Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O.[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:27]=[CH:26][C:25]=1[CH:38]1[CH2:41][NH:40][CH2:39]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH2:1]([NH:6][C:7]([N:40]1[CH2:41][CH:38]([C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:29][C:24]=2[O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:39]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: c1ccc(COc2ccc(C3CNC3)c(OCc3ccccc3)c2)cc1
Reactant: CCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCNC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
In a 10 ml round-bottomed flask, 0.15 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine trifluoroacetate is dissolved in 3 ml of tetrahydrofuran in the presence of 0.1 ml of N,N-diisopropylethylamine. 0.04 ml of pentyl isocyanate is added and the reaction mixture is then stirred for 20 minutes at ambient temperature. The reaction mixture is extracted with ethyl acetate and the organic phases are then combined and dried over magnesium sulphate. The residue is chromatographed on silica gel (9/1 heptane/ethyl acetate). 0.1 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide is obtained. Yield=67%.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][P:22](=[O:33])([O:28]C(C)(C)C)[O:23]C(C)(C)C)[C:16](=[O:34])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5].C(O)(=O)C.O>C(#N)C>[Cl:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]([CH2:20][O:21][P:22](=[O:23])([OH:33])[OH:28])[C:16](=[O:34])[CH:15]=2)=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(C)OP(=O)(OCn1ccc(-c2ccc(CNC(=O)c3c(Cl)cccc3Cl)cc2)cc1=O)OC(C)(C)C
Solvent: CC#N
Solvent: O
Solvent: CC(=O)O
Product: O=C(NCc1ccc(-c2ccn(COP(=O)(O)O)c(=O)c2)cc1)c1c(Cl)cccc1Cl
Yield: 56 %

Procedure:
Phosphoric acid di-tert-butyl ester 4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl ester from the previous step was dissolved in 20 mL acetonitrile, 20 mL acetic acid and 20 mL water, and heated at 70° C. for four hours. All volatile components were evaporated under vacuum and the residue was dissolved in 10 mL DMF. Slow addition of acetonitrile (˜60 mL) precipitated the product which was filtered, washed with more acetonitrile and dried, giving phosphoric acid mono-(4-{4-[(2,6-dichloro-benzoylamino)-methyl]-phenyl}-2-oxo-2H-pyridin-1-ylmethyl) ester (1.17 g, 56% over three steps) as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[N:41]=[C:40]([Cl:42])[CH:39]=[C:38]([CH3:43])[C:34]=1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:42][C:40]1[CH:39]=[C:38]([CH3:43])[C:34]([C:35]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:8][CH2:7]2)[CH3:5])=[O:36])=[C:33]([CH3:32])[N:41]=1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Following General Procedure C: To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 0.31 mmol) and 2,4-dimethyl-6-chloronicotinic acid (68 mg, 0.31 mmol) in DMF (4 mL) was added DIPEA (0.8 mL), HOBT (75 mg, 0.56 mmol) and EDCI (89 mg, 0.46 mmol) and the reaction stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH,) gave 42 mg (23%) of the title compound as a white solid: 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz) 1.07-1.32 (m, 2H), 1.53-1.61 (m, 1H), 1.83-1.91 (m, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 2.48 (s, 3H, 2.76-2.91 (m, 3H), 3.26-3.39 (m, 3H), 3.43 (s, 3H), 3.68-3.71 (m, 2H), 3.73-3.82 (m, 1H), 4.01-4.04 (m, 4H), 6.64 (d, 2H, J=9 Hz), 6.76 (d, 2H, J=9 Hz), 6.98 (s, 1H), 7.03 (d, 1H, J=6 Hz), 7.97 (br s, 1H), 8.26 (s, 1H), 8.29 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.60, 19.19, 22.52, 29.68, 30.58, 31.80, 39.70, 44.36, 47.79, 59.57, 60.04, 68.06, 71.53, 115.72, 120.29, 122.88, 125.50, 148.34, 149.57. ES-MS m/z 594 (M+H). Anal. Calcd. for C33H44N5ClO3.0.2CH2Cl2: C, 65.24; H, 7.32; N, 11.46. Found: C, 64.88; H, 7.36; N, 11.54.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BrH:15].[NH+]1C=CC=CC=1.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[Br:15][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=[C:7]([N+:12]([O-:14])=[O:13])[C:8]=1[NH2:9]
Reactant: CC(C)(C)c1ccc(N)c([N+](=O)[O-])c1
Reactant: Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(Br)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
A suspension of 4-tert-butyl-2-nitroaniline (1.033 g, 5.32 mmol) in glacial acetic acid (7.8 mL) was warmed with a heat gun until all solids had dissolved. The solution was then cooled and treated portion wise with pyridinium hydrobromide perbromide (1.96 g, 6.12 mmol). After addition, the solution was stirred at room temperature for 1 h. The mixture was added to water (50 mL) and treated with a small amount of sodium sulfite. After stirring for 30 min, the precipitate was collected by filtration. The solid obtained was washed with water and dissolved in EtOAc. Washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum to provide the title compound as a yellow-orange solid (1.36 g, 94%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:22](=[O:24])[NH2:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=O)(C)(C)C.[ClH:25].CCOCC>C(OCC)(=O)C>[ClH:25].[NH2:8][C@@H:9]([C:22](=[O:24])[NH2:23])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NC(=O)[C@H](N)CCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To 3.36 of benzyl t-butyloxycarbonyl-D-isoglutaminate (4, n = 2) there is added 50 ml of a saturated solution of hydrogen chloride in ethyl acetate. The reaction mixture is stored at 22° C for 10 minutes and then 75 ml of ether is added to precipitate the product, which is collected by centrifugation and carefully dried in vacuo to give benzyl D-isoglutaminate hydrochloride (5, n = 2) which is used without further purification in step B of this example.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:28][CH2:29][C:30]#[N:31])=O)(C)(C)C.[Cl-].[NH4+].[N-:34]=[N+:35]=[N-:36].[Na+].FC(F)(F)C(O)=O>CN(C)C=O.C(Cl)Cl>[Cl:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:28][CH2:29][C:30]3[NH:36][N:35]=[N:34][N:31]=3)[CH2:10]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCC#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNC(CCc2nnn[nH]2)C1
Temperature: 100 °C

Procedure:
In N,N-dimethylformamide (1.5 ml) was dissolved 1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen-2-yl) sulfonyl]-2-(2-cyanoethyl)piperazine (529 mg), followed by the addition of ammonium chloride (588 mg) and sodium azide (741 mg). The resulting mixture was stirred under heating at 100° C. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was washed with water and saturated aqueous NaCl solution, each once. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (methylene chloride:methanol=50:1), whereby a colorless foam was obtained. The resulting substance was dissolved in methylene chloride (5 ml), followed by the addition of trifluoroacetic acid (5 ml). The mixture was stirred at room temperature for 1 minutes. The reaction mixture was concentrated under reduced pressure. The precipitate thus obtained was washed with diethyl ether and collected by filtration, whereby the title compound (141 mg) was obtained as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccccc1
Product: O=C(C=Cc1ccccc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by heating a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and benzaldehyde (64 ul, 0.633 mmol) similar to Example 1 and isolated as a yellow solid (7.2 mg, 2.8%). 1H NMR (CDCl3): 7.70 (d, J=16.2 Hz, 1H), 7.62-7.59 (m, 2H), 7.45 (d, J=15.9 Hz, 1H), 7.41 (t, J=3.2 Hz, 3H), 7.29 (d, J=3.3 Hz, 1H), 7.13 (dd, J=3.3, 9.3 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 4.45-4.34 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][CH2:21][O:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:11]4([N:15]=[C:14]([NH2:16])[C:13]([CH3:17])=[N:12]4)[CH2:10][CH:9]([CH:18]4[CH2:23][CH2:22][CH2:21][O:20][CH2:19]4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC1=NC2(CC(C3CCCOC3)Oc3ccc(Br)cc32)N=C1N
Product: CC1=NC2(CC(C3CCCOC3)Oc3ccc(-c4cccc(Cl)c4)cc32)N=C1N

Procedure:
6-Bromo-5′-methyl-2-(tetrahydro-2H-pyran-3-yl)spiro[chroman-4,2′-imidazol]-4′-amine (Isomeric mixture 2 from Example 47 Step 3, 0.146 g, 0.39 mmol) was reacted with 3-chlorophenylboronic acid (0.091 g, 0.58 mmol) as described above. The isomers were separated using chiral HPLC methods:
Reaction SMILES: F[C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[O-:18][CH2:19][CH3:20].[Na+].Cl>O>[F:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:14])[C:7](=[O:13])[NH:8]2)=[C:3]([N+:15]([O-:17])=[O:16])[C:2]=1[O:18][CH2:19][CH3:20]
Reactant: CC[O-]
Reactant: O=c1[nH]c2cc(F)c(F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOc1c(F)cc2[nH]c(=O)c(=O)[nH]c2c1[N+](=O)[O-]
Yield: 91 %

Procedure:
A solution of 24 mg (0.098 mmol) of 6,7-difluoro-5-nitro-1,4-dihydroquinoxaline-2,3-dione and 24 mg (0.33 mmol) of sodium ethoxide (96%) in 0.5 mL of DMSO-d6 was kept at room temperature for 5 h. The red solution was added to 3 mL of water and acidified with 2N HCl to pH=4. The precipitate was filtered, washed with water, and dried to leave a yellow solid (24 mg, 91%); mp 293°-295° C.; 1H NMR (DMSO-d6), 1.239 (t, 3, J=7.0), 4.141 (q, 2, J=7.2), 7.152 (1, d, J=11.7), 11.975 (s, 1), 12.135 (s, 1). 19F NMR, -134.06 (mb). MS, 269 (M+, 90), 241 (100), 195 (70). HRMS, Calcd for C10H8FN3O5 269.0443, found 269.0454.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][OH:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[OH:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:25])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][N:26]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one and pyridine-2-boronic acid following procedures analogous to those described in Example 75 Step 1. LC-MS Method 2 tR=0.976 min, m/z=805.3; 1H NMR (CDCl3) 1.50 (d, 2H), 2.06-2.19 (m, 2H), 2.26 (m, 3H), 2.83 (m, 1H), 3.53 (m, 1H), 3.71 (m, 1H), 5.64 (m, 1H), 6.94 (d, 2H), 7.14 (m, 1H), 7.24 (m, 3H), 7.28 (m, 2H), 7.56 (d, 2H), 7.67 (m, 3H), 8.59 (d, 1H).
Reaction SMILES: [I-].[C:2]([O:6][C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([O:25][C:26]2[CH:31]=[C:30]([N:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]3[CH:41]([F:43])[F:42])[N:29]=[C:28]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[N:27]=2)[CH2:21][CH2:20]1)=[O:17])[CH2:11][CH2:12][S+](C)C)=[O:8])([CH3:5])([CH3:4])[CH3:3].[Cl-].[NH4+]>O1CCCC1>[C:2]([O:6][C:7](=[O:8])[NH:9][C@H:10]1[CH2:11][CH2:12][N:18]([C@H:19]2[CH2:24][CH2:23][C@H:22]([O:25][C:26]3[CH:31]=[C:30]([N:32]4[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]4[CH:41]([F:43])[F:42])[N:29]=[C:28]([N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[N:27]=3)[CH2:21][CH2:20]2)[C:16]1=[O:17])([CH3:5])([CH3:4])[CH3:3]
Reactant: C[S+](C)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@H](Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[(3S)-3-[(tert-Butoxycarbonyl)amino]-4-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-oxobutyl](dimethyl)sulfonium iodide (919 mg) was dissolved in tetrahydrofuran (9.2 mL), and cooled to 0° C. under a nitrogen air flow, and a 1.6 M solution (0.7 mL) of hexamethyldisilazanelithium in tetrahydrofuran was added dropwise thereto, followed by stirring at 0° C. for 2 hours. A 1.6 M solution (0.7 mL) of hexamethyldisilazanelithium in tetrahydrofuran was further added dropwise thereto, followed by stirring at 0° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-0:100) to obtain tert-butyl{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (154 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([N:15]([CH2:23][CH3:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[N:10]=[CH:11][N:12]=[C:13]([N:15]([CH2:23][CH3:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)[CH:14]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: CCN(c1cccc(F)c1)c1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(N(CC)c2cccc(F)c2)ncn1
Temperature: 25 °C
Yield: 41 %

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.10 g of sodium hydride (60% in oil), to which 0.5 ml of a tetrahydrofuran solution containing 0.15 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.5 ml of a tetrahydrofuran solution containing 0.43 g of 4-chloro-6-(N-ethyl-N-(3-fluorophenyl)amino)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.2 g of 6-(2-butynyloxy)-4-(N-ethyl-N-(3-fluorophenyl)amino)pyrimidine (the present compound (165)).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[CH3:14][N:15](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CNO>C1COCC1>[NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:15][CH3:14])=[O:8]
Reactant: Nc1cc(C(=O)O)c(F)cc1F
Reactant: CCN=C=NCCCN(C)C
Agent: CNO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(N)c(F)cc1F
Reaction time: 5 h
Yield: 77.6 %

Procedure:
5-amino-2,4-difluoro-benzoic acid (6 g, 34.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.3 g, 69.3 mmol) and 1-hydroxybenzotriazole (9.3 g, 69.3 mmol) was stirred in THF (100 ml). Diisopropylethylamine (7.2 ml, 41.5 mmol) and methylhydroxyamine hydrochloride (4.3 g, 51.9 mmol) were added thereto, and the solution was stirred for 5 hours. The resulting solution was extracted with ethylacetate and washed with salt solution. The resulting residue was recrystallized with diethylether to obtain the title compound 5 g (yield: 71%).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][N:9]=1)(=O)C.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc(F)cc2F)s1
Agent: Cl
Solvent: CCO
Product: Nc1ncc(Sc2ccc(F)cc2F)s1
Yield: 49.6 %

Procedure:
A mixture of 2-acetamido-5-(2,4-difluorophenylthio)thiazole (14.8 g) in a mixture of ethanol (150 ml) and concentrated hydrochloric acid (15 ml) was refluxed for 1.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 12 using aqueous sodium hydroxide with stirring under ice-cooling. The mixture was extracted with ethyl acetate, washed with water and dried over magnesium sulfate. The organic layer was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel, 230-400 mesh, Nakarai) (300 g) and eluted with a mixture of chloroform and methanol (100:1). The fractions containing the objective compound were combined and evaporated to dryness in vacuo to give 2-amino-5-(2,4-difluorophenylthio)thiazole (6.26 g, yield: 49.6%). mp: 116°-117° C. IR (Nujol): 3410, 3090, 1625, 1600, 1515 cm-1NMR (DMSO-d6, 60 MHZ, ppm): 7.07-7.76 (6H, m) MASS: M+2 246, M 244, m/e 157
Reaction SMILES: [CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2].[N+:13]([O-])([O-:15])=[O:14].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:1]([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCC1Cc2ccccc2C=N1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: CCC1Cc2ccc([N+](=O)[O-])cc2C=N1
Temperature: 25 °C
Yield: 91 %

Procedure:
To concentrated sulfuric acid (150 ml) at 0° C. was added 3-ethyl-3,4-dihydro-isoquinoline (20.1 g, 0.12 mols) and potassium nitrate (12.13 g, 0.12 mols). The reaction was allowed to warm to room temperature for 24 h. The reaction was poured onto ice (1.5 l) and then the aqueous phase was made basic with ammonium hydroxide. A solid crystallized and was collected by filtration to yield the title compound (22.3 g, 91%), m.p. 61-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27](O)(=[O:29])=[O:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:27]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)(=[O:28])=[O:29])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: C1COCCN1
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)N4CCOCC4)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 14.7 %

Procedure:
The product was obtained using the same synthetic methods as Example 54, using 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid (350 mg, 0.83 mmol, 1.00 equiv) and morpholine (1.44 g, 16.53 mmol, 20.00 equiv) as reactants. Purification by Prep-HPLC afforded 60 mg (34%) of 2,3-bis(4-methoxyphenyl)-6-(morpholinosulfonyl)quinoxaline as a white solid.
Reaction SMILES: [Cl-].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]([CH3:32])=[C:10]([CH2:12][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:11]=1.[CH:33]([C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1)=O>>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:9]([CH3:32])=[C:10](/[CH:12]=[CH:33]/[C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)[N:11]=1
Reactant: Cc1oc(-c2ccco2)nc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Cl-]
Product: COC(=O)c1ccc(/C=C/c2nc(-c3ccco3)oc2C)cc1

Procedure:
[2-(2-Furyl)-5-methyl-4-oxazolylmethyl]triphenylphosphonium chloride and methyl 4-formylbenzoate were reacted in the same manner as in Reference Example 10 to yield methyl (E)-4-[2-[2-(2-furyl)-5-methyl-4-oxazolyl]vinyl]benzoate, which was then recrystallized from ethyl acetate to yield colorless prisms having a melting point of 142°-143° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCCCCC>[CH2:18]([N:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2ccc(OC(F)(F)F)cc2)CCN(Cc2ccccc2)CC1

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 8.5, starting with 20 g of 1-bromo-4-(trifluoromethoxy)benzene in 300 ml of THF, 89.3 ml of a 1.6M solution of n-butyllithium in hexane and 24.1 ml of 1-benzyl-4-piperidinone in 50 ml of THF. 18.5 g of the expected product are obtained.