Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10](Cl)=[N:9][C:8]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1.C(OCC)C>O>[C:1]1([C:7]2[S:11][C:10]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=3)=[N:9][C:8]=2[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1nc(Cl)sc1-c1ccccc1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1nc(Nc2cccc(C(F)(F)F)c2)sc1-c1ccccc1
Reaction time: 8 h

Procedure:
A reaction vessel was charged with 2.8 g of methyl 5-phenyl-2-chloro-4-thiazolecarboxylate and 9.7 g of meta-aminobenzotrifluoride. The reaction mixture was stirred overnight and then heated and stirred at 150° C. for about 6 hours during which time a crystalline solid appeared. The mixture was treated with ethyl ether and water. The ether extract was dried with magnesium sulfate and concentrated. The residue was crystallized from anhydrous ethyl ether to provide a white amorphous powder (m.p. 147°-149° C.) identified in Table I.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[N:20]=[C:19]([NH2:21])[N:18]=[C:17]([N:22]([CH3:29])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:16]=3)[N:11]=2)=[CH:8][CH:9]=1)=[O:4].[OH-].[Na+].Cl>CO>[NH2:21][C:19]1[N:18]=[C:17]([N:22]([CH3:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:16]=[C:15]([C:12]2[N:11]=[C:10]([C:7]3[S:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[O:14][N:13]=2)[N:20]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ccc(C(=O)O)s3)n2)n1
Reaction time: 18 h
Yield: 46.5 %

Procedure:
To a stirred solution of 5-{3-[4-amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-thiophene-2-carboxylic acid methyl ester (Example 82, 1.02 g, 2.45 mmol) in methanol (5 mL) was added aqueous sodium hydroxide solution (2M, 5 mL). The mixture was stirred for 18 h then acidified with hydrochloric acid (1M, 10 mL). The precipitate formed was filtered off and dried in vacuo at 50 C for 2 h to give the title compound (450 mg, 46%). Method B HPLC-MS: MH+ requires m/z=396. Found: m/z=396, Rt=1.84 min (68%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CO[C:6](=[O:28])[C@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[NH:8][C:9](=[O:19])[CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:15]([O:14][C:12]([NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:3][CH2:1][CH3:2])=[O:28])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)=[O:19])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCN
Reactant: COC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)CNC(=O)OC(C)(C)C
Product: CCNC(=O)[C@H](Cc1ccc(F)cc1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 12 g of cooled liquid ethylamine in a small pressure bottle is added 2.8 g of t-boc-gly-4-F-phe OCH3, 6b, and the solution stirred overnight at room temperature. Evaporation of the solvent gives a solid, which when recrystallized from 95% ethanol yields 8b, m.p. 181°-182.5° C. Alternatively, 8b may be prepared from 7b, according to the procedure of Example 8a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[F:8].S(C)C.CO>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2ccc(F)c(Cl)c2)C1
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2ccc(F)c(Cl)c2)C1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
(R)-tert-Butyl 3-((R)-(3-chloro-4-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (2.28 g, 6 mmol) was dissolved in anhydrous THF (50 mL), and the solution was heated to reflux under nitrogen. A solution of 10 M of BH3.Me2S (1.8 mL, 18 mmol) in THF was added dropwise and stirring was continued under reflux overnight. The resulting solution was cooled to 0° C., CH3OH was added dropwise to quench the reaction. Evaporation of the solvent led to crude (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-4-fluorophenyl)methyl)piperidine-1-carboxylate (2 g, yield 87%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([Cl:25])[CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3cc(Cl)cc(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3,5-dichlorophenylboronic acid according to the coupling protocol of example 1. 1H NMR (DMSO-d6): δ 8.55 (s, 1H), 7.16 (dd, J=8.7, 2.3 Hz, 1H), 7.09 (d, J=8.7 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 6.84 (m, 1H), 6.82 (m, 2H), 3.28 (s, 3H), 2.00 (m, 2H), 1.92 (m, 2H), 0.82 (t, J=7.4 Hz, 6H); MS (ESI) m/z 379/381/383 ([M+H]+); MS (ESI) m/z 377/379/381 ([M−H]−); Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.10; H, 5.26; N, 7.26.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[N:3]=1.CCCCCC.C([Li])CCC.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27].O>O1CCCC1>[CH3:12][O:11][CH2:10][O:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Sn:28]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COCOCc1cccc(Br)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(COCOC)n1
Temperature: -67.5 °C
Reaction time: 0.83 h
Yield: 123.7 %

Procedure:
Under a stream of argon, compound (11) (24.7 g; 106 mmol) was dissolved in anhydrous tetrahydrofuran (270 mL), and 1.54M n-butyllithium hexane solution was added dropwise thereto over 50 minutes at −65 to −70° C. The resulting reaction mixture was stirred at −65 to −70° C. for 1 hour. To the reaction mixture, tetrahydrofuran solution of 40 g (122 mmol) of tributyltin chloride (100 mL) was added dropwise over 30 minutes. While gradually raising the temperature of the reaction solution (to −20° C.), the reaction mixture was stirred at −20° C. for 20 hours. To the reaction mixture, water (250 mL) was added, and the resulting mixture was extracted with diethyl ether three times. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 58 g of the crude title compound (12). The obtained compound was used in the next step without further purifying.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([NH2:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([O:26][C:27]([N:29]=[C:30]=[S:31])=[O:28])[CH3:25]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[CH:4]([NH:13][C:30]([NH:29][C:27]([O:26][CH2:24][CH3:25])=[O:28])=[S:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1
Reactant: CCOC(=O)N=C=S
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(=S)NC(Cc1ccc(Cl)cc1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Methyl ester 1-1 (394 mg, 1.58 mmol) was dissolved in methylene chloride (4.0 mL) and diisopropylethylamine (0.82 mL, 4.73 mmol). The solution was cooled to 0° C. and ethoxycarbonyl isothiocyanate (0.21 mL, 1.73 mmol) was added dropwise. The mixture was allowed to warm to room temperature and was stirred 30 min. Methylene chloride (20 mL) was added, and the organic layer was washed with water (20 mL), 10% aqueous HCl (20 mL), and saturated brine (20 mL). The organic layer was dried with MgSO4, filtered and the solvent was removed in vacuo to yield the product as a yellow oil in 92% yield (502 mg, 1.45 mmol). 1H NMR (300 MHz, CDCl3): δ=10.10 (d, 1H, J=6.6 Hz), 8.11 (s, 1H), 7.27 (d, 2H, J=8.1 Hz), 7.10 (d, 2H, J=8.1 Hz), 5.25 (t, 1H, J=6.3 Hz), 4.23 (q, 2H, J=7.2 Hz), 3.73 (s, 3H), 3.32 (dd, 1H; J=14.1, 6.0 Hz), 3.20 (dd, 1H, J=13.8, 6.0 Hz), 1.30 (t, 3H, J=7.2 Hz); 13C NMR (75 mHz, CDCl3): δ=179.4, 170.8, 152.6, 134.2, 133.4, 130.8, 129.0, 63.2, 59.2, 53.6, 52.8, 36.8, 14.4; ESI-MS calcd for C14H17ClN2O4S [M+Na]+: 267.0495. found 267.0495.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25]Br)=[O:5])[CH3:2].[CH2:27]([O:29][C:30](=[O:40])[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH3:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([Br:11])=[C:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:7]=1[CH2:25][N:32]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:31][C:30]([O:29][CH2:27][CH3:28])=[O:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Br)c(-c2ccc(F)cc2)n(-c2ccccc2)c1CBr
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(-c2ccc(F)cc2)n1-c1ccccc1)C(=O)OC(C)(C)C

Procedure:
Prepared in analogy to that of Example 1(c) from 4-bromo-2-bromomethyl-5-(4-fluoro-phenyl)-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester and tert-butoxycarbonylamino-acetic acid ethyl ester. The title compound, ESI MS (m/z): 625 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.CO[C:20]1C2C(=CC=CC=2)C(OC)=C[C:21]=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[Br:1][C:2]1[C:3](/[CH:16]=[C:33](\[CH2:32][CH2:21][CH3:20])/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Reactant: COc1c(Br)c(C=O)c(OC)c2ccccc12
Solvent: CCOCC
Product: CCC/C(=C\c1c(Br)c(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 98f was prepared from 38 (0.514 g, 1.75 mmol) as described above for 28a to give 0.346 g (0.849 mmol, 49%) of the product as a yellow solid following flash chromatography (1:19 Et2O:hexanes) and recrystallization from Et2O/hexanes. (0.291 g E; 0.055 g Z)
Reaction SMILES: [N:1]1([CH2:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:13]=3[O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([S:22]([N:25]([C:33]4[N:34]=[CH:35][S:36][CH:37]=4)C(=O)OC(C)(C)C)(=[O:24])=[O:23])=[C:17]([F:38])[CH:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:4][CH2:3][CH2:2]1.Cl>ClCCl.O1CCOCC1>[N:1]1([CH2:5][C:6]2[CH:11]=[C:10]([C:12]3[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:13]=3[O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([S:22]([NH:25][C:33]4[N:34]=[CH:35][S:36][CH:37]=4)(=[O:23])=[O:24])=[C:17]([F:38])[CH:16]=3)[CH:9]=[CH:8][N:7]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(CN3CCC3)c2)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2ccc(Cl)cc2-c2ccnc(CN3CCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl [(4-{2-[2-(azetidin-1-ylmethyl)pyridin-4-yl]-4-chlorophenoxy}-2,5-difluorophenyl)sulfonyl]1,3-thiazol-4-ylcarbamate, (Preparation 878, 0.325 g, 0.0005 mol) was dissolved in dichloromethane (3 mL) then 4 molar hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the crude product purified by preparative HPLC to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
Dissolve (R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (0.172 g, 0.31 mmol) in dry methanol (8 mL), add nickel chloride (0.060 g, 0.46 mmol) then sodium borohydride (0.059 g, 1.55 mmol). Stir 15 minutes, add water (˜2 mL) and concentrate. Add ethyl acetate (˜70 mL), filter (Celite®), wash with water and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH2:22]>>[CH3:18][O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[NH:22][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-tyrosine methyl ester (Bachem), the title compound was prepared as a solid (mp=85-88° C.). The reaction was monitored by tlc (Rf=0.27 in 50% EtOAc/hexanes) and the product was purified by silica gel column chromatography.
Reaction SMILES: [OH:1][C@H:2]([CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[K].[CH2:37]([O:39][C:40]([O:42][NH:43][C:44](=[O:48])[O:45][CH2:46][CH3:47])=[O:41])[CH3:38]>CN(C)C=O>[CH2:46]([O:45][C:44]([N:43]([CH2:12][C@@H:2]([OH:1])[CH2:3][P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])[O:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])=[O:48])[CH3:47]
Reactant: CCOP(=O)(C[C@H](O)COS(=O)(=O)c1ccc(C)cc1)OCC
Reactant: CCOC(=O)NOC(=O)OCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)ON(C[C@@H](O)CP(=O)(OCC)OCC)C(=O)OCC
Temperature: 70 °C
Reaction time: 10 h
Yield: 95.3 %

Procedure:
Diethyl 2(R)-hydroxy-3-tosyloxypropylphosphonate (7.3 g) was dissolved in N,N-dimethylformamide (100 ml). To the solution was added bis(trimethylsilyl)acetamide (12.2 g) under ice-cooling. After the mixture was stirred for 30 minutes at the same temperature, potassium salt of ethyl N-ethoxycarbonyloxycarbamate (5.16 g) was added thereto. The reaction mixture was stirred for 10 hours at 70° C. To this reaction mixture was added potassium salt of ethyl N-ethoxycarbonyloxycarbamate (0.86 g) and then the reaction mixture was further stirred for 2 hours at 70° C. After the resultant mixture was concentrated under reduced pressure, to the oily residue was added a mixture of ethyl acetate (200 ml) and 2% hydrochloric acid (100 ml). The ethyl acetate layer was separated, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give oily diethyl 3-(N-ethoxycarbonyl-N-ethoxycarbonyloxyamino)-2(R)-hydroxypropylphosphonate (7.05 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=[O:36])[CH2:34][CH3:35])[CH:27]=4)[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCCC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCCC3)CC2)c1

Procedure:
Example 62 was prepared from 1-(4-chloro phenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 496.4 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].B(O)(O)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccsc1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2sccc2C(=O)O)cc1

Procedure:
prepared by reaction of 2-bromo-thiophene-3-carboxylic acid with p-tolylboronic acid. LC-MS (basic): tR=0.53 min; [M−H]−=217.1.
Reaction SMILES: [CH:1]1([NH:7][C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl>[CH:1]1([NH:7][C:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([Cl:33])=[CH:35][CH:36]=4)[CH:18]=3)[CH2:14][CH2:15]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(CN2CCC(C(=O)NC3CCCCC3)CC2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1-(3-Amino-benzyl)-piperidine-4-carboxylic acid cyclohexylamide BB-1 (80 mg, 0.25 mmol) in DCM (3 mL) is treated with DIPEA (33 mg, 43 μl, 0.25 mmol) under argon and cooled to 0° C. A solution of 4-chlorobenzoylchloride (49 mg, 0.28 mmol) in DCM (1 mL) is added and the resulting solution is stirred at 0° C. for 2 h. The mixture is diluted with DCM (25 mL) and washed twice with aq. sat. NaHCO3 (25 mL). The solvent is evaporated and the title compound is obtained by prep. LC-MS F as a colorless powder: LC-MS A: tR=0.81 min; [M+H]+=454.4. 1H-NMR (DMSO-d6): δ 1-1.3 (m, 6H), 1.5-1.7 (m, 9H), 1.8-2.1 (m, 3H), 2.8-2.9 (m, 2H), 3.4-3.5 (m, 3H), 7.03 (d, J=8, 1H), 7.29 (t, J=8, 1H), 7.5-7.7 (m, 5H), 7.98 (d, J=8, 1H), 10.2 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH3:29][NH:30][CH3:31].[O:32]1CC[CH2:34][CH2:33]1.[ClH:37]>C(#N)C.C(OCC)(=O)C.CCOCC>[ClH:37].[CH3:29][N:30]([CH3:31])[CH2:34][C:33]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]2)=[O:32]
Reactant: CNC
Reactant: C1CCOC1
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOc1cc(C(CS(C)(=O)=O)N2Cc3cccc(NC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 7-amino-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (1.0 g, 2 mmol), and dimethylamine in tetrahydrofuran (3.6 mL, 2N, 7.2 mmol) in acetonitrile (25 mL) was stirred at room temperature overnight. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give a white solid. To stirred solution of the solid in ethyl acetate (10 mL) was added hydrogen chloride in ether (2.5 mL, 1N). After 5 min, ether (10 mL) was added to give a suspension. The suspension was filtered and the solid washed with ether to give 2-(dimethylamino)-N-{2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}acetamide hydrogen chloride as a yellow solid (780 mg, 74% yield); mp, 145-147° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=7 Hz, 3H, CH3), 2.87 (brs, 6H, 2CH3), 3.03 (s, 3H, CH3), 3.73 (s, 3H, CH3), 3.92-4.05 (m, 3H, CHH, CH2), 4.17 (d, J=17.9 Hz, 1H, CHH), 4.31-4.41 (m, 3H, CH2, CHH), 4.68 (d, J=17.9 Hz, 1H, CHH), 5.88 (dd, J=3.5, 10.7 Hz, 1H, NCH), 6.91-6.98 (m, 2H, Ar), 7.02 (s, 1H, Ar), 7.31 (d, J=7.3 Hz, 1H, Ar), 7.59 (t, J=7.9 Hz, 1H, Ar), 8.15 (d, J=8.0 Hz, 1H, Ar), 10.17 (s, 1H, HCl), 10.53 (s, 1H, NH); 13C NMR (DMSO-d6) δ14.72, 40.99, 43.40, 46.20, 48.81, 53.69, 55.32, 58.11, 63.93, 111.98, 112.16, 118.19, 118.58, 119.16, 119.76, 130.01, 133.01, 135.29, 142.55, 148.07, 148.88, 163.88, 167.45; Anal Calcd for C24H31N3O6S+1.1 HCl+1.5 H2O: C, 51.78; H, 6.35; N, 7.55; Cl, 7.00; H2O, 4.85. Found: C, 51.58; H, 6.13; N, 7.39; Cl, 6.87; H2O, 3.34.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][C:18](=O)[C:19]=3[C:9]1=2.[C:21]([CH2:23]P(=O)(OCC)OCC)#[N:22].C[O-].[Na+]>CO.O>[CH2:8]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17]/[C:18](=[CH:23]\[C:21]#[N:22])/[C:19]=3[C:9]1=2
Reactant: O=C1CCc2ccc3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: N#C/C=C1\CCc2ccc3c(c21)CCO3
Reaction time: 1 h
Yield: 84 %

Procedure:
To a solution of toluene (184 g), 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one (8.5 g, 48.9 mmol) and diethyl cyanomethylphosphonate (10.4 g, 58.7 mmol) was added dropwise 28% sodium methoxide solution in methanol (11.3 g) over 1 hr under ice-cooling, and reacted for 4 hrs. To the reaction solution was added dropwise water (85 g), and warmed, then the layers were separated. The organic layer was washed with water, and filtered to remove dusts under pressurization. The organic layer was concentrated under reduced pressure, and to the residue was added methanol and concentrated under reduced pressure to substitute the solvent. After stirring for 1 hr under heating with reflux, the solution was cooled and matured for 1 hr. The crystallization solution was filtered, and the crystals were dried under reduced pressure to give title compound (amount 8.1 g, yield 84.4%).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([NH2:19])[C:17]#[CH:18].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:16]([NH:19][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[C:17]#[CH:18]
Reactant: C#CCN
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C#CCNCc1ccc(Oc2ccccc2)cc1
Reaction time: 18 h
Yield: 93.6 %

Procedure:
4-Phenoxybenzaldehyde (5.0 g, 25.2 mmol) and propargylamine (1.46 g, 26.5 mmol) were dissolved in 100 mL of 1% acetic acid in methanol under an atmosphere of dry nitrogen. Sodium cyanoborohydride (1.66 g, 26.5 mmol) was added, and stirring was continued for 18 hours at which time the solvent was removed under reduced pressure. The residue was suspended in ether, washed with 5% NaHCO3 and brine, and dried over Na2SO4 to give 5.6 g (93%) of the title compound.