Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31].C(O)C.C(=O)([O-])[O-].[NH4+:39].[NH4+]>ClCCl.C(O)C>[ClH:31].[CH2:1]([NH:8][C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:26](=[NH:39])[NH2:27])=[CH:24][CH:25]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)NCc3ccccc3)ccc21
Yield: 63 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-benzylamide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 63% of theory, C24H24N6O (412.5); Rf value: 0.76 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=413.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]>CC(C)=O>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1csc(Nc2ccc(C)c(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(Nc2ccc(C)c(OCC=C(C)C)c2)n1
Yield: 57 %

Procedure:
Following the general procedure for O-alkylation, Method A, a mixture of ethyl 2-(3-hydroxy-4-methylphenylamino)thiazole-4-carboxylate (80 mg, 0.29 mmol) and K2CO3 (44 mg, 0.32 mmol) in acetone (2.9 mL) was treated with 4-bromo-2-methyl-2-butene (0.037 mL, 0.32 mmol). The reaction mixture was heated at reflux for 4 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 7/3) in 57% yield (56 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:22]=[C:21]([C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[C:30]([O:32][CH3:33])=[O:31])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1F
Reactant: COC(=O)[C@H]1CCCN1C(=O)c1cc(-c2ccc(N)cc2)no1
Product: COC(=O)[C@H]1CCCN1C(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3F)cc2)no1
Yield: 58 %

Procedure:
The title compound was prepared according to the procedure as set forth in example 151, except that 1-fluoro-2-isocyanatobenzene was used in place of 1-fluoro-3-isocyanatobenzene and (R)-methyl 1-(3-(4-aminophenyl)isoxazole-5-carbonyl)pyrrolidine-2-carboxylate was used in place of methyl 2-(3-(4-aminophenyl) isoxazole-5-carboxamido)-3-methylbutanoate to yield 58% of the title compound. MS (ES+): m/z 453 (M+1); 1HNMR (DMSO-d6, 300 MHz): δ 9.35 (s, 1H), 8.64 (s, 1H), 8.15 (m, 1H), 7.89 (d, 2H), 7.66 (s, 1H), 7.6 (d, 2H), 7.26 (m, 1H), 7.16 (m, 1H), 7.06 (m, 1H), 3.92 (t, 1H), 3.67 (s, 3H), 3.65 (m, 1H), 2.29 (m, 1H), 1.97 (m, 2H), 1.24 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][OH:9].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: BrCCCCCBr
Reactant: OCCc1ccccn1
Product: BrCCCCCOCCc1ccccn1

Procedure:
From 2-pyridineethanol (5.0 g) and 1,5-dibromopentane (16.6 ml), with a reaction time of 4 h. FCC eluting with hexane-diethyl ether (1:0→1:1) gave the title compound as a colourless oil (6.15 g), t.l.c. (ether-hexane 1:1) Rf 0.19.
Reaction SMILES: [OH-].[Na+].CO.[NH:5]1[C:9]([C:10]2[CH:11]=[C:12]([C:22]([O:24]C)=[O:23])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[N:8][N:7]=[N:6]1.Cl>O>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([C:22]([OH:24])=[O:23])[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[N:5][N:6]=[N:7]1
Reactant: COC(=O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Aqueous 2 N sodium hydroxide solution (4 mL) was added to an MeOH (40 mL) solution of methyl 5-(tetrazol-5-yl)biphenyl-3-carboxylate (1.18 g), and stirred at room temperature for 45 minutes and then at 50° C. for 5 hours. Further, aqueous 2 N sodium hydroxide solution (2 mL) was added to it, and stirred at 50° C. for 2 hours. With cooling with ice, 2 N hydrochloric acid (12 mL) and water were added to it, the formed precipitate was taken out through filtration, washed with water and dried to obtain the title compound as a white powder.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH2:15]([O:17][C:18](=[O:26])[C@H:19]([CH3:25])[NH:20][C:21](=O)[CH:22]=[CH2:23])[CH3:16].[OH-].[K+]>C(Cl)(Cl)Cl>[CH2:15]([O:17][C:18]1[O:26][C:21]([CH:22]=[CH2:23])=[N:20][C:19]=1[CH3:25])[CH3:16]
Reactant: C=CC(=O)N[C@@H](C)C(=O)OCC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=Cc1nc(C)c(OCC)o1

Procedure:
To a suspension of 1.0 mole of phosphorous pentoxide in 300 ml. of dry chloroform is added dropwise with stirring a solution of 0.5 mole of N-acryloylalanine ethyl ester. The reaction mixture is heated at gentle reflux for 5 hours and then cooled. To the cooled mixture is added with rapid stirring 750 ml. of 20% aqueous potassium hydroxide. After stirring at room temperature for 1 hour, the chloroform layer is separated and the aqueous layer extracted with 2 × 200 ml. of chloroform. The combined chloroform extracts are washed with water, dried over sodium sulfate, and concentrated in vacuo to yield 5-ethoxy-4-methyl-2-vinyloxazole.
Reaction SMILES: [K+].[Br-].[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C@H:25]([CH3:32])[C:23](=[O:24])[C@H:22]([CH3:33])[C@@H:21]([OH:34])[C@@H:20]([CH3:35])[CH2:19][CH2:18][CH2:17][C@H:15]3O[C@H:14]3[CH2:13]2)\[CH3:11])[N:5]=1.[CH3:36]C1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)[C@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC(C)=CC2)\C)N=1.CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1>CO>[CH3:3][C:4]1[S:8][CH:7]=[C:6](/[CH:9]=[C:10](/[C@H:12]2[O:30][C:28](=[O:29])[CH2:27][C@H:26]([OH:31])[C:25]([CH3:32])([CH3:36])[C:23](=[O:24])[C@H:22]([CH3:33])[C@@H:21]([OH:34])[C:20]([CH3:35])=[CH:19][CH2:18][CH2:17][CH:15]=[CH:14][CH2:13]2)\[CH3:11])[N:5]=1
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Reactant: Cc1nc(/C=C/[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CC/C=C(\C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: CC1=CCCC=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@H]1O

Procedure:
colorless amorphous solid; [α]22D −158.2 (c 0.5, MeOH); UV (MeOH) λmax nm (ε) 205 (19500), 247 (12700); IR (KBr) νmax 3447, 2972, 2927, 1737, 1690, 1450, 1252, 1181, 936 cm−1; 1H NMR (CDCl3, 400 MHz) δ 6.93 (1H, s, H-19), 6.48 (1H, bs, H-17), 5.48 (1H, ddd, J=10.7, 6.2, 6.2 Hz, H-12), 5.39 (1H, m, H-13), 5.37 (1H, M, H-9), 5.34 (1H, dd, J=8.0, 2.3 Hz, H-15), 4.29 (1H, dd, J=6.0, 2.6 Hz, H-7), 4.09 (1H, ddd, J=10.8, 7.1, 2.9 Hz, H-3), 3.59 (1H, d, J=7.1 Hz, 3-OH), 3.17 (1H, dq, J=6.0, 6.9 Hz, H-6), 2.68 (3H, s, H-21), 2.54 (1H, ddd, J=15.2, 8.1, 8.0 Hz, H-14a), 2.44 (1H, bs, 7-OH), 2.42 (1H, dd, J=15.1, 2.9 Hz, H-2a), 2.41 (1H, ddd, J=15.2, 2.3, 2.3 Hz, H-14b), 2.34 (1H, dd, J=15.1, 10.8 Hz, H2b), 2.20 (1H, m, H-10a), 2.18 (2H, m, H-11), 2.12 (1H, m, H-10b), 2.06 (3H, bs, H-27), 1.67 13 (3H, bs, H-25), 1.27 (3H, s, H-23), 1.21 (3H, d, J=6.9 Hz, H-24), 1.15 (311, s, H-22); 13C NMR, see Table 1; EIMS m/z 475 [M]+ (6), 392 (7), 304 (6), 288 (33), 204 (76), 171 (19), 168 (100), 164 (12); REIMS m/z 475.2380 (calcd. for C26H37NO5S, 475.2392).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>ClCCl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOCCOCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a stirred solution of the product of step (a) (1 g) in dichloromethane (20 mL), p -toluenesulfonyl chloride (0.66 g) and triethylamine (0.5 mL) were added and the reaction was stirred at 20° C. for 24 hours. The reaction mixture was diluted with dichloromethane (100 mL) then washed with water (100 mL) and brine (100 mL), dried and the solvent removed in vacuo. Purification by column chromatography on silica gel (Biotage), eluting with 10% ethyl acetate in cyclohexane to give the title compound (1 g). LC retention time 3.37 mins. Mass spectrum m/z 544 [MNH4+]
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:47][CH2:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:53][CH2:52]1)=[O:50]>CN(C=O)C.C(OCC)(=O)C.O>[O:50]=[C:49]([N:51]1[CH2:52][CH2:53][N:54]([C:57](=[O:68])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[C:64]([F:67])([F:66])[F:65])[CH2:55][CH2:56]1)[CH2:48][NH:47][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:11]2[N:10]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:24][CH:23]=1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-c2ncccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ncccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
DIPEA (77 mg, 0.1 mL, 0.59 mmol) was added to a stirred solution of 4-pyrimidin-2-yl-benzoic acid (40 mg, 0.19 mmol) in DMF (2 mL). HOBT (32 mg, 0.23 mmol) and EDCI (46 mg, 0.23 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (84 mg, 0.23 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and then extrated with ethyl acetate. The organic layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg (30.9%) of N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-pyrimidin-2-yl-benzamide. LCMS Purity: 97.15%. 1H NMR (DMSO-d6): δ 9-8.9 (d, 2H), 8.8-8.7 (m, 1H), 8.5 (d, 2H), 8.1-8.0 (d, 2H), 7.9-7.5 (m, 5H), 4.3-4.1 (m, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.2-3.0 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:21][CH2:22][N:17]([C:15]([C:12]2[N:13]=[CH:14][C:9]([N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]3=[O:7])=[CH:10][CH:11]=2)=[O:16])[CH2:18][CH2:19]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Reactant: CN1CCNC1=O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cn3)CC2)c(C)c1
Yield: 53.6 %

Procedure:
Using 1-methyl-2-imidazolidinone (37 mg) and (5-bromopyridin-2-yl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (140 mg) described in Preparation Example 137 and by the reaction and treatment in the same manner as in Example 1, the title compound (78 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=O)[CH2:3][CH2:2]1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH:8]=[CH:9][C:10]([NH:16][C@H:17]2[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]2)=[N:11]3)=[N:27][OH:28])[CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(c1cccc2nc(N[C@@H]3CCc4ccccc43)ccc12)C1CC1
Reaction time: 2 h
Yield: 45.6 %

Procedure:
A stirred suspension of cyclopropyl-[2-((R)-indan-1-ylamino)-quinolin-5-yl]-methanone (example 30) (150 mg, 0.46 mmol), hydroxylamine hydrochloride (95 mg, 1.37 mmol) and sodium carbonate (145 mg, 1.37 mmol) in ethanol (5 ml) was heated under reflux conditions for 18 h, the reaction mixture was poured into water (5 ml) and the mixture was stirred for 2 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (heptane/ethyl acetate) to yield the title compound as off-white solid (72 mg, 46%). M.p. 151° C.; MS: m/e=344.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:6]([F:8])([F:7])[C:5]([F:10])([F:9])[C:4]([F:12])([F:11])[C:3]=1Cl.C(N(CC)CC)C>CO.[Ni]>[F:7][C:6]1([F:8])[CH2:2][CH2:3][C:4]([F:12])([F:11])[C:5]1([F:9])[F:10]
Reactant: FC1(F)C(Cl)=C(Cl)C(F)(F)C1(F)F
Agent: [Ni]
Solvent: CO
Solvent: CCN(CC)CC
Product: FC1(F)CCC(F)(F)C1(F)F
Reaction time: 12 h
Yield: 59.5 %

Procedure:
In a 1.3 l stainless steel autoclave, 245 g (1 mol) of 1,2-dichloro-3,3,4,4,5,5-hexafluorocyclopentene were hydrogenated at 60 to 70° C. with the addition of 202 g (2 mol) of triethylamine in 200 ml of methanol and in the presence of 20 g of Raney nickel. Over a period of 12 hours, the theoretical amount of hydrogen was absorbed at a hydrogen pressure of 40 to 50 bar. The reaction mixture was filtered and the methanolic solution was diluted with 400 ml of water. The lower organic phase was separated, washed with 100 ml of 5% aqueous hydrochloric acid, and dried over sodium sulfate. Distillation through a 1-m spinning band column gave 106 g (60% of theory) of 1,1,2,2,3,3-hexafluorocyclopentane having a boiling point of 87-88° C. at 1013 mbar. The mass spectrum showed the molecular ion at m/e 178.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[C:6]([CH3:20])[N:5]=[C:4]([CH3:21])[N:3]=1.N[CH2:23][C:24]1[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=1>>[CH3:21][C:4]1[N:3]=[C:2]([NH:1][CH2:23][C:24]2[O:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:26][CH:25]=2)[C:7]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)=[C:6]([CH3:20])[N:5]=1
Reactant: Cc1nc(C)c(C#Cc2ccc(C(F)(F)F)cc2)c(N)n1
Reactant: CCOC(=O)c1ccc(CN)o1
Product: CCOC(=O)c1ccc(CNc2nc(C)nc(C)c2C#Cc2ccc(C(F)(F)F)cc2)o1

Procedure:
The method described in any one of Example 1 to Example 10 and Example 23 was repeated except that 4-amino-2,6-dimethyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine was used in place of 4-amino-6-methyl-5-{[4-(trifluoromethyl)phenyl]ethynyl}pyrimidine or ethyl 5-aminomethyl-2-furancarboxylate was used in place of ethyl (4-aminomethyl)benzoate to obtain a target substance. The target substance was subjected to e.g., proton nuclear magnetic resonance spectrometry (1H-NMR) and mass spectrometry (MS) and confirmed as the titled compound. Furthermore, MS measurement result is shown.
Reaction SMILES: Br.[N:2]1([C:7]([CH2:9][C:10]([OH:12])=O)=[O:8])[CH:6]=[CH:5][N:4]=[CH:3]1.[CH:13]1([CH2:19][CH2:20][CH2:21][C@@H:22]([C@@H:33]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:34]([NH:36][NH:37][CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[C:23](=[O:32])[NH:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N1CCOCC1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH:13]1([CH2:19][CH2:20][CH2:21][C@@H:22]([C@@H:33]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:34]([NH:36][N:37]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:10](=[O:12])[CH2:9][C:7]([N:2]2[CH:6]=[CH:5][N:4]=[CH:3]2)=[O:8])=[O:35])[C:23](=[O:32])[NH:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(O)CC(=O)n1ccnc1
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Agent: Br
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CC(=O)n1ccnc1)[C@H](CCCC1CCCCC1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.3 %

Procedure:
A solution of 0.429 g of 2-(1-imidazoyl)acetic acid hydrogen bromide and 0.467 g of 2(R)-[4-Cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was treated with 0.230 g of N-ethylmorpholine and 0.422 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and the mixture stirred overnight at room temperature. Evaporation gave a residue which was dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution then dried over anhydrous magnesium sulfate and evaporated. Purification by flash column chromatography on silica gel using methanol/dichloromethane (5:95) as the eluant gave 0.213 g of 2(R)-[4-cyclohexyl-1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]butyl]-2′-isobutyl-4-methyl-2′-[2-(1-imidazoyl)acetyl]valerohydrazide in the form of a white foam.
Reaction SMILES: [NH2:1][C:2]1[C:17]([O:18][CH3:19])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:25][C@@H:26]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[NH:40][C:41]2[C:46]([Cl:47])=[CH:45][N:44]=[C:43](Cl)[N:42]=2)(=[O:33])=[O:32])[CH2:27]1)(C)(C)C>>[Cl:47][C:46]1[C:41]([NH:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:31]([N:28]2[CH2:29][CH2:30][C@@H:26]([OH:25])[CH2:27]2)(=[O:32])=[O:33])=[N:42][C:43]([NH:1][C:2]2[C:17]([O:18][CH3:19])=[CH:16][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([OH:14])([CH3:15])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:44][CH:45]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CC(C)(C)O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@@H](O)C3)n1)CCN(CC(C)(C)O)CC2
Yield: 47 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from 1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-2-methyl-propan-2-ol and {2-[(R)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. Product was isolated as white solid (58 mg, 47%). mp: 205-206° C., MS (ESI+): 617 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.17 (s, 1H), 7.97 (m, 2H), 7.53 (m, 2H), 7.25 (m, 1H), 6.65 (s, 1H), 3.60 (br s, 1H), 3.89 (s, 3H), 3.42 (q, 6 Hz, 3H), 3.30 (m, 2H), 2.87-2.72 (m, 8H), 2.48 (s, 2H), 1.95 (m, 1H), 1.88 (m, 1H), 1.57 (s, 6H), 1.22 (s, 6H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>O1CCCC1>[Br:50][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([NH:26][C:27](=[O:29])[CH3:28])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1nc(-c2ccc(CCCO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc(CCCBr)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[4-(3-hydroxypropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (75 mg) in tetrahydrofuran (0.7 ml) were added triphenylphosphine (68.5 mg) and carbon tetrabromide (86.7 mg) at 0° C., and the mixture was stirred for 1 h at 20° C. The reaction mixture was purified by preparative thin-layer chromatography over silica gel with hexane/ethyl acetate (1:2) as an eluent to give N-{4-[4-(3-bromopropyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as colorless oil.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])=[N:27][CH:28]=1)#[N:33]
Reactant: N#Cc1ccc(N)nc1
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1ccc(C#N)cn1)CCC2
Temperature: -15 °C
Reaction time: 0.42 h

Procedure:
A solution of phenyl 7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (intermediate 3, 262 mg, 0.798 mmol) and 2-amino-5-cyanopyridine (190 mg, 1.60 mmol) in THF (7.5 ml) at −15° C. under argon was treated drop wise with LHMDS (1M in THF, 1.60 ml, 1.60 mmol). The reaction mixture was stirred at −15° C. for 25 min and then quenched by addition of sat. aq. NH4Cl and extracted with EtOAc (2×). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a white solid. (UPLC-MS 1) tR 1.09 min; ESI-MS 354.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8](O)([CH3:10])[CH3:9])[CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([CH3:10])=[CH2:9])[CH:7]=1
Reactant: CC(C)(O)c1cc(Br)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of 2-(5-bromo-2-chlorophenyl)-propan-2-ol (500 mg, 2 mmol, 1 eq) in toluene (5 ml) was added a catalytic amount of p-toluenesulfonic acid (38 mg, 0.2 mmol, 0.1 eq) and the solution was refluxed under a Dean-Stark H2O separator overnight. The reaction mixture was allowed to cool to RT and was diluted with ether. The mixture was washed with sat. NaHCO3-solution and brine, dried (MgSO4), filtered and concentrated in vacuo to give the desired product (357 mg, 77%) as a colorless oil which did not require further purification.