Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@H:14]3[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]3[C:20](=[O:22])[CH3:21])=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.FC1C=C(O)C=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@H:14]3[CH2:18][C@H:17]([OH:19])[CH2:16][N:15]3[C:20](=[O:22])[CH3:21])=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)N1C[C@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Oc1cccc(F)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)N1C[C@@H](O)C[C@@H]1C(=O)N1CCCN(C2CCC2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.1 %

Procedure:
To a heterogeneous mixture of (2R,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidin-1-yl]-ethanone (139 g, 448.5 mmol), 3-fluoro-phenol (52 mL, 462 mmol), and triphenylphosphine resin (1.52 mmol/g loading, 339 g, 516 mmol) in CH2Cl2 (4.3 L) was slowly added DIAD (91 mL, 462 mmol) over 15 min. The mixture was stirred at rt for 15 h. The resin was filtered off and washed with CH2Cl2 (4 L). The filtrate was concentrated and partitioned between methyl tert-butyl ether (MTBE; 2 L) and water (2 L). The aqueous layer was extracted with additional MTBE (2×1.8 L). The combined organic layers were concentrated to a volume of 2 L and extracted with 1 N HCl(aq) (2 L). The acidic aqueous layer was washed with MTBE (1 L) and then basified to pH>12 with 50% NaOH(aq) (118 mL). The basic aqueous layer was extracted with CH2Cl2 (2×1.5 L) and the combined organics were dried with MgSO4, filtered, and concentrated to an oil. The oil was optionally purified by FCC (0 to 5% 2 M NH3 in MeOH/95% CH2Cl2) to provide the title compound (89 g, 49%). MS (ESI): mass calcd. for C22H30FN3O3, 403.2; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.28-7.19 (m, 1H), 6.74-6.54 (m, 3H), 5.12-5.05 (m, 0.91H), 5.02-4.95 (m, 0.91H), 4.93-4.79 (m, 0.18H), 4.13-4.02 (m, 1H), 3.88-3.60 (m, 5H), 2.96-2.82 (m, 1H), 2.70-2.27 (m, 6H), 2.1-1.55 (m, 11H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.Br[CH2:13][CH2:14][CH3:15]>>[I:1][C:2]1[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: CCCBr
Reactant: Cc1cccc2c(I)n[nH]c12
Product: CCCn1nc(I)c2cccc(C)c21
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield from 3-iodo-7-methyl-indazole and 1-bromopropane according to the general procedure for Preparation 4A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.94 (3H, t, J=7.4 Hz), 1.84-1.90 (2H, m), 2.66 (3H, s), 4.50 (2H, t, J=7.4 Hz), 7.01 (1H, t, J=7.1 Hz), 7.11 (1H, d, J=6.9 Hz), 7.28 (1H, d, J=8.0 Hz). [M+H] calc'd for C11H13FN2, 301; found 301.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:8]=1[NH:18]C(=O)OC(C)(C)C)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.O1CCOCC1>CO>[NH2:18][C:8]1[CH:9]=[CH:10][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:12][C:7]=1[NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 0 %

Procedure:
To a stirred solution of tert-butyl (2-isobutyramido-4-(thiophen-2-yl)phenyl)carbamate (0.2 g, 0.52 mmol) in methanol (4 mL) was added 4M HCl in Dioxane (2 mL, 0.53 mmol, 1 equiv.) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. After completion the reaction was concentrated under reduced pressure then basified with a saturated aqueous solution of NaHCO3. The obtained solid was filtered and dried. The crude material was purified by column chromatography (silica gel, MeOH/CH2Cl2) to afford N-(2-amino-5-(thiophen-2-yl)phenyl)isobutyramide (0.05 mg, 36% yield). ESI+ MS: m/z 261 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.10 (s, 1H0, 7.5 (s, 1H0, 7.34 (d, J=4.5 Hz, 1H), 7.23-7.19 (m, 2H), 7.05-7.03 (m, 1H0, 6.75 (d, J=8.5 hz, 1H0, 5.03 (s, 2H), 2.67-2.64 (m, 1H), 1.13 (d, J=7 Hz, 6H).
Reaction SMILES: [Cl:1][CH:2]([Cl:16])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[CH3:15])=[O:4].[CH3:17][CH2:18]CC(Cl)=O.C(C1C2C(=CC=CC=2)CCN1)CC.C1C2C(=CC=CC=2)C=CN=1.[OH-].[Na+].CCl.ClC(Cl)C(Cl)=O>O>[Cl:16][CH:2]([Cl:1])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]1[CH2:15][CH2:17][CH3:18])=[O:4]
Reactant: CC1c2ccccc2CCN1C(=O)C(Cl)Cl
Reactant: CCCC(=O)Cl
Agent: CCCC1NCCc2ccccc21
Agent: CCl
Agent: O=C(Cl)C(Cl)Cl
Solvent: O
Solvent: c1ccc2cnccc2c1
Product: CCCC1c2ccccc2CCN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1, (Method A), phenethylamine and n-butyryl chloride were converted to 1-n-propyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 2.0 g of this isoquinoline compound, 10 ml 10% sodium hydroxide and 50 ml methyl chloride. With this mixture stirred, 2 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was stirred for 2 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 3.5 g of a viscous yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14](=[O:25])[C@@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])[CH3:16])C1C=CC=CC=1.[BH4-].[Na+]>>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C@@H:15]([CH3:16])[CH2:14][OH:25])=[C:18]([F:24])[CH:19]=1
Reactant: C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Product: C[C@@H](CO)c1ccc(Br)cc1F
Yield: 87 %

Procedure:
Following the procedure outlined for Example 630, (R)-4-benzyl-3-((R)-2-(4-bromo-2-fluorophenyl)propanoyl)oxazolidin-2-one (3 g, 7.4 mmol) was reacted with sodium borohydride (1.2 g, 37 mmol) to obtain the desired product (1.5 g, 87%) as light yellow oil; ESI MS m/z 234 [C11H10BrFO+H]+
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]([C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:9]=2[F:32])=[CH:6][CH:5]=[CH:4][N:3]=1)#[N:34]
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Product: CN(Cc1cn(S(=O)(=O)c2ccccc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A suspension of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (7.24 g), zinc cyanide (3.55 g) and tetrakis(triphenylphosphine)palladium (0) (3.56 g) in N,N-dimethylformamide (80 mL) was stirred at 120° C. for 20 hr. The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1) to give a mixture of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate and the title compound. A suspension of the obtained mixture, zinc cyanide (3.56 g) and tetrakis(triphenylphosphine)palladium (0) (3.38 g) in N,N-dimethylformamide (80 mL) was stirred at 120° C. for 12 hr. The reaction mixture was cooled to room temperature, and insoluble materials were filtered off. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=2:1) to give the title compound as a yellow oil (yield 5.84 g, 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]2[NH:6][C:7]3[CH:8]=[C:9]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O.N>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O.COCCOC>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:3]=[C:4]([C:21]([NH2:23])=[O:22])[C:5]3[NH:6][C:7]4[CH:8]=[C:9]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)[CH:10]=[CH:11][C:12]=4[C:13]=3[N:14]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: NC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCOCC3)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(N5CCOCC5)ccc4c3n2)cc1Cl
Temperature: 100 °C
Yield: 19.2 %

Procedure:
A mixture of 2-bromo-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (50 mg, 0.120 mmol), 3-chloro-4-methoxyphenylboronic acid (33.5 mg, 0.180 mmol), PdCl2(dppf)-CH2Cl2 adduct (9.8 mg, 0.012 mmol) in a microwave vial was flushed with nitrogen. DME (2 mL) and aq. Na2CO3 solution (0.30 mL, 0.60 mmol, 2.0 M) were added and the vial was sealed and heated at 100° C. for 3.5 hr. Preparative HPLC (100×30 mm Luna C18 column, Solvent A=10% Methanol, 90% H2O, 0.1% TFA; Solvent B=90% Methanol, 10% H2O, 0.1% TFA, 10 to 70% gradient over 20 min at 42 mL/min) followed by SCX capture and release with 2 N NH3 in MeOH gave 2-(3-chloro-4-methoxyphenyl)-7-morpholino-5H-pyrido[3,2-b]indole-4-carboxamide (10 mg, 0.023 mmol, 19% yield) as a solid. MS (ESI) m/z 437.21 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.24 (1H, s), 8.53 (1H, s), 8.35 (1H, d, J=2.14 Hz), 8.27 (1H, s), 8.24 (1H, dd, J=8.55, 2.14 Hz), 8.08 (1H, d, J=8.85 Hz), 7.82 (1H, s), 7.31 (1H, d, J=8.85 Hz), 7.22 (1H, d, J=2.14 Hz), 7.01 (1H, dd, J=8.55, 2.14 Hz), 3.95 (3H, s), 3.78-3.85 (4H, m), 3.22-3.27 (4H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 69.5 %

Procedure:
To a solution of 1.0 g of t-butyl 4-(3-ethoxy-3-oxoprop-1-enyl)-tetrahydropyridine-1(2H)-carboxylate (cf. WO9501336) in 20 ml of ethanol, 300 mg of 10% palladium-on-carbon catalyst, and stirred for 3 hours in a hydrogen atmosphere, at ambient temperature and pressure. After filtering the catalyst off, the solvent was distilled off under reduced pressure to provide 700 mg of the title compound.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][CH:31]=[C:32]([F:34])[CH:33]=3)[CH:27]=2)OC1>>[F:34][C:32]1[CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]([C:35]#[N:36])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnc3nc(C(F)(F)F)ccn23)ccc1F

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile as described in Example 1 to give 5,2′-difluoro-5′-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)biphenyl-2-carbonitrile as an off-white solid: δH (360 MHz, CDCl3) 7.25-7.31 (2H, m), 7.44-7.50 (1H, m), 7.67 (1H, ddd, J 9, 5 and 2), 7.67 (1H, s), 7.69 (1H, s), 7.88 (1H, dd, J 9 and 6), 8.11 (1H, s), 9.05 (1H, d, J 7); m/z (ES+) 401 (M++H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:25]#[N:26])(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=2)[C:25]#[N:26])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: C[Si](C)(C)C#N
Reactant: NS(=O)(=O)c1ccc(N=Cc2ccc(F)c(F)c2)cc1
Product: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)c(F)c1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3,4-difluorobenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 92%). Nuclear Magnetic Resonance Spectrum (270 MHz, hexadeuterated dimethyl sulfoxide) δ ppm:
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56](O)=[O:57])(=[O:53])=[O:52])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[N:41][C:42]([CH:45]3[CH2:50][CH2:49][N:48]([S:51]([CH2:54][C@H:55]([CH:59]([CH3:61])[CH3:60])[C:56]([NH:27][OH:28])=[O:57])(=[O:52])=[O:53])[CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(c2ncc(-c3ccc(Cl)cc3)cn2)CC1)C(=O)NO
Yield: 82 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-chlorophenyl)pyrimidin-2-yl]piperidine-1-sulfonylmethyl}-3-methylbutyric acid (0.172 g), to give the title compound as a cream solid (0.146 g, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:12]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: ClCCl
Product: O=Cc1ccc2[nH]cc(Cl)c2c1
Reaction time: 4 h
Yield: 105.6 %

Procedure:
To a stirred solution of 1H-indole-5-carbaldehyde (0.50 g, 3.44 mmol) in DCM (25 mL) was added N-chlorosuccinimide (0.44 g, 3.27 mmol). After 4 h, the mixture was washed with water (50 mL) and the organic layer was dried and concentrated to obtain the crude residue (0.62 g), which was used without purification. 1H NMR (CDCl3): 10.04 (s, 1H), 8.17-8.15 (m, 1H), 7.79 (dd, J=8.6, 1.5 Hz, 1H), 7.46 (d, J=8.6 Hz, 1), 7.29-7.28 (m,1H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:21][CH2:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5]1>CO>[OH:3][CH:4]1[CH2:5][CH2:6][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
NaBH4 (56.18 mmol, 3.0 eq.) was added portionwise to a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (18.72 mmol, 1.0 eq.) in MeOH (40 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 1 h. The solvent was evaporated under reduced pressure. The residue was dissolved in MC (100 ml) and washed with water (50 ml) and brine (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was used in the next step without further purification. Yield: 95%
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH:9]3[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][C:27](=[O:37])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[N:8]([CH:9]3[CH2:10][CH:11]([CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:12]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][C:27](=[O:37])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:30]=2[CH3:36])[CH2:18][C:19]([OH:21])=[O:20])[CH2:2][CH2:3]1
Reactant: Cc1ccc(NC(=O)CC(CC(=O)OC(C)(C)C)c2nnn(C3CC(CC(C)C)C3)c2C2CC2)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)CC(CC(=O)O)c2nnn(C3CC(CC(C)C)C3)c2C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.4 %

Procedure:
tert-Butyl 3-[5-cyclopropyl-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]-4-(2,4-dimethylphenylcarbamoyl)butyrate (100 mg) and chloroform (0.8 mL) were mixed. To the mixture was added trifluoroacetic acid (0.2 mL) at ice temperature. After stirring at RT for 6 hr, the reaction mixture was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: chloroform/methanol/acetic acid=20/1/0.1) to give the title compound (79.5 mg).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][O:82][C:83](=[O:100])[C@@H:84]([NH:92][C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C:85]1[CH:90]=[CH:89][C:88](Cl)=[CH:87][CH:86]=1>C1(C)C=CC=CC=1.O.C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][O:82][C:83](=[O:100])[C@@H:84]([NH:92][C:93]([O:95][C:96]([CH3:99])([CH3:98])[CH3:97])=[O:94])[C:85]1[CH:90]=[CH:89][C:88]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:87][CH:86]=1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(C)c1
Reaction time: 0.05 h
Yield: 67.4 %

Procedure:
Degassed toluene (0.10 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 25.2 mg, 0.0415 mmol), palladium (II) acetate (1.6 mg, 0.071 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (6.0 mg, 0.015 mmol) and potassium phosphate (24.5 mg, 0.115 mmol), and the mixture was stirred in a nitrogen atmosphere for three minutes. Then, a solution of (S)-t-butoxycarbonylamino-(4-chloro-phenyl)acetic acid methyl ester (Example 166-(1); 17.9 mg, 0.0597 mmol) in toluene (0.10 mL) and water (20 μL) were added, and the mixture was heated while stirring at an external temperature of 95 to 104° C. for one hour. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (20.8 mg, 67%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:23]([CH3:25])[CH3:24])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Li+].O.CO>O1CCCC1>[CH2:16]([O:15][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:23]([CH3:25])[CH3:24])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2n1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)n1c(C(=O)O)cc2cc(OCc3ccccc3)ccc21
Yield: 95.5 %

Procedure:
5-Benzyloxy-1-isopropyl-1H-indole-2-carboxylic acid ethyl ester (47.5 g, 1.0 eq.) and lithium hydroxide (6.56 g, 1.1 eq.) in a mixture of tetrahydofuran (360 mL), water (180 mL) and methanol (120 mL) was refluxed for 2 h then the reaction mixture was concentrated in vacuo. The residue was stirred vigorously in aqueous hydrochloric acid (2N, final pH: 2). The white precipitate was filtered, washed with water then dried in vacuo to yield 41.6 g (96%) of the desired product as white oil. MS (m/e): 308.5 (M−H, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4](P(OCC)(=O)OCC)[NH:3]1.[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=O)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][C:20]=1[CH:21]=[C:4]1[NH:3][C:2](=[O:1])[NH:6][C:5]1=[O:7])([O-:18])=[O:17]
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Reactant: O=Cc1cc(N2CCCC2)ccc1[N+](=O)[O-]
Product: O=C1NC(=O)C(=Cc2cc(N3CCCC3)ccc2[N+](=O)[O-])N1

Procedure:
Prepared from diethyl 2,4-dioxoimidazolidine-5-phosphonate and 2-nitro-5-(1-pyrrolidinyl)benzaldehyde analogous to the procedure of Example (2-1), m.p. 289° C. (dec.), crystallized from DMF-H2O.
Reaction SMILES: [CH3:1][C:2]1[C@@:3]([O:15][SiH](C)C)(C(C)(C)C)[CH2:4][C:5](=[CH2:10])[C:6]=1[CH2:7][C:8]#[CH:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.F>O1CCCC1>[CH3:1][C:2]1[C@@H:3]([OH:15])[CH2:4][C:5](=[CH2:10])[C:6]=1[CH2:7][C:8]#[CH:9]
Reactant: C#CCC1=C(C)[C@@](O[SiH](C)C)(C(C)(C)C)CC1=C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: F
Agent: [F-]
Solvent: C1CCOC1
Product: C#CCC1=C(C)[C@@H](O)CC1=C
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.1 %

Procedure:
3 To a solution of (S)-2-methyl-4-methylidene-3-(2-propynyl)-1-tert-butyldimethylsilyl-oxycyclopent-2-ene (7.52 g, obtained above) in tetrahydrofuran (50 ml) was added a solution mixture (30 ml) consisting of tetrahydrofurane solution (80 parts) of 1M tetrabutylammonium fluoride and 46% hydrogenfluoride (3 parts) under ice-water cooling. The solution was then stirred at room temperature for 14 hours. The reaction solution was poured into ice-water, and then extracted with ether (150 ml ×2). The ether layers were combined, and washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=2:1) to afford the desired product (S)-2-methyl-4-methylidene-3-(2-propynyl)cyclopent-2-ene-1-ol (3.40 g, yield 81.0%) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([NH:18][CH3:19])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([N:18]([CH3:19])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: CNc1ccc(OC)cc1
Reactant: Clc1ncnc2ccccc12
Product: COc1ccc(N(C)c2ncnc3ccccc23)cc1

Procedure:
The title compound was prepared from 4-chloroquinazoline and 4-methoxy-N-methylaniline by a procedure similar to Example 28 (79% yield). 1H NMR (CDCl3): 8.81 (s, 1H), 7.81 (d, J=8.1 Hz, 1H), 7.57 (ddd, J=8.1, 5.4 and 2.7 Hz, 1H), 7.09-7.14 (m, 2H), 7.03-7.06 (m, 2H), 6.9-6.93 (m, 2H).