Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O)[C:13]2[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[C:13](=[C:21]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CCCCCN3c1ccc(Cl)cc1Cl
Yield: 75.7 %

Procedure:
To a solution of 5-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]pentan-1-ol (Reference Example 113; 100 mg, 0.230 mmol) in pyridine (2 mL) was added methanesulfonyl chloride (0.0890 mL, 1.15 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 2 hr, the mixture was diluted with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with N,N-dimethylformamide (5 mL) and to the solution was added potassium carbonate (63.5 mg, 0.460 mmol) at room temperature. After the resultant mixture was stirred at 80° C. for 2 hr, the mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a solid (72.6 mg, 0.174 mmol, 76%). Analytically pure material was obtained by recrystallization from n-hexane.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:6][C:7]([CH3:14])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])=[CH2:3].N12CCCN=C1CCCCC2.O>CS(C)=O>[C:2]([C:4]1[C:5]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[N:6][C:7]([CH3:14])=[N:8][C:9]=1[C:10]([F:11])([F:13])[F:12])#[CH:3]
Reactant: C=C(Cl)c1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: C#Cc1c(-n2ccnc2)nc(C)nc1C(F)(F)F
Yield: 63 %

Procedure:
5-(1-Chlorovinyl)-4-imidazol-1-yl-2-methyl-6-trifluoromethyl-pyrimidine (0.20 g) was dissolved in dimethylsulfoxide (2 ml) and 1,8-diazabicyclo-[5,4,0]-undec-7-ene (0.11 g) was added at room temperature with stirring. The mixture was stirred for 2 hr in room temperature and then added water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed water and brine, respectively and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-THF) to give 5-Ethynyl-4-imidazol-1-yl-2-methyl-6-trifluoromethylpyrimidine (0.11 g) as colorless crystalline solid, mp 121-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[C:13][Si](C)(C)C)=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1)#[CH:13]
Reactant: Cc1ccc2ccc(C#C[Si](C)(C)C)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a solution of 2-methyl-7-trimethylsilanylethynyl-quinoline (140 mg, 0.59 mmol, 1.0 eq) in solution in MeOH (5 mL) was added K2CO3 (324 mg, 2.34 mmol, 4 eq), and the resulting mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure and water was then added. The aqueous layer was extracted twice with cyclohexane, and then the combined organic layers were washed with brine and dried over MgSO4. After filtration and concentration under reduced pressure the crude product was purified by column chromatography on silica gel (Cyclohexane-EtOAc 99:1) to afford 84 mg of 7-ethynyl-2-methyl-quinoline as a yellow crystal (86%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH:23]=C)[C:11]1=[O:25])=[O:4].C[N+]1([O-])CC[O:36]CC1.O>CC(C)=O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]#[C:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:8][C:9]=1[N:10]1[CH:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:14][CH2:13][C@@H:12]([CH2:22][CH2:23][OH:36])[C:11]1=[O:25])=[O:4]
Reactant: C=CC[C@@H]1CCC(C2CCCCC2)N(c2cc(C#CC(C)(C)C)sc2C(=O)OC)C1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)[C@H](CCO)CCC1C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (less polar diastereomer from previous step) (200 mg, 0.45 mmol, 1.0 equiv) in acetone (3.0 mL) at 0° C. was added N-methylmorpholine oxide (160 mg, 1.36 mmol, 3 equiv), water (1.0 mL) and OsO4 (230 mg, 0.02 mmol, 0.05 equiv). The reaction mixture was stirred at room temperature for 1 hour. The solution was partitioned between brine and EtOAc. The phases were separated and the organic layer was dried over Na2SO4, and concentrated under vacuum. The residue was dissolved in THF/water (3.0 mL/1.0 mL). To the solution was added NaIO4 (194 mg, 0.9 mmol, 2 equiv), and the resulting mixture was stirred at room temperature for 30 minutes, after which another portion of NaIO4 (0.5 equiv) was added. After stirred at room temperature for 30 minutes, the mixture was partitioned between brine and EtOAc. The organic layer was separated, dried over Na2SO4, and concentrated. The residue was dissolved in EtOH (3.0 ml) and the solution was cooled at 0° C. To the solution was added NaBH4 and the mixture was stirred at 0° C. for 15 minutes. The reaction was quenched by addition of water (2.0 mL) and EtOAc (10.0 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography, Heptane/EtOAc 1/1 to give 123 mg of the product (yield 60%). MS: 446 [M+H+]
Reaction SMILES: [B:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=2)[O:5][C:4]([CH3:7])([CH3:6])[C:3]([CH3:9])([CH3:8])[O:2]1.[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][NH:21][C:20]1=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][N:21]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([B:1]3[O:5][C:4]([CH3:7])([CH3:6])[C:3]([CH3:9])([CH3:8])[O:2]3)=[CH:11][CH:12]=2)[C:20]1=[O:25]
Reactant: CN1C(=O)CNC1=O
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1=O
Temperature: 45 °C

Procedure:
2-[4-(Bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboronate (5.00 g, 16.84 mmol), 3-methylimidazolidine-2,4-dione (2.11 g, 18.52 mmol, 1.1 equiv) and potassium carbonate (4.65 g, 33.7 mmol, 2 equiv) were combined and treated with N,N-dimethylformamide (17 mL). The mixture heated for 3 hours at 45° C., cooled to ambient temperature, diluted with ethyl acetate and washed with water (3×) and brine. The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[F:13][CH:14]([F:40])[C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24](OCC)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:18]=2[CH:19]=1>ClCCCl>[F:40][CH:14]([F:13])[C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=3)[C:18]=2[CH:19]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(F)F)oc2c1
Reactant: Cc1ccc(N)nc1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C(F)F)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
2-Amino-5-methylpyridine (264 mg, 2.44 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (2.44 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(difluoromethyl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.244 mmol) was added, and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (92 mg, 80%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 3.08 (s, 3 H) 6.75 (t, J=53.94 Hz, 1 H) 6.98 (s, 1 H) 7.12-7.20 (m, 2 H) 7.51 (d, J=1.01 Hz, 1 H) 7.58 (dd, J=8.46, 2.15 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.97 (s, 1 H) 8.11 (d, J=2.15 Hz, 1 H) 8.23 (d, J=8.46 Hz, 1 H) 8.54 (s, 1 H). LCMS m/z 473.0 (M+H)+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([F:49])=[CH:47][CH:48]=2)=O)=[CH:39][C:38]([Br:50])=[CH:37][N:36]=1.C([Mg]Cl)(C)(C)C>C1COCC1>[Br:50][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[CH:44]=[N:45][C:46]([F:49])=[CH:47][CH:48]=2)=[CH:2][O:3][CH3:4])[C:35]([NH2:34])=[N:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Agent: CC(C)(C)[Mg]Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC=C(c1ccc(F)nc1)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (1.16 g, 3.38 mmol) in THF (4 ml) at 0° C. under nitrogen was added dropwise a 1M solution of lithium bis(trimethylsilyl)amide in THF (3.4 ml, 3.4 mmol). The resulting dark red mixture was stirred at 0° C. for 10 minutes to generate the ylide reagent. To a solution of (2-amino-5-bromo-pyridin-3-yl)-(6-fluoro-pyridin-3-yl)-methanone (400 mg, 1.35 mmol) in THF (6 ml) was added dropwise a 1 M solution of tert-butylmagnesium chloride in THF (1.35 ml) at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. for 5 minutes, then the ylide reagent was added dropwise in 5 minutes. The reaction mixture was allowed to warm up to room temperature in 45 minutes before quenching with a saturated aqueous solution of ammonium chloride (50 ml) at 0° C. The mixture was stirred vigorously for 1.5 hours at room temperature. Water was added, followed by extracting ethyl acetate (three times). The combined organic layers were washed with brine, and directly adsorbed on silica gel. Purification on silica gel with a gradient of ethyl acetate/hexane afforded the title compound (single isomer) as a dark foam (220 mg, 50% yield). 1H NMR (DMSO-d6): δ 8.15 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.78 (dt, J=2.5, 8.5 Hz, 1H), 7.48 (d, J=2.5 Hz, 1H), 7.10 (dd, J=3.0, 8.5 Hz, 1H), 6.61 (s, 1H), 5.73 (broad s, 2H), 3.80 (s, 3H); MS: m/z 324, 326 [MH]+.
Reaction SMILES: C1(S([NH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:19](CC3C=C(Br)C=CC=3OCC(C)=C)[CH2:20][CH3:21])=[N:17]C=2)=[O:12])(=O)=O)C=CC=CC=1.C([NH2:37])C>CO>[CH2:20]([NH:19][C:16]1[N:17]=[N:37][C:13]([C:11]([NH2:10])=[O:12])=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCN
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)NS(=O)(=O)c2ccccc2)cn1
Solvent: CO
Product: CCNc1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloropyridazine-3-carboxamide (reference example 13, paragraphs 1 to 3) (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous ethylamine (70% solution, 77 ml). The reaction was heated at reflux for 31/2 hours. The reaction was allowed to cool to ambient temperature and stand overnight. The precipitate was filtered and washed with a small volume of water and dried to give 6-(ethylamino)pyridazine-3-carboxamide as pink solid (8.9 g). [The filtrates were evaporated to a small volume diluted with cold water (100 ml) and more of the desired solid was filtered-off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].
Reaction SMILES: C(CN)O.[Cl:5][C:6]1[O:10][C:9]([CH:11]2[C:16]3=[C:17]4[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]4=[C:19]([C:20]4[S:21][CH:22]=[C:23]([CH3:25])[N:24]=4)[N:15]3[CH2:14][CH:13]([CH2:34][N:35]3C(=O)C4C(=CC=CC=4)C3=O)[O:12]2)=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O>[NH2:35][CH2:34][CH:13]1[O:12][CH:11]([C:9]2[O:10][C:6]([Cl:5])=[CH:7][CH:8]=2)[C:16]2=[C:17]3[N:29]([CH3:30])[C:28](=[O:31])[N:27]([CH3:32])[C:26](=[O:33])[C:18]3=[C:19]([C:20]3[S:21][CH:22]=[C:23]([CH3:25])[N:24]=3)[N:15]2[CH2:14]1
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN2C(=O)c4ccccc4C2=O)OC3c2ccc(Cl)o2)n1
Solvent: Cc1ccccc1
Solvent: NCCO
Solvent: O
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
Ethanolamine (108 μl, 1.790 mmol) was added to a solution of 10-(5-chlorofuran-2-yl)-8-((1,3-dioxoisoindolin-2-yl)methyl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (106 mg, 0.179 mmol) in toluene (3087 μl). The mixture was stirred at 70° C. for 6.5 hours then at room temperature for 16 hours. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with 1M NaOH(aq) (20 ml) passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a mixture of diastereomers.
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.COC(C1(OC2C=CC(Cl)=CC=2C=O)CCC1)=O.N1CCCC1.[CH3:35][O:36][C:37]([C:39]1([O:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[CH:51]=[C:52]2[C:60]3[C:55](=[CH:56][C:57]([Cl:61])=[CH:58][CH:59]=3)[NH:54][C:53]2=[O:62])[CH2:42][CH2:41][CH2:40]1)=[O:38]>CO>[CH3:35][O:36][C:37]([C:39]1([O:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2/[CH:51]=[C:52]2\[C:53](=[O:62])[NH:54][C:55]3[C:60]\2=[CH:59][CH:58]=[C:57]([Cl:61])[CH:56]=3)[CH2:42][CH2:41][CH2:40]1)=[O:38]
Reactant: COC(=O)C1(Oc2ccc(Cl)cc2C=C2C(=O)Nc3cc(Cl)ccc32)CCC1
Agent: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Agent: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNC1
Solvent: CO
Product: COC(=O)C1(Oc2ccc(Cl)cc2/C=C2\C(=O)Nc3cc(Cl)ccc32)CCC1
Temperature: 70 °C

Procedure:
To the mixture of 6-chlorooxindole (10 g, 60 mmol) and 1-(4-chloro-2-formyl-phenoxy)-cyclobutanecarboxylic acid methyl ester (18 g, 64 mmol) in methanol (100 mL) was added pyrrolidine (4.5 g, 63 mmol) dropwise. The mixture was then heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give a mixture of E/Z 1-[4-Chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-cyclobutanecarboxylic acid methyl ester (6 g, 24%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:11]=[O:12])=[CH:5][NH:6]2.[H-].[Na+].[CH2:15](I)[CH3:16]>CN(C=O)C.ClCCl>[CH2:15]([N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[C:4]([CH:11]=[O:12])=[CH:5]1)[CH3:16]
Reactant: Cc1cccc2[nH]cc(C=O)c12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C=O)c2c(C)cccc21
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of 4-methyl-1H-indole-3-carbaldehyde (150 mg. 0.942 mmol) in dry DMF (1 mL) was added NaH (26 mg, 1.08 mmol) in 3 portions. When the evolution of gas was complete, the reaction vial was sealed and agitated for 5 m, after which time ethyl iodide (0.086 mL, 1.1 mmol) was added and agitation was continued overnight. The mixture was diluted with dichloromethane (10 mL), washed with water (2×5 mL), and brine (5 mL), dried and concentrated. This mixture was purified by flash chromatography using a gradient of ethyl acetate/hexane to provide 1-ethyl-4-methyl-1H-indole-3-carbaldehyde (111 mg, 63%). This intermediate (371 mg, 2 mmol) was dissolved in THF (3 mL) and NaBH4 (38 mg, 5 mmol) was added followed by 3 drops of water. The reaction mixture was agitated for 4 h then added to a saturated solution of NaHCO3 (10 mL). This mixture was stirred for 1 h and the intermediate, (1-ethyl-4-methyl-1H-indol-3-yl)-methanol was isolated by filtration and dried (330 mg, 88% yield). This intermediate was then convened to the title compound using methods similar to those described in Example 31. LCMS (ESMS): m/z 420 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:38].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)[C@@H:25]([OH:29])[CH2:26][C@@H:27]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:28]([OH:38])=[O:30])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H](O)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
Analogously to Example 1i), 0.502 g (1.00 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxyphenyl)-ethyl]-3(R)-(phenylmethyl)-dihydrofuran-2-(3H)-one in 16 ml of dimethoxyethane and 8.6 ml of water are hydrolysed with 4 ml of 1M lithium hydroxide solution. The reaction mixture, partially concentrated by evaporation, is poured onto a mixture of ice, 49 ml of sat. NH4Cl solution, 4.1 ml of 10% citric acid solution and methylene chloride, and ethanol is added until the precipitated solid has dissolved. The aqueous phase is extracted with 2 portions of methylene chloride/ethanol approximately 9:1, and the organic phases are washed with brine, dried with Na2SO4 and concentrated by evaporation: TLC Rf (A)=0.22.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[C:22](O)(=[O:26])[C@H:23]([CH3:25])[OH:24]>>[OH:24][C@@H:23]([CH3:25])[C:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:26]
Reactant: C[C@H](O)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)O)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and L-(+)-lactic acid, the title compound was prepared in the same manner as described for example 5a. Colourless, viscous oil (>98%). MS: m/e=355(M+H+).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:20][O:21][C:22]1[CH:31]=[C:30]2[C:25]([C:26](=[O:41])[C:27]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)([CH3:32])[CH2:28][S:29]2)=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:26]1([OH:41])[C:25]2[C:30](=[CH:31][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[S:29][CH2:28][C:27]1([C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C#CCCCCO[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2(O)C#CCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of 6-(t-butyldimethylsilyloxy)-1-hexyne (10.8 g, 50.9 mmol) in dry tetrahydrofiuran (100 ml) was added dropwise n-butyl lithium (30.1 ml, 48.9 mmol, 1.63M in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. To the reaction mixture , was then added 7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman-4-one (8.0 g, 25.5 mmol) dissolved in tetrahydrofuran at −78 C for 30 min, and the resulting mixture was stirred at −10° C. (for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (12.5 g, yield: 93%).
Reaction SMILES: [N:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:11](O)(C)([CH3:13])[CH3:12].N1C2C(=CC=CC=2)C=C1>O.CCCCCCC>[CH:12](=[N:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:11][CH3:13]
Reactant: CC(C)(C)O
Reactant: Nn1ccc2ccccc21
Agent: c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CCCCCCC
Product: CCC=Nn1ccc2ccccc21

Procedure:
To the 1H-indol-1-amine solution prepared in accordance with the procedures set forth in Example 6 in a 150-gal steel reactor, under nitrogen purge, slight exhaust, agitation ca. 150 rpm, at 10–25° C. (preferably 10–18° C.) and with slow jacket cooling, charge approximately 21.6 kg acetic acid to pH 3.9–4.0 (0.1 mL of the reaction mixture in 5 mL water) at a rate of ca. 1 kg/min. Charge incrementally more HOAc if needed to attain the pH level. Rinse pump with ca. 2 L NMP. Charge 10.8 L water (a slight temperature rise of about 3–6° C. is expected), essentially in one portion (ca. 1 min addition time). Charge 14.4 kg (13.9 kg corrected for 97% purity) propionaldehyde at ca. 0.8 kg/min (0.5–1.0 kg/min) while maintaining 10–24° C., preferably 10–20° C. A mild exotherm is expected. Depending on the rate of addition and cooling, expect about a 5° C. temperature rise. Rinse pump with ca. 3 L NMP. Agitate at 10–24° C., preferably 17–20° C., until the reaction is judged complete as evidenced by the HPLC assay, conditions of which are detailed further below (>99% conversion in 2–3 h). Monitor the progress of the reaction by withdrawing samples of the reaction mixture for HPLC assays. When the reaction is judged complete, prepare for a vacuum distillation directly from the reactor to a suitable receiver. Expect a forerun (ca. 45–50 L) of volatiles including tert-butanol and water initially at 50–70° C. and ca. 30–40 mm pressure. As the distillation rate slows, gradually increase the pot temperature to 95–100° C. and reduce the pressure to 5–25 mm and begin collecting NMP. Collect a total of about 320 kg distillates (to give a pot weight of 9.5 parts w/w with respect to the initial indole charge), then release the vacuum with nitrogen and cool to 10–25° C. If necessary, or for convenience of scheduling, the distillation can be interrupted at any time, by releasing the vacuum with nitrogen, cooling to <30° C., storing under nitrogen, and then restarting as required. Work up the reaction by charging 133 L heptane followed by, with chilled water cooling to keep exotherm temperature below 30° C., 234 L water through a reactor charging nozzle (maximum process volume of ca. 450 L is attained). Agitate for >10 min, then separate the phases. Extract the bottom aqueous phase with 54 L heptane. Combine the organic extracts, and wash with aqueous potassium bicarbonate solution (prepared from 0.6 kg potassium bicarbonate dissolved in 58 L (58–95 L) water) followed by a 58 L water wash. Concentrate the organic phase to obtain crude N-propylidene-1H-indol-1-amine as an oil. Purify by short path distillation, first pass to remove volatiles at ca. 120° C. evaporator and ca. 200–800 mbar pressure, and then a second pass at 110° C. evaporator and 0.2–0.4 mbar pressure to collect purified product.