Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:5][C:6]1[C:7]([CH2:16][O:17]C(=O)C)=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.COC(=O)[C@H](NC(OCC1C=CC=CC=1)=O)CC1C=CC(NC(OC(C)(C)C)=O)=C(C)C=1CO>>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([NH:21][C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:5][C:6]1[C:7]([CH2:16][OH:17])=[C:8]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)NC(=O)OCc1ccccc1
Agent: COC(=O)[C@@H](Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1CO)NC(=O)OCc1ccccc1
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
3-(4-Acetoxymethyl-7-chloro-1H-indazol-5-yl)-2-(R)-benzyloxycarbonylamino-propionic acid methyl ester (290 mg, 0.63 mmol) was converted into the desired product in a manner analogous to the preparation of 2-(R)-benzyloxycarbonylamino-3-(4-tert-butoxycarbonylamino-2-hydroxymethyl-3-methyl-phenyl)-propionic acid methyl ester. Crude product was obtained as an orange solid in 95% yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.15 (s, 1H); 7.27 (m, 5H); 7.14 (s, 1H); 6.10 (m, 1H); 5.01 (d, J=4.8, 2H); 4.95 (s, 2H); 4.75 (m, 1H); 3.79 (s, 3H); 3.34 (m, 1H); 3.09 (m, 1H). MS m/e (M+H)+=418.0.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24]O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[O:4][N:3]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: COc1ccc(-c2cc(O)no2)cc1
Product: COc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Yield: 83.2 %

Procedure:
3-Hydroxy-5-(4-methoxyphenyl)isoxazole (0.22 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.20 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.32 g, 84%) as a colorless powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][NH2:14])=[O:12])[N:2]=1.[N:15]([O-])=O.[Na+]>Cl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([N:13]=[N+:14]=[N-:15])=[O:12])[N:2]=1
Reactant: NNC(=O)c1cc2ccccc2cn1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cc2ccccc2cn1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 93.7 %

Procedure:
To a suspension of isoquinoline-3-carbohydrazide (43 g, 0.23 mol) in aqueous HCl (1 N, 230 mL) and water (1 L) was added a solution of NaNO2 (23.8 g, 0.34 mol) in water (200 mL) dropwise at 0-5° C. The mixture was stirred at 0-5° C. for 4 h. LC-MS indicated the reaction was not completed. Another solution of NaNO2 (11.9 g, 0.115 mol) in water (60 mL) was added and the reaction mixture was stirred at 0-5° C. until LC-MS indicated the completion of the reaction. The precipitate was filtered, washed with cold water, and dried under high vacuum to give isoquinoline-3-carbonyl azide (42.7 g, 93.8%) as a white solid. LRMS (M+H+) m/z 199.2.
Reaction SMILES: [CH2:1]1[S:4][CH:2]1[CH3:3].[CH3:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1>>[SH:4][CH:2]([CH3:3])[CH2:1][N:9]1[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]1
Reactant: CN1CCNCC1
Reactant: CC1CS1
Product: CC(S)CN1CCN(C)CC1

Procedure:
The 1-(2-mercaptopropyl)-4-methylpiperazine is prepared by heating a mixture of propylene sulphide (19 cc) and N-methylpiperazine (29 cc) at 100° C. for 16 hours. This gives a colourless oil (32 g) distilling at 105° C. under 1.3 kPa.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([O:17]CC)=[O:16])[N:12]=[C:11]2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]=[C:11]2[C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.67 g (1.9 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 0.80 mL (4.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a pale yellow solid. LC/MS 327.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][CH:13]=1)=[O:10].S(Cl)([Cl:23])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([Cl:23])=[O:20])=[CH:14][CH:13]=1)=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)cn1
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 4.5 g of 6-[(2-methylbenzeneacetyl)amino]pyridine-3-carboxylic acid and 25 ml of thionyl chloride is refluxed for 1 hour and then concentrated to dryness under vacuum. To the residue is added 20 ml of toluene and the solvent removed under vacuum. The addition and removal of toluene is repeated and the residual solid dried at room temperature under vacuum to give 5.3 g of dark brown solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1.[OH-].[Na+].Cl>CO>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc(OCC(F)(F)F)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of methyl 5-hydroxypyridine-2-carboxylate (10.1 g, 65.95 mmol) and cesium carbonate (42.9 g, 131.9 mmol) in DMF (1 L) is added a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (22.96 g, 98.93 mmol) in 20 ml of DMF over 2 hours. The reaction is stirred 4 hours at room temperature and then poured over water (1 L) and stirred for additional 1 hour. A brown solid is collected by filtration and washed with additional water. The solid is dried to a constant weight to give the intermediate compound (10.3 g 66%) of methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate which is used without further purification. To a solution of methyl 5-(2,2,2-trifluoroethoxy)pyridine-2-carboxylate (4.5 g, 19.1 mmol) in methanol (45 mL) is added sodium hydroxide 1 M solution (38.2 ml, 38.2 mmol) and the reaction is stirred for 2 hours at room temperature. The pH of the reaction mixture is adjusted with HCl 35% w/w to adjust pH=1 and then the resulting solid is isolated by filtration. The solid is washed with water and then dried under vacuum to give the title compound (3 g, 70%). ES/MS (m/z): 222.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:21][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([OH:20])=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:22])=[O:4].[CH3:23][O:24][C@@H:25]1[CH2:30][CH2:29][C@H:28](O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][O:2][C:3]([C:5]1[S:21][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[C:15]([O:20][C@H:28]4[CH2:29][CH2:30][C@H:25]([O:24][CH3:23])[CH2:26][CH2:27]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:7]=2[C:6]=1[CH3:22])=[O:4]
Reactant: CO[C@H]1CC[C@@H](O)CC1
Reactant: COC(=O)c1sc2ncnc(Nc3cccnc3O)c2c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3O[C@H]3CC[C@H](OC)CC3)c2c1C

Procedure:
Prepared analogously to example XVI.1 from 1.215 g 4-(2-hydroxy-pyridin-3-ylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and 0.6 g cis-4-methoxycyclohexanol using DTAD and triphenylphosphine (polymerically bound from Aldrich).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=O)[CH2:6]Br.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH:26][C:27]([NH2:29])=[S:28])[CH:17]=[CH:18][C:19]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1>C(Cl)Cl.C(OCC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:29]=[C:27]([NH:26][C:16]3[CH:17]=[CH:18][C:19]([N:20]4[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]4)=[C:14]([O:13][CH3:12])[CH:15]=3)[S:28][CH:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1cccc(Cl)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(Nc2nc(-c3cccc(Cl)c3)cs2)ccc1-n1cnc(C)c1
Yield: 99.1 %

Procedure:
The title compound was prepared in analogy to example 1 step e) from 77 mg (0.33 mmol) 3-chlorophenacylbromide and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The solvent was evaporated under reduced pressure and the crude reaction was stirred with methylene chloride/diethyl ether/ethanol for 15 minutes at room temperature. The product was filtered off and dried to yield 118 mg (100%) [4-(3-chloro-phenyl)-thiazol-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a light yellow solid. MS ISP (m/e): 397.1/399.2 (100/46) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.78 (s, 1H), 9.29 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.90 (d, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.52 (d, 1H), 7.48 (t, 1H), 7.38 (d, 1H), 7.24 (d, 1H), 3.95 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:10]3[C:6](=[CH:7][N:8]([CH3:11])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)=[C:16]([CH3:23])[CH:15]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: COc1ccc(B(O)O)c(C)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: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3cn(C)nc23)c(C)c1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
7-Bromo-2-methyl-2H-indazole (4; 1.76 g, 8.3 mMol) and tetrakis(triphenylphosphine)palladium(0) (0.28 g, 0.25 mMol) were stirred in 15 mL of DME under argon atmosphere for 30 min. 4-Methoxy-2-methylbenzeneboronic acid (1.52 g, 9.2 mMol) was added, immediately followed by a solution of sodium carbonate (3.1 g, 29.1 mMol) in 10 mL water. The mixture was heated at a gentle reflux for 4 hr, and then cooled to rt and diluted with EtOAc (150 mL). The organic phase was washed with brine and dried over magnesium sulfate. Evaporation of the solvent afforded an oil, which was flash chromatographed on SiO2 and eluted with hexane:EtOAc (9:1) to afford 4c (1.9 g; 91%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13]1>COCCOC>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13]2)=[N:3][CH:4]=1
Reactant: CCOC(=O)CC1CNc2ccccc21
Reactant: Clc1ncnc2ccccc12
Solvent: COCCOC
Product: CCOC(=O)CC1CN(c2ncnc3ccccc23)c2ccccc21

Procedure:
A mixture of 4-chloroquinazoline (2.3g.) and ethyl indolin-3-ylacetate (2.6g.) in 1,2-dimethoxyethane (30ml.) was heated under reflux for 15 minutes. The mixture was cooled and filtered, and the solid residue was dissolved in ice-water (40ml.). To the solution was added saturated sodium acetate solution (10ml.), and the mixture was extracted with ethyl acetate (3 × 50ml.). The combined extracts were dried (Na2SO4), and the solvent evaporated in vacuo to give ethyl 1-quinazolin-4-ylindolin-3-ylacetate as a syrup which was proved to be pure by TLC (system A).
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11]C(=O)C)=[CH:6][C:5]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(O)C.[OH-].[Na+]>O>[NH2:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=1
Reactant: CCCCCCOc1cc(NC(C)=O)c(Cl)cc1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCOc1cc(N)c(Cl)cc1C(=O)O

Procedure:
A mixture of 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (2.1 g), ethanol (10 ml), and water (30 ml) containing sodium hydroxide (2.6 g) is heated under reflux for 4 hours. The ethanol is distilled off under reduced pressure, and the resulting solution is acidified with dilute hydrochloric acid and extracted with chloroform. The organic layer is treated in the same manner as in part (2) of this Reference Example to give the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[S:9][C:5]=2[CH:4]=1)#[N:2].[ClH:15].Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:15].[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:10]([C:8]1[S:9][C:5]3[CH:4]=[C:3]([C:1]#[N:2])[CH:14]=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:19]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: N#Cc1ccc2cc(C(=O)O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1

Procedure:
320.8 mg (1.1 mmol) of 6-cyano-1-benzothiophene-2-carboxylic acid (Example 25A), 200 mg (1.0 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 458.3 mg (1.21 mmol) of HATU, 467.3 mg (3.62 mmol) of N,N-diisopropylethylamine and 4.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. The product is dissolved in a mixture of methanol and 4 M hydrogen chloride in dioxane and then concentrated and dried under high vacuum. 222.1 mg (64% of theory) of the title compound are obtained.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(COc2ccccc2)cn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-phenoxymethyl-pyridin-2-yl)-methanol described in Preparation Example 187 (167 mg, 0.776 mmol) in tetrahydrofuran (4 mL) were added phthalimide (126 mg, 0.856 mmol), triphenylphosphine (244 mg, 0.930 mmol) and diethyl azodicarboxylate (424 μL, 0.931 mmol, 40% toluene solution) at 0° C., and the solution was stirred at room temperature for 30 minutes. The reaction solution was partitioned with water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (383 mg, quantitatively) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:12][N:11]([CH:10]=[N:9][C:3]1[C:2]([F:1])=[CH:7][N:6]=[C:5]([O:8][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:4]=1)[CH3:13]
Reactant: CN(C)C=Nc1nc(O)ncc1F
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CN(C)C=Nc1nc(OC(=O)c2ccccc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.4 %

Procedure:
To a suspension of N′-(5-fluoro-2-hydroxypyrimidin-4-yl)-N,N-dimethylformamidine (0.10 g, 0.54 mmol) in pyridine (2 mL) was added benzoyl chloride (0.084 g, 0.60 mmol), and the mixture was agitated on an orbital shaker for 16 h at RT. The reaction mixture was partitioned between EtOAc and saturated aq NaHCO3, and the organic phase was dried over solid MgSO4, filtered, and evaporated to give the title compound (0.147 g 94%) as a white solid: mp 136-138° C.; 1H NMR (300 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J=2.4 Hz, 2H), 8.25-8.20 (m, 2H), 7.69-7.63 (m, 1H), 7.56-7.49 (m, 2H), 3.23 (s, 3H), 3.20 (s, 3H); HPLC-MS (ESI) m/z 289 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][Si](C)(C)C)=[CH:13][C:3]=1[O:4][C:5]1[C:6]([NH2:12])=[N:7][C:8]([NH2:11])=[N:9][CH:10]=1.[F-].[K+]>Br.CN(C=O)C.O.CCOC(C)=O.[NH4+].[OH-]>[C:17]([C:14]1[CH:15]=[CH:16][C:2]([I:1])=[C:3]([CH:13]=1)[O:4][C:5]1[C:6]([NH2:12])=[N:7][C:8]([NH2:11])=[N:9][CH:10]=1)#[CH:18]
Reactant: C[Si](C)(C)C#Cc1ccc(I)c(Oc2cnc(N)nc2N)c1
Agent: Br
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#Cc1ccc(I)c(Oc2cnc(N)nc2N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.3 %

Procedure:
A mixture of 5-(2-Iodo-5-trimethylsilanylethynyl-phenoxy)-pyrimidine-2,4-diamine (0.4 g, 2.36 mmol), potassium fluoride (41 mg, 7.07 mmol) and HBr (2 drops of 48% aqueous solution) in DMF was stirred at room temperature for 30 minutes. The reaction mixture was diluted with water and EtOAc and basified with 1 mL NH4OH. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (4% MeOH in CH2Cl2 with 0.1% NH4OH) to give 0.36 g of 5-(5-Ethynyl-2-iodo-phenoxy)-pyrimidine-2,4-diamine, MP=156-159° C., MS (M+H)=352.
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][O:13][C:14]1[CH:43]=[CH:42][C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([NH:34]C(OC(C)(C)C)=O)[CH:33]=3)=[O:26])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C1COCC1>[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][O:13][C:14]1[CH:43]=[CH:42][C:17]([O:18][C:19]2[CH:20]=[CH:21][N:22]([C:25]([O:27][CH:28]3[CH2:33][CH:32]([NH2:34])[CH2:31][NH:30][CH2:29]3)=[O:26])[CH2:23][CH:24]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1cncc(OC(=O)N2CCC(Oc3ccc(OCc4cccc(F)c4)cc3)CC2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC1CNCC(OC(=O)N2C=CC(Oc3ccc(OCc4cccc(F)c4)cc3)=CC2)C1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A 4 M hydrogen chloride/dioxane solution (1.8 ml) was added to a THF (10 ml) solution containing 5-[(tert-butoxycarbonyl)amino]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (174 mg), followed by stirring at 60° C. for 4 hours. The solvent was evaporated under reduced pressure to obtain 5-aminopiperidin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}pyridine-1-carboxylate hydrochloride (74 mg).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[F:7][C:8]([F:20])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH2:18])=[N:14][NH:15]2)=[CH:11][CH:10]=1>N1C=CC=CC=1>[F:20][C:8]([F:7])([F:19])[C:9]1[CH:17]=[C:16]2[C:12]([C:13]([NH:18][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[N:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: CCCC(=O)Cl
Reactant: Nc1n[nH]c2cc(C(F)(F)F)ccc12
Solvent: c1ccncc1
Product: CCCC(=O)Nc1n[nH]c2cc(C(F)(F)F)ccc12
Reaction time: 19 h

Procedure:
0.26 cm3 of butyryl chloride is added to 500 mg of 6-(trifluoromethyl)-1H-indazole-3-amine, prepared as described in patent U.S. Pat. No. 3,133,081, in 5 cm3 of pyridine, cooled to about 10° C. The temperature is allowed to return to about 19° C. over 19 hours. The reaction medium is evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 15 cm3 of ethyl acetate and 15 cm3 of distilled water. The organic phase is washed with 15 cm3 of distilled water and with 15 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 49 mg of N-[6-(trifluoromethyl)-1H-indazol-3-yl]butanamide are thus obtained in the form of a white solid melting at 200° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[N:15]1[CH:20]=[C:19](B(O)O)[CH:18]=[N:17][CH:16]=1>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]([CH2:2][C:19]3[CH:20]=[N:15][CH:16]=[N:17][CH:18]=3)=[CH:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1cncnc1
Reactant: BrCc1ccc(-c2ccccc2)nc1
Product: c1ccc(-c2ccc(Cc3cncnc3)cn2)cc1
Reaction time: 0.5 h

Procedure:
Synthesized using compound 61a (219 mg, 0.88 mmol) and pyrimidine-5-boronic acid (164 mg, 1.32 mmol) according to Method C. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (1:1) as eluent. After flash chromatography the product was solved in ethyl acetate and a few drops of conc. HCl and water were added. After stirring for 30 minutes the phases were separated and water phase was neutralized with aqueous Na2CO3-solution (2M). After extraction with ethyl acetate and drying over MgSO4 the solvent was removed under vacuum. White solid. Yield: 43 mg, 20%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=4.02 (s, 2H), 7.39-7.44 (m, 1H), 7.44-7.56 (m, 3H), 7.70 (dd, J=8.2, 0.9 Hz, 1H), 7.95-8.00 (m, 2H), 8.58-8.67 (m, 3H), 9.13 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=33.4, 120.5, 126.8, 128.8, 129.1, 132.2, 133.3, 136.9, 138.7, 149.7, 156.4, 156.9, 157.3; (ESI): m/z=247.83 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Product: CN1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and N-methylpiperazine were reacted to give 128bp. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1H), 6.94-7.00 (m, 2H), 6.85 (m, 1H), 6.75-6.82 (m, 2H), 6.68 (s, 1H), 5.03 (s, 2H), 3.69 (m, 2H), 3.46 (m, 2H), 3.39 (s, 3H), 3.30 (m, 2H), 3.07 (m, 2H), 2.90 (s, 3H). LCMS (ESI) m/z: 456.2.