Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[C:37](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1CCNCC1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Yield: 18.4 %

Procedure:
To 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.174 mmol) was added N,N-Dimethylformamide (DMF) (2 mL) and cesium carbonate (170 mg, 0.522 mmol). The mixture was then added iodomethane (0.014 mL, 0.226 mmol) and the reaction was let stir at room temp overnight. The reaction was then filtered using the syringe filter and the filtrate was then diluted with water (20 ml) then extracted with EtOAc (3×15 ml). The organics were combined, washed with brine, dried over MgSO4, filtered, concentrated and then loaded on to a 10 g Biotage SNAP column. Elution with 0 to 10% MeOH in DCM over 30 min gradient afforded 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methyl-4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (16 mg, 0.032 mmol, 18.30% yield) as a white solid. LC/MS (ES) m/z=503.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.08 (d, J=8.08 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.15-7.30 (m, 4H), 4.56 (d, J=3.54 Hz, 1H), 4.29 (t, J=8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 2.93 (br. s., 2H), 2.27 (s, 3H), 2.04-2.18 (m, 4H), 1.85-1.93 (m, 2H). NHs not observed.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([OH:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:51])[CH3:50])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([OH:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:47])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:50])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.6 mg (0.011 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 1 ml of abs. tetrahydrofuran, 77 μl (0.43 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 60 mg (0.108 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 52A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 18 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product obtained is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 4:1), resulting in the separation of the diastereomers.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[Br:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-bromobenzoic acid (42 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 35 mg (33%) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 506.10 (M+1)+ 96.5%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.35 (m, 5H), 4.0 (m, 1H), 3.74 (m, 4H), 3.54 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1)=[O:6]
Reactant: c1ccc2[nH]ccc2c1
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(C(=O)n2ccc3ccccc32)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3-methylbenzoic acid (1.0 g, 4.65 mmol) and 1H-indole (0.60 g, 5.12 mmol) in DCM (23.3 mL) at RT was added DCC (1.15 g, 5.58 mmol) and 4-dimethylaminopyridine (0.11 g, 0.93 mmol). The reaction was stirred at RT overnight. The reaction was quenched with water and the aqueous layer was extracted with EtOAc. The organic layer was then washed with water and brine (3× ea.), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by column chromatography (0-50% Hexene/EtOAC) to yield (2-bromo-3-methylphenyl)(1H-indol-1-yl)methanone as a clear oil.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7])(=[O:3])[CH3:2].[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:6](=[O:7])[CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:9])[CH:18]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CC(=O)OC(C)C(=O)Cl
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)OC(C)=O)c2)c(OC)c1
Yield: 68.2 %

Procedure:
A solution of 2-acetoxypropionyl chloride (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The product obtained was purified by column chromatography to give the desired product in 68.2% yield. (m.p. 179-180° C.)
Reaction SMILES: [OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[C:7]([OH:12])(=[O:11])[CH:8]([CH3:10])[OH:9]>>[OH2:9].[OH2:1].[C:7]([O-:12])(=[O:11])[CH:8]([CH3:10])[OH:9].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CC(O)C(=O)O
Agent: C[N+](C)(C)C
Product: CC(O)C(=O)[O-]
Product: O

Procedure:
Tetramethylammonium lactate dihydrate was prepared by the addition of tetramethylammonium hydroxide (25% in methanol) to an equivalent amount of lactic acid (85% aqueous solution) with cooling on ice followed by solvent removal and the addition of sufficient water to form the dihydrate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[N:34]=[C:35]=[O:36]>C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[NH:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1)=[O:36]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Yield: 84.2 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (6.1 mg, 0.021 mmol) in 0.7 mL THF was added 2-fluoro-5-(trifluoromethyl)phenyl isocyanate (0.0033 mL, 0.023 mmol) and the reaction stirred at rt. After 1 hour the reaction was quenched with MeOH, evaporated, triturated with hot EtOAc, hexane added, and the solid filtered to give the title compound as a white solid (8.8 mg, 85%). 1H NMR (Acetone-d6) δ: 9.54 (br. s, 1H), 8.77-8.82 (m, 1H), 8.63 (br. s, 1H), 8.33 (d, J=3.2 Hz, 1H), 8.09-8.13 (m, 1H), 7.54-7.59 (m, 2H), 7.29-7.48 (m, 5H), 7.06-7.12 (m, 2H), 4.34-4.42 (m, 1H), 3.79-3.87 (m, 1H), 3.54-3.69 (m, 2H), 3.00-3.11 (m, 1H).
Reaction SMILES: C([Mg]Br)=C.[CH:5]1[CH:10]=[C:9](Cl)C=[C:7]([C:12]([O:14]O)=O)[CH:6]=1.FC(F)(OCC(O)CC1OC1)C(F)F.C(O)(=O)C.O>C1COCC1>[O:14]1[C@H:7]([CH2:6][CH2:5][CH2:10][CH3:9])[CH2:12]1.[O:14]1[CH:7]([CH2:6][CH2:5][CH2:10][CH3:9])[CH2:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: C=C[Mg]Br
Agent: OC(COC(F)(F)C(F)F)CC1CO1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1CO1
Product: CCCC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
(R)-1,2-Epoxyhexane was prepared as reported by Jacobsen and coworkers (Schaus, et al., J. Am. Chem. Soc. 2002, 124, 1307-1315). Ring opening of the optically pure epoxide by vinyl magnesium bromide followed by epoxidation with mCPBA were performed in an analogous manner as 6h to give a 1:1 mixture of diastereomers. The diastereomers were resolved using Jacobsen HKR conditions. The epoxide (2.67 g, 18.5 mmol) was diluted in 2.5 mL THF. To this solution was added (1R,2R)-(−)-1,2-cyclohexanediamino-N,N′-bis(3,5-di-tbutylsalicylidene)cobalt (56.2 mg, 0.93 mmol) and glacial acetic acid (21.2 μL, 0.37 mmol). The solution was cooled to 0° C. and water (183 μL 10.2 mmol) was added dropwise. After stirring at room temperature for 24 hours, THF was removed in vacuo and the residue was distilled under vacuum at 65° C. to afford (R,R)-6b (1.18 g, 13% from racemic 1,2-epoxyhexane, >99:1 syn:anti) as a colorless oil. 1H NMR (δ, CDCl3, 300 MHz) 0.85 (t, 3J=6.9 Hz, 3H), 1.17-1.81 (m, 8H), 2.42-2.49 (m, 1H), 2.47 (d, 3J=4.2 Hz, 1H), 2.72 (t, 3J=4.2 Hz, 1H), 2.99-3.07 (m, 1H), 3.74-3.86 (m, 1H); 13C NMR (δ, CDCl3, 75 MHz) 14.13, 22.75, 27.77, 37.22, 39.84, 46.73, 50.69, 70.38.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)[CH3:2].[C:25]([O:29][C:30](=[O:33])[CH2:31]C)(=[O:28])[CH2:26][CH3:27].[OH-:34].[NH4+]>>[C:30]([OH:29])(=[O:33])[C:31]([OH:3])=[O:34].[CH2:1]([O:3][CH2:4][C:5]1([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:28])[CH2:26][CH3:27])[CH2:6][CH2:7][N:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:10]1)[CH3:2]
Reactant: CCOCC1(Nc2ccccc2)CCN(Cc2ccccc2)CC1
Reactant: CCC(=O)OC(=O)CC
Reactant: [OH-]
Agent: [NH4+]
Product: CCOCC1(N(C(=O)CC)c2ccccc2)CCN(Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 17.5 parts of 4-(ethoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 36 parts of propionic acid anhydride is stirred and refluxed for 6 hours. The reaction mixture is poured onto ice-water and the whole is basified with ammonium hydroxide. The product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is converted into the ethanedioate salt in 2-propanone. The salt is filtered off and crystallized from 2-propanol (135 parts). The product is filtered off and dried, yielding N-[4-(ethoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylpropanamide ethanedioate; mp. 181.2° C.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[CH3:11][N:12]([CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21])[CH3:13].[Cl-:28].[NH4+]>CCOCC>[ClH:28].[CH3:13][N:12]([CH:14]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1([CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[F:2])[OH:21])[CH3:11]
Reactant: [Cl-]
Reactant: Fc1ccccc1CBr
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1ccccc1F
Product: Cl
Temperature: 25 °C
Yield: 35.7 %

Procedure:
0.38 g (15.6 mmole) of magnesium turnings was stirred in 15 ml of ether of analysis purity. 1.85 g (15.6 mmole) of 2-fluorobenzyl bromide dissolved in 15 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with in each case 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 3.50 g of crude base (79.0% of theory) were obtained. 1.75 g of 2-(dimethylaminophenylmethyl)-1-(2-fluorobenzyl)cyclohexanol, hydrochloride (35.7% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 175° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (480 mg, 1.89 mmol) (obtained as described in Reference Example 73(2)) in methylene chloride (24 ml) were added methanesulfonyl chloride (439 μl, 5.67 mmol) and triethylamine (795 ml, 5.67 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 30 minutes. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether to give a solid and the solid was collected by filtration, washed with diisopropyl ether to afford 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (586 mg, yield 94%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=O)[NH:11][C:10](=O)[CH:9]=1.O=P(Cl)(Cl)[Cl:18].[ClH:21].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>>[Cl:21][C:12]1[N:11]=[C:10]([Cl:18])[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:13]=1
Reactant: Cl
Reactant: O=c1cc(-c2ccccc2Cl)[nH]c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Clc1cc(-c2ccccc2Cl)nc(Cl)n1
Temperature: 0 °C
Yield: 73 %

Procedure:
6-(2-Chloro-phenyl)-1H-pyrimidine-2,4-dione (200 mg, 0.9 mmol) was taken into 5 ml of POCl3. Triethylamine hydrochloride (495 mg) was added to the mixture and heated at 100 C for 18 hours. The mixture was cooled and evaporated in vacuo to afford a white solid. The solid was suspended in ice water and was carefully basified with saturated sodium bicarbonate. A precipitate was collected by vacuum filtration and dried overnight to afford 183 mg (73% yield) of the desired product. HPLC Rt 8.006 mins (100% purity); MS (ES+) m/e 261.0 (M+H)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([N:34]2[CH2:39][C@H:38]([CH3:40])[O:37][C@H:36]([CH3:41])[CH2:35]2)=[C:22]([F:33])[C:23]2[O:27][N:26]=[C:25]([C:28]([NH:30][NH2:31])=[O:29])[C:24]=2[CH:32]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1([C:47](N2C=CN=C2)=[O:48])C=CN=C1.CCN(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:21]([N:34]2[CH2:35][C@H:36]([CH3:41])[O:37][C@H:38]([CH3:40])[CH2:39]2)=[C:22]([F:33])[C:23]2[O:27][N:26]=[C:25]([C:28]3[O:29][C:47](=[O:48])[NH:31][N:30]=3)[C:24]=2[CH:32]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(C(=O)NN)noc3c2F)C[C@H](C)O1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc3c(-c4n[nH]c(=O)o4)noc3c2F)C[C@H](C)O1
Yield: 96.6 %

Procedure:
5-((tert-Butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carbohydrazide (Intermediate 207, 490 mg, 0.85 mmol) and di(1H-imidazol-1-yl)methanone (207 mg, 1.27 mmol) were dissolved in 8 ml of THF and was treated with DIEA (297 μl, 1.70 mmol) at room temperature for 16 hours. Reaction diluted with ethyl acetate and quenched with aq. Ammonium chloride solution. Organic layer was separated and washed with water, dried over sodium sulfate and concentrated to give 5-(5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazol-3-yl)-1,3,4-oxadiazol-2(3H)-one (495 mg, 97%)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH3:13])[CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:6]2.[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=O.C(OC)(OC)OC.[BH4-].[Na+]>CO.O>[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([O:12][CH3:13])[CH:7]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:6]2
Reactant: O=Cc1ncc[nH]1
Reactant: CCCN(CCC)CCCCC1Cc2cc(CN)ccc2C1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC(OC)OC
Product: CCCN(CCC)CCCCC1Cc2cc(CNCc3ncc[nH]3)ccc2C1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
The compound (45.0 mg) obtained in Example 127-13 was dissolved in methanol (2.25 ml) and added with 2-imidazole carboxaldehyde (19.5 mg) and trimethyl orthoformate (43.1 mg), followed by stirring at room temperature for 1 hour. Under ice-cooling, sodium borohydride (15.4 mg) was added to the solution, and the whole was stirred at room temperature for 30 minutes. The reaction solution was added with water and then subjected to separation/extraction with chloroform. The extract was washed with saturated saline solution, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (54.8 mg) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[C@@H:15]([NH:24]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[C@@H:15]([NH2:24])[CH2:16][CH2:17][C:18]2[N:19]=[N:20][N:21]([CH3:23])[N:22]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nnn(C)n2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nnn(C)n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 806 mg 4-[(S)-2-tert-Butoxycarbonylamino-4-(2-methyl-2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 8 ml dichloromethane were added 1.3 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 1.18 g.
Reaction SMILES: C(OC([N:11]1[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[C@H:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)C>[C:23]([O:22][C:20]([NH:19][C@H:13]1[C@@H:14]([CH2:16][CH2:17][CH3:18])[CH2:15][NH:11][CH2:12]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: CCC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C

Procedure:
A mixture of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-propylpyrrolidine (4.02 g, 11.09 mmol) and a 10% palladium carbon catalyst (1.0 g) in ethanol (100 mL) was stirred hard for 20 hours under an ordinary pressure in a hydrogen atmosphere. Insoluble matter was removed through filtration by use of Celite, and then ethanol was removed under reduced pressure. The residue was dissolved in diethyl ether (200 mL), and the solution was washed by a 1 mol/L aqueous sodium hydroxide solution (100 mL), followed by drying over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield the title compound as a colorless oily substance (2.34 g, 92.4%).