Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:15][C:14]1[C:10]([C:8]2[S:9][C:5]3[CH:4]=[C:3]([CH2:2][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH:18]=[CH:17][C:6]=3[N:7]=2)=[C:11]([NH2:16])[NH:12][N:13]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: C1COCCN1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN3CCOCC3)cc2s1

Procedure:
The title compound (27 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess morpholine. MS (m/z, ES+): 330.1 (M+1, 30%), 243 (M-O(CH2)4N, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][CH3:19])[CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:18][CH3:19])[CH2:9][NH2:10])=[CH:6][CH:7]=1
Reactant: COC(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(CN)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 2-(4-chlorophenyl)-2-methoxyethylcarbamate (0.129 g, 0.451 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml), and the reaction was stirred at ambient temperature for 16 hours. The reaction was concentrated and taken up in water. Sodium hydroxide (1M) was added until the pH was >13. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to yield 71 mg of the title compound (84.7% yield).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:23])([CH3:22])[C:18]([O:20]C)=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:22])([CH3:23])[C:18]([OH:20])=[O:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: COC(=O)C(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)O)ccc2n1CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
To a solution of methyl 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoate (Step G, 1.07 g, 2.64 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2N sodium hydroxide aqueous solution (5 mL) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was made acidic with 2N hydrochloric acid (pH ˜4) and concentrated under reduced pressure. The residue was dissolved in water (50 mL) and dichloromethane (50 mL). The aqueous layer was separated and extracted with dichloromethane (50 mL×2). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound (920 mg, 89%) as a white solid.
Reaction SMILES: ClC1C=CC(C(C2C=CC=CC=2C2C(C)=NOC=2/C=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=O)=CC=1.[Cl:30][C:31]1[CH:52]=[CH:51][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[C:44]([CH:49]=O)=[N:45][O:46][C:47]=2[CH3:48])=[O:36])=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:52]=[CH:51][C:34]([C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:43]2[C:44](/[CH:49]=[N:20]/[S@@:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])=[N:45][O:46][C:47]=2[CH3:48])=[O:36])=[CH:33][CH:32]=1
Reactant: Cc1onc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1noc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Product: Cc1onc(/C=N/[S@](=O)C(C)(C)C)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
This material can be made in a similar manner as (R,E)-N-((4-(2-(4-chlorobenzoyl)phenyl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide starting from 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde (1.10 g, 3.38 mmol). LC/MS m/z 429 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])[CH3:10].C[Li].CI.O1CC[CH2:25][CH2:24]1>CCOCC>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH2:24][CH3:25])[CH3:10]
Reactant: COc1ccccc1C(C)c1ccccc1OC
Reactant: C1CCOC1
Agent: [Li]C
Solvent: CI
Solvent: CCOCC
Product: CCC(C)(c1ccccc1OC)c1ccccc1OC
Reaction time: 2 h

Procedure:
1,1-Bis(2-methoxyphenyl)ethane (5.6 g) was dissolved in 25 ml of tetrahydrofuran and 25 ml of a 1.3M solution of methyl lithium in ether was added dropwise with stirring. The solution became dark red and exothermed. After 2 hours, 5.0 ml of methyl iodide was added slowly with stirring. The solution again exothermed. When all of the methyl iodide had been added the starting material was found to be completely consumed and replaced by a single product by gas-liquid chromatography. About 300 ml of ether was added and the resulting solution was extracted with 100 ml of water and then 100 ml of brine, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 5.46 g (88 percent of theory) of the title compound as a pale yellow crystalline solid melting at 49°-52° C. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>C1COCC1.O>[Cl:13][C:14]1[CH:19]=[C:18]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: OB(O)c1cccc(Cl)c1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]nc(-c2cccc(Cl)c2)c2ccccc12
Yield: 85 %

Procedure:
A solution of 1-chlorophthalazine-4-one (1.0 g, 5.5 mmol), 3-chlorophenyl boronic acid (1.3 g, 8.3 mmol), tricyclohexyphosphine (0.058 g, 0.27 mmol), and K3PO4 (2.3 g, 11.0 mmol) in THF (20 mL) and water (5 mL) was degassed with N2 for 30 min then treated with tri(dibenzylideneacetone)-dipalladium (0.050 g, 0.05 mmol) and heated at reflux overnight. The reaction mixture was diluted with water (100 mL) and the product extracted with EtOAc (2×100 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to give 4-(3-chlorophenyl)phthalazin-1(2H)-one (1.2 g), (MS: ESI +ve, 257.12 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 7.58-7.60 (m, 2H), 7.61-7.64 (m, 2H), 7.65-7.67 (m, 1H), 7.90-7.93 (m, 2H), 8.34-8.36 (m, 1H). 12.93 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:8]3[CH2:17][CH2:16][CH2:15][CH:9]3[C:10](=S)[NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[NH3:18]>>[NH2:18][C:10]1[CH:9]2[CH2:15][CH2:16][CH2:17][CH:8]2[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=2[N:11]=1
Reactant: N
Reactant: O=[N+]([O-])c1ccc2c(c1)NC(=S)C1CCCC21
Product: NC1=Nc2cc([N+](=O)[O-])ccc2C2CCCC12

Procedure:
7-Nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (47 mg, 0.19 mmol) is stirred in 7N methanolic ammonia (10 ml) for 15 hours at room temperature. The batch is concentrated by evaporation in a vacuum. The residue is purified on silica gel with dichloromethane-2-propanol/methanol: 21 mg (48%) of product.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:33])C.[OH-].[Na+]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][C:39]3[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][C:32]([OH:33])=[O:31])=[CH:37][CH:38]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(Nc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and [4(2-ethoxycarbonylethyl)phenyl]boronic acid using the procedure of example 110 followed by hydrolysis with NaOH; MS (ESI) m/z 527([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4]O.S(Cl)([Cl:15])=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH2:4][Cl:15]
Reactant: COc1ccc(F)c(F)c1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(F)c(F)c1CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-difluoro-6-methoxybenzyl alcohol (6.97 g) in toluene (100 mL) was added thionyl chloride (4.4 mL) in a dropwise manner at room temperature, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine twice, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (7.65 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:50][CH3:51].O>CN(C=O)C>[CH2:50]([O:1][CH2:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:4]=1)[CH3:51]
Reactant: CCI
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(CO)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Yield: 100 %

Procedure:
The solution of (R)-1-(3-(hydroxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (124 mg, 0.224 mmol), cesium carbonate (146 mg, 0.448 mmol) and iodoethane (26.9 μl, 0.336 mmol) in DMF was stirred at 60° C. for 24 h. Water was added into the solution and extracted with EtOAc for twice. The combined organic extracts were washed with water, brine and dried over Na2SO4. After concentration (R)-1-(3-(ethoxymethyl)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (130 mg, 0.224 mmol, 100% yield) was yielded without purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19])(=[O:7])=[O:6].[K].CC(C)([O-])C.O>CN(C=O)C>[O:6]=[S:5]1(=[O:7])[CH2:4][CH2:3][CH2:2][N:8]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(NS(=O)(=O)CCCCl)c(C)c1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCS2(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
370 mg (0.85 mmol) 70% methyl 4-(3-chloropropane-sulphonylamino)-3-methyl-benzoate dissolved in 26 ml DMF are combined with 275 mg (2.45 mmol) potassium-tert.-butoxide and stirred for 16 hours at ambient temperature. The reaction mixture is combined with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac. and the residue is purified by chromatography on silica gel (eluant: dichloromethane/isopropanol 98:2).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1/C=C/c1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2/C=C/c2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(E)-2-(4-fluorophenyl)ethenyl]phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.82 (1H, d, J=1.6 Hz), 6.96-7.04 (4H, m), 7.22-7.23 (1H, m), 7.34-7.41 (5H, m), 7.59 (1H, d, J=1.6 Hz), 7.90 (1H, s), 8.51 (1H, d, J=4.8 Hz). [M+H] Calc'd for C24H16F2N4O, 415; Found, 415.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[CH:24]1([C:27](Cl)=[O:28])[CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:27]([CH:24]3[CH2:26][CH2:25]3)=[O:28])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc2cccc(CNC(=O)C3CC3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.53 g, 1.6 mmol) in acetonitrile (10 mL), was added cyclopropane carboxylic acid chloride (0.16 mL, 1.7 mmol) and N,N-diisopropyl ethylamine (0.59 mL, 3.6 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give cyclopropanecarboxylic acid [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-amide as an off-white solid (310 mg, 54% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.50 min (98.6%); mp, decomposed at 298° C.; 1HNMR (DMSO-d6) 0.67-0.70 (m, 4H, cyclo-CH2CH2), 1.65-1.73 (m, 1H, cyclo-CH), 2.11-2.20 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 4.77-4.87 (m, 2H, CH2NH), 5.23 (dd, J=6, 12 Hz, 1H, CH), 7.31-7.78 (m, 3H, Ar), 8.44 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 6.28, 13.57, 20.76, 23.28, 30.58, 41.53, 56.47, 117.65, 124.50, 125.44, 133.89, 141.14, 148.44, 154.77, 160.94, 169.53, 172.60, 172.73. LCMS MH=369; Anal Calcd For C19H20N4O4+0.1H2O: C, 61.65; H, 5.50; N, 15.13. Found: C, 61.48; H, 5.47; N, 14.97.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:41][S:42][CH2:43]Cl>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:41][S:42][CH3:43])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCSC)c1)C(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a) in 5 ml of dimethylformamide is added dropwise to a suspension, stirred at room temperature, of 7.6 mg of a 65% NaH dispersion in 3 ml of dimethylformamide. The reaction mixture is stirred for a further 30 minutes at more temperature and then a solution of 0.017 ml of chlorodimethyl sulfide in 2 ml of dimethylformamide is added thereto. The reaction mixture is stirred for a further 24 hours and then concentrated by evaporation. The residue is partitioned between ether and water. The organic phases are concentrated by evaporation and the title compound is obtained from the residue by FC (12 g of silica gel, dichloromethane/diethyl ether=2:1): Rf (dichloromethane/diethyl ether=2:1)=0.33.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][NH:22][C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([C:29]4[CH:30]=[C:25]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:22][CH3:21])=[O:24])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cccc(-c2cc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1
Temperature: 130 °C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (80 mg, 0.28 mmol) and 3-(N-methylaminocarbonyl)phenyl boronic acid (1.4 equiv.) were suspended in 2 ml acetonitrile. Sodium carbonate (3 equiv., 92 mg) and bis(triphenylphosphine)palladium(II) chloride (0.05 equiv.) were added as a solution in water (0.5 ml). The reaction mixture was heated in microwave at 130° C. for 20 min. Water was added to the mixture, and the precipitated product was filtered and purified by column chromatography to yield 111. NMR (CDCl3): 3.11 (3H, d), 4.34 (3H, s), 6.25 (1H, br), 7.56 (1H, m), 7.63-7.70 (2H, m), 7.84 (1H, d), 7.87 (1H, s), 7.90 (1H, d), 8.00 (1H, d), 8.21 (1H, s), 8.27 (1H, s), 8.97 (1H, s). MS: MH+ 383.09 (100%)
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]#[C:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:35][C:31]3[CH:32]=[C:33]4[C:28](=[CH:29][CH:30]=3)[CH2:27][N:26]([CH3:25])[CH2:34]4)[N:24]=2)[CH:9]=[CH:8][CH:7]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ccccc1C#Cc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1Cc2ccc(N)cc2C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
N-Methyl-N-{2-[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl]-phenyl}-methanesulfonamide was prepared from N-[2-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.208 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (35.0 mg, 0.236 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.004 g, 4%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.43 (d, J=6.9 Hz, 1H), 7.68-7.61 (m, 2H), 7.56-7.49 (m, 2H), 7.47-7.35 (m, 3H), 7.20 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 6.89 (t, J=7.0 Hz, 1H), 3.96 (s, 2H), 3.90 (s, 2H), 3.61 (s, 3H), 3.21 (s, 3H), 2.61 (s, 3H). MS=473 (MH)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:23][C:24]1[CH:25]=[CH:26][C:27](F)=[N:28][CH:29]=1.O>O1CCCC1>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:28][CH:29]=1
Reactant: Fc1ccc(Br)cn1
Reactant: N#CC1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
After 1,4-dioxaspiro[4,5]decane-8-carbonitrile (2.5 g) was dissolved in tetrahydrofuran (8 ml), 1M tetrahydrofuran-solution of lithium bis(trimethylsilyl)amide (15 ml) was added at 0° C. and stirred for 30 minutes. 5-Bromo-2-fluoropyridine (2.64 g) was further added and stirred at room temperature for two hours. Water was added to the reaction solution, extracted with ethyl acetate and concentrated in vacuo. The residue was purified with silica gel chromatography (n-hexane/ethyl acetate) and the resulting solid was washed with n-hexane to give the titled compound (3.32 g).
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:6](ON1C(=O)CCC1=O)=[O:7])[CH:3]([CH3:5])[CH3:4].[NH2:33][C@H:34]([C:54]([OH:56])=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[C:52]([CH3:53])=[C:50]([CH3:51])[C:47]([O:48][CH3:49])=[CH:46][C:44]=1[CH3:45])(=[O:42])=[O:41]>>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@H:2]([C:6]([NH:33][C@H:34]([C:54]([OH:56])=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][NH:39][S:40]([C:43]1[C:52]([CH3:53])=[C:50]([CH3:51])[C:47]([O:48][CH3:49])=[CH:46][C:44]=1[CH3:45])(=[O:42])=[O:41])=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)ON1C(=O)CCC1=O
Reactant: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](N)C(=O)O)c(C)c1C
Product: COc1cc(C)c(S(=O)(=O)NCCCC[C@H](NC(=O)[C@@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(C)C)C(=O)O)c(C)c1C

Procedure:
This was prepared from Fmoc-Val-OSu 7b (20.7 mmol) and Lys(Mtr) 2 (9.09 g, 1.05 equiv) as described above for 8a (15.28 g, 100%). 1H-NMR (CDCl3/CD3OD) δ 0.85 (m, 6H), 1.20 (m, 2H), 1.59 (m, 4H), 1.99 (m, 1H), 2.41 (m, 2H), 3.71 (s, 3H), 4.21 (m, 5H), 6.78 (d, 2H), 7.29 (m, 16H), 7.51 (brt, 2H), 7.71 (d, 2H). MS (FAB) 740 (MH)+, 762 (M+Na)+. HRMS Calcd: 740.3700. Found: 740.3712.
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]3[S:24][CH:25]=[C:26]([CH3:28])[N:27]=3)[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)(C(C)(C)C)(C)C.C1COCC1.Cl>O>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:18]2[CH:17]=[C:16]([S:15][C:11]3[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=3)[CH:21]=[CH:20][N:19]=2)[S:24][CH:25]=1
Reactant: Cc1csc(Nc2cc(Sc3cccc(O[Si](C)(C)C(C)(C)C)c3)ccn2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc(Nc2cc(Sc3cccc(O)c3)ccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
A 3 dram vial was charged with 4-(3-(tert-butyldimethylsilyloxy)phenylthio)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.470 g, 1.09 mmol and THF (2 mL) and 6M HCl (1 mL) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give desired product (0.309 g, 89.6% yield) as yellow solid. 1H NMR (DMSO) δ 11.07 (s, 1H), 9.84 (s, 1H), 8.08 (d, 1H), 7.32 (t, 1H), 6.98 (m, 1H), 6.92 (m, 2H), 6.76 (d, 1H), 6.59 (dd, 1H), 6.51 (d, 1H), 2.20 (d, 3H); Mass spectrum (esi) m/z=316 (100) (M+H).