Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]3[CH2:17][NH:16][CH2:15][CH2:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][C:10]3[N:11]=[CH:12][N:13]=[C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:9]=3[CH2:17]2)=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(Nc2ncnc3c2CNCC3)cc1
Reactant: Clc1cccnc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Clc1cccnc1N1CCc2ncnc(Nc3ccccc3)c2C1
Temperature: 150 °C
Yield: 25.6 %

Procedure:
5,6,7,8-Tetrahydro-N-phenylpyrido[4,3-d]pyrimidin-4-amine (500 mg, 2.2 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (423 mg, 2.86 mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (190 mg).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH4+:16].[OH-].O>C(OCC)(=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:16])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
4-(Bromomethyl)benzoic acid (300 mg, 1.40 mmol) in ethyl acetate (5 mL) was stirred with thionyl chloride (249 μL, 3.50 mmol) at 75° C. for 9 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and stirred with 28% ammonia aqueous solution (380 μL, 5.60 mmol) under cooling with ice for 80 minutes. The reaction mixture was mixed with water, and the precipitate was collected by filtration, washed with dichloromethane to give the title compound as a colorless solid (274 mg, yield 91%).
Reaction SMILES: [C:1]([C:5]1(C(OC)=O)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].S(=O)(=O)(O)O.[OH-].[Na+]>O>[C:1]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)C1(C(=O)OC)CCOCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(=O)C1CCOCC1
Yield: 75.6 %

Procedure:
In a flask made of glass having an inner volume of 10 ml and equipped with a stirring device, a thermometer, a dropping funnel and a reflux condenser were charged 4.8 g (24 mmol) of 4-propionyl-4-methoxycarbonyltetrahydropyran synthesized in Example 2, 30 ml of water and 9.0 g of conc. sulfuric acid, and the mixture was reacted at 100° C. for 10 hours with stirring. After completion of the reaction, to the resulting reaction mixture was added 16.5 g of 50% by weight aqueous sodium hydroxide solution to adjust a pH of the mixture to 4.0. Said reaction mixture was extracted three times with 50 ml of ethyl acetate, and the organic layer was separated and concentrated under reduced pressure. The obtained concentrate was purified by silica gel column chromatography (Eluent; hexane/ethyl acetate=3/1 (volume ratio)) to give 2.58 g (Isolation yield: 76%) of 4-propionyltetrahydropyran as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[CH2:17][O:18][C:32]3[CH:31]=[CH:30][C:29]([CH2:28][C@H:22]([O:21][CH2:19][CH3:20])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:34][CH:33]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C/c1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cc(Cl)cc(Cl)c3)cc2)cc1)OCC
Yield: 73.3 %

Procedure:
The title compound (732 mg, 70%) was prepared as a yellow gum, (containing 0.25 molar equivalents of ethyl acetate) from (E)-3-(3′,5′-dichloro-biphenyl-4-yl)-prop-2-en-1-ol (559 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:24][CH:23]2[NH2:25])[CH:19]=[CH:20][CH:21]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]([CH3:13])([CH3:12])[C:9]([NH:25][CH:23]2[CH2:24][CH:22]2[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)=[O:11])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C(=O)O)c1nccnc1Cl
Reactant: COc1cccc(C2CC2N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(C2CC2NC(=O)C(C)(C)c2nccnc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
A mixture of Intermediate 29 (0.2 g, 0.997 mmol), 2-(3-methoxyphenyl)cyclopropanamine (FSSI, mixture of cis/trans, 0.163 g, 0.997 mmol), HATU (GenScript Corporation, 0.455 g, 1.196 mmol), hunig's base (Aldrich, 0.696 ml, 3.99 mmol) in DMF (0.997 ml) and DCM (0.997 ml) was stirred at room temperature overnight. Reaction mixture was diluted with DCM and washed with water and brine. The organic layer was loaded onto a Biotage samplet (25 g). Purification (0-100% EtOAc/hexane) produced 2-(3-chloropyrazin-2-yl)-N-(2-(3-methoxyphenyl)cyclopropyl)-2-methylpropanamide (0.183 g, 0.529 mmol, 53%). M+1: 346.0.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:50](=[O:51])[CH2:49][O:48][CH3:47])=[CH:42][CH:41]=2)=[N:17]1
Reactant: COCC(=O)Cl
Reactant: Nc1ccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCC(=O)Nc1ccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)cc1
Yield: 9 %

Procedure:
The title compound was prepared as described in Example 376, using 4-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.302 g, 0.50 mmol) in tetrahydrofuran (4.5 mL) was added methoxyacetyl chloride (0.07 mL, 0.75 mmol) and triethylamine (0.35 mL, 2.52 mmol). The final crude product was purified by preparative HPLC (5-100% acetonitrile to H2O, 30 min.) (0.015 g, 9% yield): 1H NMR (CD3OD) δ 8.75 (d, 1H), 8.40 (s, 1H), 8.10 (dd, 1H), 8.02 (d, 2H), 7.83 (d, 2H), 7.68 (dd, 1H), 4,09 (s, 2H), 3.52 (s, 3H); ES-MS (m/z) 349 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>>[N:26]1([S:23]([C:20]2[CH:21]=[CH:22][C:17]([NH:1][C:2]3[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:3]=3)=[CH:18][CH:19]=2)(=[O:24])=[O:25])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: NC(=O)c1cn(-c2ccccc2)nc1N
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Product: NC(=O)c1cn(-c2ccccc2)nc1Nc1ccc(S(=O)(=O)N2CCOCC2)cc1

Procedure:
3-{[4-(morpholin-4-ylsulfonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide was prepared according to the general procedure in Example 1 Step 4 using 3-amino-1-phenyl-1H-pyrazole-4-carboxamide (34 mg, 0.168 mmol) and 4-[(4-bromophenyl)sulfonyl]morpholine (51.5 mg, 0.168 mmol) as the starting materials.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.C(O)(C(F)(F)F)=O>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 49 %

Procedure:
This product was prepared using the same procedure as for intermediate 1 with tryptamine (5.0 g, 30 mmol), 4-chlorobenzaldehyde (4.6 g, 1 equiv.) and TFA (4.6 mL, 2 equiv.) to give the title compound (4.16 g, 49%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](Cl)=[N:12][OH:13])=[CH:7][CH:6]=1)=[O:4].[CH2:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[CH:28])=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19].C(N(CC)CC)C>O1CCCC1.ClCCl>[CH2:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:28]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
To a solution of 4-Methoxycarbonylphenylhydroxyiminomethyl chloride (16.98 g) and 4-n-pentyloxyphenylacetylene (18.96 g) in tetrahydrofuran (170 ml) was added triethylamine (14.4 ml) in tetrahydrofuran (140 ml) over a period of 2 hours at 40° C. and the mixture was stirred at 40° C. for 30 minutes. The mixture was diluted with dichloromethane and washed with water and brine. The separated organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was triturated with acetonitrile. The precipitate was collected by filtration and dried to give Methyl 4-[5-(4-n-pentyloxyphenyl)isoxazol-3-yl]benzoate (24.56 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:9]1[C:10]([C:25]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:32][CH:31]=3)=[N:27][N:26]=2)=[N:11][C:12]([C:15]2[CH2:24][CH2:23][C:18]3(OCC[O:19]3)[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[C:49]([O:48][C:46]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]1[C:10]([C:25]2[O:29][C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:32][CH:31]=3)=[N:27][N:26]=2)=[N:11][C:12]([C:15]2[CH2:24][CH2:23][C:18](=[O:19])[CH2:17][CH:16]=2)=[CH:13][N:14]=1)=[O:47])([CH3:50])([CH3:51])[CH3:52]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC5(CC4)OCCO5)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(=O)CC4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (680 mg, 0.94 mmol) in THF (2.0 mL) was added 1M aqueous HCl (1.9 mL of 1 M, 1.9 mmol) and the reaction mixture was heated at 60° C. for 6 h. The reaction was cooled to room temperature and diluted with EtOAc, the layers were separated and the organic layer was washed once with aqueous NaHCO3, then once with brine, dried over Na2SO4, filtered and concentrated to dryness to yield tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-oxocyclohexen-1-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (487 mg, 76%) and was used without further purification. LC/MS m/z 677.5 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:30]=[C:29]([CH:31]=[O:32])[NH:28][C:27]=1[C:33]([OH:35])=O.[NH2:36][CH2:37][C:38]1[C:39]([F:55])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:49]#[N:50])[C:41]([Cl:44])=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:25][C:26]1[CH:30]=[C:29]([CH:31]=[O:32])[NH:28][C:27]=1[C:33]([NH:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([O:45][C:46]2[CH:47]=[C:48]([C:49]#[N:50])[CH:51]=[C:52]([Cl:54])[CH:53]=2)[C:39]=1[F:55])=[O:35]
Reactant: O=Cc1cc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C=O)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 3-chloro-5-formyl-1H-pyrrole-2-carboxylic acid (0.028 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol) and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). The solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% Na2CO3 solution and dried over MgSO4. The solid was filtered off and the solvent was evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to give an orange film which was triturated in acetone to afford the title compound (0.012 g, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (s, 1H), 9.57 (s, 1H), 8.53-8.71 (m, 1H), 7.74-7.86 (m, 1H), 7.47-7.52 (m, 2H), 7.38-7.46 (m, 2H), 7.04 (s, 1H), 4.52 (d, 1H). LCMS: m/z 466.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48]C(=O)C)=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>O.C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([OH:48])=[C:43]([CH:47]=2)[C:44]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.7 %

Procedure:
4-Nitroaniline (0.414 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.080 g, 0.177 mmol, 18%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[N:9][N:8]=2)[CH:2]=1.[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:21]1([C:27]2[N:31]=[C:30]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:10]4[O:11][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[N:8][N:9]=4)=[O:20])[CH2:34][CH2:33]3)[S:29][N:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1nnc(-c2cccnc2)o1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1nnc(-c2cccnc2)o1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 34.3 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl (5-pyridin-3-yl-1,3,4-oxadiazol-2-yl)carbamate (249 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.728 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours and half. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and crystals were separated by filtration, which was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 110 mg (34.2%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:18]([N:20]=[C:21]=NCCCN(C)C)C.CN(CCCN=C=NCC)C.ON1C2C=CC=CC=2N=N1.CNC>CN(C)C=O>[CH3:18][N:20]([CH3:21])[C:14]([CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN(C)C(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3-[N-(benzyloxycarbonyl)amino]propionic acid (0.70 g, 3.14 mmol) was dissolved in N,N-dimethylformamide (15 ml), and 1-(dimethylaminopropyl)-3-ethylcarbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g, 3.13 mmol), 1-hydroxybenzotriazole (0.48 g, 3.13 mmol) and dimethylamine (2.0 M tetrahydrofuran solution, 2.40 ml, 4.80 mmol) were added, followed by stirring at room temperature for 3 days.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:22])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:22][C:23](=[O:25])[CH3:24])([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of N-t-butoxycarbonyl-4-amino-4-(2-methylbenzyl)piperidine (305 mg, 1.0 mmol), acetic anhydride (0.38 ml, 4.0 mmol), and pyridine (0.1 ml, 1.2 mmol) in CH2Cl2 is stirred at room temp. overnight. Then concentrate the reaction mixture in vacuo and purify the residue by column chromatography on silica to afford the product.
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH:17]4[CH2:20][CH:19]([C:21]([O-])=[O:22])[CH2:18]4)[C:12](=[O:24])[N:11]([CH3:25])[C:10]=3[N:9]=[C:8]2[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH:17]4[CH2:18][CH:19]([CH2:21][OH:22])[CH2:20]4)[C:12](=[O:24])[N:11]([CH3:25])[C:10]=3[N:9]=[C:8]2[O:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:35])[F:36])[CH:28]=2)=[CH:38][CH:39]=1
Reactant: Cn1c(=O)n(C2CC(C(=O)[O-])C2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(C2CC(CO)C2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of 3-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)cyclobutanecarboxylate (59 mg, 0.09 mmol) in THF (3 mL) was added LAH (6.8 mg, 0.18 mmol) in one portion and the mixture was stirred at room temperature for 2 h. The reaction was carefully quenched with ethyl acetate and filtered. The filtrate was concentrated to dryness to give a crude product which was purified via preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-(hydroxymethyl)cyclobutyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (17 mg, 34.3% yield) as white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[N:8]([CH:16]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[C:35](=[O:36])[CH2:34][C@H:33]3[CH2:37][N:38](C(OC(C)(C)C)=O)[CH2:39][C@H:32]3[CH2:31]2)=[CH:26][CH:25]=1>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([N:30]5[C:35](=[O:36])[CH2:34][C@H:33]6[CH2:37][NH:38][CH2:39][C@H:32]6[CH2:31]5)=[CH:28][N:29]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCCCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC(=O)N(c3ccc(N)nc3)C[C@@H]2C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@@H]5CNC[C@@H]5CC4=O)cn3)nc2n1C1CCCCCC1
Yield: 86 %

Procedure:
Following general N—C coupling procedure 1, 2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and cis-tert-butyl 5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate were combined and gave after purification cis-tert-butyl 5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (85 mg) in 86% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.77 (s, 1H), 8.66 (d, J=9.09 Hz, 1H), 8.48 (br s, 1H), 8.24 (s, 1H), 7.64 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.45 (s, 1H), 4.53 (m, 1H), 3.84 (dd, J1=13.14 Hz, J2=5.56 Hz, 1H), 3.70 (m, 3H), 3.31 (m, 2H), 3.17 (s, 6H), 2.82 (m, 3H), 2.63 (m, 2H), 2.51 (dd, J1=16.42 Hz, J2=5.81 Hz, 1H), 2.01 (m, 2H), 1.87 (m, 2H), 1.73 (m, 4H), 1.58 (m, 2H), 1.48 (s, 9H). LCMS m/z 617.7 (M+H)+.