35])[C@@H:25]([C:26]1[CH:27]=[CH:28][C:29]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=2)=[CH:30][CH:31]=1)[OH:33])=[O:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Reactant: O=C(N[C@H](CF)[C@H](O)c1ccc(I)cc1)C(Cl)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 110 °C
Yield: 53.8 %

Procedure:
To solution of commercially available (4-(((tert-butoxycarbonyl)-amino)methyl)-phenyl)boronic acid (1.01 gm, 4.02 mmol) in 1,4-dioxane:water (12.3:3.8 mL) is added 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-iodophenyl)propan-2-yl)acetamide (1.04 g, 2.56 mmol) and CS2CO3 (1.85 g, 5.67 mmol) and the resulting solution bubbled with nitrogen gas for 30 min. To this reaction mixture is added Pd(PPh3)4 (0.332 g, 0.29 mmol) and the resulting reaction mixture heated to 110° C. for 2 hours. The resulting reaction mixture is cooled, diluted with water and extracted with ethyl acetate. The organic layer dried over sodium sulfate and concentrated to give a crude residue, which is purified using column chromatography on silica gel eluting with 30% Ethyl acetate/hexane to give the title compound (668 mg). 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 8H), 4.30-4.32 (m, 1H), 4.34-4.35 (m, 2H), 4.44-4.47 (m, 0.5H), 4.55-4.59 (m, 1H), 4.68-4.69 (m, 0.5H), 4.85 (m, 1H), 5.15 (t, 1H, J=7.04 Hz), 5.87 (s, 1H), 7.04 (d, 1H, J=8.6 Hz), 7.34 (d, 2H, J=7.92 Hz), 7.44 (d, 2H, J=8.2 Hz), 7.53 (d, 2H, J=8.08 Hz), 7.57 (d, 2H, J=8.08 Hz). m/z (Cl) M−H 483
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:9][C:8]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])=[O:10]
Reactant: CC(=O)c1cccc(F)c1
Reactant: O=[N+]([O-])O
Product: CC(=O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
m-Fluoroacetophenone (20.0 g, 0.14 mol) was cooled to below -5° C. and fuming nitric acid (100 cm3) added dropwise at such a rate that the temperature of the reaction mixture never exceeded -5° C. When the addition was complete the mixture was poured into ice/water. The precipitated yellow solid was filtered, washed with water and dried to give 5-fluoro-2-nitroacetophenone (21.4 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Br)=[C:50]([F:56])[CH:49]=1>CN(C)C=O>[CH3:4][C:1]([O:5][C:6](=[O:44])[N:7]([CH2:52][C:51]1[CH:54]=[CH:55][C:48]([Br:47])=[CH:49][C:50]=1[F:56])[C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:23]=3)[CH2:20][CH2:21]2)=[O:15])[CH:13]=1)([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)N2CCC(c3cccc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)CC2)c1
Reactant: Fc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(C2CCN(C(=O)c3cncc(N(Cc4ccc(Br)cc4F)C(=O)OC(C)(C)C)c3)CC2)c1)C(=O)OC(C)(C)C
Reaction time: 0.05 h
Yield: 94.2 %

Procedure:
To a solution of {5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)methanoyl]-pyridin-3-yl}carbamic acid tert-butyl ester (0.0745 g, 0.1220 mmol) in dimethylformamide (2.0 mL) was added sodium hydride (61% suspension in mineral oil, 0.0216 g, 0.5499 mmol). Deprotonation was allowed to occur over 3 minutes while stirring under inert atmosphere. 4-Bromo-2-fluorobenzyl bromide (0.1559 g, 0.5819 mmol) was added to the anion solution. The mixture was stirred an additional 10 minutes, then quenched with water (5.0 mL). The reaction solution was extracted with ethyl acetate (15 mL), and the organic phase was washed with brine (2×10 mL), dried over magnesium sulfate, filtered, and evaporated to dryness. Purification of the residue on silica gel eluting first with ethyl acetate/methylene chloride/hexane (1:1:2, v/v/v) and then with ethyl acetate and methylene chloride (1:1, v/v) afforded (4-bromo-2-fluoro-benzyl)-{5-[1-(4-{3-[N,N-bis-(tert-butoxycarbonyl)aminomethyl]-phenyl}-piperidin-1-yl)-methanoyl]-pyridin-3-yl}-carbamic acid dimethyl-ethyl ester as a colorless oil (0.0917 g): TLC, 50:50-methylene chloride:ethyl acetate, Rf=0.59. 1H NMR (300 MHz, CDCl3) δ 8.47-8.51 (m, 2H), 7.61 (br s, 1H), 7.07-7.32 (m, 7H), 4.89 (s, 2H), 4.78 (s, 2H), 4.77-4.92 (m partially obscured, 1H), 3.68-3.83 (br m, 1H), 3.09-3.24 (br, m, 1H), 2.70-2.97 (m, 2H), 1.45 (s, 18H), 1.44 (s, 9H), 1.30-2.04 (m partially obscured, 4H); 13C NMR (75 MHz, CDCl3) δ 167.0, 160.4 (d, 250.8), 154.0, 152.7, 148.5, 144.9, 139.0, 138.7, 132.2, 131.9, 130.7, 129.7, 127.9 (d, 3.4), 125.8, 125.7, 125.3, 123.8 (d, 14.5), 121.8 (d, 9.7), 119.3 (d, 24.8), 82.5, 82.2, 49.5, 46.9, 42.6, 32.8 (br), 28.4, 28.2, 28.0; 19F NMR (282 MHz, CDCl3) δ-114.9; MS (CI) m/z 797 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH3:19])([S:15]([CH3:18])(=[O:17])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>C(N(CC)CC)C.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.[Cu]I>[CH3:19][C:10]([S:15]([CH3:18])(=[O:17])=[O:16])([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:3][CH:4]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(CCc1ccc(Br)cc1)S(C)(=O)=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)C(C)(CCc1ccc(C#C[Si](C)(C)C)cc1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 18 h
Yield: 168.1 %

Procedure:
To a stirring suspension of methyl 4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.3, 6.36 g, 18.23 mmol), bis(triphenylphosphine)palladium(II) chloride (1.28 mg, 1.82 mmol) and copper(I) iodide (347 mg, 1.82 mmol) in triethylamine (30 mL) was added ethynyltrimethylsilane (0.92 mL, 6.49 mmol) and the reaction mixture was heated to 80° C. briefly, and then allowed to stir at room temperature for 18 hr. Volatiles were removed under reduced pressure and the resulting residue was purified by flash chromatography (silica gel/15-50% EtOAc/hexanes) to yield methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.0 g, 59.9% yield). MS: m/z calcd for C18H26O4SSi 366.13. found [M+H]+ 367.2.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[NH2:26][C@@H:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]1[OH:33]>>[OH:33][C@@H:28]1[CH2:29][CH2:30][CH2:31][CH2:32][C@H:27]1[NH:26][C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=c1c2c(ncn2Cc2ccccc2)nc(Cl)n1Cc1ccccc1
Product: O=c1c2c(ncn2Cc2ccccc2)nc(N[C@@H]2CCCC[C@H]2O)n1Cc1ccccc1

Procedure:
Treat 2-chloro-1,7-bis(phenylmethyl)purin-6-one with trans-2-aminocyclohexanol as described in Preparative Example 5 to give the title compound, a tan foam. FAB MS: M+1=430.
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]([C:36]2[CH:41]=[CH:40][C:39]([O:42][Si](C(C)(C)C)(C)C)=[CH:38][CH:37]=2)[OH:35])=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si](C(C)(C)C)(C)C)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([OH:35])[C:36]2[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=2)=[CH:32][CH:33]=1)[CH2:9][C@@H:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O)c3cccc(Cl)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.4 %

Procedure:
To a solution of [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethyl]amino]-ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]oxy]phenyl]-methanol (1.1 g) in tetrahydrofuran (15 ml) was added 1M tetrabutylammonium fluoride in tetrahydrofuran (5.0 ml) at 0° C., and the mixture was stirred at room temperature for 24 hours under nitrogen. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give 4-[[4-[2-[N-benzyl-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyl](hydroxy)methyl]phenol (550 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[N:24]=[CH:23][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH:34]=O)=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:34][C:30]1[CH:29]=[C:28]2[C:33]([C:25]([C:22]3[CH:23]=[N:24][C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)=[CH:20][CH:21]=3)=[N:26][NH:27]2)=[CH:32][CH:31]=1
Reactant: CN1CCN(c2ccc(-c3n[nH]c4cc(C=O)ccc34)cn2)CC1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: CN1CCN(c2ccc(-c3n[nH]c4cc(C=C5C(=O)Nc6ccc(Br)cc65)ccc34)cn2)CC1
Yield: 88.2 %

Procedure:
The title compound (E/Z=3:4, 65 mg, 88%) was synthesized as an orange solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one-(oil temp 75° C., reflux 3 h) using 5-bromoindolin-2-one (32 mg, 0.15 mmol) and 3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-indazole-6-carbaldehyde (46 mg, 0.143 mmol). 1H NMR (400 MHz, DMSO-d6) E isomer: δ 13.41 (s, 1H), 10.80 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 2H), 7.91 (s, 1H), 7.87 (s, 1H), 7.67 (d, 1H), 7.48-7.40 (m, 2H), 7.99 (d, J=8.8 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); Z isomer: δ 13.48 (s, 1H), 10.84 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.20-8.03 (m, 5H), 7.38 (d, J=8.0 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 3.57 (t, 4H), 2.41 (t, 4H), 2.23 (s, 3H); MS ESI 515.4 [M+H]+, calcd for [C26H23BrN6O+H]+ 515.1.
Reaction SMILES: [Cl:1][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:3]([O:5]CC)=O.[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[CH:21]([NH:24][C:3](=[O:5])[CH:2]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:12][CH:13]=1)[Cl:1])([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: CCOC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1
Solvent: CCOCC
Product: CC(C)NC(=O)C(Cl)c1ccc(-c2ccccc2Cl)cc1

Procedure:
A mixture of 5 g. (0.016 moles) of ethyl α, 2'-dichloro-4-biphenylylacetate and 5.5 ml. of anhydrous isopropylamine are stirred over Linde 4A molecular sieve for 16 hours at room temperature. The reaction mixture is taken up in ether and washed 3 times with 15 ml. of 10% hydrochloric acid. The ether layer is dried over sodium sulfate, filtered, and the ether is removed. The residue is triturated with n-hexane and the precipitate is collected to obtain N-isopropyl α, 2'-dichloro-4-biphenylylacetamide.