Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([NH:11][CH2:12][C@@H:13]([OH:28])[C@@H:14]([NH:24][C:25](=[O:27])[CH3:26])[CH2:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=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>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[CH:19]=1)[CH2:15][C@H:14]([NH:24][C:25](=[O:27])[CH3:26])[C@H:13]([OH:28])[CH2:12][NH:11][C:8]1([C:4]2[CH:3]=[C:2]([C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(Br)c2)CC1
Reactant: COc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(-c2cccc(C3(NC[C@@H](O)[C@H](Cc4cc(F)cc(F)c4)NC(C)=O)CC3)c2)c1
Temperature: 90 °C
Yield: 31.4 %

Procedure:
To a solution of N-[(1S,2R)-3-{[1-(3-bromophenyl)cyclopropyl]amino}-1-(3,5-difluorobenzyl)-2-hydroxypropyl]acetamide (0.030 g) in DMF (0.75 mL) was added 3-methoxyphenylboronic acid (0.030 g), Cs2CO3 (0.085 g) and Pd(Ph3P)4. The mixture was heated for 12 h at 90° C. The cooled solution was diluted with EtOAc (15 mL) and washed with brine (10 mL×2). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The resulting residue was purified by column chromatography to give 0.010 g of the title compound. ES+ found (M+H+):481.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:23])[N:13]([C:16]3[CH:21]=[CH:20][N:19]([CH2:24][CH3:25])[C:18](=[O:22])[CH:17]=3)[C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c(C)n1-c1cc[nH]c(=O)c1
Reactant: CCI
Product: CCn1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1=O

Procedure:
The title compound, light brown solid, MS: m/e=353.3, 355.2 (M+H+), was prepared in accordance with the general method of example 3 from 4-[4-(2-chloro-pyridin-4-ylethynyl)-2,5-dimethyl-imidazol-1-yl]-1H-pyridin-2-one and ethyl iodide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([CH3:18])[C:3]=1[NH:19][C:20](=[O:33])[C:21]1[CH:26]=[C:25]([F:27])[C:24](F)=[C:23]([N+:29]([O-:31])=[O:30])[C:22]=1[F:32].[C-:34]#[N:35].[Na+]>CN(C)C=O>[C:34]([C:24]1[C:25]([F:27])=[CH:26][C:21]([C:20]([NH:19][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([C:8]([F:17])([C:13]([F:15])([F:16])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=2[CH3:18])=[O:33])=[C:22]([F:32])[C:23]=1[N+:29]([O-:31])=[O:30])#[N:35]
Reactant: [C-]#N
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(F)c([N+](=O)[O-])c1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-2,4,5-trifluoro-benzamide (6.77 g, 13.75 mmol) (Example I15) in N,N-dimethylformamide (137 ml) at 0° C. was added sodium cyanide (740 mg, 15.13 mmol). The reaction mixture was stirred at 0° C. for one hour and then at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue partitioned between water and dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 8:2) to give 4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (3.2 g, 46.6% yield). 1H-NMR (400 MHz, CDCl3): 2.35 (6H, s), 7.38 (2H, s), 7.83 (1H, d), 8.29 (1H, m) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[CH3:13][O: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:26]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:22][N:23]=[C:24]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]3)=[CH:35][CH:34]=2)[N:25]=1
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCCN(C(=O)OC(C)(C)C)C3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 79 %

Procedure:
To a nitrogen de-gassed solution of methyl 2-(2-ethynylphenyl)acetate (I4) (0.137 g, 0.788 mmol) in dry DMF (7 mL) were added triethylamine (0.366 mL, 2.63 mmol) followed by tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I24) (0.300 g, 0.657 mmol), triphenylphosphine (0.026 g, 0.098 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.046 g, 0.066 mmol) and CuI (0.019 g, 0.098 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes and then concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-70% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I25) (0.310 g, 79% yield) as a yellow sticky oil; 1H NMR (400 MHz, d6-DMSO) 10.44 (s, 1H), 8.81 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (td, J=7.6, 1.3 Hz, 1H), 7.50-7.34 (m, 2H), 7.24 (d, J=8.6 Hz, 2H), 4.02-3.87 (m, 4H), 3.61 (s, 3H), 2.90-2.51 (m, 4H), 1.88 (d, J=12.0 Hz, 1H), 1.76-1.55 (m, 2H), 1.51-1.34 (m, 10H). LCMS Method C: rt 6.98 min; m/z 539.2 [M-C4H9 (t-Bu)+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8](Br)[CH:7]=1)[CH3:2].[F:15][C:16]1[CH:17]=[CH:18][C:19](B2OC(C)(C)C(C)(C)O2)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:7]=[C:8]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:9]=[C:10]([Cl:12])[CH:11]=1)[CH3:2]
Reactant: CC1(C)OB(c2ccc(F)cc2C=O)OC1(C)C
Reactant: CCOC(=O)Cc1cc(Cl)cc(Br)c1
Product: CCOC(=O)Cc1cc(Cl)cc(-c2ccc(F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (3-bromo-5-chloro-phenyl)-acetic acid ethyl ester and 5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][C:16]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:17]=1[CH:18]=[CH:19][C:20](O)=O>>[CH3:15][C:16]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: Cc1ccc(C)c(C=CC(=O)O)c1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cc(C)ccc3C)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.20 g (18.2 mmol) of 2,5-dimethylcinnamic acid. Then, the resultant crude crystals were recrystallized from ethanol/toluene to give 2.56 g (yield of Compound 96 as white needles.
Reaction SMILES: C1(C2NN=C(N[C:10]3[C:15]([F:16])=C[C:13]([CH2:17]N4CCOCC4)=[C:12]([NH:24][C@H:25](C4C=CC(F)=CC=4)C)[N:11]=3)C=2)CC1.[BH4-].[Na+].C[OH:37]>>[F:16][C:15]1[CH:25]=[N:24][C:12]([CH:13]([OH:37])[CH3:17])=[N:11][CH:10]=1
Reactant: CO
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1CCOCC1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1ncc(F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
1-(5-Fluoropyrimidin-2-yl)ethanone (Method 75, 0.77 g) was dissolved in MeOH (15 ml), and the solution was cooled to 0° C. NaBH4 (0.210 g, 5.55 mmol) was added. The mixture was stirred at room temperature for 1 hour and then partitioned between EtOAc and H2O. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated to give the title compound as a yellowish oil (0.79 g, 99%). 1H NMR (CDCl3) δ 8.65 (s, 2H), 5.20 (m, 1H), 4.00 (br s, 1H), 1.80 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]2[NH:7][C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)(=[O:29])[CH3:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:27]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:6]=2[NH:7][C:8](=[O:12])[CH2:9]1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CNC2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CN(C(C)=O)C2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
To a slurry of 7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (100 mg, 0.42 mmol) in dichloromethane (10 mL) was syringed N,N-diisopropylethylamine (0.15 mL, 0.84 mmol). The mixture was cooled in an ice-water bath and acetyl chloride (0.04 mL, 0.55 mmol) was added via syringe. After 15 minutes LCMS indicated completion of the reaction. Dichloromethane (10 mL) and 10% aqueous citric acid (10 mL) were added and the mixture was stirred while being allowed to warm to room temperature. The mixture was filtered and the collected solid was washed with water and dried to constant weight to give 4-acetyl-7-methoxy-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (70 mg, 60%) as a yellow solid. NMR analysis indicated a mixture of two conformational isomers, similar to that observed for the related trifluoroacetyl analog (see procedure 6c); NMR (400 MHz, DMSO-d6) δ 10.19/10.17 (2s, 1H), 7.69/7.66 (2s, 1H), 7.46/7.35 (2s, 1H), 4.78/4.67 (2s, 2H), 4.36/4.37 (2s, 2H), 3.90/3.92 (2s, 3H), 2.05 (s, 3H); MS (m/e) 278 (M−1); mp 266° C. (dec.).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]([C:21]([CH3:29])([CH3:28])[O:22][SiH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:12]=1[O:30][CH2:31][O:32][CH3:33])=[O:5].Br[C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=1>>[C:24]([SiH2:23][O:22][C:21]([CH3:29])([CH3:28])[C:13]1[C:12]([O:30][CH2:31][O:32][CH3:33])=[C:11]([CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[C:4]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][O:44][CH3:45])=[CH:38][CH:37]=2)=[O:5])[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: COCOc1cc(C2CCCC2C(=O)N(C)OC)c(OCOC)c(C(C)(C)O[SiH2]C(C)(C)C)c1
Reactant: COCOc1ccc(Br)cc1
Product: COCOc1ccc(C(=O)C2CCCC2c2cc(OCOC)cc(C(C)(C)O[SiH2]C(C)(C)C)c2OCOC)cc1
Yield: 76.4 %

Procedure:
Use conditions analogous to those described in Step E of Examples 1A and 1B to couple (±)-2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-2,5-bis-methoxymethoxy-phenyl]-cyclopentanecarboxylic acid methoxy-methyl-amide (0.622 g, 1.25 mmol) and 1-bromo-4-methoxymethoxy-benzene (0.543 g, 2.50 mmol). Purify the material by silica gel chromatography eluting with Hex:EtOAc (90:10) to afford the subtitled product (0.549 g, 76%) as an oil. 1H NMR (CDCl3) δ 0.02 (s, 3H), 0.04 (s, 3H), 0.90 (s, 9H), 1.72-1.77 (m, 1H), 1.91-2.12 (m, 4H), 2.21-2.30 (m, 1H), 3.38 (s, 3H), 3.43 (s, 3H), 3.59 (s, 3H), 3.80-3.87 (m, 1H), 4.18-4.25 (m, 1H), 4.55 (dd, J=13.6, 44.7 Hz, 2H), 4.89 (dd, J=5.9, 7.5 Hz, 2H), 4.95 (dd, J=6.6, 20.3 Hz, 2H), 5.12 (dd, J=6.8, 7.9 Hz, 2H), 6.61 (d, J=3.0 Hz, 1H), 6.75 (d, J=3.0 Hz, 1H), 6.81 (d, J=8.9 Hz, 2H), 7.63 (d, J=8.9 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCO)c1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Yield: 96.1 %

Procedure:
To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0° C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min. The addition is exothermic and the methanesulfonyl chloride is added at a rate to keep the temperature below 10° C. After the addition is complete, warm the reaction to ambient temperature. Wash the solution with water (2×500 mL), and then brine (750 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction without further purification. An analytical sample is obtained by flash column chromatography eluting with 100% diethyl ether. 1H NMR (300 MHz, CDCl3), δ 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H, J=8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDCl3), δ 158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; 13C NMR (300 MHz, DMSO-d6), δ 157.58, 136.79, 127.81, 122.91, 122.00, 109.33, 70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm−1; MS (ES+) m/z 257 (M+H)+; Anal. Calc'd. for C13H20O7S2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68; N, 0.13; Rf=0.72 eluting with 95:5 DCM/methanol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([O:21]C)=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:19]([OH:21])=[O:20])[CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:11]=1
Reactant: COCCOc1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCOc1cc(C(=O)O)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 5-(2-methoxyethoxy)-4′-methylbiphenyl-3-carboxylate (703 mg, 2.34 mmol) in tetrahydrofuran (40 mL) was added 2.5 M aqueous lithium hydroxide solution (9.6 mL, 24 mmol). After being stirred at room temperature overnight, the mixture was acidified to pH=5 by addition of 2N HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford the title compound. 1H NMR (CD3OD, 400 MHz): 7.84 (t, 1H, J=1.6 Hz), 7.55-7.51 (m, 3H), 7.34 (t, 1H, J=2.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 4.22 (m, 2H), 3.79 (m, 2H), 3.45 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[CH2:4][C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]#[N:31])=[CH:24]5)[CH2:16][CH2:15]3)[C:7]=2[CH:6]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:30]([C:25]1[N:26]([CH2:36][C:37]([NH2:39])=[O:38])[C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:12]3[C:7]4[CH:6]=[C:5]([CH2:4][C:3]([F:33])([F:2])[F:34])[S:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]1)=[CH:29][CH:28]=2)#[N:31]
Reactant: NC(=O)CBr
Reactant: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2n1CC(N)=O
Yield: 40.3 %

Procedure:
760 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride (1.5 mmol) and 207 mg of bromoacetamide (1.5 mmol) were dissolved in 3.6 mL of dry DMF. 1.96 g of cesium carbonate (6 mmol) was added and reaction mixture was stirred for 4 hs. Then it was quenched with 50 mL of water and extracted with DCM-MeOH 10:1. Combined organic extracts were evaporated with silica gel and loaded on column. The product was eluted with DCM-MeOH 10:1 mixture. After evaporation of product containing fractions it was recrystallized from MeOH to produce 319 mg of 2-(2-cyano-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide, which was converted to hydrochloride salt by dissolving in 5 mL of MeOH, adding of 1 eq of 1M HCl in water. Hydrochloride salt can be recrystallized further from MeOH. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.44 (s, 1H), 7.91 (s, 1H), 7.57 (m, 2H), 7.41 (s, 1H), 5.10 (s, 2H), 4.53 (m, 1H), 4.47 (s, 1H), 3.89 (q, 2H, J=10.3 Hz), 3.62 (m, 2H), 3.24 (m, 2H), 2.35 (m, 2H), 1.93 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 171.07, 157.66, 153.62, 140.17, 130.77, 129.55, 127.95, 127.10, 125.64, 123.46, 121.90, 118.31, 114.76, 113.69, 113.52, 112.60, 61.96, 52.67, 49.60, 47.98, 47.40, 35.52 (q, J=33 Hz), 29.96. ESI MS [MH+]: 528.1783.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9]([N:12]([CH3:18])[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])(=[O:11])=[O:10].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21]>CC(C)=O>[CH3:8][S:9]([N:12]([CH3:18])[N:13]([S:14]([CH3:17])(=[O:15])=[O:16])[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[O:21])(=[O:10])=[O:11]
Reactant: CN(NS(C)(=O)=O)S(C)(=O)=O
Reactant: COc1ccc(OC(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(OC(=O)N(N(C)S(C)(=O)=O)S(C)(=O)=O)cc1
Reaction time: 1 h

Procedure:
1,2-Bis(methylsulfonyl)-2-[(4-methoxyphenoxy)carbonyl]-1-methylhydrazine (compound 9) was synthesized as follows: Triethylamine (0.269 g, 0.0029 mol) was added to a stirred solution of 1,2-bis(methylsulfonyl)-1-methylhydrazine (0.50 g, 0.0025 mol) and 4-methoxyphenyl chloroformate (0.63 g, 0.0033 mol) in acetone (30 ml) and the mixture stirred for 1 hr. The reaction mixture was filtered and the filtrate evaporated to dryness in vacuo. The residue was triturated with petroleum ether (5 ml) and the petroleum ether layer decanted. Column chromatography of the residue on silica gel (70-270 mesh, 60 Angstroms, CHCl3), followed by crystallization from ethanol gave 0.14 g (16.1%) of the desired compound. Mp was approximately 101-102° C. 1H NMR (acetone-d6) : δ 7.3 and 7.0 (4H, 2d, aromatic H), 3.9 (3H, s, OCH3), 3.6, 3.4 and 3.2 (9H, 3s, 2 CH3SO2 and NCH3).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(O)(C)C.[NH2:8][N:9]1[C:14](=[O:15])[CH:13]([F:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[C:10]1SC>C(O)(=O)C>[NH2:8][N:9]1[C:14](=[O:15])[CH:13]([F:16])[N:12]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:11]=[C:10]1[N:2]([CH3:3])[CH3:1]
Reactant: CSC1=NN(C(C)(C)C)C(F)C(=O)N1N
Reactant: CNC
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CN(C)C1=NN(C(C)(C)C)C(F)C(=O)N1N
Temperature: 25 °C
Yield: 68.8 %

Procedure:
13.6 g (0.3 mole) of dimethylamine were introduced into a mixture of 350 ml of isopropanol and 12 g of glacial acetic acid, while cooling with ice. 21.8 g (0.1 mole) of 4-amino-6-fluoro-tert.-butyl-3-methylthio-1,2,4-triazin-5-one (obtained as described in Example 2) were then added to this reaction solution. The mixture was allowed to warm to room temperature and was then heated under reflux for 15 hours. Thereafter, the reaction mixture was concentrated and the oily residue was stirred into water. The mixture was extracted with methylene chloride and the extract was dried over sodium sulphate and concentrated. The oily residue was taken up in diisopropyl ether, seed crystals were added and the solid which crystallized out was filtered off and dried. 15.9 g (69% of theory) of 4-amino-3-dimethylamino-6-fluoro-tert.-butyl-1,2,4-triazin-5-one of melting point 86°-87° C. were obtained.
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11](N1[C@@H](C(C)C)COC1=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[C:11]([OH:12])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)C1CCCCC1)Cc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)C[C@@H](Cc1ccccc1)C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.4 %

Procedure:
100 mg (2.42 mmole) of lithium hydroxide were added to a solution of 500 mg (1.21 mmole) of 3-[2(R)-benzyl-4-(N-cyclohexyl-N-methylamino)-4-oxobutyryl]-4(S)-isopropyl-2-oxazolidinone (which had been prepared by a similar procedure to those described in Preparations 12-14) in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with an aqueous solution of sodium bicarbonate and extracted with methylene chloride. The aqueous layer was adjusted to a pH value of 2 by the addition of an aqueous solution of citric acid and was then extracted with methylene chloride. The latter methylene chloride extract was dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure, to afford 130 mg of the title compound as an amorphous product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:32])[CH3:31]>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:36]4[CH2:37][CH2:38][N:33]([CH:30]([CH3:32])[CH3:31])[CH2:34][CH2:35]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 35 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-isopropylpiperazine to give the title compound in 35% yield; NMR Spectrum: 0.91 (d, 6H), 2.38 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.51-2.56 (m, 1H), 2.76 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.47 (br s, 1H), 8.59 (d, 1H); Mass Spectrum: 523 (MH+).