Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:49][S:50]([CH3:52])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])[C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:49][S:50][CH3:52])[CH2:22][CH2:21]1)=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OCSC)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (25 mg, 0.054 mmol) in DMSO (0.2 mL) was added a mixture of acetic acid and acetic anhydride (1:5.6) (0.17 mL). After stirring for 1.5 h at room temperature it was held at 40° C. for 5 h. It was cooled to room temperature and stirred for 16 h. The mixture was cooled in ice-bath and NaHCO3 solution was added carefully. It was extracted with ether. The extract was washed with water and brine, dried over MgSO4 and evaporated. Xs Pure 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-methylsulfanylmethoxy-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester was obtained by chromatography over silica gel (hexane:EtOAc=−4:1) (22 mg, 77%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=1.[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:25][C:26]2[C:27]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:10])=[C:6]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=1
Reactant: CSCc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Product: CSCc1ccc(C(=O)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 71 %

Procedure:
Using a procedure analogous to Example 1-G, 2-[4-methylthiomethyl-2-[3-(t-butoxycarbonylamino)propoxy]benzoic acid and 3-amino-6-methyl-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white glassy solid (1.41 g, 71%).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][C:9]=1[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])[CH3:4]>C(O)(=O)C(C)C>[CH2:3]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH:9]1[NH:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)C1=C(NCc2ccccc2)CC(C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)C(=O)O
Product: CCOC(=O)C1CCC(C)CC1NCc1ccccc1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
In a separate flask, sodium borohydride (3.8 g) was added in portions to isobutyric acid (60 mL) cooled to about 15° C. under nitrogen. After 15 minutes, the reaction was cooled to 0° C. and the above reaction solution containing 2-benzylamino-4-methyl-cyclohex-1-enecarboxylic acid ethyl ester was added dropwise. After stirring for 2 hours, the reaction was carefully quenched with 40 mL of 3 M aqueous hydrochloric acid. The organic layer was separated, and the aqueous layer washed with 50% ethyl acetate/hexanes. After making the aqueous layer basic with 2M sodium hydroxide, extraction with four portions of ethyl acetate was conducted. The organic layer was concentrated to about 50 mL, cooled to 0° C., and made acidic with 30% HBr in propionic acid. After 1 hour, a solid was collected (1.1 g). The mother liquor was made basic and extracted with ethyl acetate. After concentration, the residue was subjected to flash chromatography using hexanes/ethyl acetate to afford 1.31 g of 2-benzylamino-4-methyl-cyclohexanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[N:16]=[C:15](N2C3C=CC=CC=3N=N2)[CH:14]=[N:13][C:12]=1[CH3:26].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=1[Mg]Br.[C:39]1([CH3:45])C=CC=C[CH:40]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[C:12]([CH3:26])=[N:13][CH:14]=[C:15]([C:45]2([C:30]3[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[CH2:39][CH2:40]2)[N:16]=1
Reactant: COc1cc(Cl)c(-c2nc(-n3nnc4ccccc43)cnc2C)cc1C
Reactant: Cc1ccccc1
Reactant: COc1ccc(OC)c([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C2(c3cnc(C)c(-c4cc(C)c(OC)cc4Cl)n3)CC2)c1
Temperature: 150 °C

Procedure:
To 46 mg 1-[6-(2-Chloro-4-methoxy-5-methyl-phenyl)-5-methyl-pyrazin-2-yl]-1H-benzotriazole (0.12 mmol) in 200 μL toluene was added 100 μL 0.5 M 2,5-dimethoxyphenyl magnesium bromide in THF. The solution is subjected three times to 3 GHz microwave radiation heating to 150° C. for 15 min. After quenching with saturated ammonium chloride, the organic phase was directly subjected to column chromatography eluting with hexanes DCM followed by hexane ethyl acetate (0.1% Et3N) . Fractions containing the desired product were pooled and concentrated to give a residue that was further purified by RP—HPLC eluting with acetonitrile water (0.03% TFA) giving 2.6 mg of the title compound.
Reaction SMILES: [CH2:1]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)(Cl)=O.CN(C)[CH:21]=[O:22]>>[CH2:1]([C:9]1[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cccs1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCc1ccc(C=O)s1

Procedure:
To a stirred solution of 80.1 g. of 2-octylthiophene in 70 ml. dimethylformamide is added dropwise 42.4 ml. of phosphorus oxychloride. After addition, the solution is made warmed at 100° for 1 hour, then poured into 600 ml. ice. After neutralization with sodium acetate, the resulting oil is extracted with ether. The ether is washed with water and aqueous potassium carbonate, dried, and distilled in vacuo to give the title compound as an oil.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH2:2]
Reactant: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCO
Product: O
Reaction time: 0.02 h

Procedure:
Equal amounts of octanol and a phosphate buffer were mixed together and [125I]I-BzA-TBOA was added thereto. After repeatedly shaking for 1 minute and allowing to stand for 1 minute three times, the mixture was allowed to stand for 20 minutes. After repeating this procedure three times, it was centrifuged (1,000×g, 10 min, 4° C.) and the radioactivity of each layer was measured. Thus, the partition coefficient was calculated (Table 1).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[CH:4][C:3]=1F.COC(=O)C1C=C(OC2C=CC(N)=C(F)C=2)C=NC=1>>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([CH:16]=2)[C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Agent: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Product: CNC(=O)c1cncc(Oc2ccc(N)cc2)c1

Procedure:
The title compound was prepared in the same manner described for 5-(4-amino-3-fluorophenoxy)-N-methylnicotinamide, substituting 5-(4-aminophenoxy)nicotinic acid methyl ester for 5-(4-amino-3-fluorophenoxy)nicotinic acid methyl ester. 1H NMR (DMSO-d6) δ 8.65 (m, 2H), 8.40 (d, J=2.7 Hz, 1H), 7.52 (t, J=2.2 Hz, 1H), 6.84 (d, J=8.7 Hz, 2H), 6.62 (d, J=8.7 Hz, 2H), 5.01 (s, 2H), 2.75 (d, J=4.4 Hz, 3H); MS LC-MS [M+H]+=244.2, RT=0.29 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=[O:18].[Na+].Cl>CN(C)C=O.O>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[N:17]=[O:18]
Reactant: Nc1cc(=O)[nH]c(=O)n1Cc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 6-amino-1-benzyl-1,3-dihydropyrimidine-2,4-dione (2.0 g, 9.2 mmol) in a mixture of 15 ml of N,N-dimethylformamide and 5 ml of water at 90° C. was added sodium nitrite (1.27 g, 69 mmol). To this reaction mixture was added concentrated hydrochloric acid until there was no deepening of color, and the mixture was heated at 70° C. for 1 hour. The solvent was removed under reduced pressure, the residue dissolved in water, and concentrated hydrochloric acid added to produce a pH of 4.0. The precipitate was filtered off, washed with water, and dried under reduced pressure, to provide 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (23).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][N:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[N:29]1[C:33]([CH3:34])=[N:32][CH:31]=[N:30]1)[C:23](O)=[O:24]>>[CH:1]1([N:4]([CH:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:12]=[CH:13][C:14]([CH2:17][CH3:18])=[CH:15][N:16]=3)[CH2:7][CH2:6]2)[C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:28]([N:29]3[C:33]([CH3:34])=[N:32][CH:31]=[N:30]3)=[C:20]([F:19])[CH:21]=2)[CH2:2][CH2:3]1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1F
Reactant: CCc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3ccc(-n4ncnc4C)c(F)c3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from cyclopropyl-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yl]-amine and 3-fluoro-4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 90. LC (method 19): tR=3.69 min; Mass spectrum (ESI+): m/z=450 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:23]C)=[C:5]([O:21]C)[CH:6]=[C:7]([CH:20]=1)[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:9])#[N:2].B(Br)(Br)Br.CO>C(Cl)Cl>[C:1]([C:3]1[C:4]([OH:23])=[C:5]([OH:21])[CH:6]=[C:7]([CH:20]=1)[C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:14][CH:15]=1)=[O:9])#[N:2]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc(C#N)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc(O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.5 g of 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone (dissolved in 75 ml of methylene chloride) are treated at 5° with 2.18 ml of boron tribromide, whereupon the mixture is stirred at room temperature for 18 hours. The reaction mixture is subsequently diluted with 50 ml of methylene chloride. The mixture is heated under reflux for an additional 4 hours, treated at -70° with 15 ml of methanol, stirred at room temperature for 2 hours, evaporated, the residue is dried in vacuo and partitioned between ethyl acetate and ice-water. The aqueous phase is extracted twice more with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The thus-obtained material is stirred at 130° for 6 hours with 10 ml of acetic anhydride and 1 ml of pyridine. The mixture is evaporated and the residue is partitioned between ice-water and methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated, and the residue is chromatographed on 30 g of silica gel with methylene chloride. The thus-obtained diacetate is dissolved in 10 ml of methanol. The solution is treated with 4.2 ml of 1N sodium hydroxide solution, stirred at 0° for 1 hour, neutralized with acetic acid, evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate phases are dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride. There is obtained 5-cyano-3,4-dihydroxy-4'-(trifluoromethyl)benzophenone of melting point 204°-206°.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([Si](C)(C)C)[N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[CH:14][N:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)c1cn(C2CCC3(CC2)OCCO3)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: c1cn(C2CCC3(CC2)OCCO3)nn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-trimethylsilanyl-1H-[1,2,3]-triazole (1.60 g, 5.68) in 41 mL of dry THF is treated by a 1M solution of tetrabutylammonium fluoride in THF (9.0 mL, 9.0 mmol). The resulting mixture is stirred for 48 h at room temperature under nitrogen. It is diluted with EtOAc, washed with saturated aqueous ammonium chloride, water and brine, dried over Na2SO4 and concentrated to give 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,3]triazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[CH3:11][O:12][CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[CH:34][C:33](Br)=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH2:18][CH2:17]1>C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][Si@H:16]1[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]3[CH:35]=[CH:34][C:33]([C:2]4[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=4)=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH2:20][CH2:21]1
Reactant: COCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(Br)cc3)CC2)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)cc3)CC2)CC1

Procedure:
19.3 g (0.1 mol) of 1-bromo-3,4-difluorobenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of tetrakis triphenylphosphine palladium and 43.8 g (0.1 mol) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)phenyl bromide. After a conventional after treatment, purification was conducted by means of chromatography to obtain 28.9 g (yield 61.3%) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)-3',4'-difluorobiphenyl was obtained.
Reaction SMILES: C[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([CH3:20])=[C:15]([CH2:21][CH3:22])[N:14]=1>>[CH3:20][C:16]1[C:17]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:2]2)=[N:18][C:13]([Cl:12])=[N:14][C:15]=1[CH2:21][CH3:22]
Reactant: CCc1nc(Cl)nc(Cl)c1C
Reactant: CC1NCCc2ccccc21
Product: CCc1nc(Cl)nc(N2CCc3ccccc3C2)c1C
Yield: 56.7 %

Procedure:
In accordance with the same procedure as in Step 1 of Example 1, except that 1-methyl-1,2,3,4-tetrahydroisoquinoline (2.3 g, 15.6 mmol) and 2,4-dichloro-5-methyl-6-ethylpyrimidine (2.7 g, 14.1 mmol) prepared in Preparation 4 were used as starting materials, 2.3 g of the titled compound was prepared. (Yield: 54%)
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:10]1[C:11]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]=[C:15](OS(C(F)(F)F)(=O)=O)[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N-:41]=[N+:42]=[N-:43].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:7][CH2:8][C@@H:9]([O:36][C:37]([CH3:39])([CH3:40])[CH3:38])[C:10]1[C:11]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]1[N:41]=[N:42][N:43]=[C:15]1[CH:14]=[CH:13]2)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2nc(OS(=O)(=O)C(F)(F)F)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 90 °C
Yield: 23.9 %

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-(trifluoromethylsulfonyloxy)quinolin-6-yl)ethyl pivalate (compound of Example 26)(30 mg) and sodium azide (32 mg) in DMF (1 mL) was heated at 90° C. for 4 hours. The mixture was diluted with ethyl acetate, and washed with water and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyltetrazolo[1,5-a]quinolin-7-yl)ethyl pivalate (5.9 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C27H32ClN4O3: 495.2. Found: 495.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH3:18])=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(CC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(CC)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-ethyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.95 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-ethyl-quinoline-3-carboxylic acid ethyl ester (250 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10](Cl)(=[O:13])[CH:11]=[CH2:12].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]2[C:26]3[C:39]([NH2:40])=[N:38][CH:37]=[N:36][C:27]=3[N:28]3[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31][CH2:30][C:29]=23)[CH:16]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O>[NH2:40][C:39]1[C:26]2[C:25]([C:17]3[CH:16]=[N:15][C:24]4[C:19]([CH:18]=3)=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:29]3[CH2:30][CH2:31][C@H:32]([NH:35][C:10](=[O:13])[CH:11]=[CH2:12])[CH2:33][CH2:34][N:28]3[C:27]=2[N:36]=[CH:37][N:38]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC[C@@H](N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=CC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2CC1
Reaction time: 0.25 h
Yield: 61.6 %

Procedure:
N,N-Diisopropylethylamine (0.192 ml) and a solution of acryloyl chloride (83.3 mg) in acetonitrile (0.83 ml) were added to an acetonitrile (1.6 ml)-water (1.6 ml) solution of the (S)-5-(quinolin-3-yl)-7,8,9,10-tetrahydro-6H-pyrimido[5′,4′:4,5]pyrrolo[1,2-a]azepin-4,8-diamine (317 mg) obtained in Step 9 under ice-cooling. After being stirred at the same temperature for 15 minutes, the mixture was poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a light-yellow solid (226 mg).
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[C:7]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[C:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncnc2-n2cnnc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1nc2c(c(-n3cnnc3)n1)CCNC2
Reaction time: 2 h
Yield: 90 %

Procedure:
To the product of Example 109 step a (574 mg, 1.9 mmol) in DCM (9.5 mL) was added TFA (3.8 mL). After stirring 2 h the reaction was concentrated in vacuo. The residue was redissolved in DCM and treated with Dowex 550A resin to neutralize the TFA salt. The resin was removed by filtration and concentration afforded a yellow solid (347 mg, 90%). This material was used without further purification. MS (ESI) mass calcd. C9H10N6, 202.2. m/z found 203.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:29][N:30]=[C:31]=NCCCN(C)C.Cl.CNC.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([N:30]([CH3:31])[CH3:29])=[O:23])[CH:18]=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)O)cn3)nc2N1C1CCCC1
Agent: CNC
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cc(C(=O)N(C)C)cn3)nc2N1C1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44, 0.14 g, 0.378 mmol) was dissolved in 2 mL of DCM and EDCI (79 mg, 0.415 mmol), dimethylamine hydrochloride (46 mg, 0.567 mmol), HOAt (5 mg, 0.0379 mmol) and triethylamine (115 mg, 1.13 mmol) were added. The resulting solution was stirred at rt for 48 hours after which the reaction mixture was diluted with DCM and washed with 0.1 N aqueous HCl then 1 N aqueous NaOH, dried with Na2SO4, filtered, concentrated under vacuum and purified by preparative HPLC to give the title compound. 1H NMR (CDCl3) δ: 7.55-7.57 (s, 1H), 7.40-7.51 (m, 2H), 4.26-4.51 (m, 2H), 3.11-3.39 (m, 9H), 1.64-2.18 (m, 10H), and 0.97 ppm (m, 3H); LCMS: 398.1 m/z (M+H)+; ret. Time: 3.267 min (Analytical Method A).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)([CH2:14][O:15][C:16]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:51]2[CH:59]=[C:57]([CH3:58])[C:55](=[O:56])[NH:54][C:52]2=[O:53])[C@@H:10]1[OH:60])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(=O)([O-])O.[Na+].ClCCl>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@H:10]2[O:60][CH2:39][C@:13]1([CH2:14][O:15][C:16]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)[O:12][C@H:11]2[N:51]1[CH:59]=[C:57]([CH3:58])[C:55](=[O:56])[NH:54][C:52]1=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(OC[C@@]2(COS(=O)(=O)c3ccc(C)cc3)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cc(C)c(=O)[nH]c4=O)O2)[C@H]3OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 95.4 %

Procedure:
To a solution of nucleoside 7 (4.22 g, 5.06 mmol) in anhydrous DMF (25 cm3) at 0° C. was added a 60% suspension of sodium hydride in mineral oil (w/w, 0.607 g, 1 5.7 mmol, added in four portions during 20 min) and the reaction mixture was stirred at room temperature for 25 h, cooled to 0° C. and diluted with dichloromethane/pyridine (100 cm3, 99.5:0.5, v/v). A saturated aqueous solution of sodium hydrogen carbonate (120 cm3) was added whereupon extraction was performed using dichloromethane (75 cm3×2). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (60 cm3×3) and brine (40 cm3×3), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5–1.5% methanol; 0.5% pyridine, v/v/v) as eluent yielding nucleoside 8 (3.2 g, 96%) as a white solid material after evaporation of the solvents under reduced pressure.