Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)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>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H). LCMS Method C: rt 6.52 min; m/z 578.3 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([OH:10])[CH:9]=1)=[O:4].[CH3:12][C:13]1[O:17][N:16]=[C:15]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:14]=1[CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[C:8]([O:10][CH2:24][C:14]2[C:15]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:16][O:17][C:13]=2[CH3:12])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(O)nn1C
Reactant: Cc1onc(C2CCOCC2)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCc2c(C3CCOCC3)noc2C)nn1C
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (4.68 g, 30 mmol) and [5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-yl]-methanol (5.92 g, 30 mmol) in THF (400 mL) at 5° C. under argon was added triphenylphosphine (10.6 g, 39 mmol), then diisopropyl azodicarboxylate (8.23 mL, 39 mmol) was added dropwise. The reaction mixture was warmed to room temperature overnight. The reaction mixture was then extracted with ethyl acetate and the organic extract washed with water, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=1:1) afforded the title compound (7.26 g, 85%) as a white solid. MS: m/e=336.2 [M+H]+.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:37])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C@H:26]([C:33]([O:35]C)=[O:34])[CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:24])[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.[OH-].[Na+].Cl>>[NH2:7][C:8]1[N:9]=[C:10]([OH:37])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:25][C@H:26]([C:33]([OH:35])=[O:34])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:24])[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: COC(=O)CC[C@H](NC(=O)CCCCCC1CNc2nc(NC(=O)C(C)(C)C)nc(O)c2C1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)O)C2

Procedure:
A solution of 0.5 g. of dimethyl N-[6-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d] -pyrimidin-6-yl)hexanoyl]-L-glutamate in 75 mL. of 1.0 N aqueous sodium hydroxide is stirred at room temperature for 120 hours and the pH then adjusted to 7.0 through the careful addition of 5.0 N hydrochloric acid. Water was removed under reduced pressure and the concentrated solution then cooled in an ice-bath. The solid which formed was collected by filtration and dried at 80° C. to yield N-[6-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido-[2,3-d]pyrimidin-6-yl)hexanoyl]-L-glutamic acid, m.p. foaming at 135° C., melting at 180°-195° C. NMR (DMSO-d6 300 MHz) delta: 9.80 (s, br, 1H), 7.90 (s, J=8 Hz, 1H), 6.20 (s, 1H), 5.95 (s, 2H), 4.08 (m, 1H), 3.10 (m, 1H), 2.63 (t, J=10 Hz, 1H), 2.40 (m, 1H), 2.20 (t, J=8 Hz, 2H), 2.05 (t, J=8 Hz, 2H), 1.84 (m, 1H), 1.70 (m, 2H), 1.55 (m, 3H), 1.20 (m, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:30][CH2:31][O:32]C2CCCCO2)[C:14]1=[O:39])=[O:11].Cl.O>CC(C)=O>[OH:32][CH2:31][CH2:30][N:15]1[C:16]2[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=2[C:18]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:19][CH:13]([NH:12][C:10]([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:11])[C:14]1=[O:39]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOC2CCCCO2)C1=O)c1cc2ccccc2[nH]1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCO)C1=O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 79.5 %

Procedure:
To a suspension of a mixture (0.42 g)of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1 -{2-((RS)-2-tetrahydropyranyloxy)ethyl}-2H-1,4-benzodiazepine-2-one and (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-1-{2-((SR)-2-tetrahydropyranyloxy) ethyl}-2H-1,4-benzodiazepine-2-one in acetone (10 ml) was added 6N-hydrochloric acid (0.4 ml) under stirring at ambient temperature. After the yellow clear solution was stirred for 45 minutes, the additional 6N-hydrochloric acid (0.4 ml) and water (1 ml) were added thereto. The mixture was stirred for 0.5 hour at ambient temperature. Neutralization with an aqueous solution of sodium bicarbonate and removal of acetone gave yellow precipitates, which were collected by filtration, washed with water and dried. The crude product was purified by column chromatography on silica gel with an eluent of a mixture of chloroform and ethyl acetate (5:1) to afford pure (3RS)-1,3-dihydro-1-(2-hydroxyethyl)-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.28 g) as an amorphous. This was triturated in diethyl ether to give light yellow powder.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13](O)=[O:14])=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2].[F:25][C:26]([F:36])([F:35])[C:27]1[N:32]=[CH:31][C:30]([CH2:33][NH2:34])=[CH:29][CH:28]=1>>[CH:1]([C:4]1[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:34][CH2:33][C:30]1[CH:31]=[N:32][C:27]([C:26]([F:36])([F:25])[F:35])=[CH:28][CH:29]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:16][CH3:17])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3ccccn3)c2c1
Product: COc1ccc2c(C(=O)NCc3ccc(C(F)(F)F)nc3)c(C(C)C)n(Cc3ccccn3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxylic acid (Compound 139) and (6-(trifluoromethyl)pyridin-3-yl)methanamine by General Procedure C.
Reaction SMILES: Cl(O[C:6]([C:44]1[CH:49]=[CH:48][C:47]([N:50]([CH2:53][CH3:54])[CH2:51][CH3:52])=[CH:46][CH:45]=1)([C:33]1[CH:38]=[CH:37][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:35][CH:34]=1)[CH:7]=[CH:8][CH:9]=[C:10]([C:22]1[CH:27]=[CH:26][C:25]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:24][CH:23]=1)[C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=1)(=O)(=O)=O.[OH-:55].[Na+]>CO>[CH2:51]([N:50]([CH2:53][CH3:54])[C:47]1[CH:46]=[CH:45][C:44]([C:6]([C:33]2[CH:34]=[CH:35][C:36]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:37][CH:38]=2)=[CH:7][CH:8]([OH:55])[CH:9]=[C:10]([C:22]2[CH:23]=[CH:24][C:25]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:26][CH:27]=2)[C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:49][CH:48]=1)[CH3:52]
Reactant: [OH-]
Reactant: CCN(CC)c1ccc(C(=CC=CC(O[Cl+3]([O-])([O-])[O-])(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Agent: [Na+]
Solvent: CO
Product: CCN(CC)c1ccc(C(=CC(O)C=C(c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)c2ccc(N(CC)CC)cc2)cc1
Yield: 87 %

Procedure:
15.1 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-2,4-pentadiene-1-ol perchlorate prepared in Synthesis Example 5 was dissolved in 200 ml of methanol. To this solution, 2.53 g of sodium hydroxide was added. The mixture was refluxed for 2 hours and then cooled. Crystals separated out in the reaction mixture. The crystals were filtered off, washed with water several times, and dried in reduced pressure. The crystals were recrystallized from cyclohexane, whereby 11.7 g of 1,1,5,5-tetra-(p-diethylaminophenyl)-3-hydroxy-1,4-pentadiene was obtained in the form of light green crystals. The melting point of the product was 136.5° to 137.5° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:35])[F:34])=[CH:27]2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:34])[F:35])=[CH:27]2
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCCCN1CCCC1
Yield: 71.9 %

Procedure:
Using an analogous procedure to that described in Example 44, 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.3 mmol), (prepared as described for the starting material in Example 9), was reacted with 5-hydroxy-2-trifluoromethylindole (75 mg, 0.37 mmol), (prepared as described for the starting material in Example 44), to give 6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline (105 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH:14]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Reactant: Nc1cccc(N)n1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1cccc(N)n1
Temperature: 25 °C

Procedure:
In a manner similar to that described in Preparation CD, 2-formyl-piperidine-1-carboxylic acid tert-butyl ester (360 mg, 1.69 mmol) was treated with 2,6-diaminopyridine (184 mg, 1.69 mmol) and stirred at RT to give a light brown oil. MS m/z: 307.3(M+H). Calc'd. for C16H26N4O2-306.21.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.OC1C2N=NNC=2C=CC=1.[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52](O)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1>CN(C)C=O>[OH:43][C:44]1[CH:56]=[CH:55][C:47]2[O:48][C:49]([C:52]([N:12]3[CH2:11][CH2:10][N:9]([CH:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH2:14][CH2:13]3)=[O:53])=[CH:50][O:51][C:46]=2[CH:45]=1
Reactant: O=C(O)C1=COc2cc(O)ccc2O1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, add 5.5 mmol of 1-[bis(4-fluorophenyl)methyl]piperazine, 5.5 mmol of EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) and 5.5 mmol of HOBt (hydroxybenzotriazole) in succession to a solution at 0° C. of 5 mmol of 6-hydroxy-1,4-benzodioxin-2-carboxylic acid in 25 cm3 of N,N-dimethylformamide. Stir for 2 hours at 0° C. and then for 12 hours at room temperature, and concentrate the reaction mixture under reduced pressure. Extract the resulting amide with diethyl ether and then, after concentration to dryness, purify the crude product by chromatography on a silica column (eluant: petroleum ether then an increasing gradient of ethyl acetate in petroleum ether). 6-Hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin is thereby obtained in a yield of 85%. The product obtained is precipitated from 10 ml of pentane and is then filtered and recrystallised from cyclohexane. Melting point: 163° C. ##STR58##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1(C)[O:18]C(=O)[CH2:16][C:15](=O)[O:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9](=[O:11])[CH2:12][C:13]([O:14][CH2:15][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-(4-chlorophenyl)acetic acid and 2,2-dimethyl-1,3-dioxane-4,6-dione according to the procedure for the preparation of Example 162, part A.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][O:33][CH3:34])[NH:17][CH:16]2[C:37](O)=[O:38])[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:46][C@@H:45]([CH2:47][CH2:48][NH2:49])[CH2:44][O:43]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:46][C@H:45]([CH2:44][OH:43])[CH2:47][CH2:48][NH:49][C:37]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:36])([CH3:35])[CH2:32][O:33][CH3:34])[NH:17]1)=[O:38]
Reactant: COCC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 64.7 %

Procedure:
In a manner similar to the method described in Examples 42c and 42d, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 110c (0.45 g, 0.74 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.32 g, 2.2 mmol), HATU (0.5 g, 1.3 mmol) and iPr2NEt (0.64 mL, 3.7 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(3-methoxy-2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.28 g, 65%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH:12]1[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:12]2[CH2:22][CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)C1CCCN(c2nc(Cl)nc3[nH]cnc23)C1
Yield: 34.9 %

Procedure:
A solution of 2,6-dichloropurine (189 mg, 1.00 mmol), ethyl nipecotate (0.155 mL, 1.00 mmol) and DIEA (0.300 mL, 1.72 mmol) in CH3CN (5 mL) was stirred at room temperature for 20 h, during which time white solids precipitated out, which was collected to give ethyl 1-(2-chloro-9H-purin-6-yl)piperidine-3-carboxylate (108 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C@@H:11]([CH3:16])[CH2:10][C@H:9]2[NH:17][CH:18]=[O:19].Cl>C(Cl)Cl.N1C=CC=CC=1>[C:1]([N:12]1[C:13]2[C:8](=[CH:7][C:6]([Br:5])=[CH:15][CH:14]=2)[C@H:9]([NH:17][CH:18]=[O:19])[CH2:10][C@@H:11]1[CH3:16])(=[O:3])[CH3:2]
Reactant: C[C@H]1C[C@@H](NC=O)c2cc(Br)ccc2N1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1c2ccc(Br)cc2[C@H](NC=O)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (21 mL, 0.29 mol) was added dropwise at 0° C. to a solution of ((cis)-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl)formamide (for a preparation see Intermediate 41) (71 g, 0.26 mol) in a mixture of DCM (1 L) and pyridine (350 mL). After stirring 2 hours at 0° C. the mixture was poured into a mixture of crushed ice (2 kg) and concentrated HCl (450 mL). The product was extracted with DCM (1 L) washed with brine and dried over Na2SO4. Concentration under vacuo afforded the expected product as an off white solid (82 g, 100%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].ClC1C=C(C2C=CC=C(Cl)C=2)C=CC=1.Cl[C:39]1[CH:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[CH:60]=4)[CH:53]=3)[CH:46]=2)[CH:42]=[CH:43][CH:44]=1>O.C1(C)C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][C:43]1[CH:42]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[C:54]([O:58][C:59]4[CH:64]=[CH:63][CH:62]=[C:61]([O:65][C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[CH:60]=4)[CH:53]=3)[CH:46]=2)[CH:40]=[CH:39][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)c1
Agent: Clc1cccc(-c2cccc(Cl)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(Oc2cccc(Oc3cccc(Oc4cccc(-c5cccc(Oc6cccc(Oc7cccc(Oc8ccccc8)c7)c6)c5)c4)c3)c2)cc1
Yield: 80 %

Procedure:
A 250 ml. four-necked flask, equipped with stirrer, dropping funnel, thermometer, and Dean-Stark trap surmounted by a Friedrichs condenser was charged with 59.8 g. (0.215 mole) of m-(m-phenoxyphenoxy)phenol to which 13.0 g. 0.208 mole) of potassium hydroxide was added at 90°C. followed by addition of 50 ml. of toluene. The stirred reaction mixture was heated to azeotrope water, followed by distillation of toluene until the temperature of the reaction mixture reached 230°C. To this mixture after cooling was added 50 ml. of diglyme, 2.5 g. of cuprous chloride, 0.5 g. of copper powder, and 20 g. (0.09 mole) of 3,3'-dichlorobiphenyl over a 30 min. period at 175 C. Diglyme was distilled from the reaction mixture which was then heated at 230°-260°C. for 18 hr. The cooled very thick semi-solid mass resulting was dissolved in 500 ml. of ethyl ether and the suspended salts removed by centrifugation. The resulting ethereal solution was washed thoroughly with 10% potassium hydroxide solution and with water until neutral, and finally dried over anhydrous magnesium sulfate. After concentrating this solution, it was distilled using a 25 ml. still pot attached to a Claisen head and fraction cutter. Distillation using a Wood's metal bath on the still pot gave 10 g. of viscous red-orange liquid, bp 348°-352°C/0.09 mm. at a pot temperature of 428°C. Elemental analysis showed this cut to be about 80% of the desired product and 20% 3-chloro-3'-[m-(m-phenoxyphenoxy)phenoxy]biphenyl. The pot residue was dissolved in 300 ml. of ethyl ether, treated with 1 g. of activated charcoal and filtered through filter aid. The ether was removed under vacuum to yield a light orange product, bp 380°-390°C/0.05 mm., nD25 1.658.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[C:4]=23)[CH2:18]1
Reactant: CCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Yield: 79 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-butyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (176 mg, 0.366 mmol) was stirred in TFA (3 mL) at room temperature for 1.5 hours. The solvent was evaporated in vacuo, and the residue purified by reverse phase chromatography (Biotage SP4, C-18 12M+, 2-50% CH3CN/water, 16CV). The isolated product was taken up in a minimal volume of methanol and added to a stirred solution of 2N HCl-Et2O. The salt formed was collected by filtration, washed with acetonitrile and dried under vacuum to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide (110 mg, 66% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.27 (s, 1H), 7.54 (s, 1H), 3.52-3.23 (m, 4H), 3.15-3.05 (m, 1H), 2.38 (t, 2H), 2.19-2.10 (m, 1H), 1.93-1.85 (m, 1H), 1.78-1.60 (m, 3H), 1.58-1.42 (m, 1H), 0.97 (t, 3H). LCMS (APCI+) m/z 380, 383.1 (M+H)+, Retention time=2.38 minutes.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:10][CH:9]=1>C1(C)C=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.[Pd]>[C:30]([O:29][C:27]([NH:26][CH:15]([CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:1]=[O:4])[CH:9]=2)=[CH:9][CH:10]=1)[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Br)cc1)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(C=O)c2)cc1)C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 71 %

Procedure:
23 ml (45.9 mmol) of an aqueous 2M potassium carbonate solution and 1.77 g (1.50 mmol) of tetrakis palladium are introduced into a solution containing 6.64 g (15.3 mmol) of benzyl 3-(4-bromophenyl)-2-tert-butoxycarbonylaminopropionate and 3.45 g (23 mmol) of 3-boronic acid-benzaldehyde (Example 28b) in 75 ml of toluene. The reaction medium is heated at 80° C. for 20 h and, after a return to ambient temperature, extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue obtained is purified by chromatography on a column of silica and eluted with an 8/2 heptane/ethyl acetate mixture. 5.0 g of coupled product are obtained with a 71% yield.