Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[CH2:14][N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cccc(Sc2ccccc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1cccc(Sc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
(3-Phenylsulfanyl-phenyl)-methanol described in Preparation Example 93 (212 mg, 0.980 mmol), phthalimide (144 mg, 0.980 mmol), diethylazodicarboxylate (170 μl, 1.08 mmol) and triphenylphosphine (308 mg, 1.18 mmol) were dissolved in tetrahydrofuran (4 mL), and the solution was stirred overnight at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (124 mg, 0.359 mmol, 37%) was obtained as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:53]([CH:56]2[CH2:58][CH2:57]2)(=[O:55])=[O:54])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:23][OH:24])[CH:20]([F:22])[F:21])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:40]([O:39][C:38]([N:37]([C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][C@H:12]3[C:10](=[O:11])[N:9]([CH3:52])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:53]([CH:56]4[CH2:57][CH2:58]4)(=[O:54])=[O:55])[NH:1][C:59](=[O:60])[O:24][CH2:23][C@H:19]([CH:20]([F:21])[F:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:25])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)[C:45](=[O:46])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(Cl)Cl
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@H](CO)C(F)F
Solvent: CC#N
Solvent: ClCCl
Product: Cc1cc2ccc1[C@@H](C(F)F)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 16K (0.144 g, 0.175 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C. was added phosgene solution (20% in toluene, 0.101 mL, 0.192 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.195 mL, 1.398 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The reaction mixture was stirred at rt over night. The solvent was removed and the crude product was purified by flash chromatography (0-80% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give a mixture of diastereoisomers (0.12 g, 0.141 mmol, 81% yield). The diastereoisomers were separated using a prep chiral HPLC equipped with a Whelko-01 column to give 16L (34 mg, 48% yield). MS (ESI) (m/z): 850.0 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=1)=[O:6])#[N:2].Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+].N#N>C1(C)C=CC=CC=1>[N:2]1[NH:44][N:45]=[N:46][C:1]=1[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([CH:12]([S:17][C:18]2[CH:23]=[C:22]([CH3:24])[C:21]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=3)=[C:20]([CH3:35])[CH:19]=2)[C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:10][CH:11]=1)=[O:6]
Reactant: Cc1cc(SC(c2ccc(C(=O)NCC#N)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(SC(c2ccc(C(=O)NCc3nn[nH]n3)s2)C(C)(C)C)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
A solution of 5-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-ylsulfanyl)-2,2-dimethyl-propyl]-thiophene-2-carboxylic acid cyanomethyl-amide (Isomer 1) (220 mg, 0.436 mmol) in toluene (8.7 mL) is treated with triethylamine hydrochloride (300 mg, 2.18 mmol) and sodium azide (142 mg, 2.18 mmol), then heated at reflux overnight (thermal conditions) or alternatively, placed in a CEM microwave reactor for 20 min (300 W, 180° C., N2 cooling) (microwave conditions). After cooling to room temperature, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, and the combined organic layers are dried and concentrated to give the title compound (105 mg). MS (ES): 548.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([Cl:11])[CH:9]=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=1[OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][N:6]2[C:7]=1[C:2]([O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[F:12])=[N:3][CH:4]=[N:5]2
Reactant: Clc1ccn2ncnc(Cl)c12
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A mixture of 4,5-dichloropyrrolo[2,1-f][1,2,4]triazine (3.73 g, 19.8 mmol), 2-fluoro-4-nitrophenol (3.43 g, 21.8 mmol) and potassium carbonate (5.47 g, 39.6 mmol) in DMF (100 mL) was stirred at 60° C. for 1 h. After cooling to rt, the reaction was filtered through a short plug of silica gel with ethyl acetate and then concentrated in vacuo. The crude product was purified by recrystallization from ethyl acetate/hexanes (1:1) to give the title compound (4.37 g, 71%) as a white solid. 1H NMR (CDCl3) δ 8.22-8.17 (m, 2H), 7.92 (s, 1H), 7.77 (d, 1H, J=2.8 Hz), 7.58 (t, 1H, J=7.2 Hz), 6.87 (d, 1H, J=3.2 Hz); MS(ESI+) m/z 309.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])(C)C.[K+].[CH3:27][O:28][C:29](=[O:42])[CH:30](I)[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].S([O-])(O)(=O)=O.[K+]>C1COCC1>[CH3:27][O:28][C:29](=[O:42])[CH:30]([N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1)[CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:39])([CH3:38])[CH3:40])([CH3:35])[CH3:36]
Reactant: COC(=O)C(I)CCO[Si](C)(C)C(C)(C)C
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CCO[Si](C)(C)C(C)(C)C)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 349.6 %

Procedure:
A suspension of 0.313 g (0.100 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 5A) in 10 ml of THF was treated at 0° C. with 0.135 g (0.120 mmol) of potassium tert-butylate. After 10 min, 0.394 g (0.110 mmol) of (rac)-4-(tert-butyl-dimethyl-silanyloxy)-2-iodo-butyric acid methyl ester (intermediate 1) was added. The reaction was stirred 1 h at 0° C., 15 h at RT and then neutralized with cold 10% aq. potassium hydrogensulfate solution and extracted with diethyl ether (3×). The organic phases were washed with sat. aq. sodium hydrogencarbonate solution, 10% aq. sodium chloride solution, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane/ethyl acetate 1:1 to 2:3) to yield 0.19 g (35%) of the titled compound as light yellow viscous oil. MS: 543.3 (MH+, 2Cl).
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC>C1COCC1>[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]([OH:21])([CH3:27])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Reactant: O=C([O-])[O-]
Agent: C[Mg]Br
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)(C)O
Temperature: 0 °C
Yield: 45.5 %

Procedure:
To a solution of methylmagnesium bromide (83.4 mmol, 27.8 ml, 3.0 M in Et2O) in 83 mL THF at 0° C. was added 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (2.523 g, 8.3 mmol, from Example 16) in portions. After 16 h the mixture was cooled to 0° C. and was quenched by the addition 10% NH4Cl. H2O was added and the mixture was extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over NaHCO3, filtered and concentrated in vacuo. The crude solid was taken up in 31 ml DMF. K2CO3 (0.65 g, 4.7 mmol) and iodomethane (0.098 ml, 1.6 mmol) were added and the mixture was warmed to 50° C. Additional portions of iodomethane (0.019 mL, 0.6 mmol) was added at 1, 2 and 3 hr. After 16 h the mixture was cooled and 10% NH4Cl and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give 2-[5-(2,4-diaminopyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-propan-2-ol (0.711 g, yield) as a white solid. [MH]+=333.
Reaction SMILES: [CH2:1]([N:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4](=[O:27])[CH2:5][N:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:7](=[O:20])[CH2:8][N:9]1C(=O)C2=CC=CC=C2[C:10]1=[O:19])[CH3:2].O.NN.[CH3:37][C:38]1[CH:39]=[C:40]([N:44]=C=O)[CH:41]=[CH:42][CH:43]=1>>[CH2:1]([N:3]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:4](=[O:27])[CH2:5][N:6]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:7](=[O:20])[CH2:8][NH:9][C:10]([NH:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([CH3:37])[CH:39]=1)=[O:19])[CH3:2]
Reactant: CCN(C(=O)CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccccc1)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Agent: NN
Solvent: O
Product: CCN(C(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1)c1ccccc1
Yield: 30.5 %

Procedure:
The procedure is analogous to that described in Example 23, but 3.1 g of N-ethyl-N-phenyl-2-(N-phenyl-2-phthalimidoacetamido)acetamide, 0.4 g of hydrazine hydrate and 0.54 g of 3-methylphenyl isocyanate are used as the starting material. The product obtained is purified by chromatography on 20 g of silica (0.065-0.200 mm) contained in a column 1.7 cm in diameter [eluent: methylene chloride], collecting 20 cm3 fractions. Fractions 10 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization from diethyl ether, 0.55 g of N-ethyl-N-phenyl-2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetamide melting at 158° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[C:8](Cl)(=[O:10])[CH3:9]>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:8]([N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1])(=[O:10])[CH3:9]
Reactant: Cc1c[nH]c(C)n1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)n1cc(C)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 9.6 g (0.10 M) of 2,4-dimethylimidazole in 50 ml of chloroform and 50 ml of toluene was stirred at room temperature and 3.6 ml (0.05 M) of acetyl chloride was added via syringe over 1 minute. The mixture was stirred at room temperature for 2 hours, then the mixture was filtered to remove insoluble solids, and the filtrate concentrated leaving 6.9 g (100%) of 1-acetyl-2,4-dimethylimidazole as a white crystalline solid: nmr (CDC3) (δ): 7.00 (s, 1H); 2.68 (s, 3H); 2.57 (s, 3H); 2.21 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([Cl:19])[N:3]=1.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1>C(#N)C.CCO>[Cl:19][C:4]1[N:3]=[C:2]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: COc1cnc2[nH]cc(-c3cc(Cl)nc(Cl)c3)c2c1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CCO
Solvent: CC#N
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(N[C@H]4CC[C@H](O)CC4)c3)c2c1

Procedure:
A mixture of Example 149e (43.9 mg, 0.146 mmol) and trans-4-aminocyclohexanol (0.337 g, 2.92 mmol) in acetonitrile (1.5 mL) and EtOH (1.5 mL) was heated at 190° C. for 3 hours in a Biotage microwave reactor. The solvent was evaporated. The residue was treated with 5% citric acid and brine, and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, concentrated, and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (5:95) to 100% EtOAc to give 22.0 mg of the title compound. 1H NMR (500 MHz, DMSO-d6) ppm 1.15-1.33 (m, 3H), 1.84 (d, J=10.98 Hz, 2H), 1.96 (d, J=11.29 Hz, 2H), 2.07 (m, 1H), 3.40 (m, 1H), 3.59 (m, 1H), 3.89 (s, 3H), 6.76-6.90 (m, 2H), 7.78 (d, J=2.75 Hz, 1H), 8.07 (dd, J=6.71, 2.75 Hz, 2H), 12.03 (s, 1H). MS (APCI+) m/z 373.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19](F)[N:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[N:11]=[C:12]2[CH3:15])[N:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Fc1cccc(F)n1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(F)n1

Procedure:
The title compound, off-white cristalline solid, MS: m/e=313.2, 315.1 (M+H+) was prepared in accordance with the general method of example 1b from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,6-difluoropyridine.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:15][CH3:16])[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCc1cc(C(=O)OC)cc(C#N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)O)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
Methyl 3-cyano-5-ethyl-4-methoxybenzoate (480 mg) was dissolved in tetrahydrofuran (6 mL) and water (2 mL), and lithium hydroxide monohydrate (370 mg) was added to the solution, and then the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure and 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (403 mg) as a colorless crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=2)=[N:10]1.CO.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[N:10]1
Reactant: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1nccc2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
To a solution of methyl 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoate (2.70 g) in a mixed solvent of methanol (20 mL) THF (20 mL) and water (10 mL) was added 8N aqueous sodium hydroxide solution (4.27 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The aqueous layer was neutralized with 1N hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (2.59 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:37][C:31]1[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(Cl)cc1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: CC(C)(C)NC(=O)c1cc(Cl)ccc1CC(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (1.56 g, 4.8 mmol) and N-tert-butyl-5-chloro-2-methyl-benzamide (3.25 g, 14 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH3:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=[S:35])[NH:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CNC(=S)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 151 %

Procedure:
To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.40 g, 1.17 mmol, 1.0 equiv) in THF (12 mL) under a nitrogen atmosphere, was added Lawesson's reagent (0.28 g, 0.70 mmol, 0.6 equiv). The yellow solution was then heated to 50° C. (oil bath). After stirring for 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-100% ethyl acetate/hexane) to provide the title compound (0.38 g, 90% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 1H), 7.45-7.57 (m, 2H), 7.29-7.42 (m, 3H), 5.25 (s, 2H), 3.93-4.12 (m, 4H), 3.17 (d, J=5.04 Hz, 3H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 360.19.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[N:5]=[CH:4]1.F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(Cl)Cl>CN(C)C=O>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:3]1[CH:7]=[C:6]([CH2:8][C:9]#[N:10])[N:5]=[CH:4]1
Reactant: Fc1ccccn1
Reactant: N#CCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCc1cn(-c2ccccn2)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
Sodium hydride (63% mineral oil dispersion, 4.71 g) was added over 15 minutes to a solution of 1H-imidazol-4-ylacetonitrile (13.25 g) in N,N-dimethylformamide (46 mL) cooled to 0° C. Then, a solution of 2-fluoropyridine (12.61 g) in N,N-dimethylformamide (23 mL) was added thereto at room temperature, and the mixture was stirred at 100° C. for 5 hours. To the reaction solution, ice water was added, and methylene chloride was added. The formed solid was removed by suction filtration, and the organic layer was then separated and dried over anhydrous magnesium sulfate. Volatile matter was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (18.5 g, mixture with N,N-dimethylformamide).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1OC
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(OC)c3)n2)cc1OC

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3,4-dimethoxyaniline were reacted to yield N2,N4-bis(3,4-dimethoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.90 (d, 1H, J=1.8 Hz), 7.13 (d, 2H, J=4.8 Hz), 7.08 (d, 1H, J=8.7 Hz), 6.94 (d, 2H, J=10.5 Hz), 6.81 (d, 1H, J=8.7 Hz), 6.76 (d, 1H, J=8.7 Hz), 6.70 (s, 1H), 3.87 (s, 3H), 3.84 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H); 19F NMR (CDCl3): δ −47433; LCMS: ret. time: 19.64 min.; purity: 95%; MS (m/e): 401 (MH—).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[S:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29])(=[O:20])=[O:19].[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][S:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29])(=[O:20])=[O:19]
Reactant: [H][H]
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccccc1-c1ccc2cccc-2o1
Yield: 27.7 %

Procedure:
2-[[(E)-2-(4-Benzofuran-2-ylphenyl)ethenyl]sulfonylamino]benzenesulfonamide (Example 3, 43 mg, 95 μmol) was dissolved in ethyl acetate (5 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C). The material obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (12 mg, 28%) as a white solid. The compound of Example 2 was also obtained.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=287.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2,6-dimethyl benzoic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([Br:38])=[CH:34][N:33]=1>>[Br:38][C:35]1[CH:36]=[CH:37][C:32]([N:13]2[CH2:14][CH2:15][C:11]3([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]4[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=4)=[O:18])[CH2:8]3)[CH2:12]2)=[N:33][CH:34]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(Br)cn4)C3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 2 (step 2.6.). Starting with 1.7 g (3.90 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate (isomer 5) and 0.68 g (3.90 mmol) of 2-fluoro-5-bromopyridine, and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 1.00 g of pure product is thus obtained in the form of a gum.