Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.Cl.[CH3:17][O:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1.CCN(C(C)C)C(C)C.[Cl-].[Na+]>C(OCC)(=O)C.CN1C(=O)CCC1>[Br:8][C:6]1[N:7]=[C:2]([NH:25][C@H:22]2[CH2:23][CH2:24][C@H:19]([O:18][CH3:17])[CH2:20][CH2:21]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: CO[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ncc(Br)nc1N[C@H]1CC[C@H](OC)CC1
Temperature: 125 °C

Procedure:
Alternatively, ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (1 equiv) and trans-4-methoxycyclohexanamine hydrochloride (1.5 equiv), NMP and DIPEA were combined and heated to 125° C. and maintained at that temperature for 18 h. Upon reaction completion, the mixture was cooled to room temperature and transferred to a mixture of ethyl acetate and aqueous sodium chloride. The aqueous layer was removed and the organic layer was washed successively with aqueous sodium chloride and water. The organic layer was concentrated by vacuum distillation to a low volume, cooled to ambient temperature and the solids were collected and dried to give ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate. A mixture of ethyl 2-(5-bromo-3-(trans-4-methoxycyclohexylamino)pyrazin-2-ylamino)acetate (1 equiv), water (161 equiv) and 85% phosphoric acid (16.5 equiv) was heated at 80° C. Upon reaction completion, the mixture was cooled to 25° C., filtered and the solids were washed with water. The solids were resuspended in water and the filtration and wash were repeated. The resulting material was dried to give 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 7-Bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol (1.08 equiv) and PdCl2(AmPhos)2 (0.0025 equiv) were combined in tetrahydrofuran. The mixture was treated with a solution of potassium carbonate (2.5 equiv) and heated to reflux. After cooling to 40° C., toluene was added, and the layers were separated. The organic layer was washed with potassium dihydrogenphosphate solution and treated with a metal scavenger (SiliaBond® Thiol). The mixture was filtered and distilled with the addition of toluene until the temperature reached 100° C. Upon cooling the resulting solids were collected by filtration and dried. The solid was combined with butylated hydroxyl toluene (BHT) (9×10−4 equiv) in IPA and water (3×:5×vol). The mixture was heated to 65° C. and while maintaining this temperature, water (5×vol) was added. A small amount of the title compound (0.02 equiv) in water was added. The mixture was allowed to stand for 2 h, cooled to room temperature and stirred. The resulting solids were collected by filtration and dried to give 7-(6-(2-hydroxypropan-2-yl)pyridin-3-yl)-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([CH3:18])[CH:8]=1)=O.Cl.[S:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][CH:28]=1)(=[O:26])(=[O:25])[NH2:24]>C(O)C>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:33]([C:30]3[CH:29]=[CH:28][C:27]([S:23]([NH2:24])(=[O:26])=[O:25])=[CH:32][CH:31]=3)[N:34]=[C:3]([C:2]([F:21])([F:20])[F:1])[CH:4]=2)=[CH:8][C:9]=1[CH3:18]
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1-c1ccco1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2cc(C(F)(F)F)nn2-c2ccc(S(N)(=O)=O)cc2)ccc1-c1ccco1
Temperature: 25 °C
Yield: 19.9 %

Procedure:
To a stirred soluition of 4,4,4-trifluoro-1-[4-(2-furyl)-3-methylphenyl]butane-1,3-dione (0.53 g, 1.80 mmol) in ethanol (22.5 ml) was added (4-sulfamoylphenyl)hydrazine hydrochloride (0.44 ml, 1.98 mmol), and the mixture was heated at reflux temperature for 16 hours. The mixture was cooled down to room temperature, and concentrated in vacuo. The residue was dissolved in ethyl acetate. washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/hexane (1/3). The resulting solid was recrystallized with dichloromethane-hexane to give the title compound (0.16 g, 20% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])(C)(C)C.C(O[C:28](=[O:45])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:43]=[N:42][C:41]([CH3:44])=[N:40][CH:39]=2)[CH:33]=1)=O)(C)(C)C>>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:28](=[O:45])[CH2:29][C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]4[N:43]=[N:42][C:41]([CH3:44])=[N:40][CH:39]=4)[CH:33]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1ncc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1ncc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)nn1

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (160 mg, 0.5 mmol) and 3-[3-(3-methyl-[1,2,4]triazin-6-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K46) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (8 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[C:10](OC([O-])=O)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>CO.[Ni]>[C:13]([O:12][C:10](=[O:11])[NH:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: N#Cc1ccnc(Cl)n1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccnc(Cl)n1
Yield: 83.5 %

Procedure:
2-Chloropyrimidine-4-carbonitrile (24 g), 40.8 g of t-butyl dicarbonate (Boc2O) in 1.2 L of methanol and 5 g of Raney nickel (Raney 2400) were charged in an autoclave. The autoclave was sealed and purged with hydrogen. The hydrogenation was run at 30 psi hydrogen gas. The reduction was carried out to completion and the reactor was vented and purged with nitrogen. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated. The residue was purified by chromatography to yield the title compound (35 g, 84%) as white solid of melting point of 86-88° C.
Reaction SMILES: C(O)C.B([O-])([O-])O[C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH:10]=[C:6]1[C:18]1[CH:19]=[CH:20][C:21]2[S:27](=[O:29])(=[O:28])[CH2:26][CH2:25][C:24]([C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:47])[CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[CH:35][CH:34]=3)=[O:31])=[CH:23][C:22]=2[CH:48]=1
Reactant: [O-]B([O-])Oc1cc2ccccc2o1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4cc5ccccc5o4)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
In toluene (15 ml), ethanol (1.5 ml) and water (1.5 ml) were suspended benzofuran-2-yl borate (122 mg), 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) and potassium carbonate (208 mg), and the suspension was stirred under argon atmosphere for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred, under argon atmosphere, at 100° C. for 8 hours and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography and recrystallized from ethanol (120 ml) to give colorless crystals of 7-(benzofuran-2-yl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 138) (188 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[NH2:17].C(O)(=O)C>O>[CH3:22][O:21][C:19]1[CH:18]=[C:16]([N:17]=[CH:8][C:7]2[C:2]([NH2:1])=[N:3][C:4]([S:10][CH3:11])=[N:5][CH:6]=2)[CH:15]=[C:14]([O:13][CH3:12])[CH:20]=1
Reactant: CSc1ncc(C=O)c(N)n1
Reactant: COc1cc(N)cc(OC)c1
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N=Cc2cnc(SC)nc2N)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a suspension of 4.36 g (23.7 mmol) of 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (made as described in WO 98/33798) and 3.65 g (23.7 mmol) of 3,5-dimethoxyaniline in 165 mL of water was added 4.5 mL of glacial acetic acid. The reaction was stirred at 25° C. overnight and filtered. The filter pad was washed with water, and the filtrate was dried in vacuo to give 7.02 g (96%) of the title compound, which was used as is in the next step.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][O:26][CH2:27][C:28](O)=[O:29])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:29])[CH2:27][O:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:24]=1
Reactant: CNOC
Reactant: O=C(O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4.03 mmol of (1-trityl-1H-imidazol-4-ylmethoxy)acetic acid and 4.44 mmol of N,O-dimethylhydroxylamine hydrochloride in 100 ml of dichloromethane is mixed with 20.2 mmol of triethylamine and 4.44 mmol of propanephosphonic acid cyclic anhydride [68957-94-8] (50% in ethyl acetate). The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is obtained as a pale yellowish solid from the residue by flash chromatography (SiO2 60F). Rf=0.45 (dichloromethane-methanol 95:5); Rt=4.11 (gradient I).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:20][C:14]=2[N:13]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:30]1[CH:34]=[C:33]([CH2:35][C:36](O)=[O:37])[N:32]=[CH:31]1>>[CH2:1]([O:8][CH2:9][C@H:10]([NH:11][C:36](=[O:37])[CH2:35][C:33]1[N:32]=[CH:31][NH:30][CH:34]=1)[C:12]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:20][C:14]=2[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N[C@@H](COCc1ccccc1)c1nc2cc(Oc3ccc(F)cc3)ccc2[nH]1
Yield: 39 %

Procedure:
Proceeding as in Example 1, but substituting (R)-2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethanamine and 4-imidazoleacetic acid hydrochloride gave Compound 59, (R)—N-(2-(benzyloxy)-1-(5-(4-fluorophenoxy)-1H-benzo[d]imidazol-2-yl)ethyl)-2-(1H-imidazol-4-yl)acetamide (75 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.56 (d, J=9.2 Hz, 1H), 7.33-7.25 (m, 5H), 7.20-7.16 (m, 3H), 7.00-6.96 (m, 3H), 6.89 (dd, J=8.8, 2.0 Hz, 1H), 5.35-5.30 (m, 1H), 4.52 (s, 2H), 3.95-3.84 (m, 2H), 3.56-3.46 (m, 2H); ESI MS: m/z 486.2 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3]/[CH:4]=[CH:5]/[C:6](NC1C=CC=C(NC2C=C(NC3C=CC=CC=3)N=CN=2)N=1)=[O:7].C(#N)C.Cl.CN(/C(=C\C)/C(O)=O)C.C(Cl)(=O)C([Cl:46])=O>CN(C=O)C>[CH3:1][N:2]([CH2:3]/[CH:4]=[CH:5]/[C:6]([Cl:46])=[O:7])[CH3:29]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C)C/C=C/C(=O)Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Agent: C/C=C(/C(=O)O)N(C)C
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN(C)C/C=C/C(=O)Cl
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
Synthesis of (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) To a stirred solution of acetonitrile (20 mL) and DMF (0.05 mL) under N2 was added N,N-dimethylamino crotonic acid hydrochloride (0.47 g, 2.8 mmol). After 10 min this solution was cooled to 0-5° C. Oxalyl chloride (0.44 g, 3.5 mmol) was added and the reaction mixture was maintained at 0-5° C. for 30 min. It was allowed to warm to rt and stirring was continued for 2 h. It was then heated to 40° C. for 5 min and again brought to rt and stirred for 10 min to get a light greenish colored solution of dimethylaminocrotonyl chloride that was used as such for next step. To a stirred solution of N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (0.2 g, 0.7 mmol) in NMP (10 mL) was added dropwise under N2 atmosphere at 0° C. the solution of dimethylaminocrotonyl chloride. The reaction mixture was maintained at this temperature for 30 min and was warmed to rt and stirred for 2 h. The mixture was quenched with sodium bicarbonate solution (1 mL) and was extracted with EtOAc (2×35 mL). The combined ethyl acetate extract was washed with water (20 mL) and brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, product was eluted at 4-6% methanol in chloroform) to give (E)-4-(dimethylamino)-N-(6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-73) as a yellowish solid. 1H NMR (DMSO-d6) δ ppm: 2.24 (s, 6H), 3.13 (d, J=5.76 Hz, 2H), 6.56 (d, J=15.52 Hz, 1H), 6.80 (d, J=15.36 Hz, 1H), 6.95 (t, J=7.36 Hz, 1H), 7.11 (t, J=1.16 Hz, 1H), 7.29 (t, J=7.56 Hz, 2H), 7.58 (s, 1H), 7.65-7.7 (m, 4H), 8.31 (d, J=2.44 Hz, 1H), 9.23 (s, 1H), 9.68 (s, 1H), 10.16 (s, 1H); LCMS: m/e 390.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=O.[Cl-].[OH:16][NH3+:17].C([O-])(=O)C.[Na+]>C(O)C.O>[F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1)=[N:17][OH:16]
Reactant: CSc1ccc(C(=O)C(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CSc1ccc(C(=NO)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 97 %

Procedure:
49.3 g (0.224 mol) of 2,2,2-trifluoro-1-(4-methylthiophenyl)-ethanone are dissolved in 250 ml of ethanol at 80° C. To the solution are added dropwise 16.3 g (0.235 mol) of hydroxylammonium chloride and 31.2 g (0.381 mol) of sodium acetate dissolved in 125 ml of water. The reaction mixture is refluxed for 6.5 hours, and poured into ice water. Filtration of the precipitate yields 51.1 g of 2,2,2-trifluoro-1-(4-methylthiophenyl)-ethanone oxime, as a yellow solid. The crude product is used in the next reaction step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1>C(#N)C.Cl[Pd]Cl>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH2:16][OH:17])[CH:15]=1
Reactant: COc1cc(OC)c(CO)cc1C#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2cc3ccccc3[nH]2)cc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
To a solution of [5-(2-aminophenylethynyl)-2,4-dimethoxyphenyl]methanol (Ex-57B, 9.65 g, 34 mmol) in 1 L of acetonitrile, was added PdCl2 (0.6 g, 3.4 mmol). The mixture was heated to reflux for about 0.5 h and the reaction was complete as indicated by HPLC. The mixture was cooled to room temperature and filtered. The filtrate was treated with 20 g of 3-mercaptopropyl functional silica gel with stirring for 30 min and then filtered. The filtrate was concentrated and the residue was recrystallized from EtOAc/hexanes to give 6.25 g (67.8%) of [5-(1H-indol-2-yl)-2,4-dimethoxyphenyl]methanol as off-white solid. 1H-NMR (Acetone-d6) δ 10 50 (br, 1H), 7.84 (s, 1H), 7.48 (d, J=7 Hz, 1H), 7.37 (d, J=8 Hz, 1H),6.91–7.03 (m, 2H), 6.79 (d, J=2 Hz, 1H), 6.77 (s, 1H), 4.59 (s, 2H), 3.98 (s, 3H), 3.88 (s, 3H).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:24][CH2:23][CH2:22][C@@H:21]4[C:25]4[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=4)=[N:16][C:15]=23)=[O:10])[CH2:4][O:3]1.Cl>C1COCC1.CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([C:11]1[CH:12]=[N:13][N:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][CH2:23][CH2:22][C@@H:21]3[C:25]3[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([F:31])[CH:30]=3)=[N:16][C:15]=12)=[O:10]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H]3COC(C)(C)O3)c2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)NC[C@H](O)CO)c2n1
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of N—(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (36 mg, 0.077 mmol) in THF (2 mL) was added HCl (3 N aq.) at ambient temperature. The resulting mixture was stirred for 5 hours. The reaction was diluted with EtOAc, washed with saturated NH4Cl and brine, then dried (MgSO4), filtered and concentrated. The crude material was rinsed with ether to yield the final product as white solid (30 mg, 91%). LCMS (apci) m/z=431.1 (M+H).
Reaction SMILES: I[C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)[C:4]=2[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(=[O:28])[CH:26]=[CH2:27].C(N(CC)CC)C>CN(C=O)C>[NH2:8][C:5]1[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[CH:10][S:11][C:3]=2[C:2](/[CH:27]=[CH:26]/[C:25]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:7][N:6]=1
Reactant: Nc1ncc(I)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12
Temperature: 80 °C
Yield: 59.8 %

Procedure:
A mixture of Example 10B (0.417 g, 0.94 mmol), tert-butyl acrylate (0.26 mL, 1.74 mol) and triethylamine (0.7 mL, 5 mmol) in DMF (3 mL) was degassed with nitrogen for 45 minutes, treated with PdCl2(o-tol3P)2 (0.032 g, 0.046 mmol), and heated to 80° C. overnight. The resulting mixture was cooled to room temperature, then partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 30% ethyl acetate/hexanes to provide 0.25 g (61% yield) of the desired product. MS (ESI(+)) m/e 445 (M+H)+.
Reaction SMILES: [CH2:1]([C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]C.C[O-].[Na+].CS(C)=O.[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32]Cl>O>[Cl:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[C:25]=2[CH2:32][O:12][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:11]
Reactant: CCCCCCCCCC(=O)O
Reactant: ClCc1c(Cl)ccc2cc(Cl)cnc12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC(=O)OCc1c(Cl)ccc2cc(Cl)cnc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
16 parts by weight of nonanecarboxylic acid, 20 parts by weight of 30% strength sodium methylate solution and 440 parts by weight of dimethylsulfoxide are stirred for 1 hour at 100° C. Thereafter, 24.5 parts by weight of 3,7-dichloro-8-chloromethylquinoline are introduced and the reaction mixture is stirred for a further 2 hours at 100° C. The reaction solution is then cooled, water is added and the precipitated solid is filtered off under suction and recrystallized from toluene. 32.5 parts by weight (89% of theory) of 3,7-dichloro-8-octylcarbonyloxymethylquinoline of melting point 92° C. are obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17](O)=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:28])[F:29])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([N:38]([CH3:39])[CH3:36])=[O:18])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)N(C)C)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (470 mg, 1.04 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (250 mg, 1.56 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine (2.0N in THF, 1.0 ml, 2.0 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was dissolved in ethyl acetate (30 ml) and extracted with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC (CH3CN: Water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-N,N-dimethyl-propionamide as a white solid (160 mg, 30%): mp 80–82° C.; 1H NMR: δ(CDCl3): δ 0.33–0.39 (m, 2H), 0.60–0.68 (m, 2H), 1.21–1.30 (m, 1H), 2.25 (s, 3H), 2.90 (s, 3H), 2.97 (dd, J=5 Hz, the other doublet is buried, 1H), 3.05 (s, 3H), 3.87 (d, J=7.5 Hz, 2H), 3.94 (dd, J=10 Hz, the other doublet is buried, 1H), 5.83 (dd, J=5, 10 Hz, 1H), 6.69 (t, JH-F=75 Hz, 1H), 7.12–7.15 (m, 3H), 7.45 (d, J=7.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 8.73 (d, J=8.5 Hz, 1H), 9.53 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.8, 25.6, 35.4, 36.1, 37.7, 51.9, 74.5, 112.6, 116.7, 120.8, 114.9, 116.0, 118.5, 120.9, 123.4, 125.3, 131.9, 136.4, 138.0, 138.6, 140.7, 151.2, 168.7, 169.8, 169.9, 170.6; Anal. Calcd. for C26H27F2N3O6: C, 60.58; H, 5.28; N, 8.15. Found: C, 60.23; H, 5.26; N, 8.02.