Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[NH+:8]([O-:13])[C:7]([CH3:15])([CH3:14])[CH2:6]1)[CH2:2][CH3:3].[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.O.[Pt]>[CH3:18][C:17]([CH3:20])([CH3:19])[C:16]([O:13][N:8]1[C:7]([CH3:14])([CH3:15])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH2:10][C:9]1([CH3:12])[CH3:11])=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCOC1CC(C)(C)[NH+]([O-])C(C)(C)C1
Agent: [Pt]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOC1CC(C)(C)N(OC(=O)C(C)(C)C)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.4 g (0.1 mol) of 4-propoxy-2,2,6,6-tetramethylpiperidine N-oxide (for preparation, see DE-A4 219 459) are hydrogenated to saturation at 4 bar in 20 ml of toluene using 0.05 g of platinum (10% on carbon). The catalyst is filtered off and 13 g (0.108 mol) of pivaloyl chloride are slowly added dropwise to the colourless filtrate under nitrogen. After the slightly exothermic reaction has abated, the mixture is stirred for another 1 hour at room temperature and diluted with 20 ml of water. The organic phase is washed with 4% NaOH solution, dried over MgSO4 and freed of the toluene on a rotary evaporator. This gives 13.5 g (45%) of the compound 110 which is in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:35]=[CH:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([C:32]4[CH:33]=[C:34]([CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:44])([CH3:43])[CH3:45])[CH:35]=[CH:36][CH:37]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CNC(=O)OC(C)(C)C)c3)c(C)sc2n1
Temperature: 100 °C
Yield: 47.3 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (Example 61) (85 mg, 0.197 mmol) was dissolved in 1,4-dioxane (1.5 mL) and water (0.5 mL). 1,1-Dimethylethyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate (98 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium(0) (22.75 mg, 0.020 mmol) and potassium carbonate (54.4 mg, 0.394 mmol) were added and the mixture heated in a microwave at 100° C. for 10 min (×2). Ethyl acetate (10 mL) was then added and the mixture washed with water (2×5 mL). The organic layer was then dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-30% ethyl acetate in cyclohexane and then further purified by normal phase chromatography, eluting with ethyl acetate and cyclohexane (0-30%), to give the title compound (52 mg). LCMS (A) m/z: 558 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6]([NH2:15])([C:12]([OH:14])=[O:13])[CH2:7]2.C(N(CC)CC)C.[C:23](=O)([O:39]N1C(=O)CCC1=O)[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>C(#N)C.O>[C:23]([CH:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][C:6]1([NH2:15])[C:12]([OH:14])=[O:13])([O:24][CH2:25][CH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39]
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: NC1(C(=O)O)CCc2c(Cl)cccc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: NC1(C(=O)O)CCc2c(Cl)cccc2C1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.7 %

Procedure:
A mixture of racemic 5-chloro-2-aminotetraline-2-carboxylic acid (402 mg, 1.78 mmole), triethylamine (0.38 ml, 2.73 mmole), 9-fluorenylmethyl succinimidyl carbonate (Fmoc-OSu, 904 mg, 2.68 mmole) in acetonitrile (20 ml) and water (20 ml) was stirred at room temperature for two days. TLC analysis of the reaction after two days indicated the presence of starting material amino acid. 9-fluorenylmethyl succinimidyl carbonate (0.12 g) and triethylamine (0.1 ml) was added and the mixture was stirred at room temperature for another day. The reaction mixture was concentrated in vacuo to remove most of the acetonitrile, acidified to pH ˜3 with 10% aqueous citric acid solution, and the white emulsion extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate. Filtration and concentration gave a crude oil which was purified by column chromatography (eluted with 3→6→8% methanol/methylene chloride) to give racemic Fmoc-5-chloro-2-aminotetraline-2-carboxylic acid (540 mg, 68% yield) as a white solid. HRMS (EI): C26H22ClNO4 (M) calc. 447.1237; observed: 447.1234.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([C:33](=[O:35])[CH3:34])=[N:22][C:21]=1[CH3:36])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:18][CH2:19][C:20]1[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[C:23]([C:33](=[O:35])[CH3:34])=[N:22][C:21]=1[CH3:36]
Reactant: CC(=O)c1nc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)c(CO)n1COCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
The compound (1.85 g) obtained in (3) was dissolved in THF (20 mL), followed by addition of TBAF (1.0 M THF solution, 3.54 mL) under stirring, and the stirring was continued for 1 hour. The reaction solution was diluted with water, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=5%→70%) using amino column (product name: SNAP Cartridge NH 55 g, manufactured by Biotage, Ltd.) to afford the title compound (1.01 g).
Reaction SMILES: C([O:8][C@@H:9]1[C@H:13]([O:14]CC2C=CC=CC=2)[C@@H:12]([CH2:22][O:23]CC2C=CC=CC=2)[O:11][CH:10]1[N:31]1[CH:35]=[C:34]([I:36])[CH:33]=[C:32]1[CH:37]=[O:38])C1C=CC=CC=1.CO.[NH4+].[OH-].O>ClCCl.B(Br)(Br)Br>[C@@H:10]1([N:31]2[CH:35]=[C:34]([I:36])[CH:33]=[C:32]2[CH:37]=[O:38])[O:11][C@H:12]([CH2:22][OH:23])[C@@H:13]([OH:14])[C@H:9]1[OH:8]
Reactant: O=Cc1cc(I)cn1C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(I)cn1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reaction time: 2 h

Procedure:
To 1-(2,3,5-tri-O-benzyl-D-ribofuranosyl)-4-iodopyrrole-2-carbaldehyde in dichloromethane (15 ml), BBr3 (1 M, 8.5 ml) was added at −78° C. The reaction mixture was stirred for 2 hours, followed by addition of 50% methanol in CH2Cl2 (30 ml). After this solution was stirred at −78° C. for 10 minutes, 28% NH4OH (4 ml) was added and the reaction mixture was stirred until it reached room temperature. The solution was added to CH2Cl2 and H2O. The aqueous layer was partitioned and washed three times with CH2Cl2, and the residue was concentrated under reduced pressure. The product was purified by reversed-phase C18 HPLC to give 1-(β-D-ribofuranosyl)-4-iodopyrrole-2-carbaldehyde (330 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([OH:34])=O)[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:56]C=2C=1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:56])=[O:34])[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 50 mg (75 μmol) of the compound of Example 39, 29 mg (0.15 mmol) of EDC and 20 mg (0.15 mmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 5 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min and then concentrated on a rotary evaporator, acidified with 2.5 N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 42 mg (84% of theory) of the title compound.
Reaction SMILES: [Cl:1][CH:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](C)[N:3]1N.ClC1N=C(Cl)N=C(N)N=1.ClC1N=C(Cl)N=[C:23]([NH:28][C:29]([NH2:31])=[O:30])N=1>>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:28]([CH3:23])[C:29]([NH2:31])=[O:30])[N:3]=1
Reactant: NC(=O)Nc1nc(Cl)nc(Cl)n1
Reactant: CC1=NC(Cl)=NC(Cl)N1N
Agent: Nc1nc(Cl)nc(Cl)n1
Product: CN(C(N)=O)c1nc(Cl)nc(Cl)n1

Procedure:
By using 89 parts of 2,4-dichloro-6-methyl-amino-s-triazine instead of 82.5 parts of 2,4-dichloro-6-amino-s-triazine and otherwise carrying out the procedure as described in Example 1 for the manufacture of N-(2,4-dichloro-s-triazin-6-yl)-urea, there are obtained 79.5 parts of N-(2,4-dichloro-s-triazin-6-yl)-N-methyl-urea with a melting point of 172°-174°C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.[ClH:45].C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:100][CH2:101][C:102]1[CH:103]=[N:104][CH:105]=[CH:106][CH:107]=1>>[ClH:45].[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:100][CH2:101][C:102]4[CH:103]=[N:104][CH:105]=[CH:106][CH:107]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[N:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Reactant: NCc1cccnc1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6cccnc6)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-[1,2,3]triazol-2-yl)-cyclopentane-1,2-diol. (Intermediate FC) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethylpyridine with 3-aminomethylpyridine. MS (ES+) m/e 729.55 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.O=[CH:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21]>[Na].C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: COC(=O)CCC=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: COC(=O)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21

Procedure:
The title compound was prepared in a manner similar to PREPARATION x63 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol), methyl 4-oxobutanoate (128 mg, 1.103 mmol), titanium(IV) chloride in CH2Cl2 (1M, 1.654 mL, 1.654 mmol) and sodium triacetoxyhydroborate (514 mg, 2.427 mmol) in CH2Cl2 (8 mL) (164 mg, 46%). ESI-MS m/z [M+H]+ calc'd for C14H19ClN4O3, 327.12. found 327.2.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCc1cnc(O)nc1
Product: CCCCCc1cnc(Cl)nc1

Procedure:
In 500 ml of phosphorus oxychloride was added 120.4 g (0.724 mol) of the 2-hydroxy-5-pentylpyrimidine described above, and heated to reflux for 5 hours. Excess amount of phosphorus oxychloride was distilled off under a reduced pressure, and the residue was added into an ice water. The product was extracted with toluene, and the extract was washed with aqueous solution of 2N aqueous solution of sodium hydroxide and water in turn, and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure. The residue was purified by distillation to obtain 76.3 g (0.413 mol) of 2-chloro-5-pentylpyrimidine. Yield of this product was 57%.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)C.C(O)(C(F)(F)F)=O.O>C(Cl)Cl>[O:3]=[CH:4][CH2:5][O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: CCOC(COC(=O)c1ccc(OC)cc1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(C(=O)OCC=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
A solution of 4-methoxybenzoic acid 2,2-diethoxy-ethyl ester (2b, 7.5 g, 28 mmol) in Cl2CH2 (75 ml) was treated with TFA (16.7 g, 11.3 ml, 140 mmol) and water (7.5 g, 7.5 ml, 28 mmol). The homogeneous solution was stirred for 3.5 hours at room temperature until GC showed complete reaction. The solution was concentrated in vacuo at 40° C. and then diluted with hexane and concentrated in vacuo several times to remove traces of TFA. The product, 4-methoxybenzoic acid 2-oxo-ethyl ester (2c, 5.9 g, 28 mmol, 100%) was isolated as an amorphous white solid and was used in the next step without any further purification. GC (Rt=11.0 min, 95%); 1H-NMR (CDCl3) δ: 9.72 (1H, s, HCO—), 8.06 (2H, d, J=8.8, ArH), 6.95 (2H, d, J=8.8, ArH), 4.87 (2H, s, HCOCH2O—), 3.87 (3H, s, OCH3).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[NH:5][N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C([O:36][C:37](=[O:64])[C@H:38]([CH2:62][OH:63])[CH2:39][C@H:40]([NH:54]C(OC(C)(C)C)=O)[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:44][CH:43]=1)C.Cl.O1CCOCC1>CN(C=O)C.CC#N>[C:45]1([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:44]=[CH:43][C:42]([CH2:41][C@@H:40]([NH:54][C:7]([C:4]2[NH:5][N:6]=[C:2]([Cl:1])[N:3]=2)=[O:9])[CH2:39][C@@H:38]([CH2:62][OH:63])[C:37]([OH:64])=[O:36])=[CH:47][CH:46]=1
Reactant: O=C(O)c1nc(Cl)n[nH]1
Reactant: CCOC(=O)[C@H](CO)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CC#N
Product: O=C(N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@H](CO)C(=O)O)c1nc(Cl)n[nH]1
Reaction time: 0.08 h
Yield: 60.8 %

Procedure:
5-Chloro-2H-1,2,4-triazole-3-carboxylic acid (51.8 mg, 351 μmol, 1.5 eq.) and HATU (133 mg, 351 μmol, 1.5 eq.) were dissolved in DMF (3.0 mL), and the resulting mixture was stirred for 5 minutes to yield the activated acid. (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid ethyl ester (100 mg, 234 μmol, 1.0 eq.) was dissolved in MeCN (2 mL) followed by the addition of 4 M of HCl in dioxane (0.5 mL, 2.0 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated to dryness. The activated acid was added and the resulting mixture was stirred for 2 minutes, followed by the addition of DIPEA (81.5 μL). The mixture was stirred at room temperature for 1 hour. The reaction was quenched with water, and the solvent removed under vacuum. The dried solid was dissolved in EtOH (2.0 mL) followed by the addition of 1.0 M of LiOH in water (2.0 mL). The mixture was stirred at room temperature for 3 hours, and the reaction was quenched with AcOH. The solvent was removed under vacuum, the residue was dissolved in AcOH/MeCN and purified by preparative HPLC. The clean fractions were combined and lyophilized to yield the title compound (61 mg, 95% purity). MS m/z [M+H]+ calc'd for C21H21ClN4O4, 429.13. found 429.4.
Reaction SMILES: [Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:4]
Reactant: CC(C)C[C@@H](Br)C(=O)O
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)C[C@@H](Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
2(R)-Bromo-4-metylpentanoic acid (28.5 g, 146 mmol), benzyl alcohol (18.1 ml, 175 mmol) and 4-dimethylaminopyridine (1.90 g, 14.6 mmol) were dissolved in CH2Cl2 (140 ml), and added with EDC (35.6 g, 175 mmol) under ice-cooling and stirring The mixture was stirred under ice-cooling for 1 hour and further at room temperature overnight and washed for separation with water, a saturated aqueous solution of NaHCO3 and then a saturated aqueous solution of NaCl two times respectively. The organic layer was dried over an hydrous MgSO4, evaporated under reduced pressure and purified by column chromatography (silica gel; 700 g, elution with the mixed solvent; n-hexane:AcOEt=40:1), giving the title compound (32.0 g, 77%) of a colorless oil.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:22]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])([O-:24])=[O:23].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.C(O)C>[F:9][C:2]1([F:1])[CH2:3][CH:4]([C:6]([NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[N+:22]([O-:24])=[O:23])=[O:8])[CH2:5]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1[N+](=O)[O-])C1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
[step 1] 3,3-Difluorocyclobutanecarboxylic acid (500 mg, 3.67 mmol) was dissolved in DMF (18 mL), 1,1′-carbonyldiimidazole (1.19 g, 7.35 mmol) was added, and the mixture was stirred at room temperature for 1 hr. To the mixture were added 2-nitroaniline (1.02 g, 7.35 mmol) and triethylamine (1.02 mL, 7.35 mmol), and the mixture was stirred at 80° C. for 13 hr. To the mixture were added 5% aqueous citric acid solution and ethanol (5 mL), and the mixture was stirred for 1 hr. The precipitated crystals were collected by suction filtration to give 3,3-difluoro-N-(2-nitrophenyl)cyclobutanecarboxamide (527 mg, 56%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[CH:6][C:7]2[C:16](=[O:17])[N:15]([C:18]3[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=3)[C:21](OCC)=[O:22])[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:29]=1)[CH3:2].[NH2:30][NH2:31].[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[C:32]([NH:30][NH:31][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][CH:28]=[C:18]([N:15]2[CH2:14][CH:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]3[N:29]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[CH:6][C:7]=3[C:16]2=[O:17])[CH:19]=1)(=[O:34])[CH3:33]
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)OCC)c1)C2=O
Reactant: NN
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCCC1CN(c1cccc(C(=O)NNC(C)=O)c1)C2=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
Compound 18 (169 mg, 0.427 mmol) obtained in Example 18 was dissolved in ethanol (2.1 mL), and the mixture was stirred overnight at 80° C. after adding hydrazine.monohydrate (0.207 mL, 4.27 mmol). The reaction mixture was then concentrated under reduced pressure, and vacuum dried. The resulting residue was dissolved in DMF (2 mL), and stirred overnight after adding acetyl chloride (0.0455 mL, 0640 mmol) and triethylamine (0.119 mL, 0.854 mmol). Then, the reaction mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was then purified by silica gel column chromatography to give the title compound (Compound 19) (74.0 mg, 41% (2 steps)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][O:20]1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH:19]3[CH2:23][CH2:22][CH2:21][O:20]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: BrCC1CCCO1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc2ccn(CC3CCCO3)c12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in N,N-dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine (30 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=90/10→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (200 mg) as a colorless oil.