Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[C:31]([NH:33][NH2:34])=[O:32].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:34][NH:33][C:31]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][N:25]=3)=[O:32])=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NNC(=O)c1cnccn1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=O)c1cnccn1
Temperature: -60 °C
Reaction time: 1 h
Yield: 19.4 %

Procedure:
In a 25 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in dichloromethane (5 mL) and cooled to −60° C. where pyrazine-2-carbohydrazide (0.216 g, 1.1 eq.) was introduced. T3P (50% in EtOAc) (3.39 mL, 4 eq.) was added dropwise followed by DIPEA (0.5 mL, 2 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)—N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)pyrazine-2-carbohydrazide (0.13 g, yield: 19.4%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7]1.CN1CCOCC1.[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>C(Cl)Cl>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:6]([CH2:5][C:4]3[CH:32]=[CH:33][CH:34]=[C:2]([NH:1][C:42](=[O:45])[CH2:43][CH3:44])[CH:3]=3)[N:7]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CCC(=O)Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
N-[1-(3-Amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide prepared in example 58 (110 mg, 0.22 mmol) was dissolved in methylene chloride (2 mL) and N-methyl-morpholine (26 μL, 0.24 mmol) was added. Propionyl chloride (19 μL, 0.22 mmol) was added and the reaction stirred at 25° C. for 30 min. The reaction was concentrated in vacuo to give a beige foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 20% ethyl acetate/methylene chloride) afforded 2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[1-(3-propionylamino-benzyl)-1H-pyrazol-3-yl]-propionamide (75 mg, 61%) as a white powder: ESI-LRMS m/e calcd for C28H33ClN4O4S [M+] 556.19, found 557.27 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.07-1.19 (m, 2H, CH2), 1.23 (t, J=7.5 Hz, 3H, CH3), 1.41-1.92 (m, 8H, 4×CH2), 2.15-2.27 (m, 1H, CH), 2.36 (m, 2H, NCOCH2), 3.25 (s, 3H, SO2CH3), 3.56 (t, J=7.75 Hz, 1 H, CH), 5.09 (s, 2H, NCH2), 6.68 (d, J=2.0 Hz, 1H, Ar), 6.86 (d, Jo=7.8 Hz, 1H, Ar), 7.18-7.23 (m, 1H, Ar), 7.24 (s, 1H, NH), 7.30 (d, J=2.0 Hz, 1H, Ar), 7.33-7.42 (m, 2H, Ar), 7.44 (d, Jo=8.2 Hz. 1H, Ar), 7.58 (s, 1H, Ar), 8.04 (d, Jo=8.2 Hz. 1H, Ar), 8.05 (brs, 1H, NH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][O-:18].[Na+]>>[CH:11]([N:10]([CH:14]([CH3:16])[CH3:15])[C:8]([C:7]1[C:2]([O:18][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:9])([CH3:13])[CH3:12]
Reactant: C[O-]
Reactant: CC(C)N(C(=O)c1cccnc1Cl)C(C)C
Agent: [Na+]
Product: COc1ncccc1C(=O)N(C(C)C)C(C)C
Yield: 98 %

Procedure:
In a similar manner but by refluxing 2-chloro 3-diisopropylaminocarbonyl pyridine and sodium methylate for 45 hours, 3-diisopropylaminocarbonyl 2-methoxy pyridine is obtained.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[NH:12][N:11]=[C:10]([C:13]3[CH:14]=[C:15]([C:19]4([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)[CH:9]=2)=[CH:5][CH:4]=1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:32]=[CH:31][C:6]([O:7][C:8]2[CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4([NH:23][C:24]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:30])[CH2:22][O:21][CH2:20]4)[CH:14]=3)[N:11]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[N:12]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(-c3cc(Oc4ccc(C(F)(F)F)cc4)[nH]n3)c2)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1nc(Oc2ccc(C(F)(F)F)cc2)cc1-c1cccc(C2(NC(=O)OC(C)(C)C)COC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl {3-[3-(5-(4-trifluoromethylphenoxy)-1H-pyrazol-3-yl)phenyl]oxetan-3-yl}carbamate (98 mg, 0.21 mmol), ethyl bromoacetate (80 mg, 0.47 nimbi), and potassium carbonate (67 mg, 0.48 mmol) were combined in 0.5 mL of DMF and the mixture was stirred at ambient temperature under argon atmosphere for 4 h, then warmed to 60° C. for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g silica gel column using 0-5% MeOH:CHCl3 over 16 min at 30 mL/min. The fractions containing the first-eluting product were combined and evaporated under reduced pressure to give ethyl [3-(4-trifluoromethylphenoxy)-5-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product A) as an oil, calcd (M+1)+: 562.6. Found: 562.2. 1H NMR (400 MHz, CDCl3) δ 7.6 (m, 5H), 7.50 (t, J=7, 1H), 7.37 (d, J=7, 1H), 7.29 (s, 1H), 5.99 (s, 1H), 5.85 (br s, 1H), 5.00 (d, J=5, 2H), 4.85 (br d, 2H), 4.79 (s, 2H), 4.21 (q, J=7, 2H), 1.27 (t, J=7, 3H). The fractions containing the second-eluting product were combined and evaporated under reduced pressure to give ethyl [5-(4-trifluoromethylphenoxy)-3-(3-{3-[(tert-butyloxycarbonyl)amino]oxetan-3-yl}phenyl)-1H-pyrazol-1-yl]acetate (product B) as an oil, calcd (M+1)+: 562.6. Found: 562.9. 1H NMR (400 MHz, CDCl3) δ 7.88 (br s, 1H), 7.6 (m, 3H), 7.50 (d, J=7, 1H), 7.42 (t, J=7, 1H), 7.32 (d, J=6, 2H), 6.03 (s, 1H), 5.82 (br s, 1H), 5.00 (br s, 2H), 4.90 (overlapping brs s and sharp s, 4H), 4.21 (q, J=7, 2H), 1.25 (t, J=7, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(F)(F)F.OP(O)(O)=O>ClCCl>[C:1]1([C:7]2([C:16]3[CH:17]=[CH:18][C:13]([OH:19])=[CH:14][CH:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: C1=C(c2ccccc2)CCCC1
Agent: FB(F)F
Agent: O=P(O)(O)O
Solvent: ClCCl
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1-Phenyl-1-cyclohexene (1 g, 6.3 mmol), phenol (1.5 g, 15.9 mmol) and BF3.H3PO4 (0.05 mL) were mixed and shaken at 80° C. overnight. Dichloromethane (30 mL) was added and the organic phase was washed with saturated NaHCO3 (aq.) (2×10 mL), dried (Na2SO4) and concentrated. The title compound was crystallised from a mixture of methanol and water. Yield: 1040 mg. 1H NMR (400 MHz, CDCl3): δ 7.28-7.25 (m, 4H), 7.16-7.10 (m, 3H), 6.75-6.70 (m, 2H), 4.51 (br. s, 1H), 2.28-2.22 (m, 4H), 1.60-1.52 (m, 4H), 1.52-1.45 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 153.25, 149.15, 141.22, 128.63, 128.39, 127.29, 125.55, 115.21, 45.89, 37.50, 26.63, 23.14. LC-MS purity (UV/MS): 100/100%, Rt 5.07 min, M−1: 251.62.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:29]([O:24][C@@H:11]1[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:14][C@@H:13]([N:15]2[CH:22]=[C:21]([I:23])[C:19]([NH2:20])=[N:18][C:16]2=[O:17])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(I)c(N)nc2=O)C[C@@H]1O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H]1C[C@H](n2cc(I)c(N)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
To a stirred solution of 21 (1.18 g; 2.52 mmol) in anhydrous THF (43 mL) was added 95% NaH powder (128 mg; 5.07 mmol). The suspension was stirred at room temperature for 45 min. Allyl bromide (240 μL, 2.79 mmol) was then added at 0° C. and the reaction was stirred at room temperature for 14 h with exclusion of moisture. Saturated aqueous NaHCO3 (10 mL) was added at 0° C. and stirred for 10 min. Most THF was evaporated and the residue was dissolved in ethyl acetate (150 mL). The solution was washed by saturated aqueous NaHCO3 and NaCl respectively, and dried over anhydrous Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using ethyl acetate as the eluent to afford 22 as white solid (537 mg; 42% yield): 1H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H, 6-H), 6.12 (dd, J=5.6, 8.0 Hz, 1H, 1′-H), 4.17 (m, 1H, 4′-H), 4.14 (m, 1H, 3′-H), 3.98-4.10 (m, 2H, CH2CH═CH2), 3.93 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 3.83 (dd, J=2.8, 11.5 Hz, 1H, one of 5′-H), 2.53-2.60 (ddd, J=1.7, 5.6, 13.6 Hz, 1H, one of 2′-H), 1.94-2.02 (ddd, J=5.9, 8.0, 13.6 Hz, 1H, one of 2′-H), 0.94 (s, 9H, C(CH3)3), 0.17 (s, 3H, one of SiCH3), 0.16 (s, 3H, one of SiCH3); 13C NMR (100 MHz, CD3OD) δ 165.4, 156.7, 147.7, 135.5, 117.2, 88.2, 87.0, 80.4, 70.9, 64.8, 57.3, 40.1, 26.7, 19.4, −4.7, −4.9; HRMS (FAB+) calcd for C18H31O4N3SiI (M+H+): 508.1129. Found: 508.1123.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:24])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: S=C=Nc1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (5.0 g, 25 mmol), phenyl isothiocyanate (3.72 g, 25 mmol) and toluene (20 ml) was heated at reflux for 1.5 hours, then left at room temperature overnight. The solution was diluted with ether, and the product filtered off; yield 5.6 g (67%), m.p. 107°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:23][CH2:22]3)[C:14]=2[CH:13]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:11][C:12]1[N:17]=[CH:16][C:15]2[C:18]([CH3:26])([CH3:25])[C:19](=[O:24])[N:20]([CH:21]3[CH2:22][CH2:23]3)[C:14]=2[CH:13]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccnc(Cl)c3)ncc21

Procedure:
Prepared in analogy to example 26 from 2-chloroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (example 79c). The title compound was obtained as light yellow foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20](/[C:23](=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([Cl:37])[CH:28]=2)/[C:24]#[N:25])=[C:19]([F:38])[CH:18]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:26]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:36])[F:35])=[C:29]([Cl:37])[CH:28]=2)[C:23]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][C:19]=2[F:38])([C:24]#[N:25])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)c1ccc(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2ccc(C(F)(F)F)c(Cl)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 30.3 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-acrylonitrile (2.5 g, 6.9 mmol) prepared in Example 71a, AgF (1 g, 8 mmol), and triethylamine (2.4 mL, 17 mmol) in dichloromethane (120 mL) at room temperature for 18 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-4-trifluoromethyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.2 g, 30%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[O:15]=[C:16]1[CH:20]([C:21]([OH:23])=O)[CH2:19][CH2:18][N:17]1[C:24]1[CH:25]=[C:26](C)[CH:27]=[CH:28][CH:29]=1.O=[C:32]1C(C(O)=O)CCN1C1C=C(C)C=CC=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([CH:20]1[CH2:19][CH2:18][N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:32])[C:16]1=[O:15])=[O:23]
Reactant: Cc1cccc(N2CCC(C(=O)O)C2=O)c1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 44.3 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid 2-oxo-1-o-tolylpyrrolidine-3-carboxylic acid (0.095; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.076 g (44%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-oxo-1-o-tolylpyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH2:12].C(=O)(O)[O-].[Na+].[C:18](Cl)(Cl)=[S:19]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:9][CH2:10]2)[CH:5]=[C:4]([CH3:11])[C:3]=1[N:12]=[C:18]=[S:19]
Reactant: Cc1cc(C2CC2)cc(Cl)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C2CC2)cc(Cl)c1N=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
Compound 2 (775 mg, 4.3 mmol) was dissolved in 9 mL of dichloromethane. Sodium bicarbonate (4.5 mL, sat. solution) and thiophosgene (0.33 mL, 4.3 mmol) were added and the mixture stirred at room temperature for 1 h. Then, the organic layer was separated, dried over sodium sulfate and concentrated to afford 935 mg of 1-chloro-5-cyclopropyl-2-isothiocyanato-3-methylbenzene (3) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5](=O)[CH2:6][C:7]([C:9]1[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:8])[CH3:2].Cl.[NH2:35]O.O>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([Br:15])[C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:10]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:8][N:35]=1)=[O:33])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1

Procedure:
69.3 g of 4-(2,4-Bis-benzyloxy-5-bromo-phenyl)-2,4-dioxo-butyric acid ethyl ester (0.135 mol, 1 eq) were dissolved in 750 ml ethanol. 14.11 g hydroxylamine hydrochloride (0.203 mol, 1.5 eq) were added. The mixture was refluxed for 2.5 hours and cooled down. It was then poured onto 1000 ml water, the precipitate was filtered off. The filter cake was washed with 500 ml of water followed by 75 ml diethyl ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH2:18])[CH3:14].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][NH:18][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:3]=1[O:2][CH3:1])[CH3:14]
Reactant: COc1cccc(C=O)c1OC
Reactant: CCOC(CN)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(CNCc1cccc(OC)c1OC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,3-dimethoxybenzaldehyde (2 g, 12 mmol) in MeOH (50 mL) was added aminoacetaldehyde diethyl acetal (1.49 mL, 12 mmol) and acetic acid (1.03 mL, 18 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was added to a stirred solution of sodium cyanoborohydride (829 mg, 13 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure. Then H2O and ethyl acetate were added to the reaction mixture. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. The crude compound was used next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:18])([CH3:17])[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:19])[C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]N1C(=O)CCC1=O>C1C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:26][CH:10]([C:9](=[O:16])[C:8]([N:5]1[C:4](=[O:19])[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:2]([CH3:1])[O:7][CH2:6]1)([CH3:17])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)C(Br)C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Yield: 65.1 %

Procedure:
A mixture of ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (500 mg), N-bromosuccinimide(258 mg) and benzoyl peroxide (10 mg) was refluxed under a lamp whilst stirring in benzene for 10 minutes. After cooling, the solid was filtered, the filtrate evaporated and the residue purified by column chromatography (hexane/ethyl acetate 4:1) to give ethyl 2-bromo-4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (Compound 190, 400 mg ) as a yellow gum, NMR 1.21(t,3H), 1.55(d,6H), 1.94(s,3H), 4.15(q,2H), 5.23(s,1H), 5.26(d--d,2H) and 7.21-7.37(m,5H).
Reaction SMILES: [F:1][C@:2]1([CH3:19])[C@H:6]([OH:7])[C@@:5]([F:10])([CH2:8][OH:9])[O:4][C@H:3]1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]1=[O:18].C([Mg]Cl)(C)(C)C.Cl[C:27]1[CH:44]=[CH:43][CH:42]=[CH:41][C:28]=1[O:29][P:30](=[N:32][C@@H:33]([CH3:40])[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])=[O:31].CO>C1COCC1>[CH:37]([O:36][C:34](=[O:35])[C@@H:33]([N:32]=[P:30]([O:29][C:28]1[CH:41]=[CH:42][CH:43]=[CH:44][C:27]=1[O:9][CH2:8][C@:5]1([F:10])[C@@H:6]([OH:7])[C@:2]([F:1])([CH3:19])[C@H:3]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[NH:13][C:12]2=[O:18])[O:4]1)=[O:31])[CH3:40])([CH3:38])[CH3:39]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CO)[C@H]1O
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccccc1Cl
Agent: CC(C)(C)[Mg]Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1ccccc1OC[C@@]1(F)O[C@@H](n2ccc(=O)[nH]c2=O)[C@](C)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
To a solution of chiral 1-((2R,3R,4S,5S)-3,5-difluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione (42 mg, 151 μmol) prepared in Preparation 6 in THF (8.00 ml) was added a THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (377 μl, 377 μmol) dropwise. The mixture was stirred at room temperature for 15 min. followed by the addition of THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate (755 μl, 377 μmol). The reaction mixture was stirred at room temperature for 1 hr, followed by the addition of THF solution (Aldrich, 1 M) of tert-butylmagnesium chloride (189 μl, 189 μmol) and THF solution (0.5 M) of (2S)-isopropyl 2-(chloro(phenoxy)phosphorylamino)propanoate (378 μl, 189 μmol). The reaction mixture was then stirred at room temperature for 2 h. Methanol (2 mL) was added to quench the reaction, The mixture was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) and dried in vacuo to give the title compound as a light-yellow solid (18 mg, 22%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:14][C:15]#[N:16].[H][H]>CO.[Ni]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: [H][H]
Reactant: N#CCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Agent: [Ni]
Solvent: CO
Product: NCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Yield: 93.4 %

Procedure:
A mixture of (±)-3-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl)amino]propanenitrile (0.069 mol) in methanol (250 ml) was hydrogenated with Raney nickel (5 g) as a catalyst. After uptake of hydrogen (2 eq.), the catalyst was filtered off and the filtrate was evaporated, yielding 20 g (94% crude residue) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N-(phenylmethyl)-1,3-propanediamine (interm. 4-c).
Reaction SMILES: [CH2:1]1[C:13]2[N:4]([C:5](=O)[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH:12]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>P(Cl)(Cl)(Cl)=O.CO>[CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12]2)[CH2:3][CH2:2]1
Reactant: O=c1c2ccccc2cc2n1CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc2c(c1)CC1CCCN1C2
Temperature: 0 °C
Yield: 41.6 %

Procedure:
A suspension of 2,3-dihydropyrrolo[1,2-b]isoquinolin-5(1H)-one (10.8 g, 58.3 mmol) [G. M. Coppola, J. Heterocycl. Chem., 181, 18, 767] in phosphorus oxychloride (100 ml) was heated at reflux for 1.5 h. Upon cooling, the solvent was removed in vacuo to give an oil. This oil was immediately taken up in cold methanol (275 ml) and sodium borohydride (4.0 g) was added portionwise to this solution while maintaining the reaction mixture at 0° C. The solvent was concentrated and the residue was dissolved in water and washed twice with ethyl acetate. The aqueous solution was made basic with potassium carbonate solution and extracted with ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated to give an oil. Column chromatography on silica gel gave unreacted starting material (3.57 g, 36%) and the title compound (4.2 g, 63% based on recovered starting material) as a light oil; MS 174 (M+H)+ ; NMR (CDCl3) 7.0-7.2 (broad m, 4H), 4.13 (d, 1H, J=15), 3.40 (d, 1H, J=15), 3.27 (dt, 1H), 2.9-3.1 (M, 1H), 2.71 (t, 1H), 1.4-2.4 (m, 6H).