Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:22]=3)=[N:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1>FC(F)(F)C(O)=O>[ClH:2].[Cl:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:17][C:18]3[CH:19]=[N:20][N:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:22]=3)=[N:12][CH:13]=[N:14]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Yield: 197.1 %

Procedure:
A solution of tert-butyl (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetate hydrochloride (7.33 g, 16.1 mmol) in trifluoroacetic acid (60 ml) was stirred at room temperature for 30 minutes. The mixture was concentrated and the residue was suspended in water (120 ml), basified to pH 12 with 40% aqueous sodium hydroxide solution and then re-acidified to pH 4.8 with 2N aqueous hydrochloric acid to give (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (5.74 g, 98% yield) as a cream coloured solid:
Reaction SMILES: [Na].[CH2:2]([NH:9][C:10]1[N:19]=[C:18]2[C:13]([C:14]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)=[N:15][C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17]2)=[N:12][C:11]=1Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][OH:35]>O1CCOCC1>[CH2:2]([NH:9][C:10]1[N:19]=[C:18]2[C:13]([C:14]([N:26]3[CH2:31][CH2:30][S:29](=[O:32])[CH2:28][CH2:27]3)=[N:15][C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[N:17]2)=[N:12][C:11]=1[O:35][CH3:34])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S1CCN(c2nc(N3CCNCC3)nc3nc(NCc4ccccc4)c(Cl)nc23)CC1
Reactant: CO
Agent: [Na]
Solvent: C1COCCO1
Product: COc1nc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc2nc1NCc1ccccc1

Procedure:
A solution of 0.23 g (0.01 mol) of sodium in 10 ml of methanol was poured into a solution of 2.9 g (0.006 mol) of 7-benzylamino-6-chloro-4-(1-oxido-thiomorpholino)-2-piperazino-pteridine in 100 ml of dioxane. The resulting mixture was refluxed for 30 minutes and then the solvent was substantially distilled off in vacuo. The residue was taken up in about 70 ml of water, and the reaction product which precipitated was suction-filtered off, washed with water and dried at about 60° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[O:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=3[F:28])[CH:10]=2)=[CH:5][CH:4]=1.[CH3:29][N:30]([CH3:36])[C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>COCCOC>[F:28][C:20]1[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:19]=1[O:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:33]4[CH2:34][CH2:35][C@H:31]([N:30]([CH3:36])[CH3:29])[CH2:32]4)=[CH:8][CH:7]=3)[S:17][C:16]=12
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(CCl)cc4)sc23)c(F)c1
Reactant: CN(C)[C@H]1CCNC1
Solvent: COCCOC
Product: CN(C)[C@H]1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc([N+](=O)[O-])cc5F)c4s3)cc2)C1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a suspension of 52 (1.0 g, 2.41 mmol) in DME (˜20 ml) was added (S)—N,N-dimethylpyrrolidin-3-amine (413 mg, 3.62 mmol) and TEA (486 mg, 2 eq, 4.82 mmol) and the reaction mixture was heated to reflux for an hour. The reaction mixture was cooled to RT, filtered then concentrated. The mixture was partitioned between EtOAc/H2O and the biphasic system was filtered and the resultant yellow solid was collected was collected by filtration to afford title compound 60 (450 mg, 38% yield). The organic phase was separated from the biphasic system; it was then dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (9:1 EtOAc:MeOH+1% conc NH4OH solution) to afford an additional amount of 60 (82 mg, 7% yield). MS (m/z): 493 (M+H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH:8]=[O:9])=[N:4][C:3]=1[C:10](=[N:37][O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:11]([NH:13][CH:14]1[C:35](=[O:36])[N:16]2[C:17]([C:22]([O:24]CC3C=CC([N+]([O-])=O)=CC=3)=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12)=[O:12]>CO.O1CCCC1.C(O)(=O)C.[C].[Pd]>[Cl:1][C:2]1[S:6][C:5]([NH:7][CH:8]=[O:9])=[N:4][C:3]=1[C:10](=[N:37][O:38][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:11]([NH:13][CH:14]1[C:35](=[O:36])[N:16]2[C:17]([C:22]([OH:24])=[O:23])=[C:18]([Cl:21])[CH2:19][S:20][C@H:15]12)=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1nc(NC=O)sc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1nc(NC=O)sc1Cl
Yield: 80.1 %

Procedure:
p-Nitrobenzyl 7-[2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer) (6.2 g) was dissolved in a mixed solution of methanol (60 ml), tetrahydrofuran (40 ml) and glacial acetic acid (0.5 ml). After adding 10% palladium carbon (3.1 g) to the solution, the mixture was subjected to catalytic reduction at room temperature under atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was adjusted to pH 7.5 with saturated aqueous sodium bicarbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was evaporated to give 7-[2-(5-chloro-2-formamidothiazol-4-yl)-2-t-butoxycarbonylmethoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (4.03 g).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:4]1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[CH3:35][N:2]([CH3:1])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[CH:25]=[N:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=45)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:4]1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A mixture of N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 135, 198.7 mg, 0.42 mmol), iron (139 mg, 2.49 mmol) and NH4Cl (15.6 mg, 0.29 mmol) in ethanol (15 mL) and water (5 mL) was heated at reflux for 2.5 h. The mixture was then allowed to cool to r.t., filtered and concentrated in vacuo. Part-purification by ion exchange chromatography, using an SCX column, eluting with 0.7M methanolic ammonia provided crude material as a yellow gum. Further purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave the title compound (159 mg, 85%) as a brown foam; 1H NMR (CDCl3): 1.83-1.97 (3H, m), 2.05-2.17 (3H, m), 2.29 (6H, s), 2.83-2.91 (1H, m), 2.98-3.08 (2H, m), 3.15-3.20 (2H, m), 3.24 (2H, t), 3.69 (2H, s), 3.83 (3H, s), 4.20 (2H, t), 6.69 (1H, s), 6.78 (1H, d), 7.45 (1H, s), 7.97 (2H, d), 8.29 (1H, d); m/z: ES+ MH+ 449.65.
Reaction SMILES: Br[C:2]1[N:3]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH:13]([CH3:15])[CH3:14])[N:5]=2.[CH3:22][O-:23].[Na+]>CO>[CH3:14][CH:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:23][CH3:22])[N:3]2[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[C:8]([NH2:11])[N:7]=1)[CH3:15]
Reactant: C[O-]
Reactant: CC(C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OC(C)C)nc2n1C1CCCCO1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To a stirred suspension of 8-bromo-2-[(1-methylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (690 mg, 1.937 mmol) in methanol (15 ml) was added sodium methoxide (30% wt/v solution in methanol, 2.4 ml) and the reaction mixture heated at 50° C. for 2 hours. The reaction mixture was then heated to 70° C. and stirred for 2.5 hours. The solvent was evaporated and the residue partioned between saturated aqueous ammonium chloride solution (15 ml) and ethyl acetate (20 mL). The layers were separated, the aqueous phase was extracted with additional ethyl acetate (2×10 mL) and the organic extracts were combined, dried by passage through a hydrophobic frit and evaporated to give the title compound as a yellow solid (573 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]([OH:15])[CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>O=[Mn]=O.C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:12](=[O:15])[CH2:13][CH3:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: CCC(O)c1ccc2cccnc2c1N
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCC(=O)c1ccc2cccnc2c1N
Yield: 80.7 %

Procedure:
In a similar fashion using route 27 general procedure 68, 1-(8-amino-quinolin-7-yl)-propan-1-ol 408 (1.0 g, 4.95 mmol), MnO2 powder (4.3 g, 49.5 mmol) and DCM (10 ml) gave the title compound (800 mg, 80%) which was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[C:2]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[C:10]([CH:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2cc1O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccccc4cc3O)c2cc1OC
Temperature: 130 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
Naphthalene-2,3-diol (1.00 g), 4-chloro-6,7-dimethoxyquinoline (691 mg), and 4-dimethylaminopyridine (1.14 g) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. for one hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform-methanol to give the title compound (627 mg, yield 58%).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C[C@@H](O)CCCCCC.[CH2:62]([O:64][C:65](=[O:71])[CH2:66][C:67]([CH2:69][Cl:70])=[O:68])[CH3:63]>>[CH2:62]([O:64][C:65](=[O:71])[CH2:66][CH:67]([OH:68])[CH2:69][Cl:70])[CH3:63]
Reactant: CCOC(=O)CC(=O)CCl
Agent: CCCCCC[C@@H](C)O
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Product: CCOC(=O)CC(O)CCl

Procedure:
100 mM potassium phosphate buffer (pH 6.5), 139.8 mg NADH, 0.06 U (R)-2-octanol dehydrogenase from Candida utilis, and 0.5% 4-chloroacetoacetic acid ethyl ester were reacted overnight at 30° C. The optical purity of the 4-chloro-3-hydroxybutyric acid ethyl ester produced was determined in the same way as Example 32. As a result, 4-chloro-3-hydroxybutyric acid ethyl ester produced by this invention was more than 97% ee of S form.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].[NH2:9][N:10]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[CH2:12][CH2:11]1>CO.C(N(CC)CC)C>[F:27][C:24]([F:25])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([O:17][CH:15]2[C:14]3[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=3[CH2:12][CH2:11][N:10]([NH:9][C:3](=[O:4])[C:2]([F:1])([F:7])[F:8])[CH2:16]2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(F)(F)F
Reactant: NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NN1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Reaction time: 8 h
Yield: 78 %

Procedure:
Methyl trifluoracetate (4.2 g) was added to a solution of 3-amino-2,3,4,5-tetrahydro-1-(4trifluoromethylphenoxy)-1H-3-benzazepine (8.4 g) in 100 mL anhydrous methanol and triethylamine (3.3 g). The solution was allowed to stand overnight at ambient temperature and thereafter concentrated. The residue was triturated with ether and the resultant product was collected and dried to yield 8.5 g white solid, mp 192°-195°.
Reaction SMILES: [CH:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C:8]1=[CH:7][CH2:6][C:5]2=[O:23])([CH3:3])[CH3:2]>O1CCOCC1.[Ni].[H][H]>[CH:1]([C@:4]12[CH2:12][CH2:11][C:10]3[C:13]4[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=4[CH2:19][CH2:20][C:9]=3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C(C)C)C(=O)CC=C12
Agent: [Ni]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C(C)C)C(=O)CC[C@@H]12
Yield: 59.6 %

Procedure:
Shake 13β-isopropyl-3-methoxygona-1,3,5(10),8,14-pentaen-17-one (2 g) in dioxan (50 cc) with a freshly prepared but moderately active Raney nickel catalyst (ca. 0.5 g) in hydrogen at atmospheric pressure. When, after several hours the theoretical amount of hydrogen for half-hydrogenation (160 cc) has been absorbed, filter off the nickel catalyst and remove the solvent by evaporation. Crystallize the residual gum from methanol to obtain the title product (1.2 g), m.p. 85°-100°C; ultraviolet absorption peak at 280 mμ (ε11,800).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([O:15]C)=[S:14])=[CH:3]1.C(N1C(C2C=CC=CC=2)=CC(C(O)=S)=C1)C>>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:5][C:4]([C:13]([OH:15])=[S:14])=[CH:3]1
Reactant: COC(=S)c1cc(-c2ccccc2)n(C)c1
Agent: CCn1cc(C(O)=S)cc1-c1ccccc1
Product: Cn1cc(C(O)=S)cc1-c1ccccc1

Procedure:
By the same process the corresponding 1-ethyl derivative of Example 5 is converted to 1-ethyl-5-phenylthiopyrrole-3-carboxylic acid.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[F:6][C:7]([F:33])([F:32])[C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](Cl)=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:10][CH2:9]1.C1COCC1>CO>[F:32][C:7]([F:6])([F:33])[C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:12][CH2:13]1
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Reactant: NCC(F)F
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Reaction time: 20 h

Procedure:
2,2-Difluoroethylamine (0.18 mL, 2.53 mmol) is slowly added to a mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-chloro-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (prepared according to WO2010/34799, 1.00 g, 2.3 mmol) and 10 mL THF at 0° C., 2 mL MeOH is added and it is stirred for 20 h. The mixture is concentrated and the solid residue is washed with water and dried. Yield: 0.96 g.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][NH:13][C:14]([CH:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)=[O:15])=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31].[NH+]1C=CC=CC=1.FC(F)(F)C(O)=O>>[O:1]=[C:2]1[N:8]2[CH2:9][C@@H:4]([CH2:5][CH2:6][C@H:7]2[C:10]([NH:12][NH:13][C:14]([CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[O:15])=[O:11])[N:3]1[O:29][S:30]([OH:33])(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)CC1
Agent: c1cc[nH+]cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OS(=O)(=O)O)C1CCNCC1
Yield: 37.2 %

Procedure:
All the amount of the pyridine salt was deprotected with trifluoroacetic acid and purified by octadecyl silica gel column chromatography to afford 150 mg of the title compound (yield 37.2%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([C:13]1[S:50][C:16]2[N:17]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([C:42]4[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:38][CH:37]=3)[C:18](=[O:34])[N:19]([CH:22]([CH3:33])[CH:23]([OH:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([C:13]1[S:50][C:16]2[N:17]([CH2:35][C:36]3[CH:37]=[CH:38][C:39]([C:42]4[C:43]([C:48]#[N:49])=[CH:44][CH:45]=[CH:46][CH:47]=4)=[CH:40][CH:41]=3)[C:18](=[O:34])[N:19]([CH:22]([CH3:33])[C:23]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[O:32])[C:20](=[O:21])[C:15]=2[CH:14]=1)[CH3:12]
Reactant: CCc1cc2c(=O)n(C(C)C(O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCc1cc2c(=O)n(C(C)C(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a mixture of oxalylchloride (0.12 mL) and methylene chloride (10 mL) were added a solution (5 mL) of dimethyl sulfoxide (0.096 mL) in methylene chloride and a solution (5 mL) of 4′-{[6-ethyl-3-[2-hydroxy-2-(4-methoxyphenyl)-1-methylethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.68 g) in methylene chloride at −78° C., and the mixture was stirred at the same temperature for 15 min. Triethylamine (0.86 mL) was added, and the mixture was allowed to warm to room temperature. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.27 g, 40%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([CH:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:13](=[O:15])[C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=3)[S:61][C:51]=2[C:52]([CH:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: COc1cnc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccnc(N2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(C2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12

Procedure:
From 2-(4-morpholinyl)-4-pyridinecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-(tetrahydro-pyran-4-yl)thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH:15]=[C:16](Cl)[CH3:17])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C1(C)C=CC=CC=1>O>[NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]#[C:16][CH3:17])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)=Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C)nc(Nc2ccccc2)n1
Yield: 37.4 %

Procedure:
Into a 100 ml reaction flask equipped with a stirrer, a thermometer and a condenser, 5.2 g (0.02 mol) of 2-anilino-4-methyl-6-(2-chloropropen-1-yl)pyrimidine, 1.3 g (0.024 mol) of finely pulverized KOH and 50 ml of toluene were charged, and the mixture was reacted for 10 hours under reflux. The reaction mixture was cooled, water was added, and the mixture was subjected to liquid separation. The toluene layer was washed with water. The toluene layer was concentrated and subjected to column chromatography to obtain 1.67 g of 2-anilino-4-methyl-6-(1-propynyl)pyrimidine having a melting point of from 125° to 126° C. The yield was 37.4%.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:10])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[C:26](Cl)(=[O:29])[O:27][CH3:28].[NH4+].[Cl-]>C1COCC1>[N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3][C:4]([C:26]([O:27][CH3:28])=[O:29])([C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:6]1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (1.3 g, 5.35 mmol, 1.0 eq) in dry THF (35 mL) was added LDA (2N, 3.25 mL, 6.42 mmol, 1.2 eq) dropwise at −78° C. under N2. Then the mixture was stirred at −78° C. for 1 h. Then methyl carbonochloridate (0.55 g, 5.89 mmol, 1.1 eq) was added dropwise to this mixture. The resulting mixture was warmed to rt slowly for 4 h. Saturated NH4Cl solution was added to this mixture, extracted with EtOAc (75 mL×2), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 1-tert-butyl 4,4-dimethyl piperidine-1,4,4-tricarboxylate as yellow oil (1.25 g, Y: 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.BrC1C=NC(Cl)=NC=1.[F:18][C:19]1([F:65])[CH2:24][CH2:23][CH:22]([C:25]2[C:34]3[CH:33]([O:35]CC4C=CC(OC)=CC=4)[CH2:32][C:31]([CH3:46])([CH3:45])[CH2:30][C:29]=3[N:28]=[C:27]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[C:26]=2[CH:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:21][CH2:20]1>>[C:8]([C:5]1[CH:4]=[N:3][C:2]([N:50]2[CH2:49][CH2:48][CH:47]([C:27]3[C:26]([CH:53]([F:64])[C:54]4[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=4)=[C:25]([CH:22]4[CH2:23][CH2:24][C:19]([F:18])([F:65])[CH2:20][CH2:21]4)[C:34]4[CH:33]([OH:35])[CH2:32][C:31]([CH3:46])([CH3:45])[CH2:30][C:29]=4[N:28]=3)[CH2:52][CH2:51]2)=[N:7][CH:6]=1)#[N:9]
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: N#Cc1cnc(Cl)nc1
Agent: Clc1ncc(Br)cn1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(C#N)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of the first step of Example 2 and Example 38 were performed except for using 2-chloropyrimidine-5-carbonitrile, which was synthesized by the method described in A. Takamizawa et al., Journal of Organic Chemistry, 1964, Vol. 29, pp. 1740-1742, instead of 5-bromo-2-chloropyrimidine, and from 78 mg (0.12 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 60 mg of the title compound was obtained as a white solid (yield: 79%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:20]([NH2:22])[CH3:21].C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CN1C(=O)CCC1>[CH2:20]([NH:22][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([B:11]2[O:12][C:13]([CH3:19])([CH3:18])[C:14]([CH3:16])([CH3:17])[O:15]2)=[CH:10][C:2]=1[CH3:1])[CH3:21]
Reactant: CCN
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN1CCCC1=O
Product: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 15 g (57 mmol) 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid in NMP (20 mL) were added 85.84 mL (171.68 mmol) ethylamine and 72.8 mL 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (114.45 mmol, 2M in THF) and the mixture was stirred for 2 h at rt to give after working up and purification 16.00 g (96.7%) of the title compound.