Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)=O.O1CCCC1>C(OCC)(=O)C>[NH2:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:32][O:33][CH2:34][CH:35]=[CH2:36])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:25]=1
Reactant: C=CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCON=C(C(=O)OCC)c1csc(N)n1
Yield: 82.9 %

Procedure:
A solution of ethyl 2-(2-tritylaminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 8.7 g.), 50% formic acid (42.5 ml.) and tetrahydrofuran (42.5 ml.) was stirred at 60° C. for 40 minutes. After concentthe resultant solution in vacuo, the residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. After concentrating the resultant solution in vacuo, the residue was subjected to column chromatography on silica gel with benzene and ethyl acetate in turn, to give ethyl 2-(2-aminothiazol-4-yl)-2-allyloxyiminoacetate (syn isomer, 3.7 g.), mp. 102° to 104° C.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][C:4]=1[CH3:11].[F:12][C:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[CH:15][N:14]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:12][C:13]1[CH:18]=[C:17]([C:3]2[C:4]([CH3:11])=[CH:5][C:6]([CH2:9][NH2:10])=[CH:7][N:8]=2)[CH:16]=[CH:15][N:14]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: Cc1cc(CN)cnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: Cc1cc(CN)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a reaction vial was added (6-chloro-5-methylpyridin-3-yl)methanamine HCl salt 30-4 (738 mg, 3.8 mmol), 2-fluoropyridin-4-ylboronic acid 30-5 (800 mg, 5.7 mmol), Pd(OAc)2 (106 mg, 0.47 mmol), S-Phos (194 mg, 0.47 mmol) and K3PO4 (2.0 g, 9.5 mmol). The vial was evacuated and backfilled with nitrogen, and 2-butanol (5 mL) was added via syringe. The reaction was stirred at room temperature for 10 mins and then 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was partitioned between DCM and H2O, and extracted with DCM three times. The organic phase was combined and dried. The crude product was purified by silica gel flash chromatography, eluted with 10% methanol in DCM to give (2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methanamine 30-5. MS m/z 218.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][C:8](=[O:15])[CH2:7][CH2:6]2.[N+:16]([C:19]1[C:24]([CH:25]=O)=[CH:23][C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[CH:23][C:24]=1[CH:25]=[C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:15])([O-:18])=[O:17]
Reactant: COc1cc2c(cc1OC)CC(=O)CC2
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Product: COc1cc(C=C2C(=O)CCc3cc(OC)c(OC)cc32)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 6,7-Dimethoxy-2-tetralone and 6-nitroveratraldehyde; mp 65-66° C.; IR (Nujol): 2855,1720, 1540; 1H NMR: δ2.71 (2H, t), 2.98 (2H t), 3.35 (3H, s), 3.66 (3H, s), 3.89 (3H, s), 3.97 (3H,s), 6.41 (1H, s), 6.62 (1H, s), 6.73 (1H, s), 7.74 (1H, s), 7.91 (1H, s); 13C NMR: δ28.4, 39.7, 56.5, 56.6, 56.8, 56.9, 107.7, 108.6, 111.2, 113.1, 128.1, 129.3, 130.3, 132.2, 133.3, 148.9, 149.0, 150.0, 153.3, 200.7.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[N:5]=[CH:4][CH:3]=1.[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:56][O:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)[C:26]1=[O:57]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[CH3:24][N:25]1[C:26](=[O:57])[C:27]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][N:50]([CH:53]4[CH2:54][O:55][CH2:56]4)[CH2:49][CH2:48]3)=[CH:43][N:42]=2)=[CH:28][C:29]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[N:5]=[CH:4][CH:3]=2)=[CH:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 103b (600 mg, 1.0 mmol), 1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)pyridin-2(1H)-one 101l (468 mg, 1.0 mmol), Pd(dppf)Cl2 (81 mg, 0.1 mmol), K3PO4.3H2O (678 mg, 3.0 mmol), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 4 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (40:1) to afford 103c as yellow solid (510 mg, 73%). MS: [M+H]+ 635.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([Br:21])[CH:18]=[C:17]([NH2:22])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:26]=[N:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.C(Cl)CCl>ClCCl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([NH:22][C:31]([C:28]3[N:29]=[CH:30][C:25]([Br:24])=[CH:26][N:27]=3)=[O:32])[CH:18]=[C:19]([Br:21])[CH:20]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)cc(Br)c2)COC1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cc(NC(=O)c3ncc(Br)cn3)c2)COC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(3-Amino-5-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (33 mg, 0.082 mmol), 5-bromo-pyrimidine-2-carboxylic acid (18 mg, 0.090 mmol) and HOBT (16 mg, 0.106 mmol) were dissolved in dichloromethane under N2 at 0° C. DIPEA (10.54 mg, 0.082 mmol) and EDC (17 mg, 0.090 mmol) were added. The mixture was stirred at 0° C. for 10 min, then allowed to warm to room temperature, stirred for 17 h at room temperature, quenched with 1M aqueous KHCO3 solution and extracted with dichloromethane. The organic phase was washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by automated column chromatography (cyclohexane/ethyl acetate) to yield the title compound as a tan foam. MS: 569 [(M+H)+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:10].[C:11]1([CH3:20])[C:12]([C:17](Cl)=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1>>[C:11]1([CH3:20])[C:12]([C:17]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:10])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1Cl
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)NCCc1ccccc1Cl

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and o-toluoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-(o-toluoylamino)-2-(2-chlorophenyl)ethane having a melting point of 91.6° C. The product was successively reacted in the same way as in steps (b), (c), (d), (e), (f), (g), and (h) of Example 13 to afford 1-(2-methylphenyl)isoquinoline-5-acetonitrile having a melting point of 120.3° to 120.4° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.F[C:34](F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[O:31][CH3:32])=[C:4]2[CH:10]=[C:9]([C:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH3:34])[CH2:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(Cl)cnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CC=C(c2cc3c(-c4cc(F)ccc4OC)c(Cl)cnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Example 229E (0.072 g, 0.157 mmol) in dichloromethane (1.429 mL) was treated with 2,2,2-trifluoroacetic acid (0.121 mL, 1.572 mmol) and the mixture was stirred at room temperature for 8 hours. The mixture was concentrated and the residue was partitioned in ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was back-extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to provide the title compound. MS (ESI+) m/z 358.1 (M+H)+.
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH2:12]1[O:20][CH:13]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>C(OC(C)C)(=O)C.[Zn]>[OH:20][CH:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CBr
Reactant: c1ccc(C2CO2)cc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CCC(O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 15.1 g of zinc powder (231 mmol) in 90 ml of isopropyl acetate. After 3.7 ml of trimethylchlorosilane (29 mmol) had been added, the mixture was heated to 60° C. for 20 min, then allowed to cool to 55° C. and 32.6 g of undiluted methyl bromoacetate (213 mmol) were subsequently added dropwise within 10 min, and the temperature was maintained at 60° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 5° C., 21.3 g of undiluted styrene oxide (178 mmol) were added, and the temperature was maintained at 5° C. by external cooling. After stirring had been continued at 5° C. for 30 min, the mixture was heated to 25° C. within 20 min and stirred at this temperature for a further 30 min. After cooling to 0° C., the mixture was acidified using 33 ml of 20% hydrochloric acid to a pH of 1 and stirred for 30 min. Excess zinc was then filtered off and the organic phase removed. The organic phase was then stirred at 0° C. with 40 ml of 1 N hydrochloric acid and finally washed with 20 ml of concentrated ammonia solution. After the phase separation, drying was effected over sodium sulfate and the solvent was distilled off under reduced pressure (>90% of the solvent isopropyl acetate was recovered). After distillation, methyl 4-hydroxy-4-phenylbutyrate was obtained in a yield of 30.9 g (90% of theory) and had a boiling point of 128° C. (4 mbar).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([CH3:15])[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(C)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c2c1F
Yield: 95 %

Procedure:
A mixture of 30 g of ethyl 1-cyclopropyl-6,8-difluoro-7-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 210 ml of glacial acetic acid, 160 ml of water and 23.5 ml of concentrated sulphuric acid is heated under reflux for 2 hours. The hot suspension is then poured onto ice and the precipitate is filtered off with suction, rinsed thoroughly with water and dried in vacuo at 100° C. 25.9 g of pure 1-cyclopropyl-6,8-difluoro-7-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 227°-229° C. are obtained in this manner.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:17][C:18]=2[O:19][CH3:20])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([CH2:21][P:22](=[O:29])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])=[N:17][C:18]=4[O:19][CH3:20])[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)n1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)n1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl [(5-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-6-methoxypyridin-2-yl)methyl]phosphonate (Compound 286A, 100 mg, 0.22 mmol) and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one (115 mg, 0.44 mmol). The crude material was purified by MDP to obtain the title compound (82 mg, 55% yield). 1H NMR (400 MHz, methanol-d4) δ=1.31 (t, J=6.9 Hz, 6 H), 1.38-1.53 (m, 2 H), 1.62-1.77 (m, 2 H), 1.84-1.93 (m, 2 H), 2.04-2.14 (m, 2 H), 2.53-2.64 (m, 1 H), 3.17 (s, 3 H), 3.44 (d, J=21.7 Hz, 2 H), 3.62-3.72 (m, 1 H), 4.01 (s, 3 H), 4.10-4.21 (m, 4 H), 4.51 (s, 2 H), 6.99 (dd, J=8.1, 2.8 Hz, 1 H), 7.39 (d, J=8.6 Hz, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 8.37 (s, 2 H). MS (ES+): m/z 679.31 (100) [MH+]; HPLC: tR=1.06 min (UPLC, purity).
Reaction SMILES: C1C2(N(C3C=CC=CC=3)CNC2=[O:8])CCN(CCCC(C2C=CC(F)=CC=2)=O)C1.CCC[N:33]1[C@H:38]2CO[C:41]3[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][C:42]=3[C@@H:37]2OCC1.C(O)C(N)(CO)CO.Cl.[Cl-].[K+].[Mg+2].[Cl-].[Cl-].[Cl-].[Cl-].[Ca+2].CC([C@]1(O)C[C@H]2N(C[C@H]3C4C2=CC=CC=4CCC2C=CC=CC3=2)CC1)(C)C>>[NH2:33][CH2:38][CH2:37][C:42]1[CH:41]=[CH:46][C:45]([OH:8])=[C:44]([OH:47])[CH:43]=1
Reactant: O=C(CCCN1CCC2(CC1)C(=O)NCN2c1ccccc1)c1ccc(F)cc1
Reactant: CCCN1CCO[C@H]2c3cc(O)ccc3OC[C@@H]21
Agent: CC(C)(C)[C@@]1(O)CCN2C[C@@H]3c4ccccc4CCc4cccc(c43)[C@H]2C1
Agent: Cl
Agent: NC(CO)(CO)CO
Product: NCCc1ccc(O)c(O)c1
Reaction time: 1.5 h

Procedure:
[3H]Spiperone binding assays. [3H]spiperone binding assays for D2-like receptors were performed as previously described in detail (29,31) and as described for [3H]PD 128907 except for the following. Assays were performed using membranes prepared from rat caudate-putamen, which predominantly express the D2 subtype of D2-like receptors, and the final membrane homogenate concentration was 1.5 mg o.w.w./ml. The assay buffer was 50 mM Tris-HCl, 5 mM KCl, 2 mM MgCl2, and 2 mM CaCl2, pH 7.4 at 23° C.; the concentration of [3H]spiperone (24 Ci/mmol; Amersham) was 0.2 nM; and the incubation time was 90 minutes at 23° C. Nonspecific binding was defined in the presence of 1 μM (+)-butaclamol. Ki values were determined using the KD value for [3H]spiperone of 0.1 nM (29).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23][CH3:24])[N:8]=1.C1C=C(Cl)C=C(C(OO)=[O:38])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][O:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([S:23]([CH3:24])=[O:38])[N:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Solvent: ClCCl
Product: COc1ccc(COc2nc(S(C)=O)ncc2C(=O)NCc2ccccn2)cc1Cl

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)-N-(pyridin-2-ylmethyl)pyrimidine-5-carboxamide (180 mg, 0.42 mmol) was dissolved in 20 ml of dichloromethane, m-CPBA (80 mg, 0.46 mmol) was added and reacted at room temperature for 12 h, washed with water after reaction, extracted with dichloromethane, the organic layer was dried, dried by rotation to obtain yellow solid, and this product was directly used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23]C(=O)OC(C)(C)C)=[N:21][CH:22]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([CH2:16][NH:15][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[N:14]=2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 5-((3-(3,5-dichlorophenylamino)-1H-1,2,4-triazol-5-ylamino)methyl)pyridin-2-ylcarbamate Compound 6 (50 mg, 111 μmol) in DCM (1 ml) was added TFA (1 ml) and the reaction was stirred for 1 hour. The reaction mixture was concentrated in vacuo and was partitioned between DCM (5 ml) and sat. NaHCO3 (3 ml). The layers were separated and the aqueous layer was extracted with DCM (3×5 ml). The combined organic solution was washed with brine (5 ml), dried over Na2SO4, filtered and concentrated to give a white solid as desired product (10.2 mg, 26% yield). MS +m/z: 350 (M+H)+
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].N1C=CC=CC=1.[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])=[N+:19]=[N-:20]>C(Cl)Cl.CCOC(C)=O>[N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])=[N+:19]=[N-:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=NCCCCCCCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCCCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.7 %

Procedure:
TsCl (955 mg, 5.0 mmol) and pyridine (435 μL, 5.4 mmol) were added to a solution of 7-azidoheptanol (700 mg, 4.5 mmol) in CH2Cl2 (5 mL). The solution was stirred for 18 h at r.t. The solution was diluted with EtOAc (20 mL) and washed with 5% aqueous KHSO4 solution, sat. aqueous NaHCO3 solution and pH 7 phosphate buffer. The org. layer was concentrated and the residue was treated with water (10 mL) for 4 h to hydrolyse excess TsCl. The mixture was diluted with EtOAc (20 mL), washed with aqueous NaHCO3, dried (Na2SO4), and filtered. Concentration under reduced pressure yielded 7-azidoheptyltosylate (920 mg, 66%). The product was pure enough for further reactions.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[NH:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.Cl.[OH-].[Na+]>O1CCOCC1>[CH:23]1([NH:22][C:21]([CH:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([NH2:7])[CH:9]=3)[CH2:20][CH2:19]2)=[O:29])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Temperature: 60 °C

Procedure:
A solution of [3-(4-cyclohexylcarbamoyl-piperidin-1-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (4.6 g, 11.1 mmol) in 1,4-dioxane (110 mL) is cooled down to 0° C. and treated with a 4N HCl solution in 1,4-dioxane (24.9 mL, 99.6 mmol). The reaction mixture is heated to 60° C. for 1 h. The reaction mixture is cooled down to RT and treated with aqueous 2N sodium hydroxide. After evaporation of 1,4-dioxane under reduced pressure the reaction mixture is extracted twice with DCM (110 mL). The combined organic phases are dried over MgSO4 and evaporated to yield the title compound as a yellowish powder: LC-MS A: tR=0.50 min; [M+H]+=316.32.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[F:23].Cl>C1COCC1>[CH2:8]([O:7][C:1](=[O:6])[CH:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[F:23])[C:3](=[O:4])[CH3:5])[CH3:9]
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1F)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
Ethyl acetoacetate (37.4 mL, 294 mmol) was added at 0° C. to a suspension of sodium hydride (65%, 10.8 g) in THF (600 mL), and the mixture was stirred at 0° C. for 30 minutes. It was added dropwise at 0° C. to a solution of 1-bromomethyl-2-fluoro-3-nitrobenzene (compound 1a-1) (68.7 g, 294 mmol) in THF (400 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude product was obtained by vacuum concentration, and purified by column chromatography (ethyl acetate:hexane=1:3) to yield the title compound (52.2 g, 63%) as a yellow oil.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[C:5]([CH3:13])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8].B(F)(F)F.O(CC)CC>C1COCC1>[OH:8][CH2:7][C:6]1[C:5]([CH3:13])=[C:4]([OH:3])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1c(O)cccc1C(=O)O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(O)cccc1CO
Temperature: 10 °C
Reaction time: 0.75 h

Procedure:
To a 5 L 3 neck RB equipped with overhead stirrer was charged NaBH4 (87.0 g, 2.30 mol) and THF (3.0 L) and the resulting slurry was cooled to 10° C. To the slurry was then added 3-hydroxy-2-methyl benzoic acid (175 g, 1.15 mol) portionwise over 20 min (Tmax 17° C.). A stirrable slurry formed, and was aged for an additional 45 min at 10-15° C. after which BF3-OEt2 (321 mL, 2.53 mol) was added slowly over 1.5 hours. The slurry was aged at 10° C.-15° C. for 2 h then assayed for reaction completion (98.5% conversion). The slurry was cooled to <10° C. and quenched with 931 mL MeOH slowly over 1.5 h (gas evolution). The resulting slurry was aged overnight at RT. The batch was cooled to <10° C. then quenched with 1 N HCl (1.5 L) to get a homogeneous solution (pH solution˜1), which was aged for 30 min and then the organic solvents were removed by rotary evaporation to approximately 1.8 L of total reaction volume (bath temperature was set to 50° C.; internal temp of concentrate after rotary evaporation was ˜40° C.). The slurry was held at 45° C. for 30 min then cooled slowly to 15° C. The solids were filtered and washed with cold (15° C.) water (2×300 mL), providing 3-hydroxymethyl-2-methyl phenol.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:10])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[NH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1ccccc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1ccccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.2 %

Procedure:
That is, 1-acetyl-aminobenzene (300 mg, 2.2 mmol) was dissolved in methanol, sodium borohydride (418 mg, 11 mmol) was added, the temperature was raised from under ice-cooling to room temperature, and the mixture was stirred for 1 hr. Then, water was added to the reaction mixture, and unreacted sodium borohydride was decomposed. Then, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (eluent; chloroform:methanol (30:1)) to give 1-(aminophenyl)ethanol (yield; 242 mg, 80%). According to the final step in Example 2 (step for condensing Y222 and Y491), compound Y491 (the aforementioned) (196 mg, 4.3 mmol) and 1-(aminophenyl)ethanol (147 mg, 10.8 mmol) were condensed to give the title compound (yield; 157 mg, 66%).