Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[N:14]=[C:15]([OH:16])[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:26][CH2:25][C:11]2[N:12]=[C:13]([C:17]3[CH:18]=[C:19]([Cl:24])[CH:20]=[C:21]([Cl:23])[CH:22]=3)[N:14]=[C:15]([O:16][CH2:28][C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1nc(-c2cc(Cl)cc(Cl)c2)nc2c1CN(Cc1ccccc1)CC2
Product: O=C(O)c1ccc(COc2nc(-c3cc(Cl)cc(Cl)c3)nc3c2CN(Cc2ccccc2)CC3)cc1

Procedure:
The title compound was prepared from 6-benzyl-2-(3,5-dichloro-phenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (which was obtained in Intermediate 7) and methyl 4-(bromomethyl)benzoate according to Method A and Method B; LC retention time 2.77 min; MS: m/z (ESI) 520 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.O.[C:25]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[C:10]([O:12][CH3:25])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 96.7 %

Procedure:
To a solution of 15.6 g (49 mmol) (2S)-3-(4-hydroxyphenyl)-2-[(phenylmethoxy)carbonylamino]propanoic acid in 120 mL methanol was added 9.4 g (49 mmol) of p-toluenesulfonic acid monohydrate. The solution was heated to 70 ° C. for 2 h. After solution was cooled to room temperature, the methanol was removed under reduced pressure. The solid obtained was redissolved in 120 mL methylene chloride. The organic solution was then washed with dilute NaHCO3 solution twice and brine. The organic layer was dried with anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude mixture was chromatographed on a silica gel column using 40% ethyl acetate in hexanes as the eluent to yield 15.6 g (96%) of white solid as product: 1H NMR (300 MHz, CDCl3) δ7.38-7.30 (m, 5H), 6.93 (d, J=8.41 Hz, 2H), 6.81 (d, J=8.41 Hz, 2H), 5.39 (br s, 1H), 5.24 (d, J=9.29 Hz, 1H), 5.11 (d, J=12.32 Hz, 1H), 5.06 (d, J=12.29 Hz, 1H), 4.61 (m, 1H), 3.71 (s, 3H), 3.06 (dd, J=5.88, 14.06 Hz, 1H), 2.98 (dd, J=5.88, 14.06 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:51])[CH3:52])=[CH:45][CH:44]=2)[C:20]([N:22]([CH2:32][C:33]2[C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[S:36][CH:37]=2)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 76 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([C:11]#[C:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.N1C=CC=CC=1>[C:5]1([C:11]#[C:12][CH2:13][Br:2])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCC#Cc1ccccc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: BrCC#Cc1ccccc1
Temperature: 40 °C
Yield: 248.9 %

Procedure:
Phosphorous tribromide (2.62 mL, 27.6 mmol) was added to a solution of 3-phenyl-2-propyn-1-ol (10.0 g, 76 mmol) and pyridine (0.14 mL, 1.77 mmol) in diethyl ether (22 mL) at a rate to maintain reflux. After addition, the mixture was heated at 40° C. for 2 h. The mixture was cooled and poured onto ice. The organic layer was separated and diluted with diethyl ether (100 mL), washed with saturated sodium bicarbonate (2×50 mL) and saturated sodium chloride (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford 1-phenyl-3-bromo-1-propyn (13.4 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9]Cl.[C:17]1([CH3:29])[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:5]2[C:6](=[O:11])[C:7]=1[CH2:8][CH2:9][N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([CH3:29])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Cc1nc2ccc(Cl)cn2c(=O)c1CCCl
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4ccc(Cl)cn4c3=O)CC2)c1
Yield: 39.9 %

Procedure:
A mixture of 1.3 g of 2-methyl-3-(2-chloroethyl)-7-chloro-4H-pyrido[1,2-a]pyrimidin-4-one, 2.1 g of 1-(m-tolyl)piperazine and 20 ml of toluene was refluxed for 30 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by means of column chromatography using alumina and recrystallized from a mixture of ethanol and n-hexane to give 0.8 g of the desired compound as pale yellow scales, m.p. 119° - 120°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:20](OC)(OC)OC.O>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:20]2)=[CH:14][CH:15]=1
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 60d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room temperature. Water was added to the mixture. The resulting solid was filtered, washed, with water, and dried. The crude product 60e was used in the next reaction without purification. MS m/z (M+H+) 271.1.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:14][CH2:13][CH2:12][C:11]3[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=[C:9]([CH3:16])[CH:10]=3)[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cc1cc(CCC=O)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CCCN2CCN(c3ccccc3)CC2)n(-c2ccccc2)n1

Procedure:
60 mg (81%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-methyl-1H-pyrazol-5-yl)propanal (44 mg, 0.206 mmol), 1-phenylpiperazine (0.031 mL, 0.206 mmol), DIPEA (0.054 mL, 0.310 mmol) and NaBH(OAc)3 (131 mg, 0.621 mmol).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]2[C:32]([CH3:33])=[N:31][N:30]([C:34]([CH3:37])([CH3:36])[CH3:35])[C:18]2=[N:19][C:20]=1[N:21]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[CH2:22][CH:23]1[CH2:25][CH2:24]1.[Br:47][C:48]1[CH:49]=[N:50][C:51](Cl)=[N:52][CH:53]=1.O>CN(C=O)C>[F:46][C:8]([F:45])([F:7])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=1)[CH2:12][N:13]([CH2:14][C:15]1[CH:16]=[C:17]2[C:32]([CH3:33])=[N:31][N:30]([C:34]([CH3:36])([CH3:37])[CH3:35])[C:18]2=[N:19][C:20]=1[N:21]([CH2:26][CH:27]1[CH2:29][CH2:28]1)[CH2:22][CH:23]1[CH2:24][CH2:25]1)[C:51]1[N:52]=[CH:53][C:48]([Br:47])=[CH:49][N:50]=1
Reactant: Clc1ncc(Br)cn1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CNCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ncc(Br)cn3)cc12

Procedure:
Potassium carbonate (0.43 g, 3 mmol) was added to a mixture of 5-(((3,5-bis(trifluoromethyl)benzyl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine (0.6 g, 1 mmol) and 5-bromo-2-chloropyrimidine (0.6 g, 3 mmol) in DMF. The resultant mixture was stirred at 100° C. for 12-16 h. The reaction mixture was treated with water and extracted with ethylacetate (100 ml). The organic layer was washed with brine and dried over Na2SO4, concentrated under reduced pressure to obtain the crude product. This product was further purified by column chromatography using silica gel (60-120 mesh) and 5% ethyl acetate in petroleum ether as eluent.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[S:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([C:23]3([OH:26])[CH2:24][CH2:25][S:21][CH2:22]3)[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1CCSC1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCSC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirring suspension of magnesium turnings (3.45 g) in dry tetrahydrofuran (60 mL) is treated with 1,2-dibromoethane (0.8 mL), and the mixture is stirred under a nitrogen atmosphere for 30 minutes. It is then treated dropwise with a solution of 4-bromo-2-cyclopentyloxyanisole (25 g); which is prepared as described in Reference Example 4 in tetrahydrofuran (20 mL), and the resulting solution is heated at reflux for 30 minutes. The solution is then cooled to room temperature and treated with a solution of tetrahydrothiophen-3-one (6.9 mL) in tetrahydrofuran (20 mL), and allowed to stand for 16 hours. It is then treated with saturated aqueous ammonium chloride solution (50 mL), and the mixture is partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous phase is further extracted with dichloromethane (100 mL). The combined organic phases are dried over magnesium sulphate and evaporated. The resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxytetrahydrothiophene, in the form of a viscous oil.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Na+].[Na+].O.[CH2:27]([CH2:30]OC)[O:28][CH3:29]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][O:28][CH2:27]/[CH:30]=[CH:20]/[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: COCCOC
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Product: COC/C=C/c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), trans-2-methoxy-1-propenylboronic acid pinacol ester (198 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml), and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, 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=1:1) to give the desired product (200 mg, 62.3%) as an oil.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][NH:20]C(OCC2C=CC=CC=2)=O)=[CH:13][CH:12]=1)[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]>[Pd]>[NH2:20][CH2:19][CH2:18][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH:2]([CH3:1])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:16][CH:15]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCN)cc1
Yield: 116 %

Procedure:
Scheme Vc, step B: N-{3-[4-(1-Methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}(phenylmethoxy)carboxamide (1 g, 2.31 mmol) and 10% palladium on carbon (0.5 g, 25 mole %) were combined and hydrogenation was carried out in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, {2-[4-(3-aminopropyl)phenyl]propyl}[(methylethyl)sulfonyl]amine, (0.8 g, 87%) as a colorless oil. Electron spray M.S. 299 (M*+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[NH:12][N:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([C:34](=O)[CH2:35][CH2:36][CH3:37])[C:29](OCC)=[O:30])=[CH:23][CH:22]=1)#[N:14].N12CCCN=C1CCCCC2.C(N(CC)C1C=CC=CC=1)C>Cl>[O:30]=[C:29]1[C:28]([CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:16]3[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:22][CH:23]=2)=[C:34]([CH2:35][CH2:36][CH3:37])[N:12]2[N:11]=[CH:10][CH:9]=[C:8]2[N:7]1[CH:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1
Reactant: c1cc(NC2CCOCC2)[nH]n1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 180 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A mixture of N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (1.00 g), ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4.20 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 mL) and N,N-diethylaniline (10 mL) was stirred at 180° C. overnight, allowed to cool, and poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate 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 to give the title compound as a colorless solid (2.39 g, 88%).
Reaction SMILES: CSC1N=NC(C(NC(=O)OC(C)(C)C)C)=CN=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:31][C:32]2[N:33]=[N:34][C:35]([CH:38]([NH:40]C(=O)OC(C)(C)C)[CH3:39])=[CH:36][N:37]=2)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28].[ClH:48]>CO.O1CCOCC1>[ClH:48].[NH2:40][CH:38]([C:35]1[N:34]=[N:33][C:32]([NH:31][C:23]2[CH:22]=[C:21]([O:20][CH3:19])[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=2)=[N:37][CH:36]=1)[CH3:39]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)OC(C)(C)C)nn2)cc(OC)c1OC
Agent: CSc1ncc(C(C)NC(=O)OC(C)(C)C)nn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a stirred solution of tert-butyl 1-[3-(methylthio)-1,2,4-triazin-6-yl]ethylcarbamate (Intermediate 8) (1.2 g, 3.1 mmol) in methanol (10 mL) was added 4N HCl in dioxane (10 mL). After stirring for 30 minutes the volatiles were removed under reduced pressure to provide 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine hydrochloride as a foam. The foam was dissolved in methanol, ammonium hydroxide was added to neutralize the acid, and silica gel (5 g) was added followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to an isocratic elution using dichloromethane: methanol: ammonium hydroxide (95:4:1) using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (680 mg) as a yellow solid. 1H NMR (CDCl3): δ8.42 (s, 1H), 7.38 (s, 1H), 6.97 (s, 2H), 4.38 (d, J=7.0 Hz, 1H), 3.90 (s, 6H), 3.84 (s, 3H), 1.62 (br, 2H), 1.52 (d, J=7.0 Hz, 3H), 1.43 (s, 9H). MS m/z 306 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]([F:47])([F:46])[C:9]1[CH:10]=[C:11]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[C:29]([C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])=[O:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:15]=[N:14]1.O>C1COCC1>[F:47][C:8]([F:7])([F:46])[C:9]1[CH:10]=[C:11]([CH:39]=[C:40]([C:42]([F:43])([F:45])[F:44])[CH:41]=1)[CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:16]([C:24]2[C:29]([CH:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[OH:31])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:15]=[N:14]1
Reactant: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Add LiAlH4 (2.6 mL, 2.6 mmol, 1.0 M in THF) dropwise to a stirred solution of {2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (1.28 g, 2.18 mmol) in THF (20 mL, anhydrous) at RT. After 15 min, add water (2.6 mL) dropwise with rapid stirring to quench. Add 1N NaOH solution (2.6 mL) dropwise, followed by dropwise addition of water (7.8 mL). Filter out solids and rinse with THF. Concentrate, dissolve in CH2Cl2, wash with saturated NaHCO3 solution (2×), dry over MgSO4 and concentrate. Purify the solid by flash chromatography on silica gel eluting with 0-15% ACN/Et2O to afford the title compound (882 mg, 69%); MS(IS) 590 (M+1); TLC: Rf=0.32 (7.5% EtOH/CHCl3).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH2:7].Cl[C:10]([N:12]1[CH:21]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14][CH2:13]1)=[O:11].CCOC(C)=O>C1COCC1.CCN(CC)CC>[CH3:2][O:3][C:4](=[O:8])[CH2:5][CH2:6][NH:7][C:10]([N:12]1[CH:21]2[CH:16]([CH2:17][CH2:18][CH2:19][CH2:20]2)[CH2:15][CH2:14][CH2:13]1)=[O:11]
Reactant: COC(=O)CCN
Reactant: O=C(Cl)N1CCCC2CCCCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCNC(=O)N1CCCC2CCCCC21
Yield: 67.1 %

Procedure:
0.5 g (3.5 mmol) of the 3-aminopropionic acid methyl ester hydrochloride are dissolved in 5 mL of anhydrous THF and 0.9 mL of Et3N. Once dissolved, 650 mg of 1-chlorocarbonyloctahydroquinoline are slowly added and it is refluxed for 18 h. AcOEt is then added and the resulting solution is sequentially washed with water, 1N HCl and brine. The organic phase is dried over anhydrous Na2SO4, it is filtered and the solvent is evaporated under reduced pressure yielding 580 mg of intermediate IIIb.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:19])[C:7]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccc(F)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2ccc(F)cc2C1=S
Reaction time: 2 h
Yield: 125.6 %

Procedure:
To 1.0 g (0.0039 mole) of 2-(2-chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-one in 30 ml of acetonitrile was added 0.7 g (0.0016 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux. After 2 hr, another 0.4 g (0.009 mole) of phosphorus pentasulfide was added and heating continued for 2 hr. The reaction mixture was diluted with 70 ml of toluene and filtered. The filtrate was washed carefully with 3×50 ml of saturated sodium bicarbonate and 50 ml of water, dried over sodium sulfate, filtered, charcoaled, filtered and concentrated by rotary evaporation. The crude material was recrystallized from diisopropyl ether to give 0.55 g (52%) of yellow crystals, m.p. 135°-137° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:21])[C:12]([CH3:20])([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH3:13])=[CH:7][CH:6]=1.SC[CH2:24][C:25]([OH:27])=O.O.C1(C)C=CC([S:35](O)(=O)=O)=CC=1.[OH-].[Na+]>>[CH3:20][C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)([CH3:13])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([S:4][CH2:3][CH2:2][O:1][C:25](=[O:27])[CH2:24][SH:35])=[CH:6][CH:7]=1)=[O:21]
Reactant: CC(C)(C(=O)c1ccc(SCCO)cc1)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C(=O)c1ccc(SCCOC(=O)CS)cc1)N1CCOCC1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
70 g (0.266 mol) of 1-[4-(2-hydroxyethylthio)-phenyl]-2-methyl-2-morpholin-4-yl-propan-1-one, 39 ml (0.452 mol) of 3-mercaptopropionic acid, and 47 g (0.249 mol) of p-toluenesulfonic acid monohydrate are mixed and stirred at 140° C. for 4 h. Then the solution is cooled to room temperature and neutralized with 1N NaOH. The crude product is extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with ethyl acetate-hexane (30:70) as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.31 (s, 6H), 1.65 (t, 1H), 2.57 (t, 4H), 2.65 (t, 2H), 2.76 (dt, 2H), 3.26 (t, 2H), 3.70 (t, 4H), 4.33 (t, 2H), 7.33 (d, 2H), 8.51 (d, 2H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:30]1[CH:35]=[C:34](Br)[C:33]([Br:37])=[CH:32][CH:31]=1>>[Br:37][C:33]1[CH:34]=[C:35]([C:25]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)([OH:29])[CH:26]([CH3:28])[CH3:27])[CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1ccccc1Br
Product: CC(C)C(O)(c1cccc(Br)c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 76.5 %

Procedure:
By the reaction in the same manner as in Example 1-(ii) using 1-(1-trityl-1H-imidazol-4-yl)-2-methyl-1-propanone (34.90 g) and O-dibromobenzene (50.7 g), the title compound (37.7 g) was obtained as a colorless solid.