Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11][C:12]([NH:14][CH3:15])=O)[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CCNC)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11][CH2:12][NH:14][CH3:15])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Agent: CNCCC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNCCC(c1ccc2cc[nH]c2c1)c1ccccc1OC
Yield: 76 %

Procedure:
[3-(1H-Indol-6-yl)-3-(2-methoxy-phenyl)-propyl]-methyl-amine XXXIX was prepared from 3-(1H-indol-6-yl)-3-(2-methoxy-phenyl)-N-methyl-propionamide as a white solid in 76% yield using the procedure described above for [3-(1H-indol-7-yl)-3-phenyl-propyl]-methyl-amine XX (see Example 4). MS (M+H)=295
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]1[C:9]2[C:10]([F:24])=[CH:11][C:12]([N:14]3[CH2:18][C@H:17]([C:19]([O:21]C)=O)[O:16][C:15]3=[O:23])=[CH:13][C:8]=2[O:7][C:6]1=[O:25])[CH3:4]>CO>[CH2:3]([N:5]1[C:9]2[C:10]([F:24])=[CH:11][C:12]([N:14]3[CH2:18][C@H:17]([C:19]([NH:2][CH3:1])=[O:21])[O:16][C:15]3=[O:23])=[CH:13][C:8]=2[O:7][C:6]1=[O:25])[CH3:4]
Reactant: CCn1c(=O)oc2cc(N3C[C@H](C(=O)OC)OC3=O)cc(F)c21
Reactant: CN
Solvent: CO
Product: CCn1c(=O)oc2cc(N3C[C@H](C(=O)NC)OC3=O)cc(F)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of methylamine in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(3-ethyl-4-fluoro-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 87, Step 4, 0.250 g, 0.771 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.10 g, 40%); MS for C14H14FN3O5 m/z 324 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 8.40 (m, 1H), 7.51 (d, 1H), 7.44 (dd, 1H), 5.07 (dd, 1H), 4.27 (t, 1H), 4.02 (dd, 1H), 3.85 (q, 2H), 2.65 (d, 3H), 1.28 (t, 3H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[CH2:20][CH2:21][S:22]/2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[CH3:4][C:2]([C:5]1[CH:6]=[C:7](/[CH:16]=[C:17]2/[C:18](=[O:24])[N:19]([CH3:23])[CH2:20][CH2:21][S:22]/2=[O:30])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CCS/C(=C\c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Solvent: ClCCl
Product: CN1CCS(=O)/C(=C\c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Reaction time: 0.42 h
Yield: 79.5 %

Procedure:
A solution of (Z)-2-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]methylene]-4-methyl-3-thiomorpholinone (1.25 g, 3.6 mmol) in dichloromethane (18 ml) was cooled under nitrogen to 0° C. A solution of m-chioroperoxybenzoic acid (0.78 g, 3.6 mmol) in dichloromethane (llml) was then added dropwise over 5 minutes. The reaction mixture was stirred an additional 25 minutes and washed once with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate. Rotary evaporation gave crude product which was crystallized from ethyl acetate-hexane to give desired product (1.04 g, 79%):
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OCC)(=O)C.C[Si](C=[N+]=[N-])(C)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorobenzoic acid (5.00 g) was added to ethyl acetate (35 mL) and methanol (35 mL). Trimethylsilyldiazomethane (2M solution in diethyl ether, 12.56 mL) was added slowly and the solution was mixed at room temperature for 30 minutes. The solvent was removed under vacuum, and the crude material was dissolved in ethyl acetate. The solution was extracted with 0.5M sodium hydroxide and dried with brine then anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to afford crude product of sufficient purity for subsequent use.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[CH2:14][CH:13]1[C:12](=[O:15])[O:11][C:10]2=[O:16]>ClCCl>[C:1]1([NH:7][NH:8][C:12]([C@H:13]2[CH2:14][C@H:9]2[C:10]([OH:16])=[O:11])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: NNc1ccccc1
Solvent: ClCCl
Product: O=C(NNc1ccccc1)[C@H]1C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1.2 g (11.1 mmol) of phenylhydrazine was dissolved in 20 ml of dichloromethane and 1.24 g (11.1 mmol) of 3-oxa-bicyclo[3.1.0]hexane-2,4-dione were added. The resulting solution was stirred at room temperature for 16 h. The precipitated product was isolated by filtration and washed with dichloromethane. Yield: 1.85 g.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:38])[C:15]=1[OH:39].[C:40]([O:49][CH3:50])(=[O:48])[C@H:41]([CH2:43][C:44]([O:46][CH3:47])=[O:45])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1.C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[CH:43]([O:39][C:15]1[C:16]([Br:38])=[CH:17][C:18]([C:20]2[C:29]3[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[S:32][C:28]=3[C:27]([Br:37])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:19][C:14]=1[Br:13])[CH2:41][C:40]([O:49][CH3:50])=[O:48]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: COC(=O)C[C@H](O)C(=O)OC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COC(=O)CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)OC
Temperature: 79 °C
Yield: 50 %

Procedure:
Diethylazodicarboxylate (0.254 mL, 1.61 mmol) was added dropwise to a stirred, room temperature suspension of 2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenol (0.600 g, 1.10 mmol), dimethyl (S)-(-)-malate (0.213 mL, 1.61 mmol) and triphenylphosphine (0.421 g, 1.61 mmol) in benzene (7.5 mL) under a dry nitrogen atmosphere. The solution was heated in an 79° C. oil bath for 23 h. Additional Dimethyl (S)-(-)-malate (0.043 mL, 0.321 mmol) and triphenylphosphine (0.084 g, 0.321 mmol) and diethylazodicarboxylate (0.050 mL, 0.321 mmol) were added and the reaction mixture was heated for an additional 10 hours. The reaction mixture was cooled to room temperature, diluted with methylene chloride combined with silica gel (20 mL) and concentrated. The silica adsorbate was flash chromatographed (92:8 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.389 g, 51%): mp 118-121° C.: NMR (CDCl3); δ8.36 (dd, J=8, 0.5 Hz, 1 H), 7.83 (dd, J=8, 0.5 Hz, 1 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.61 - 7.59 (m, 3 H), 7.55 -7.43 (m, 2 H), 7.26 - 7.21 (m, 1 H), 6.79 (d, J=8 Hz, 1 H), 5.46 (t, J=6 Hz, 1 H), 3.90 (s, 3 H), 3.77 (s, 3 H), 3.32 - 3.30 (m, 1 H); MS (EI): [M+], 3 bromine isotope pattern, 704 (5%), 706 (15%), 708 (15%), 710 (4%); Anal. Calc. for C28H19Br3O5S: C, 47.55, H, 2.71, N, 0.00. Found: C, 47.93, H, 2.65, N, 0.14.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[S:3])[NH2:2].[CH3:16]I>O1CCCC1>[NH:2]=[C:1]([S:3][CH3:16])[C:4]1[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: CI
Reactant: COC(=O)c1cc(C(N)=S)c(C)cc1C
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=N)SC)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-carbamothioyl-2,4-dimethylbenzoate (compound 130.1, 3.10 g, 12.5 mmol, 1.00 equiv, 90%) in tetrahydrofuran (30 mL) was added CH3I (3.95 g, 27.8 mmol, 2.00 equiv) and the resulting mixture was stirred overnight at 25° C. The organic layer was washed with 2×30 mL of Na2S2O4 (aq.) and 1×30 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 2.10 g (64%) of methyl 5-(imino(methylthio)methyl)-2,4-dimethylbenzoate as a yellow oil.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]#[CH:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1>[Cu]I.C(N(CC)CC)C>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]#[C:13][C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:24])([F:23])[F:14])=[CH:17][CH:18]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: C#C[C@H]1CC[C@H](CCCCC)CC1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCCCC[C@H]1CC[C@H](C#Cc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 0.06 mol of trans-4-pentylcyclohexylacetylene, 0.06 mol of 4-trifluoromethyl-bromobenzene, 250 ml of triethylamine, 1.2 mmol of Pd(II) catalyst and 0.6 mmol of CuI is stirred at room temperature for 15 hours. The reaction mixture is diluted with petroleum ether and filtered. Evaporation and purification give 1-(trans-4-pentylcyclohexyl)-2-(4-trifluoromethylphenyl)acetylene of M.=43°.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2F)=O)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.Cl.[CH2:21]([NH:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1(C)C(C)=CC=CC=1>[CH2:21]([N:28]1[C:7]2[C:6](=[CH:11][CH:10]=[C:9]([OH:12])[CH:8]=2)[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(c1ccc(O)cc1F)C1CC1
Reactant: NNCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Oc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropyl(2-fluoro-4-hydroxyphenyl)methanone (6.51 g) which can be prepared according to the method described in Reference example 2, etc., sodium acetate (14.3163 g; manufactured by Wako Pure Chemical Industries, Ltd.), and benzylhydrazine-dihydrochloride (10.72 g; manufactured by Sigma-Aldrich Co.) were suspended in xylene (180 mL). By using a dean-stark apparatus, the mixture was stirred overnight at reflux. After cooling to room temperature, the mixture was added with water and extracted twice with ethyl acetate. The organic layer was washed twice with water and brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, insoluble matters were dissolved by adding n-hexane to the residue and the title compound was obtained as a crude product (10.97 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:7]2[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:8]=[C:7]2[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCn1cc(Cc2cccnc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCn1cc(Cc2cccnc2)c2cc(N)ccc21
Yield: 96 %

Procedure:
A mixture of methyl 5-nitro-3-(3-pyridylmethyl)-1H-indole-1-propanoate (1.20 g) and 10% palladium on carbon (120 mg) in methanol (75 ml) was hydrogenated at 50° C. and 4.5 atm. until reduction was complete (2hours). The mixture was filtered and the catalyst was washed well with methanol. The filtrate and washings were combined and evaporated to give the title compound as an oil (1.05 g), Rf. 0.2(SS2). δ(CDCl3): 2.76(2H,t), 3.45(2H,br), 3.63(3H,s), 3.98(2H,s), 4.32(2H,t), 6.66-6.68(1H,dd), 6.72(1H,d), 6.77(1H,s), 7.11(1H,d), 7.14-7.18(1H,m), 7.48-7.51(1H,m), 8.42-8.44(1H,m), 8.56(1H,d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][CH2:20][C:21](OCC)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.CCCCCC.C(=O)=O.CC(C)=O>ClCCl.CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][CH2:20][CH:21]=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cn(C)c2ccc(OCc3ccccc3)cc12
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C=O
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cn1cc(CCC=O)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
Under nitrogen, to a stirred solution of ethyl 3-(5-benzyloxy-1-methylindol-3-yl)propionate (12.0 g, 35.6 mmol) in dichloromethane (120 ml) was added dropwise 1.0 M DIBAL in hexane (37.4 ml, 35.6 mmol) at −78° C. (dry-ice/acetone) for 25 minutes. After 30 minutes, methanol (5.7 ml) was added dropwise at −78° C. and then the mixture was stirred at room temperature for 30 minutes. The mixture was filtered through Celite and washed with dichloromethane. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (90 g) chromatography eluted with toluene/ethyl acetate (10:1 to 5:1) to give 3-(5-benzyloxy-1-methylindol-3-yl)propionaldehyde (8.03 g, 77.0%)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][S:11][C:12]2[NH:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][N:13]=2)=[CH:5][C:4]=1[F:23])#[N:2].C(N(CC)C(C)C)(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.CS(OS(C)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][S:11][C:12]3=[N:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]23)=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CCOC(=O)c1cnc(SCC(O)c2ccc(C#N)c(F)c2)[nH]1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2n1C(c1ccc(C#N)c(F)c1)CS2
Reaction time: 24 h

Procedure:
To a solution of alcohol from Step H (2.99 g, 8.92 mmol) and N,N-diisopropylethylamine (4.66 mL, 26.8 mmol) in methylene chloride (100 mL)/ DMF (10 mL) was added di-tert-butyl dicarbonate (2.34 g, 10.7 mmol) at 0° C. The reaction was stirred for 24 hours, then methanesulfonic anhydride (3.11 g, 17.8 mmol) was added in one portion. The reaction was stirred for 3 hours at 25° C. and 16 hours at reflux. The reaction was poured onto saturated aqueous sodium bicarbonate and extracted with methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a yellow oil. The crude product was purified by column chromatography (30→80% ethyl acetate/hexane) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[C:26]([Cu])#[N:27]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:26]#[N:27])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(Oc3ccc(OC)cc3)cccc2c1O
Reactant: N#C[Cu]
Product: COC(=O)c1nc(C#N)c2c(Oc3ccc(OC)cc3)cccc2c1O

Procedure:
The title compound was synthesized from 1-bromo-4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and CuCN in analogy to example 3a; MS-(+)-ion: M+1=351.4.
Reaction SMILES: [OH:1][C@H:2]([C@@H:20]([NH:28]C(=O)C(F)(F)F)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([O-])([O-])=O.[K+].[K+]>CO>[OH:1][C@H:2]([C@@H:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere, 2.0 g (4.10 mmol) of 1-[2(S)-hydroxy-3(S)-(trifluoroacetylamino)-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine (Example 96b) dissolved in 316 ml of MeOH are heated to 70° C., 103 ml of 1M aqueous K2CO3 solution are added dropwise, and the mixture is stirred for 18 h at 70° C. The reaction mixture is concentrated by evaporation under HV and the residue is partitioned between 3 portions of methylene chloride, 2 portions of water and brine. Concentration by evaporation of the organic phases, which have been dried with Na2SO4, yields the title compound: 1H-NMR (200 MHz, CD3OD): 1.42 (s, 9 H, Boc), 0.8-2.1 (m, 11H, cyclohexyl), 2.35-3.0 (m, 7H), 3.51 (m, 1H), 7.25 (m, 5H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[CH:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.O>CO>[OH:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(CC=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(CCO)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (2.5 g, 67 mmol) was added in small portions to a solution of 6-(2-oxoethyl)pyridine-3-carbonitrile (5.0 g, crude) in 80 mL of MeOH at 0° C. The mixture was stirred at room temperature for 30 minutes and poured to 50 mL of water. The mixture was extracted with EtOAc (100 mL×5) and the combined organic layer was condensed. The residue was purified by flash chromatography to afford 6-(2-hydroxyethyl)pyridine-3-carbonitrile. TEA (2.1 g, 21 mmol) was added drop wise to a solution of 6-(2-hydroxyethyl)pyridine-3-carbonitrile (3.0 g, 20 mmol) and MsCl (2.3 g, 20 mmol) in 200 mL of DCM at 0° C. The mixture was stirred at RT for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum below 30° C. to afford the title compound which was used immediately without further purification.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>CN(C=O)C>[NH2:21][S:20]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)(=[O:23])=[O:22]
Reactant: NS(=O)(=O)Cl
Reactant: NCc1csc2cncn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NS(=O)(=O)NCc1csc2cncn12
Temperature: -25 °C
Reaction time: 4 h

Procedure:
A 770 mg potin of 3-aminomethylimidazo[5,1-b]thiazole was dissolved in 15 ml of DMF, and 4.78 ml of N,N-diisopropylethylamine and 1.04 g of sulfamoyl chloride were further added at -60° C., followed by stirring at -30 to -20° C. for 4 hours. The reaction solution was concentrated under reduced pressure and then dissolved in 30 ml of water, and the solution was adjusted to pH 7.5 with an aqueous sodium hydrogencarbonate solution. After purification by Diaion HP-20 Resin, crystallization was carried out from methanol to obtain 636 mg of the title compound.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Al](CC(C)C)CC(C)C)C(C)C.[H-].C([Al+]CC(C)C)C(C)C.[I:33]I.OS(O)(=O)=O.CC(C)C.C(N(CC)CC)C>CCCCCCC.O1CCCC1>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])/[CH:2]=[CH:1]/[I:33]
Reactant: C#CC(O)CCCCC
Reactant: II
Agent: CC(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCCCCC(O)/C=C/I
Temperature: -50 °C
Yield: 40 %

Procedure:
To 1.26 g. (0.01 moles) of 1-octyn-3-ol in 8 ml. in dry heptane was added dropwise 6.18 ml. (0.03 moles) of triisobutylaluminum at 10°-15° C.; 1.82 ml. (0.01 moles) of diisobutylaluminum hydride was then added and the reaction mixture was heated at 50°-55° C. for 2 hours. The solution was then cooled and the heptane removed under reduced pressure. The residue obtained was diluted with 12 ml. of dry tetrahydrofuran. After cooling the solution to -50° C., 10.26 g. (0.04 moles) of iodine in 16 ml. of dry tetrahydrofuran was added dropwise. The dark solution was warmed to room temperature and the alane was decomposed at 20°-30° C. with 20% H2SO4. After the isobutane evolution had diminished, the reaction mixture was poured into ice and extracted four times with pentane. The pentane extract was washed successively with saturated NaHCO3, sodium thiosulfate, saturated NaHCO3 and saturated NaCl solutions. After drying the pentane over MgSO4, it was evaporated to give a dark oil. To remove the iodo-3-hydroxyoctane, the mixture was heated for 16 hours at 90° c. with 0.005 moles of triethylamine. The excess triethylamine was evaporated off and water was added to the residue. Most of the dark oily residue dissolved in the aqueous layer and the total mixture was extracted with pentane. The pentane extract was washed with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions and dried over magnesium sulfate. After evaporation of the pentane, the residue was distilled in vacuo to yield pure 3-hydroxy-1-iodo-1-trans-octene (40-50% molar basis). Some 1-octyn-3-ol was recovered.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[N:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[N:33][CH:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cncc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyrazine.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[C:13]([C:16]1[CH:21]=[CH:20][C:19]([C:2]2[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=2)=[CH:18][CH:17]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Product: CC(=O)c1ccc(-c2cc(C(N)=O)c([N+](=O)[O-])s2)cc1

Procedure:
The title compound was prepared according to the general procedure in Intermediate 10 Step 5 using 5-bromo-2-nitrothiophene-3-carboxamide (Intermediate 10, Step 4) (0.5 g, 1.992 mmol) and (4-acetylphenyl)boronic acid (0.392 g, 2.390 mmol) as the starting materials.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[OH:12].Br[CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>>[Cl:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[O:12][CH:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]
Reactant: Oc1cc(Cl)cc(Cl)c1Cl
Reactant: CCC(Br)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC(Oc1cc(Cl)cc(Cl)c1Cl)C(=O)O
Temperature: 15 °C
Yield: 69.1 %

Procedure:
44.0 g (0.55 mole) of 50% aqueous sodium hydroxide was added to a mixture of 42.5 g (0.22 mole) of 2,3,5-trichlorophenol and 43.4 g (0.26 mole) of 2-bromobutyric acid, with rapid stirring at an initial temperature of 15° C. The temperature rose to 45° C over the course of the addition during which time a cold water bath was applied. At the completion of the sodium hydroxide addition, the cold bath was removed and the mixture was heated to 110° C for a 15-minute period. Then 50 ml of water, 53 ml of perchloroethylene, and 42 ml of concentrated hydrochloric acid were added and the mixture was heated to 85° C, then phase-separated. The organic layer was cooled and the product, α-(2,3,5-trichlorophenoxy)butyric acid, crystallized. The acid was isolated by filtration to give 43.1 g (69.1% yield) of α-(2,3,5-trichlorophenoxy)butyric acid, m.p. 106°-114° C.