Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([CH3:30])=[C:24]([CH3:29])[CH:25]=5)[C:20]4=[O:31])[CH2:14][CH2:13]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)C>CO.O>[C:2]1([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:18][C@@H:19]4[CH2:28][CH2:27][C:26]5[C:21](=[CH:22][C:23]([CH3:30])=[C:24]([CH3:29])[CH:25]=5)[C@H:20]4[OH:31])[CH2:16][CH2:17]3)[C:11](=[O:32])[NH:10][CH2:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc1C)C(=O)C(CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1C)[C@@H](O)[C@H](CN1CCC3(CC1)C(=O)NCN3c1ccccc1)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A slurry of 9.0 of 1-phenyl-8-[(1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalenyl)methyl]-1,3,8-triazaspiro[4.5]decan-4-one, hydrochloride (1:1) (see example 192) in 200 ml of methanol is treated with 3.8 g of sodium borohydride in 40 ml of water. The sodium borohydride is added dropwise with ice cooling. The resulting mixture is stirred for 16 hours under nitrogen at room temperature. The mixture is diluted with water and extracted with methylene chloride. Concentration of the dried methylene chloride solution yields a crude solid. Trituration with absolute ethanol gives 6.6 g of the title compound, melting point 232°-233° C.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.Br[CH2:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][CH2:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])=[CH:39][CH:38]=1>CN(C=O)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:4](=[O:5])[C:3]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=3[NH2:1])=[CH:11][CH:10]=2)=[CH:50][CH:49]=1)[CH:47]=[CH2:48]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reactant: C=CCOC(=O)COc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3cc(Cl)ccc3N)cc2)cc1

Procedure:
A solution was formed by dissolving 2-amino-5-chloro-4'-hydroxybenzophenone (1.72 g, 8.07 mmol) in 40 mL of DMF. Potassium bis(trimethylsilyl)amide that was 0.5M in toluene (16.1 mL, 8.07 mmol, 1.0 equivalents) was added dropwise with stirring. Allyl 2-(4-bromomethylphenoxy)acetate (2.30 g, 8.07 mmol, 1.0 equivalents) was then added and the resulting orange slurry was stirred at ambient temperature for 45 minutes. The slurry was concentrated in vacuo, then diluted with CH2Cl2 (150 mL) and was extracted with 1N aqueous sodium bicarbonate (100 mL) and with 1N aqueous sodium chloride (100 mL), then dried over sodium sulfate and concentrated in vacuo to give the product as a yellow solid which was approximately 95% pure and was taken to the next step without purification. The product had Rf of 0.55 in 50:50:2 ethyl acetate/hexane/triethylamine. The structure was confirmed by proton NMR, carbon-13 NMR, and electron impact mass spectroscopy.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:14][C:15]1[C:16]2[C:17]3[C:21](=[C:22]([Cl:24])[CH:23]=1)[N:20]=[C:19](S)[C:18]=3[CH:26]=[CH:27][CH:28]=2.C(O)C.[ClH:32]>CC(C)=O>[ClH:14].[ClH:32].[Cl:14][C:15]1[C:16]2[C:17]3[C:21](=[C:22]([Cl:24])[CH:23]=1)[N:20]=[C:19]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:18]=3[CH:26]=[CH:27][CH:28]=2
Reactant: NCCCCCCCn1ccnc1
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCCCCCn1ccnc1
Temperature: 25 °C

Procedure:
The free base of the title compound was prepared by the method of Example 55, utilizing 5.4 grams of 7-(1H-imidazol-1-yl)heptanamine, 7.6 grams of 6,8-dichlorobenz(cd)indol-2-thiol, 9.5 grams of mercuric acetate, and 500 ml of ethanol. A solution of 2.5 grams of the free base in 100 ml warm ethanol was treated with 30 ml of 2.3 N ethanolic hydrogen chloride. The resultant mixture was taken to dryness in vacuo, and the residual syrup boiled up in 400 ml of acetone. Cooling at room temperature gave 1.9 grams of the title compound mp 198° C.-201° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[Br:15]/[C:16](=[CH:20]\[CH3:21])/[C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Br:15]/[C:16](=[CH:20]\[CH3:21])/[C:17]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:18]
Reactant: Nc1cccc(F)c1
Reactant: C/C=C(\Br)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: C/C=C(\Br)C(=O)Nc1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
To a stirred solution of 4.2 grams (0.038 mole) of 3-fluoroaniline in 35 ml of chloroform was added 3.1 ml of pyridine. The reaction mixture was cooled to 0° and 7.0 grams (0.038 mole) of [Z]-2-bromo-2-butenoyl chloride (Step C product) was added dropwise at such a rate that the reaction mixture temperature did not exceed 10°. Upon completion of addition, the reaction mixture was stirred at 0° for one hour, then was allowed to warm to ambient temperature where it was stirred for 16 hours. The reaction mixture was washed with 10 ml of water, two portions of 10 ml each of aqueous 0.1N hydrochloric acid, 10 ml of water, and finally 10 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was crystallized from hexane using silica gel as a decolorant to give 6.7 grams of [Z]-2-bromo-N-(3-fluorophenyl)-2-butenamide; mp 44°-45.5°.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:16]1([CH3:25])[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1C

Procedure:
A mixture of EXAMPLE 31B (1.08 g), ortho-tolylboronic acid (1.1 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (140 mg) in dimethoxyethane:2N aqueous Na2CO3 (25 mL:5 mL) was stirred under nitrogen at 80° C. for 16 hours, diluted with ethyl acetate and was washed with water and brine. The organic phase was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash chromatography on silica gel with 0-10% ethyl acetate/hexanes.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[F:16][C:17]1[C:18]([CH3:40])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=2)[C:20]([CH3:31])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>CCCCCC.O1CCCC1.C1(C)C=CC=CC=1>[F:16][C:17]1[C:18]([CH3:40])=[C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:33]=2)[C:20]([CH3:31])=[CH:21][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28]
Reactant: Cc1cc(OCCCS(C)(=O)=O)c(F)c(C)c1-c1cccc(CO)c1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OCCCS(C)(=O)=O)c(F)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.729 g, 3.50 mmol), {3′-fluoro-2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (1.28 g, 3.50 mmol) and tributylphosphine (1.13 g, 5.60 mmol) in a mixed solvent of toluene (45 mL) and tetrahydrofuran (5 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (1.41 g, 5.60 mmol) was added, and the mixture was stirred at room temperature for 4 hr under nitrogen atmosphere. Hexane (50 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=40:60-80:20) and basic silica gel column chromatography (ethyl acetate:hexane=40:60-100:0), and the obtained crystals were recrystallized from heptane-ethyl acetate to give the title compound (1.50 g, yield 77%) as colorless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:13].[OH2:14].C1(C)C=C(C)C=C(C)C=1S(O)(=O)=O.O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O
Agent: Cc1cc(C)c(S(=O)(=O)O)c(C)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: OC1CN(Cc2ccccc2)CC1O
Yield: 85.9 %

Procedure:
To a solution of 15.9 g (0.1 mol) of l-benzyl-3-pyrroline, 56.7 g (0.24 mol) of 2-mesitylenesulfonic acid dihydrate (produced by Aldrich Chemical Co., Inc.), 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at 40° C. without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 16.6 g of 1-benzyl-3,4-dihydroxypyrrolidine (yield 85.9%) was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([OH:10])[CH2:7][NH:8][CH3:9].[NH2:11][C:12](=[O:38])[CH2:13][N:14]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])[C:17](=[O:31])[C:16]2[S:32][C:33]([CH2:36]Cl)=[C:34]([CH3:35])[C:15]1=2>>[NH2:11][C:12](=[O:38])[CH2:13][N:14]1[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:21])[C:17](=[O:31])[C:16]2[S:32][C:33]([CH2:36][N:8]([CH2:7][CH:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[OH:10])[CH3:9])=[C:34]([CH3:35])[C:15]1=2
Reactant: CNCC(O)c1ccco1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12
Product: Cc1c(CN(C)CC(O)c2ccco2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(CC(N)=O)c12

Procedure:
Prepared from 1-(2-furyl)-2-(methylamino)ethanol (Preparation 8) and 4-(2-amino-2-oxoethyl)-N-(4-chlorobenzyl)-2-(chloromethyl)-3-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide by the procedure described for Example 2. Recrystallization from acetonitrile afforded 17 mg of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:23]=[CH:22][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]#[N:21])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:30](N)[CH2:31][NH2:32].[S]>CN(C=O)C>[NH:21]1[CH2:30][CH2:31][N:32]=[C:20]1[C:16]1[CH:15]=[C:14]([O:13][C:12]2[CH:22]=[CH:23][C:9]([NH:8][C:6]3[CH:5]=[C:4]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:3]=[C:2]([NH2:1])[N:7]=3)=[CH:10][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: N#Cc1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1
Reactant: NCCN
Agent: [S]
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(Oc3ccnc(C4=NCCN4)c3)cc2)cc(-c2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino]phenoxy}pyridine-2-carbonitrile (0.2 g, 0.53 mmol, prepared in Example 8), ethylene diamine (0.095 g, 1.58 mmol), and sulfur (0.05 g, 1.58 mmol) in DMF (3 mL) was heated at 80° C. for 3 days. The solvent was then removed by evaporation under reduced pressure. The residue was purified by preparative HPLC followed by preparative TLC (EtOAc:NH4OH=99:2) to afford pure product, 0.01 g (5%). 1H NMR (DMSO-d6) δ 9.39 (s, 1H), 8.41 (d, 1H), 7.84 (m, 4H), 7.42 (m, 3H), 7.37 (d, 1H), 7.09 (m, 3H), 6.95 (s, 1H), 6.46 (s, 1H), 6.37 (s, 2H); MS ES 424 (M+H)+calc 424.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:36]([CH3:37])=[CH:35][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[C:18]3=O)[S:16][C:12]=2[C:11]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](O[C@@H](C1C(C)=CC2N=C(N3CCNC(C4C=C5C(=CC=4)N(C)N=C5)C3)SC=2C=1C1C=CC(Cl)=CC=1)C(OCC)=O)(C)(C)[CH3:46]>>[C:1]([O:5][C@@H:6]([C:10]1[C:36]([CH3:37])=[CH:35][C:13]2[N:14]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[N:29]([CH3:33])[N:28]=[CH:27]5)[CH2:18]3)[S:16][C:12]=2[C:11]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:45][CH3:46])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCNC(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(N3CCN(C)C(c4ccc5c(cnn5C)c4)C3)sc2c1-c1ccc(Cl)cc1

Procedure:
(2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate (16 mg) was prepared in a similar manner as (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(4-methyl-3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid except using (2S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)piperazin-1-yl)benzo[d]thiazol-6-yl)acetate instead of (2S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxopiperazin-1-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C35H41ClN5O3S: 646.2 (M+H+); Found: 646.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OS1C2N=CC=CC=2N=C1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:65](=[O:68])[NH:66][CH3:67])[CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(NC(C)C)(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:65](=[O:68])[NH:66][CH3:67])[CH2:59][C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O[SH]1C=Nc2cccnc21
Solvent: O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.30 g; 1.22 mmol) was dissolved in methylene chloride (10 ml). 1-Hydroxy-7-azabenzotiazole (0.17 g; 1.22 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.26 g; 1.34 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.22 mmol) in methylene chloride (10 ml) was added to the reaction mixture. Diisopropylamine (0.21 ml; 1.22 mmol) was added. The reaction mixture was stirred 12 hours at room temperature. Water (10 ml) and methylene chloride (10 ml) were added.The phases were separated and the organic phase was washed with aqueous sodium hydrogensulfate (10%; 20 ml), saturated aqueous sodium hydrogencarbonate (20 ml), dried over magnesium sulfate and the solvent was removed in vacuo. The crude product was chromatographed on silica (2×20 cm) using ethyl acetate/methylene chloride (1:1) as eluent to afford 0.66 g of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert butylester.
Reaction SMILES: [F:1][CH2:2][C:3]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH2:6][CH2:7][CH2:8][CH2:9]OS(C)(=O)=O)[C:4]#[N:5].[I-:26].[Na+]>CC(C)=O.CCOCC>[F:1][CH2:2][C:3]([N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])([CH2:6][CH2:7][CH2:8][CH2:9][I:26])[C:4]#[N:5]
Reactant: CS(=O)(=O)OCCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: N#CC(CF)(CCCCI)N1C(=O)c2ccccc2C1=O

Procedure:
2-Fluoromethyl-2-phthalimido-6-methanesulfonyloxyhexanenitrile (10.84 g, 29.5 mmol) and sodium iodide (8.8 g, 2 equivalents) are refluxed in acetone overnight. The reaction mixture is filtered and solvent is removed by evaporation. The residue obtained is dissolved in ether and washed with water, sodium bisulfite, and water again. Upon concentration, 2-fluoromethyl-2-phthalimido-6-iodoheanenitrile crystallizes (9.0 g).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C[CH:21]([O:23]C(/N=N/C(OC(C)C)=O)=O)C.Br[C:35]1[C:40]([CH:41](O)[CH3:42])=[CH:39][CH:38]=[CH:37][N:36]=1.[C:44]1([CH3:62])[CH:49]=[CH:48][C:47]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])=[CH:53][CH:52]=2)=[CH:46][CH:45]=1>C1COCC1>[CH3:21][O:23][C:35]1[C:40]([CH:41]([N:57]([C:54]2[CH:55]=[CH:56][C:51]([O:50][C:47]3[CH:46]=[CH:45][C:44]([CH3:62])=[CH:49][CH:48]=3)=[CH:52][CH:53]=2)[S:58]([CH3:61])(=[O:60])=[O:59])[CH3:42])=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: Cc1ccc(Oc2ccc(NS(C)(=O)=O)cc2)cc1
Reactant: CC(O)c1cccnc1Br
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ncccc1C(C)N(c1ccc(Oc2ccc(C)cc2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of PPh3 (0.26 g, 1.0 mmol) and DIAD (0.2 mL, 1.0 mmol) in dry THF (3 mL) at 0 C was added a solution of 1-(2-bromo-pyridin-3-yl)-ethanol (0.14 g, 0.67 mmol) from Step A and N-(4-p-tolyloxy-phenyl)-methanesulfonamide (0.19 g, 0.7 mmol) from Example 42 step B in dry THF (2 mL). After 1 h, the reaction was warmed to room temperature and stirred for 3 h. The reaction was then concentrated under the reduced pressure. The residue was diluted with EtOAc and the precipitates were filtered. The filtrate was brought to the usual work-up. The crude material was purified by chromatography (silica gel, 30% EtOAc/hexanes) to give the desired product. MS (EI) 413 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15]([O:17]C(C)(C)C)=O)[C@H:12]([C:22]([OH:24])=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]([CH2:32]C(Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:36]1([CH2:46][NH2:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:8][N:9]=[C:10]1[CH2:14][N:13]([C:15](=[O:17])[CH2:32][O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:12]([C:22]([NH:47][CH2:46][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)=[O:24])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(=NOCc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(Cl)COc1ccccc1
Product: O=C(NCc1cccc2ccccc12)[C@@H]1CC(=NOCc2ccccc2)CN1C(=O)COc1ccccc1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(benzyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, phenoxyacetyl chloride, and 1-naphthylmethylamine the title compound was obtained in 74% purity by LC/MS. MS(ESI+): m/z=508.4.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1>S(Cl)(Cl)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[C:20]([N:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Reactant: O=C(O)c1ccc(Br)s1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(Br)s2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
5-Bromo-2-thiophenecarboxylic acid (0.375;1.8 mmol) was heated at reflux in thionyl chloride (8 ml) for 30 minutes, cooled, evaporated in vacuo and the residue azeotroped with toluene. The residue was redissolved in CH2Cl2 (10 ml) and treated with dry triethylamine (0.25 ml;1.81 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.4 g;1.81 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as a brown gum which crystallised on standing (0.388 g;52%), and was converted to the oxalate salt, mp=114°-115° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-:19].[K+]>O>[OH:2][C:1]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[O:5][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:19][C:4]1[CH:6]=[CH:7][CH:8]=[C:1]([OH:2])[CH:3]=1
Reactant: BrCCCCCCCCBr
Reactant: Oc1cccc(O)c1
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(OCCCCCCCCOc2cccc(O)c2)c1
Temperature: 10 °C
Yield: 27 %

Procedure:
A five neck five liter round bottom flask equipped with a mechanical stirrer, two condensers, and a dropping funnel was purged with nitrogen then charged under a nitrogen blanket with 1.6 kg (14.5 moles) resorcinol, 160 grams deionized water, and 296.7 grams (1.091 moles) 1,8-dibromooctane. The easily stirable reaction mass was slowly heated to reflux under a slow nitrogen purge. A solution of 181 grams (2.74 moles) 85 percent KOH pellets in 184 grams water was added dropwise at reflux under a nitrogen blanket over a period of two hours. After about 25 percent of the KOH had been added, the reaction mass had dissolved to light tea colored solution then it becomes increasingly clouded as salt was formed. The reaction mixture was refluxed an additional hour after all the KOH had been added. The pH of the reaction mixture was basic. The reaction was quenched with 1.5 liters of water and acidified with 40 percent sulfuric acid. The reaction mixture was then poured into 4 liters of water, cooled in an ice bath to a temperature of 10° C. and filtered to recover a tan colored solid which was slurried in 1.2 liters boiling water to wash out resorcinol and KBr. The cooled slurry was then filtered and 350 grams of crude product was recovered. Crystallization from 400 ml acetone yield 170 grams white crystals, 88 percent pure by HPLC peak area, and recrystallization from 500 ml acetone yields 97.4 grams product of 96 percent purity by HPLC peak area and high purity by gel permeation chromatography (m.p. 78°-82° C.).