Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[S-].[Na+].[Cl:4][C:5]1[N:10]=[C:9]([S:11]([CH3:14])(=O)=O)[N:8]=[C:7]([NH:15][CH:16]([CH3:18])[CH3:17])[C:6]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]>C1COCC1.CN(C=O)C.CC(OC)(C)C>[Cl:4][C:5]1[N:10]=[C:9]([S:11][CH3:14])[N:8]=[C:7]([NH:15][CH:16]([CH3:18])[CH3:17])[C:6]=1[C:19]1[C:24]([F:25])=[CH:23][C:22]([F:26])=[CH:21][C:20]=1[F:27]
Reactant: CC(C)Nc1nc(S(C)(=O)=O)nc(Cl)c1-c1c(F)cc(F)cc1F
Agent: C[S-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CSc1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NC(C)C)n1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 120.8 %

Procedure:
70 mg (1.0 mmol) of sodium thiomethoxide, dissolved in 3 ml of anhydrous THF, were added to a solution of 216 mg (0.5 mmol) of [6-chloro-2-methanesulfonyl-5-(2,4,6-trifluorophenyl)pyrimidin-4-yl]isopropylamine (abbr. sulfone 2) in 2 ml of anhydrous DMF. The mixture was stirred at 20-25° C. for 16 hours and then diluted with MTBE, washed with water and dried. Distillative removal of the solvent and chromatography on silica gel gave 0.21 g of the title compound of m.p. 112-116° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]/[C:33](=[N:36]/[H])/[NH:34]O.[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:36]=[C:33]([CH2:32][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])[N:34]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Reactant: [H]/N=C(/Cc1ccccc1Cl)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccccc3Cl)no2)c(=O)c2[nH]c(Cl)nc21
Yield: 48.6 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-(2-chlorophenyl)-N-hydroxyethanimidamide (30 mg, 0.18 mmol; Entry 1, table 7) were heated in EtOH (0.75 ml) with 21% ethanolic sodium ethoxide (0.083 ml, 0.22 mmol) at 140° C. for 10 min. The mixture was then partitioned between EtOAc and 2M HCl and the organic phase evaporated. The product was purified by MDAP to yield the title compound as a solid (34.8 mg).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:22][CH2:23][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:25][CH2:26]2)=[CH:17][CH:16]=1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1cc(N2CCNCC2)ccn1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)nnn2CCCCN1CCN(c2ccncc2)CC1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(4-pyridyl)piperazine (4.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.6 g compound (I-44) with a yield of 65.3%. ESI-MS [M+H]+: m/z 336.2.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:35][CH2:34][C:18]2[N:19]=[C:20]([NH:23][C:24](=[O:33])[C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)[N:21]=[CH:22][C:17]=2[CH2:16]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[F:45][C:46]([F:57])([F:56])[C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)C(O)=O.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([Cl:31])[CH:28]=1)[C:24]([NH:23][C:20]1[N:21]=[CH:22][C:17]2[CH2:16][N:15]([C:13](=[O:12])[C:54]3[CH:53]=[CH:49][CH:48]=[C:47]([C:46]([F:57])([F:56])[F:45])[CH:55]=3)[CH2:35][CH2:34][C:18]=2[N:19]=1)=[O:33]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cc(Cl)cc(Cl)c3)ncc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ncc2c(n1)CCN(C(=O)c1cccc(C(F)(F)F)c1)C2)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Trifluoroacetic acid 5.0 ml (65 mmol) was added to a solution of 2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 404 mg (0.954 mmol) in CH2Cl2 (7 ml) under nitrogen as inert gas and stirring was performed for 2 h at RT. After removal of the solvent, the intermediate (3,5-dichloro-N-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl)-benzamide trifluoroacetate) was dissolved in CH2Cl2 (10 ml) and DIPEA 340 μl and 3-trifluoromethylbenzoic acid 200 mg (1.05 mmol) were added. After cooling the reaction mixture to 0° C., EDCI 201 mg (1.05 mmol) and HOAt 20 mg (0.15 mmol) were added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at RT. After removal of the solvent, purification was performed by means of column chromatography and the product 3,5-dichloro-N-[6-(3-trifluoromethyl-benzoyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-2-yl]-benzamide 260 mg (0.53 mmol, 55% of theoretical) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[CH:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44]3)[CH:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(N3CCCC3)c2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (214 mg, 0.75 mmol) and 3-oxo-3-[3-(2-pyrrolidin-1-yl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K63) (275 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white amorphous substance (334 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]2[C:12](=[O:13])[N:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([OH:17])=O)[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH2:53]([O:60][NH2:61])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Cl>CN(C=O)C>[CH2:53]([O:60][NH:61][C:15](=[O:17])[CH:14]([N:11]1[C:12](=[O:13])[CH:8]([CH2:7][O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:23][CH:22]=2)[NH:9][C:10]1=[O:21])[CH:18]([CH3:20])[CH3:19])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C(C(=O)O)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(C(=O)NOCc1ccccc1)N1C(=O)NC(COc2ccc(Br)cc2)C1=O
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of the compound obtained in step h above (22h) (300 mg, 0.782 mmol), NMM (0.19 mL, 1.72 mmol) and HOBt (179 mg, 1.329 mmol) in DMF (11 mL) were stirred at 0° C. for 10 minutes, then the reaction was cooled to −15° C., and EDCl (165 mg, 0.860 mmol) was added. The reaction was stirred for 30 minutes at −15° C. and then allowed to warm to room temperature, BnONH2HCl (137 mg, 0.860 mmol) was added. After being stirred overnight, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with brine. The combined organic layers were dried and concentrated; the residue was purified by silica gel column chromatography which gave the title compound as colorless oil (426 mg, 83% yield).
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7](=[O:32])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]#[C:19][Si](C)(C)C)[C:11]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1)[CH3:5].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:4]([O:6][C:7](=[O:32])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:18]#[CH:19])[C:11]([CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:10]1)[CH3:5]
Reactant: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(C#C[Si](C)(C)C)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C#Cc1cccc2c(CCCC(=O)OCC)cn(CC(=O)OCC)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an ethanol (2 mL) solution of ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate (98 mg), potassium carbonate (50 mg) was added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated to obtain the titled compound having the following physical properties (74 mg). Herein, ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate was prepared by the same operation as in Example 3, except for using ethyl 4-{7-bromo-1-[2-(ethyloxy)-2-oxoethyl]-1H-indol-3-yl}butanoate and ethynyl(trimethyl)silane.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:11]=1>>[CH3:36][S:33]([C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:20][CH2:19]1)=[O:17])(=[O:35])=[O:34]
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)nc1C
Yield: 53.5 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-methanesulfonylphenyl) [4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (253 mg) described in Preparation Example 122 and by the reaction and treatment in the same manner as in Example 4, the title compound (151 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[Cl:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[Cl:15].[Al+3].[Cl-].[Cl-].[Cl-]>[N+](C)([O-])=O>[CH2:1]([O:3][C:4](=[O:8])[C:5]([C:12]1[S:11][C:10]([Cl:9])=[C:14]([Cl:15])[CH:13]=1)=[O:6])[CH3:2]
Reactant: Clc1ccsc1Cl
Reactant: CCOC(=O)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)C(=O)c1cc(Cl)c(Cl)s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
At 5-10° C., Chloro-oxo-acetic acid ethyl ester (5.43 ml, 48.7 mmol) was added to 2,3-Dichlorothiophene (5 g, 32.6 mmol). A solution of AlCl3 (6.49 g, 48.7 mmol) dissolved in nitromethane (13 ml) was added dropwise such that the internal reaction temperature did not rise above 10° C. After 1 hour, the reaction mixture was poured into ice water and extracted with CH2Cl2 (2×100 ml). The organic layer was washed with 10% NaHCO3 (2×50 ml), water (1×50 ml) and brine (1×50 ml). Drying (Na2SO4) and concentration provided a light orange solid that was purified by silica gel chromatography (EtOAc/hexane-gradient) providing 6.8 g (82%) of the subtitle compound.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]2[CH2:12][O:11]2)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[C:4]([C:3]1[C:2]([F:1])=[C:9]([CH:10]([OH:11])[CH2:12][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@H:23]2[CH2:27][OH:28])[CH:8]=[CH:7][C:6]=1[F:13])#[N:5]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: N#Cc1c(F)ccc(C2CO2)c1F
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc(F)c(C#N)c2F)[C@H](CO)C1
Temperature: 150 °C

Procedure:
2,6-Difluoro-3-(oxiran-2-yl)benzonitrile (1.50 g, 8.28 mmol) and (S)-4-N-BOC-2-hydroxymethylpiperazine (2.40 g, 11.1 mmol) were suspended in ethanol (15 mL) then heated in a microwave apparatus for 30 min at 150° C. The reaction mixture was cooled and evaporated dryness. The residue was purified by chromatography through a 120 g Redi-sep column eluting with 5% MeOH/95% EtOAc to yield the title compound LC-MS: M+1=398.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:9][CH:8]=1.O>CN(C=O)C>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[CH:16]=[CH:15][S:14]2)=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1ccsn1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc(-n2sccc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
Sodium azide (6.0 mg, 0.0923 mmol) was added to a solution of 2-(4-bromomethylphenyl)isothiazol-3-one 31 (18.2 mg, 0.0674 mmol) in DMF (1 mL) and stirred for 20 h at room temperature. Water (10 mL) was added and the mixture was extracted with diethyl ether. The combined organic layer was dried (MgSO4), filtered and evaporated. The residue was purified on flash silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:1), afforded the desired compound 32 (11.7 mg, 75%). 1H-NMR (CDCl3, 300 MHz) δ 4.38 (s, 2H), 6.34 (d, J=6.3 Hz, 1H), 7.41 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 8.17 (d, J=6.3 Hz, 1H). HRMS: Found 233.0496. Calcd for C10H9N4OS (M+H)+233.0497.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][CH2:9]1.C([Li])CCC.[CH3:23][C:24]1([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26](=[O:32])[CH2:25]1.O>O1CCCC1.C(OCC)(=O)C>[CH:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:26]3([OH:32])[CH2:25][C:24]([CH3:23])([CH3:33])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27]3)[CH2:9][CH2:10]2)[CH2:17][CH2:16]1
Reactant: Brc1ccccc1N1CCN(CC2CC2)CC1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)CC(C)(C)CC(O)(c2ccccc2N2CCN(CC3CC3)CC2)C1
Reaction time: 0.25 h
Yield: 87.1 %

Procedure:
To a solution of 1-(2-bromophenyl)-4-cyclopropylmethylpiperazine (700 mg, 2.37 mmol) produced in Example (108a) in anhydrous tetrahydrofuran (7 mL) was added dropwise n-butyllithium (1.60 M solution in hexane, 1.63 mL, 2.61 mmol) over a period of 3 minutes at an external temperature of −70° C. After stirring for 45 minutes under the same conditions, 3,3,5,5-tetramethylcyclohexanone (0.49 mL, 2.85 mmol) was added dropwise to the reaction mixture over a period of 4 minutes at an external temperature of −70° C. Stirring was continued for 15 minutes under the same conditions, and then for 18 hours and 30 minutes while warming until the external temperature reached room temperature. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/heptane) to give 765 mg of the title compound as a light yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[SH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([S:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[O:10][CH3:11]
Reactant: COc1cc(Br)c(C=O)cc1OC
Reactant: CCOC(=O)CCCS
Product: CCOC(=O)CCCSc1cc(OC)c(OC)cc1C=O
Yield: 27 %

Procedure:
Ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate was synthesized from 6-bromoveratraldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After vacuum concentration of an extracted solution, the residue was crystallized from isopropyl ether to yield ethyl 4-(3,4-dimethoxy-6-formylphenylthio)butyrate (Yield 27%) as slightly yellow crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[NH:9][C:10](=S)[O:11][C:7]=2[CH:6]=1)=[O:4].Cl.Cl.[NH:18]1[CH2:22][CH2:21][C@@H:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19]1>C1(C)C(C)=CC=CC=1.ClCCl>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]2[N:9]=[C:10]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]4)[CH2:19]3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1ccc2[nH]c(=S)oc2c1
Reactant: C1CCN([C@@H]2CCNC2)CC1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc2nc(N3CC[C@@H](N4CCCCC4)C3)oc2c1
Temperature: 150 °C

Procedure:
N,N-Dimethyl-2-thioxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide (Example 92C, 44 mg, 0.119 mmol) and (R)-1-(pyrrolidin-3-yl)piperidine dihydrochloride (Reference Example 5c, 54 mg, 0.238 mmol) were combined in xylene (1 mL) and heated to 150° C. for 30 minutes. The mixture was diluted with dichloromethane, washed with water, and the organic layer was absorbed on silica gel. The crude mixture was purified by silica gel chromatography eluting with a gradient of methanol in dichloromethane (2-20%) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.43-1.53 (m, 2 H) 1.59-1.70 (m, 4 H) 1.91-2.07 (m, 1 H) 2.23-2.35 (m, 1 H) 2.40-2.62 (m, 4 H) 2.93-3.13 (m, 7 H) 3.41-3.51 (m, 1 H) 3.55-3.66 (m, 1 H) 3.80-3.90 (m, 1 H) 3.96 (dd, J=10.00, 7.29 Hz, 1 H) 7.22-7.28 (m, 1 H) 7.30-7.35 (m, 1 H) 7.37-7.40 (m, 1 H); MS (ESI+) m/z 343.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Solvent: CCO
Product: Nc1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 1.9 %

Procedure:
In ethanol (300 ml) was dissolved 4-(4-nitrobenzyl)morpholine (25.8 g), and to the mixture was added dried 10% palladium on carbon (Pd-C) (1.00 g). Under hydrogen atmosphere, the mixture was stirred at room temperature under atmospheric pressure for 20 hours. The palladium was filtered off, and the filtrate was concentrated. The residue was separated and purified with column chromatography (ethyl acetate) to give 4-(4-aminobenzyl)morpholine (430 mg) as pale yellow crystals.
Reaction SMILES: BrC1C=CC=C2C=1C(=O)C(=O)N2CCCCC.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23](=[O:34])[C:22]2=[O:35].O1C2C=CC(O)=CC=2OC1.[O:46]1[C:50]2[CH:51]=[C:52]([OH:55])[CH:53]=[CH:54][C:49]=2[CH2:48][CH2:47]1>>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:23](=[O:34])[C:22]2([OH:35])[C:53]1[C:52]([OH:55])=[CH:51][C:50]2[O:46][CH2:47][CH2:48][C:49]=2[CH:54]=1
Reactant: CCOC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: Oc1ccc2c(c1)OCC2
Agent: CCCCCN1C(=O)C(=O)c2c(Br)cccc21
Agent: Oc1ccc2c(c1)OCO2
Product: CCOC(=O)CN1C(=O)C(O)(c2cc3c(cc2O)OCC3)c2cc(Cl)ccc21

Procedure:
Following the procedure as described in PREPARATION 1C, and making non-critical variations to replace 4-bromo-1-pentyl-1H-indole-2,3-dione with ethyl (5-chloro-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate, and 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol, the title compound was obtained (85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.70 (br, 1H), 7.31-7.24 (m, 2H), 6.92 (d, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.53-4.46 (m, 2H), 5.09-4.40 (d, 2H), 4.18 (q, 2H), 3.08-2.88 (m, 2H), 1.23 (t, 3H); MS (ES+) m/z 387.8 (M−17).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CCCCCC>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)Cn1c(CN2CCNCC2)cc2cnc(C#N)nc21
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)Cn1c(CN2CCN(Cc3ccc(F)cc3)CC2)cc2cnc(C#N)nc21
Temperature: 50 °C
Yield: 90.5 %

Procedure:
7-(2,2-Dimethyl-propyl)-6-piperazin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.4 mmol) and 1-bromomethyl-4-fluoro-benzene (0.6 mmol) is dissolved in DMF (5 ml) and potassium carbonate (0.6 mmol) is added to the solution. The reaction mixture is heated at 50° C. for 3 h. After the mixture is diluted with AcOEt, the organic layer is washed with brine, dried over magnesium sulfate and filtrated. AcOEt is evaporated and the residue is purified by reverse phase HPLC. The product is obtained in 90.5% yield. Rf=0.32 (n-hexane:AcOEt=1:5).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:20](=[O:21])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1CO
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)OCc1ccccc1[N+](=O)[O-]
Yield: 67.9 %

Procedure:
10 ml of toluene, 5.75 g of 2-nitrobenzyl alcohol and 5 g of benzyl isocyanate were heated to reflux for 3 hours in a nitrogen atmosphere. Following cooling of the mixture, 50 ml of toluene was added. This reaction solution was washed several times with water, and was then dehydrated with sodium sulfate. The sodium sulfate was then filtered out, and the solvent was removed from the filtrate by means of a rotary evaporator. The solid obtained was recrystallized from a hexane-toluene mixed solvent, producing 7.3 g of o-nitrobenzyl benzylcarbamate in the form of plate yellow crystals. This compound had a melting point of 110° to 111° C., and the infrared absorption spectrum was 3308 cm-1 : N--H, 1696 cm-1 : C=O, 1520 cm-1 : N--O.
Reaction SMILES: [CH3:1][C:2]1([NH:13][C:14]2[C:15]([C:30]([F:33])([F:32])[F:31])=[CH:16][C:17]3[O:28][CH2:27][C:20]4=[N:21][NH:22][C:23](=[O:26])[C@@H:24]([CH3:25])[N:19]4[C:18]=3[CH:29]=2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH3:25][C@@H:24]1[C:23](=[O:26])[NH:22][N:21]=[C:20]2[CH2:27][O:28][C:17]3[CH:16]=[C:15]([C:30]([F:32])([F:31])[F:33])[C:14]([NH:13][C:2]4([CH3:1])[CH2:3][NH:4][CH2:5]4)=[CH:29][C:18]=3[N:19]12
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of (R)-tert-butyl 3-methyl-3-((1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (Enantiomer 1, SFC (Table 1, Method 16) Rt: 6.686 min, 0.270 g, 0.55 mmol) in DCM (10 mL) was added TFA (2 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give (R)-1-methyl-9-((3-methylazetidin-3-yl)amino)-8-(trifluoromethyl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one trifluoroacetic acid (Example #100-1, Enantiomer 1, SFC (Table 1, Method 18) Rt: 9.62 min, 0.275 g, 99%) as a pale solid. LC/MS (Table 1, Method 5) Rt=2.005 min; MS m/z: 370 [M+H]+.