Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]([NH2:15])=[O:14])[N:3]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>CN(C=O)C.C(O)C>[C:13]([C:4]1[N:3]=[C:2]([OH:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:23](=[O:25])[CH3:24])[CH:10]=2)[N:5]=1)(=[O:14])[NH2:15]
Reactant: NC(=O)c1nc(O)c2cc(O)ccc2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2nc(C(N)=O)nc(O)c2c1
Reaction time: 8 h

Procedure:
4,6-Dihydroxy-quinazoline-2-carboxylic acid amide (12 mmol) are dissolved in warm D (20 ml) and triethylamine (13.2 mmol) is added to the stirred mixture. After cooling to RT a solution of acetic acid anhydride in DMF (10 ml) is added dropwise and the mixture is stirred overnight. The solvent is removed and the solid material formed is suspended in ethanol and the solid filtered of and dried (vacuum). A powder with mp. 250° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@H:12]4[CH:17]=[N:16][CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C(N(CC)CC)C.[I-].[K+]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[C@@H:12]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:13]4[N:5]([C:6]=23)[CH2:4][CH2:3]1
Reactant: CN1CCN2c3c(cccc31)[C@H]1C=NCC[C@@H]12
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(=O)c3ccc(F)cc3)CC[C@@H]12

Procedure:
A suspension of (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxaline (ca. 11.8 g, ca. 50 mmol), 4-chloro-4′-fluorobutyrophenone (15.0 g, 74.8 mmol), triethylamine (30 mL, 214 mmol), and potassium iodide (12.6 g, 76 mmol) in dioxane (65 ml) and toluene (65 ml) is heated to reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4) and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5N HCl ether solution. The solid is filtered off and washed with ether and then dissolved in water. The resulting aqueous solution is basified with 2N NaOH and extracted with DCM. The DCM layers are combined, washed with brine (2×200 mL) and dried (Na2SO4). Evaporation of the solvent and chromatography of the residue over silica gel gives 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3′,4′:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[C:13]([CH3:20])[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH4+].[Cl-]>[Zn].CO.C1COCC1>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:9][C:6]=2[C:7]#[N:8])=[CH:12][C:13]=1[CH3:20]
Reactant: Cc1cc(Oc2ccc(F)cc2C#N)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccc(F)cc2C#N)ccc1N
Reaction time: 0.17 h

Procedure:
Intermediate (24t) (14.3 g, mmol) and zinc dust (17.2 g, 263 mmol) were suspended in mixed solvent of MeOH/THF (1:1, 125 mL) and saturated NH4Cl (125 mL) was added. The reaction mixture became warm. There was an obvious change in the zinc suspension. The reaction was finished in 10 minutes. The reaction mixture was filtered through a silica plug and diluted with EtOAc and saturated NaHCO3. The layers were separated and the combined organics dried over MgSO4 and concentrated under reduced pressure. The crude residue (25t) was pure enough on NMR spectra. 1HNMR (400 MHz, d6-DMSO) δ 7.83 (dd, J=8.5, 3.1 Hz, 1H), 7.47 (td, J=8.9, 3.1 Hz, 1H), 6.83-6.77 (m, 2H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.88 (s, 1H), 2.06 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:39]1([C@H:45]([NH2:47])[CH3:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5](=[O:7])[NH:47][C@@H:45]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:46])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cc(Br)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Br)cc(C(=O)N[C@H](C)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.8 %

Procedure:
A mixture of 3-bromo-5-(methoxycarbonyl)benzoic acid (0.60 g, 2.32 mmol) and HATU (1.06 g, 2.78 mmol) in DMF (15 mL) was stirred at room temperature for 10 min. Then (R)-1-phenylethanamine (0.28 g, 0.3 mL, 2.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with H2O (3 times) and brine, dried over sodium sulfate, and concentrated under vacuum to give the title compound (0.839 g, 99.9% yield): HPLC retention time: 2.17 min (method A). MS (ESI) (M+H)+ 362/364.
Reaction SMILES: CS(O[CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]#[N:22])=[CH:11][N:10]=1)[CH2:7][CH3:8])(=O)=O.C(N(CC)CC)C.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>C(Cl)Cl.O>[N:30]1([CH:6]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]#[N:22])=[CH:13][CH:14]=2)[CH2:7][CH3:8])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: c1c[nH]cn1
Reactant: CCC(OS(C)(=O)=O)c1ccc(-c2ccccc2C#N)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCC(c1ccc(-c2ccccc2C#N)cn1)n1ccnc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.1 %

Procedure:
To solution of 1-(5-(2-cyanophenyl)pyridin-2-yl)propyl methanesulfonate (0.050 g, 0.15 mmol) in DCM was added triethyl amine (0.030 g, 0.30 mmol) followed by imidazole (0.20 g, 0.30 mmol) at room temperature. The reaction mixture was stirred for 12 h at room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL). The organic extracts were dried over sodium sulphate, filtered and concentrated to obtain the crude compound which was purified by preparative TLC by using 5% MeOH/DCM to give 2-(6-(1-(1H-imidazol-1-yl)propyl)pyridin-3-yl)benzonitrile (10 mg, 24%). 1H NMR (400 MHz DMSO-d6): δ 8.77 (s, 1H), 8.04 (dd, 1H), 7.98 (d, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.63 (t, 1H), 7.44 (d, 1H), 7.34 (s, 1H), 6.92 (s, 1H), 5.43 (dd, 1H), 2.31-2.20 (m, 2H), 0.83 (t, 3H); LC-MS m/z calcd for [M+H]+ 289.14. found 289.5.
Reaction SMILES: N1CCC(CCCC(N(CC)CC(N[C@H](C([NH:24][C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=O)CC(=O)O)=O)=O)CC1.[CH:38]1(C[C@@H](C(O)=O)N)CCCCC1>CO.Cl>[CH3:38][O:35][C:33](=[O:34])[C@H:25]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[NH2:24]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)O)C(=O)CCCC1CCNCC1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CC1CCCCC1

Procedure:
N-[N-[N-(4-(piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-β-cyclohexylalanine ##STR6##A. β-cyclohexylalanine (1.12 g) is dissolved in of methanol (50 ml) and hydrogen chloride gas is bubbled through the solution for about 15 minutes. The solution is evaporated in vacuo and toluene azeotroped from the residue to give β-cyclohexyl-L-alanine methyl ester as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18](Br)=[CH:17][N:16]=2)=[C:11]([F:22])[C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([C:36]3[CH:35]=[N:34][C:33]([O:32][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:38][CH:37]=3)=[CH:17][N:16]=2)=[C:11]([F:22])[C:10]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1c(OCc2ccccc2)ccc(-c2ncc(Br)cn2)c1F
Reactant: CCCCCCCCOc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2cnc(-c3ccc(OCc4ccccc4)c(F)c3F)nc2)cn1
Yield: 60.7 %

Procedure:
The reaction of 35 mmol of 2-(4-benzyloxy-2,3-difluorophenyl)-5-bromopyrimidine, 44 mmol of 2-octyloxypyridine-5-boronic acid, 70 mmol of sodium carbonate and 0.4 mmol of tetakis(triphenylphosphine)palladium(0) in 120 ml of toluene, 60 ml of ethanol and 60 ml of water is carried out analogously to the procedure indicated for Example 1a). Corresponding chromatographic purification and recrystallization from ethyl acetate gives 10.7 g (61%) of colorless crystals, m.p. 120° C., cl.p. 182-183° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[OH:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH3:16][N:12]1[C:11]([C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:28][C:19]3[CH:20]=[CH:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=3)[CH:9]=2)=[O:17])=[CH:15][N:14]=[CH:13]1
Reactant: Oc1ccc2ccccc2c1
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(=O)c1ccc(C#N)c(Oc2ccc3ccccc3c2)c1
Temperature: 60 °C

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (as described in Example 22, Step E) (0.172 g, 0.743 mmol), 2-naphthol (0.107 g, 0.743 mmol) and Cs2CO3 (0.727 g, 2.23 mmol) were dissolved in anhydrous DMF (5 mL) and heated at 60° C. under Ar for 2 days. The reaction was diluted with EtOAc, washed with satd. NaHCO3 solution, water, and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (1-2% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:34][C:35](=[NH:44])[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=1>CN(C=O)C.O>[C:1]1([N:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[O:18][N:44]=[C:35]([C:36]4[CH:41]=[CH:40][C:39]([CH2:42][OH:43])=[CH:38][CH:37]=4)[N:34]=3)[CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1C(F)(F)F
Reactant: N=C(NO)c1ccc(CO)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: OCc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-Phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (2 g, 7.81 mmol), HOBT (1.315 g, 8.59 mmol) and EDC (1.646 g, 8.59 mmol) were dissolved in DMF (18 mL) under nitrogen at room temperature. The resulting clear, pale yellow solution was stirred for 20 minutes, then N-hydroxy-4-(hydroxymethyl)benzimidamide, Int.2, (1.297 g, 7.81 mmol) was added in several portions. The reaction was placed in an oil bath preheated to 140° C. for 10 hours. The reaction was cooled to room temperature, poured into water (150 mL), stirred vigorously and placed in a sonicator bath for 1 hour. The solids were collected by filtration, washed with water, air dried and then placed under vacuum to give (4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.5 g, 6.47 mmol) as a very light yellow solid. The compound had an HPLC retention time=3.76 min.−Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=387.1 1H NMR (500 MHz, MeOD) δ ppm 4.70 (s, 2H), 7.53-7.57 (m, 4 H), 7.57-7.62 (m, 1H), 7.61 (d, J=6.4 Hz, 2H), 8.12 (d, J=8.2 Hz, 2H), 8.48 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([N:11]([C:13]1[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:31]([OH:46])[C:32]([N:34]2[CH2:45][CH2:44][CH2:43][C@H:35]2[C:36]([NH:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=1)[CH3:12])=[O:10]>C(Cl)(Cl)Cl>[C:5]([OH:10])(=[O:4])[CH3:6].[O:4]1[CH2:5][CH2:6][N:1]([CH2:8][C:9]([N:11]([C:13]2[CH:55]=[CH:54][C:16]([O:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@@H:30]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:31]([OH:46])[C:32]([N:34]3[CH2:45][CH2:44][CH2:43][C@H:35]3[C:36]([NH:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:33])=[O:28])[CH2:23][C:24](=[O:26])[NH2:25])=[O:20])=[CH:15][CH:14]=2)[CH3:12])=[O:10])[CH2:2][CH2:3]1
Reactant: CN(C(=O)CBr)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reactant: C1COCCN1
Solvent: ClC(Cl)Cl
Product: CC(=O)O
Product: CN(C(=O)CN1CCOCC1)c1ccc(OCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc2ccccc2)[C@H](O)C(=O)N2CCC[C@H]2C(=O)NC(C)(C)C)cc1
Reaction time: 96 h
Yield: 92.8 %

Procedure:
0.11 ml (1.3 mmol) of morpholine was added to 100 mg (0.13 mmol) of 1-[(2S,3S)-3-{N2 -[4-(N-bromoacetyl-N-methylamino)phenoxy]acetyl-L-asparaginyl}amino-2-hydroxy-4-phenylbutyryl]-N-t-butyl-L-prolinamide (prepared as described in Example 30), and the resulting mixture was allowed to stand for 4 days. At the end of this time, the reaction mixture was diluted with chloroform, and the diluted solution was washed with water. The solvent was then removed by distillation under reduced pressure, and the residue was purified by preparative thin layer chromatography, using a 16:4:1 by volume mixture of chloroform, methanol and 32% v/v aqueous acetic acid. The product was triturated with diethyl ether, to obtain 49 mg of the title compound as a colorless powder, melting at 114°-122° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>O1CCCC1>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: COc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
Aluminium chloride (1,62 g, 12,2 mmol) was added in 3 portions to a solution of 2-methoxynaphthalene (1,28 g, 8,09 mmol) in tetrahydrohydrofuran (20 mL) at 5° C. Ethyl pyruvate (1,41 g, 12,2 mmol) in tetrahydrofuran (10 mL) was added oveer 1 hour at this temperature. The reaction was allowed to proceed for 1 hour and warmed to 20° C. for 1 hour. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed in 2% yield with 98% recovery of the starting material.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([CH:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C[Si](CCOCCl)(C)C.ClC1N=CNC2=NC=CC=12>C(O)C>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3].[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:26])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Agent: C[Si](C)(C)CCOCCl
Agent: Clc1nc[nH]c2nccc1-2
Solvent: CCO
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@@H](CC#N)C4CCCC4)c3)ncnc21
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Reaction time: 0.27 h
Yield: 90.8 %
Yield: 92.3 %

Procedure:
A solution of racemic (4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 5.2 g, 12.36 mmol) in a mixture of ethanol and hexanes (1:9 by volume) was injected into preparative HPLC system equipped with the chiral column (30×250 mm) packed with a silicagel based packing coated with cellulose tris(3,5-dimethylphenyl)carbamate (available from Daicel Chemical Industries, Ltd. (Daicel) as “Chiralcel® OD-H” (5 μm)). The chiral column was eluted with mobile phase made by a mixture of ethanol (EtOH) and hexanes in a 1 to 9 volume ratio at a flow rate of 32 mL/min at room temperature. The column elution was monitored by UV at wavelength 220 nm. Under these conditions, baseline separation of the two enantiomers was achieved and the retention times were 16.4 minutes (Peak 1, the undesired (S)-enantiomer (S)-21) and 21.0 minutes (Peak 2, the desired (R)-enantiomer (R)-21), respectively. Each injection was 1.4 mL of feed solution at a concentration of 50 mg/mL and each run cycle was 14 minutes by using stack injections. Total 75 injections were taken for this separation process. Fractions for Peak 1 (the undesired (S)-enantiomer, (S)-21) and Peak 2 (the desired (R)-enantiomer, (R)-21) were collected separately from each injection, and fractions collected for each peak were concentrated under reduced pressure. The residue from each evaporator was further dried under high vacuum to constant weight to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-21, 2.36 g, 2.6 g theoretical, 90.8% yield) from Peak 2 as off-white solids and (S)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((S)-21, 2.4 g, 2.6 g theoretical, 92.3% yield) from Peak 1 as off-white solids.
Reaction SMILES: [CH3:1][Si:2](Cl)([CH3:4])[CH3:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][Si:2]([O:13][C:10]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (11 ml, 87 mmol) was added dropwise to a stirred solution of 4-bromophenol (10.0 g, 58 mmol) in toluene (25 ml) and pyridine (20 ml) at a 0° C. The stirred mixture was heated to ambient temperature during 3 hours. The reaction mixture was filtered and the organic solution evatorated to yield pure 4-bromophenyl trimethylsilyl ether. The silyl ether can be further purified by distillation (b.p. 122° C., 20 mmHg). Yield after distillation: 13.70 g (75%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: OCC1CCNCC1
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC(CO)CC4)c(OC)cc23)c2c1OCO2
Yield: 79.9 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (192 mg, 0.38 mmol) and 4-piperidinemethanol (220 mg, 1.9 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (177 mg, 80%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.10-1.20 (m, 2H), 1.35 (m, 1H), 1.64 (d, 2H), 1.88 (t, 2H), 1.95 (quintet, 2H), 2.45 (t, 2H), 2.72 (t, 2H), 2.89 (d, 2H), 3.26 (t, 2H), 3.32 (s, 3H), 3.53 (t, 2H), 3.94 (s, 3H), 4.18 (t, 2H), 4.37 (t, 1H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:18])[CH2:16][Cl:17])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5])[CH3:2].[CH2:20]([NH2:23])[CH:21]=[CH2:22].Cl>CS(C)=O>[ClH:17].[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:18])[CH2:16][NH:23][CH2:20][CH:21]=[CH2:22])[CH:11]=[CH:10][C:9]=2[OH:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C(=O)CCl)ccc(O)c2[nH]1
Reactant: C=CCN
Agent: Cl
Solvent: CS(C)=O
Product: C=CCNCC(=O)c1ccc(O)c2[nH]c(C(=O)OCC)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.8 g of 4-chloroacetyl-7-hydroxyindole-2-carboxylic acid ethyl ester is combined with 1.5 ml of allylamine and 15 ml of absolute dimethyl sulfoxide and stirred at room temperature for one hour. Then 150 ml of 2N hydrochloric acid is added to the reaction mixture, the immediately formed precipitate is vacuum-filtered, and the filtrate is allowed to stand and thus yields, in crystalline form, 1.5 g of 4-allylaminoacetyl-7-hydroxyindole-2-carboxylic acid ethyl ester hydrochloride, mp 264°-265° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([C:20]1([C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][CH:27]=[CH:26]3)[CH2:22][CH2:21]1)[CH:18]=O.O.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([C:20]4([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[CH:28][CH:27]=[CH:26]6)[CH2:22][CH2:21]4)=[CH:18][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)ccc1Br

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (80.0 mg, 0.297 mmol, Example 7, Steps 1-5) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.088 g, 0.36 mmol) in isopropyl alcohol (3 mL) and a drop of water was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 with triethylamine. The volatiles were removed under reduced pressure. The residue was purified by chromatography on silica gel with EtOAc in CH2Cl2 (0-60%) to afford the desired product. LCMS: (M+H)=459.9/461.9.
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH:7]([OH:9])[CH3:8].[Br:10]N1C(=O)CCC1=O.C1(C(OOC(=O)C2C=CC=CC=2)=O)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7](=[O:9])[CH3:8]
Reactant: Cc1scnc1C(C)O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)c1ncsc1CBr
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a solution of 1-(5-methyl-1,3-thiazol-4-yl)ethan-1-ol (1.0 g, 7.0 mmol) in anhydrous carbon tetrachloride (50 mL) was added recrystallized 1-bromopyrrolidine-2,5-dione (1.4 g, 7.7 mmol) and benzoyl benzenecarboperoxoate (170 mg, 0.7 mmol). The mixture was stirred at reflux for 5 hours. After cooling to room temperature, the solid material was removed by filtration. The filtrate was recovered and evaporated. The residue was dried in vacuo, affording 1-[5-(bromomethyl)-1,3-thiazol-4-yl]ethan-1-one (615 mg, 40%). The product was used for the next step without further purification.