Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]=[S:31]>>[ClH:17].[CH3:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[N:29]=[C:30]1[N:9]([C@@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[S:31]1
Reactant: C[C@@H](NCC(C)(C)O)C1CCCCC1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(C)(C)CN1[C@H](C)C1CCCCC1
Product: Cl

Procedure:
(1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1R)-1-Cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2f to afford 2-(2-methyl-4-nitrophenylimino)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[CH:14]([Mg]Br)([CH3:16])[CH3:15].O1CCC[CH2:20]1.[Cl-].[NH4+]>O1CCCC1>[CH2:7]([C:5]1[S:6][C:2]([CH2:15][CH:14]([CH3:16])[CH3:20])=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: C1CCOC1
Reactant: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)c1cc(CC(C)C)sc1CC
Reaction time: 1.5 h
Yield: 80 %

Procedure:
To a solution of ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.00 g) synthesized in Example 69 (4) in tetrahydrofuran (50 mL) was added dropwise 1.0M isopropylmagnesium bromide-tetrahydrofuran solution (28.5 mL) at −40° C., and the mixture was stirred for 1.5 hr under an argon atmosphere. Isobutylaldehyde (8.67 mL) was added dropwise, and the mixture was stirred at −40° C. for 1 hr and at room temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. To a solution of the residue in trifluoroacetic acid (50 mL) was added triethylsilane (9.10 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:24, volume ratio) to give the title compound (3.67 g, 80%) as a pale-yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:8])[C:6]=1[NH2:7].N1C=CC=CC=1.Cl[C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:8])[C:6]=1[NH:7][C:16](=[O:17])[O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1ncc(Br)c1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: Cn1ncc(Br)c1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-5-amine (500 mg, 2.84 mmol) and pyridine (0.270 ml, 3.41 mmol) in tetrahydrofuran (9.5 ml) was added 2,2,2-trichloroethyl chloroformate (0.472 ml, 3.41 mmol) with ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 289 mg (28.9%) of the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:10]([CH3:11])[C:9](=[O:12])[N:8]2[C:4](=[N:5][C:6]3[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=32)[NH:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>CC(C)=O>[CH3:18][S:19]([N:5]1[C:6]2[CH:16]=[CH:15][CH:14]=[CH:13][C:7]=2[N:8]2[C:9](=[O:12])[N:10]([CH3:11])[C:2]([CH3:17])([CH3:1])[N:3]=[C:4]12)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)n2c(nc3ccccc32)NC1(C)C
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN1C(=O)N2C(=NC1(C)C)N(S(C)(=O)=O)c1ccccc12

Procedure:
The general procedure of Example 17 was employed to prepare the title compound by reaction of 1,2-dihydro-2,2,3-trimethyl-1,3,5-triazino[1,2-a]benzimidazol-4(3H)-one, methanesulfonyl chloride and triethylamine in acetone solution. The title compound was isolated and purified by liquid chromatography giving a solid, mp 147° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:21][C@H:22]1[CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:24]1[CH2:25][CH2:26][C@H:22]([OH:21])[CH2:23]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: O[C@H]1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (S)—N-Boc-4-fluorophenylalanine (5.08 g, 17.9 mmol) and (S)-3-hydroxypyrrolidine (1.05 mL, 19.7 mmol) in anhydrous DMF (200 mL), was added DIPEA (6.87 mL, 39.5 mmol) and HOBt.H2O (3.02 g, 19.7 mmol). The reaction mixture was stirred for 10 min at room temperature then EDCI (4.13 g, 21.5 mmol) was added and the resulting mixture stirred for 20 h at rt. The volatiles were removed in vacuo then the residue partitioned between water (200 mL) and ethyl acetate (200 mL). The layers were separated and the aqueous layer extracted with ethyl acetate (3×50 mL). The combined organics were washed with aqueous sodium hydroxide solution (2M, 3×50 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The oily residue was purified via flash chromatography (SiO2, methanol/dichloromethane, 1:19, v/v) to give the title compound as a colourless oil which became a white solid on standing. m/z (ES+)=353 [M+H]+; RT=3.17 min.
Reaction SMILES: O[C@@H:2]([C:8]([CH3:16])=[CH:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1)[CH2:3][CH:4]=[C:5]([I:7])[CH3:6].C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:31]([C@H:2]([C:8]([CH3:16])=[CH:9][C:10]1[N:11]=[C:12]([CH3:15])[S:13][CH:14]=1)[CH2:3][CH:4]=[C:5]([I:7])[CH3:6])=[N+:32]=[N-:33]
Reactant: CC(I)=CC[C@@H](O)C(C)=Cc1csc(C)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(I)=CC[C@H](N=[N+]=[N-])C(C)=Cc1csc(C)n1
Temperature: 25 °C

Procedure:
A solution of (5R)-5-hydroxy-2-iodo-6-methyl-7-(2-methylthiazol-4-yl)-2,6-heptadiene (1.74 g) in 30 mL of toluene is cooled to 0° C. and treated with diphenylphosphoryl azide (1.65 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.91 g) for 2 hours. The mix is warmed to ambient temperature and diluted with ethyl acetate. The solution is washed sequentially with water, sat. NaHCO3, and brine, then dried over MgSO4, filtered, and evaporated. The product is purified by SiO2 chromatography (7.5% ethyl acetate/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][O:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:4]=1[Cl:16])(=[O:20])[CH3:19]
Reactant: CC(=O)OCCCCBr
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Yield: 92.9 %

Procedure:
This compound was prepared in a manner analogous to that set forth in Step B of Example 1, using 25 grams (0.093 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 19.5 grams (0.10 mole) of 4-bromobutyl acetate and 19.4 grams (0.14 mole) of potassium carbonate in 400 mL of DMF, differing in that the reaction mixture was warmed to 80 C., where it was maintained prior to work-up. The crude reaction product was purified with column chromatography on silica gel using 1:1 methylene chloride:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 33.1 grams of compound the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.[Cl:13]C(Cl)(Cl)[C:15]([C:17]1[NH:18][CH:19]=[CH:20][CH:21]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[ClH:13].[NH2:12][C:9]1[NH:10][CH:11]=[C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:15]([C:17]2[NH:18][CH:19]=[CH:20][CH:21]=2)=[O:16])[N:8]=1
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Reactant: NCCCc1c[nH]c(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1nc(CCCNC(=O)c2ccc[nH]2)c[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine dihydrochloride 16 (0.100 g, 0.458 mmol), 2-trichloroacetyl pyrrole 6 (0.103 g, 0.488 mmol), and anhydrous sodium carbonate (0.172 g, 1.63 mmol), were dissolved in anhydrous N-dimethylformamide (5 mL). The reaction was stirred at ambient temperature for 16 h. Evaporation of the reaction under reduced pressure and purification of the residue by column chromatography (CH2Cl2/MeOH sat. NH3 85:15) afforded the desired compound in its free base form. Addition of a single drop of concentrated hydrochloric acid to a methanol solution (8 mL) and evaporation under reduced pressure yielded 0.078 g (63%) of the title compound 17 as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 11.59 (s, 1H), 11.45 (s, 1H), 8.14 (t, 1H, J=5.1 Hz), 7.30 (s, 2H), 6.81 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 6.04 (s, 1H), 3.19 (dt, 2H, J=6.6, 12.6 Hz), 2.42 (t, 2H, J=6.9 Hz), (tt, 2H, J=6.6, 13.8 Hz); 13C NMR (100 MHz, DMSO-d6) δ 160.74, 146.76, 126.43, 126.40, 121.13, 110.28, 108.65, 108.50, 37.59, 28.14, 21.60; HRMS (ESI) calcd for C11H16N5O (MH+) 234.1349. found 234.1354.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])[C:10]([CH2:17][CH3:18])=[N:11]2.CO.O.[OH-].[Li+]>C(O)(=O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:28][CH:29]([F:30])[F:31])=[C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1F

Procedure:
A solution of [3-(2,4-difluorobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.54 g), methanol (20 mL), water (1.0 mL) and 5.0 M aqueous lithium hydroxide solution (0.5 mL) was stirred at room temperature for 2 hours. The pH of the solution was adjusted to 5 by the addition of glacial acetic acid and the solvent removed under reduced pressure. The residue was diluted with water and the solid collected by filtration, washed with water and dried to afford title compound as a cream solid, 0.089 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:8].[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])(=[O:33])=[O:32])[CH2:27][CH2:26]1)(=[O:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:1][C:2]2[S:3][C:4]3[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=3[C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[O:38])(=[O:32])=[O:33])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC(=O)N1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Reactant: COc1ccc(NC(=O)c2c(N)sc3c2CCCC3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc(NC(=O)c2c(NC(=O)c3cccc(S(=O)(=O)N4CCN(C(C)=O)CC4)c3)sc3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 10.6 mg of 2-amino-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, 10.9 mg of 3-(4-acetyl-piperazine-1-sulfonyl)benzoic acid, 16.0 mg of HATU, 0.012 mL of N,N-diisopropylethylamine, and 1 mL of DMA was stirred at room temperature overnight. The reaction mixture was separated by the addition of chloroform and water, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to obtain 5.2 mg of 2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.C(OCC)(=O)C>[CH2:9]([N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C1CCCN1Cc1ccccc1
Reaction time: 5 h

Procedure:
14.4 g (0.33 mol) of 50% sodium hydride dispersion in oil are added in batches to 25.5 g (0.3 mol) of 2-pyrrolidone in 300 ml of absolute dimethylsulphoxide. The mixture is then stirred for 5 hours at 40° to 50° C. and at 25°-30° C. 56.4 g=39.2 ml (0.33 mol) of benzyl bromide are added dropwize. After stirring for 10 hours at ambient temperature the reaction mixture is dissolved in 500 ml of ethyl acetate and extracted several times with water. The organic phase is separated off, dried over magnesium sulphate and the solvent is eliminated in vacuo. The residue obtained is purified over 900 g of aluminium oxide (neutral, activity II) with methylene chloride and 0.1% ethanol. Yield: 35.6 g (67.7% of theory), Rf value: 0.77 (aluminium oxide, neutral, eluant: 5% ethanol in methylene chloride).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:12]1[CH2:15][NH:14][CH2:13]1.Cl.[CH3:17][N:18]1[CH2:23][CH2:22][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35](O)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:17][N:18]1[CH2:19][CH2:20][C:21]2([CH2:32][C:31]3[C:26](=[N:27][CH:28]=[C:29](/[CH:33]=[CH:34]/[C:35]([N:14]4[CH2:13][CH:12]([C:4]5[O:5][C:6]6[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=6[C:3]=5[CH3:2])[CH2:15]4)=[O:36])[CH:30]=3)[NH:25][C:24]2=[O:38])[CH2:22][CH2:23]1
Reactant: Cc1c(C2CNC2)oc2ccccc12
Reactant: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)O)cnc1NC2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C2CN(C(=O)/C=C/c3cnc4c(c3)CC3(CCN(C)CC3)C(=O)N4)C2)oc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.7 %

Procedure:
To a solution of 3-(3-methylbenzofuran-2-yl)azetidine hydrochloride (21.7 mg, 0.097 mmol) and (E)-3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylic acid hydrochloride (22.0 mg, 0.065 mmol) in DMF (3 mL) were added EDCI.HCl (18.9 mg, 0.099 mmol), HOAt (13.9 mg, 0.102 mmol) and N,N-diisopropylethylamine (57 μL, 0.333 mmol). The reaction was stirred at rt for 20 h., after which the mixture was partitioned between DCM and H2O. The layers were separated and the aqueous layer extracted with DCM (3×). The combined organic layers were washed with brine (3×), dried over Na2SO4 and concentrated and the residue was purified by flash chromatography (DCM/MeOH, 5%→20%). The product (10.6 mg, 35%) was obtained as a white powder.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25]O)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(P(CCCC)CCCC)CCC.N(/C(N1CCCCC1)=O)=N\C(N1CCCCC1)=O>C1COCC1>[CH2:8]([O:15][C:16]([NH:18][C@@H:19]([CH2:25][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C[C@H](CO)NC(=O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C[C@H](CSc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 70.4 %

Procedure:
To a solution of benzenethiol (11.16 ml, 108.65 mmol), (R)-methyl 3-(benzyloxycarbonylamino)-4-hydroxybutanoate (INTERMEDIATE 4, 26.4 g, 98.77 mmol) and tributylphosphine (34.5 ml, 138.28 mmol) in anhydrous THF (350 ml) under nitrogen atmosphere was added. A solution of (E)-diazene-1,2-diylbis(piperidin-1-ylmethanone) (34.9 g, 138.22 mmol) in anhydrous THF (350 ml) was added dropwise over a 30 minute period. During the addition a white precipitate was formed and stirring was continued for 2 hours after the addition was complete. The white precipitate was filtered off and evaporation of the volatiles under reduced pressure gave a residue, which was purified by column chromatography (ISCO, eluting with 0→100% EtOAc/hexanes) to give the title product (25.0 g, yield: 70%).
Reaction SMILES: [N:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].C(Cl)[Cl:27]>>[ClH:16].[Cl:27][C:24]1[CH:23]=[CH:22][C:18]([C:19]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])[CH2:6][CH2:5]2)=[O:20])=[CH:17][CH:25]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: ClCCl
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Product: Cl
Product: O=C(CN1CCN(C(=O)c2ccc(Cl)cc2)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of piperazinoacetic acid morpholide and 4.2 g of chlorobenzoyl chloride are brought together in 50 ml of methylene chloride at 0° C. The mixture is stirred at room temperature for 2 hours and cooled again to 0° C., whereupon a precipitate separates out, and is recrystallised from isopropanol.
Reaction SMILES: C[C@H](P)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:30]([C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[CH2:40][CH2:39][C:38]=1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:30]([C@H:37]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([O:47][CH3:48])[CH:45]=2)[CH2:40][CH2:39][C@H:38]1[NH:49][C:50](=[O:53])[CH2:51][CH3:52])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Agent: [Rh+]
Agent: C[C@H](P)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@@H]1CCc2ccc(OC)cc2[C@@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 15 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.072 g, 0.292 mmol), Josiphos SL-J216-1 (0.197 g, 0.307 mmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (19.75 g, 61.4 mmol) were combined in a 500 ml SS pressure bottle, and the vessel was inerted with argon. Degassed methanol (200 ml) was added, the vessel was again inerted, then the mixture was stirred under 20 psig of argon at 50° C. for 20 min. The vessel was then pressurized with 60 psig of hydrogen and stirred at 55° C. for 14 hrs. HPLC analysis (YIYINADH.M, s.m. 9.08 min. with a 1.5 PA % impurity at 12.14 min., product enantiomers 9.45 and 13.41 min.) indicated 100% conversion and 95.6% ee. Crystallization from MeOH afforded the title compound (yield: 15%; ee: 99.5%).
Reaction SMILES: [C:1]([C:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[F:9][C:10]1[C:11](I)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:9][C:10]1[C:11]([C:2]#[C:1][C:3]2([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])/[C:13]/2=[CH:20]\[C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: C#CC1(O)CCCC1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC3(O)CCCC3)c21

Procedure:
Using Method C above, 1-ethynyl-1-cyclopentanol (35.8 mg, 0.33 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg) and Cul (2.5 mg) as catalyst in DMF (4 mL) and Et3N (4 mL) as solvent at 80 IC for 5 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[(1-hydroxy-cyclopentyl)ethynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 32 mg, 67%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[N:35]=[C:34]3[C:28]([N:29]([CH3:42])[C:30](=[O:41])[CH2:31][CH2:32][N:33]3[CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:27][N:26]=2)=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)=[O:8].Cl.C(O)(C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[N:35]=[C:34]3[C:28]([N:29]([CH3:42])[C:30](=[O:41])[CH2:31][CH2:32][N:33]3[CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:27][N:26]=2)=[CH:4][C:5]([F:23])=[C:6]([CH:22]=1)[C:7]([NH:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)=[O:8]
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)cc3Cl)ncc21
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)N[C@@H]4CCNC4)cc3Cl)ncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
tert-butyl (3R)-3-[[5-chloro-4-[(2-cyclopentyl-6-methyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-2-fluoro-benzoyl]amino]pyrrolidine-1-carboxylate (Example 324; 175 mg, 0.29 mmol) was dissolved in 1,4-dioxane (5 mL) and 4M HCl(aq) in 1,4-dioxane (10 mL) added. The mixture was stirred at room temperature for 2 hours. TFA (2 mL) was added an the reaction stirred for a further 1 hour. The reaction was concentrated, dissolved in DCM (10 mL) and TFA (3 mL) added. The reaction was stirred at room temperature for 1 hour, concentrated and the residue dissolved in methanol, absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and the residue purified by column chromatography (7.5% ammonia in methanol/DCM) to yield the title compound as a white foam (112 mg, 77%).