Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19](OC)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1.B(Cl)(Cl)[Cl:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:18])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH:19]([Cl:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH:3]=1
Reactant: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(OC)c1ccccc1F
Reactant: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1-c1ccc(Cl)cc1C(Cl)c1ccccc1F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 20.1 g of 3-[4-chloro-2-(2-fluoro-α-methoxy-benzyl)-phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole in 250 ml methylene chloride is added 54 ml of a 1.4 molar boron trichloride solution in methylene chloride, and the mixture is stirred during 16 hours. Ice/water is then added; the organic layer separated, washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The aqueous layers are reextracted with methylene chloride. After removal of the solvent, the 3-[4-chloro-2-(α-chloro-2-fluoro-benzyl)phenyl]-4-ethoxycarbonyl-2-methyl-pyrazole is obtained as the solid residue, which is directly used in the next step.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=2[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1.Br.Br.[C:23]12[CH2:30][NH:29][CH2:28][C:27]=1[CH2:26][NH:25][CH2:24]2.N12CCCN=C1CCCCC2>C(#N)C>[F:16][C:10]1[CH:9]=[C:8]2[C:13](=[C:12]([F:14])[C:11]=1[N:25]1[CH2:26][C:27]3[CH2:28][NH:29][CH2:30][C:23]=3[CH2:24]1)[N:4]([CH2:3][CH2:2][F:1])[CH:5]=[C:6]([C:18]([OH:20])=[O:19])[C:7]2=[O:17]
Reactant: C1NCC2=C1CNC2
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(CCF)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 76.2 %

Procedure:
1-(2-Fluoroethyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.29 g), 3,7-diazabicyclo [3.3.0]oct-1(5)-ene dihydrobromide (0.33 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU, 0.46 g) were dissolved in acetonitrile (15 ml) and refluxed for 3 hours. The reaction mixture was kept at room temperature overnight and the precipitate was collected by filtration, washed with acetonitrile and methanol to give the title compound (0.29 g, yield 76%).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]([O:29][C:30]1[N:35]=[C:34]([C:36]([OH:38])=O)[CH:33]=[N:32][C:31]=1[N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)([CH3:28])[CH3:27].[CH3:45][O:46][C:47](=[O:54])[C:48]([NH2:53])([CH2:51][CH3:52])[CH2:49][CH3:50]>>[CH3:45][O:46][C:47](=[O:54])[C:48]([CH2:51][CH3:52])([NH:53][C:36]([C:34]1[CH:33]=[N:32][C:31]([N:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)=[C:30]([O:29][CH:26]([CH3:27])[CH3:28])[N:35]=1)=[O:38])[CH2:49][CH3:50]
Reactant: CC(C)Oc1nc(C(=O)O)cnc1N1CCCCC1
Reactant: CCC(N)(CC)C(=O)OC
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(N2CCCCC2)c(OC(C)C)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-Propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 6-Isopropoxy-5-piperidin-1-yl-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 393.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[C:19]([F:22])([F:21])[F:20]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:14][C:13]=1[C:19]([F:20])([F:21])[F:22]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: O=Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-chloro-3-trifluoromethyl-phenol.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[C:18](Cl)(=[O:20])[CH3:19]>C1(C)C=CC=CC=1>[C:18]([N:7]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)(=[O:20])[CH3:19]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N(C(C)=O)c1ccccc1S2
Temperature: 0 °C

Procedure:
30 g (0.118 mol) of 2-acetylphenothiazine and 9.28 g (1 eq.) of acetyl chloride are introduced into a 500 ml flask containing 150 ml of toluene. The reaction mixture is heated to reflux for 45 minutes before the introduction of a new portion of 4.6 g (0,5 eq.) of acetyl chloride. Stirring is maintained under heating at reflux for another 2 hours. The reaction medium is then poured onto approximately 200 g of ice. After stirring, the organic phase is decanted and washed successively with 100 ml of water and 100 ml of salt water. The organic solution is dried over sodium sulphate, filtered and concentrated to dryness using a rotary evaporator. A yellow solid (33 g; 100%) is obtained which is used in the following stage without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]([O:21]C)=[O:20].[OH-].[K+]>O.C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:18]([C:19]([OH:21])=[O:20])[O:10][C:4]=2[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2ccc(Br)cc2o1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
8.0 g (39.8 mmol) of 4-bromo-2-hydroxybenzaldehyde and 1.47 g (3.98 mmol) of tetra-N-butylammonium iodide are, together with 22 g (159.19 mmol) of anhydrous potassium carbonate, initially charged. 9.07 g (83.57 mmol) of methyl chloroacetate are added. The reaction mixture is heated at 130° C. for 4 h and then cooled to 0° C. using an ice bath. 100 ml of THF and 13.4 g (238.8 mmol) of potassium hydroxide in 50 ml of water are added and the mixture is then stirred at RT overnight. The solvent is removed under reduced pressure. The residue is diluted with water and acidified with conc. hydrochloric acid. The product is filtered off and dried under high vacuum. For fine purification, the product is purified on silica gel 60 (mobile phase: toluene→toluene/acetic acid 50:1→toluene/ethyl acetate/acetic acid 35:5:1). The solvent is removed under reduced pressure. 3.8 g (40% of theory) of the title compound are isolated.
Reaction SMILES: C([O:5][C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:41])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][NH:9][C:10]([NH:33][C:34]1[C:35]([CH3:41])=[CH:36][CH:37]=[CH:38][C:39]=1[CH3:40])=[N:11][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1)([OH:7])=[O:5]
Reactant: COc1cc2c(N=C(NCC(=O)OC(C)(C)C)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(N=C(NCC(=O)O)Nc3c(C)cccc3C)ncnc2cc1OCC1CCN(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of N-(tert-butoxycarbonylmethyl)-N′-(2,6-dimethylphenyl)-N″-[6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazolin-4-yl]guanidine (0.09 g), trifluoroacetic acid (1 ml) and methylene chloride (1 ml) was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixture of methylene chloride and a 2M solution of ammonia gas in methanol as eluent. There was thus obtained the title compound in 67% yield: NMR Spectrum: (DMSOd6, 100° C.) 1.2–1.5 (m, 3H), 1.7–1.9 (m, 2H), 2.0–2.1 (m, 2H), 2.14 (s, 3H), 2.19 (s, 6H), 2.84 (d, 2H), 3.82 (s, 3H), 3.95–4.05 (m, 4H), 7.08 (s, 1H), 7.17 (s, 3H), 7.71 (s, 1H), 8.43 (s, 1H); Mass Spectrum: M+H+ 507.
Reaction SMILES: [Li]CCCC.[Br-].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[F:18])[N:14]=[C:13]([CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:12]=[CH:11]2.[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:61][CH2:60]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=O)[CH:50]=1>CCCCCC.C1COCC1>[Br:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][CH2:47][C@@H:48]([S:57][CH2:58][C:59]1([CH2:62][C:63]([O:65][CH3:66])=[O:64])[CH2:60][CH2:61]1)[C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([CH:55]=[CH:19][C:13]2[CH:12]=[CH:11][C:10]3[C:15](=[CH:16][C:17]([F:18])=[C:8]([F:7])[CH:9]=3)[N:14]=2)[CH:50]=1
Reactant: Fc1cc2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2cc1F
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=O)c2)CC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=Cc3ccc4cc(F)c(F)cc4n3)c2)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
At -78° C., 1.6M BuLi in hexane (700 μL) was added to a suspension of the phosphonium salt of Step 9 (646 mg, 1.1 equiv.) in 6 mL of anh. THF and the mixture was stirred at -10° C. for 10 min. At -78° C., a solution of the aldehyde of Step 8 (515 mg, 1.12 mmol) in 4 mL of THF was then added dropwise. The mixture was stirred at -78° C. for 30 min. and at -10° C. for 30 min. and was quenched with 25% aq. NH4OAc. The product was extracted in EtOAc, dried over Na2SO4, is and purified by flash chromotography on silica with EtOAc:toluene 2.5:97.5 and 5:95.
Reaction SMILES: [CH:1](O)=[O:2].[CH3:4][O:5][C:6]([C:8]1([NH2:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1)=[O:7].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>CN(C1C=CN=CC=1)C>[CH3:4][O:5][C:6]([C:8]1([NH:20][CH:1]=[O:2])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9]1)=[O:7]
Reactant: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)C1
Reactant: O=CO
Agent: CN(C)c1ccncc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CN1CCOCC1
Product: COC(=O)C1(NC=O)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Added formic acid (200 mg, 4.34 mmol) to solution of 3-Amino-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (1T) (900 mg, 3.688 mmol); 2-Chloro-4,6 dimethoxy-1,3,5-Triazine (CDMT) (800 mg, 4.556 mmol); DMAP (20 mg), and NMM (400 mg, 4 mmol) at room temperature, then stirred overnight. The solvent was evaporated and the residue extracted with MeCl2 (200 ml), washed with H2O (50 ml), dried over MgSO4, filtered and solvent evaporated yielding a solid which chromatographed on silica gel eluting with 5% MeOH/MeCl2 containing 2% NH4OH yielding 2T as a white solid (725 mg, 72%) LCMS (MH 273) Retention time=2.53 minutes.
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18]Br)=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[P:21]([O:30]C(C)C)([O:26][CH:27]([CH3:29])[CH3:28])[O:22][CH:23]([CH3:25])[CH3:24]>>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]([CH2:18][P:21]([O:26][CH:27]([CH3:29])[CH3:28])([O:22][CH:23]([CH3:25])[CH3:24])=[O:30])=[CH:8][CH:9]([NH:15][CH:16]=[O:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C=C(CBr)CC(C)OC(C)=O)NC=O
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CCOC(=O)C(C=C(CC(C)OC(C)=O)CP(=O)(OC(C)C)OC(C)C)NC=O
Reaction time: 18 h

Procedure:
18.0 g (51.4 mmol) of ethyl 6-acetoxy-4-bromomethyl-2-formylamino-hept-3-enoate and 56.3 ml (205.6 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography on silica gel with ethyl acetate/isopropanol (7:2), giving ethyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hept-3-enoate as an orange oil. yield.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][NH:13][C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C([O-])=O.[NH4+:41]>O>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:41]=[C:14]([C:16]4[S:17][C:18]5[C:24]([N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=5[N:20]=4)[NH:13][CH:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3ccc4c(c3)OCCO4)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4ccc5c(c4)OCCO5)c[nH]3)nc12
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 0.19 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid [2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethyl]-amide and 0.54 g ammonium triflouroacetate was melted at 175° C. for 45 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 6:4 gave 0.13 g (71%) 2-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-1H-imidazol-2-yl]-4-methoxy-7-morpholin-4-yl-benzothiazole as yellow solid; M.p.: 235–237° C.; MS (ISP): m/e=451 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:23][NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][CH3:37])=[O:26])[CH:19]=2)[C:14]=1[Br:38])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O.Cl>CO>[Br:38][C:14]1[C:15]2[C:20](=[CH:19][C:18]([CH2:23][NH:24][C:25]([C:27]3[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[O:29][C:28]=3[CH2:36][CH3:37])=[O:26])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:39])=[O:2]
Reactant: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1oc2ccccc2c1C(=O)NCc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A mixture of 2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (0.200 g, 0.341 mmol), prepared in the previous step, 1N NaOH (1.02 mL, 1.02 mmol), 10 mL of water and 100 mL of methanol was stirred under nitrogen at room temperature for 20 h (overnight). The reaction was acidified with 1N HCl until acidic by litmus paper. The methanol was removed under reduced pressure. The solid that precipitated and was collected by filtration and dried under reduced pressure to give the title compound (0.0576 g, 29%) as a white solid, mp 162-165° C.
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li]CCCC.[F:18][C:19]([F:26])([F:25])[C:20](OCC)=[O:21].[NH4+].[Cl-]>C1COCC1>[F:18][C:19]([F:26])([F:25])[C:20](=[O:21])[C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9]
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: CCOC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C#CC(=O)C(F)(F)F)(C(C)C)C(C)C
Reaction time: 0.5 h

Procedure:
To a solution of (triisopropylsilyl)acetylene (6.50 mL, 29.0 mmol) in THF (80 mL) at −78° C. was added n-BuLi (2.5 M in hexane, 12.2 mL, 30.4 mmol) while maintaining the internal temperature below −70° C. After 30 min., ethyl trifluoroacetate (4.14 mL, 34.8 mmol) was added dropwise, keeping the internal temperature below −73° C. After 15 min. at −78° C., the mixture was allowed to reach 0° C. After 2 h, a saturated solution of NH4Cl was added. The aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with brine, dried (Na2SO4) and concentrated affording the title compound. 1H NMR (400 MHz, acetone-d6): 1.27 (m, 3H), 1.16 (d, 18H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12]C)=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[NH2:15][NH2:16]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:15][NH2:16])=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: NN
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2[nH]ccc2c1

Procedure:
A 100 mL round bottomed flask was charged with methyl 1H-indole-5-carboxylate (1.6 g, 9.13 mmol) and ethanol (20 mL). To this was added hydrazine monohydrate (10 g) and the mixture was placed under reflux for 7 days. The reaction mixture was concentrated to dryness and chloroform (80 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (1.54 g, 96%) was dried en vacuo and 1H NMR analysis was consistent with the solid compound. 1H NMR (DMSO d6, 400 MHz) δ 10.7 (br s, 1 H), 9.6 (br s, 2H), 8.21-8.15 (m, 1 H), 7.71 (dd, J=8.6 and 1.7 Hz, 1 H), 7.50 (d, J=8.6 Hz, 1 H), 7.44-7.39 ( m, 1 H) and 6.58-6.53 (m, 1 H).
Reaction SMILES: [OH:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2.[CH3:28][C:29](OC(C)=O)=[O:30]>CC(O)=O>[C:29]([O:1][CH:2]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][C:4]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:3]1=2)(=[O:30])[CH3:28]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(O)c1cc(-c3ccccc3)cnc1C=C2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)OC1c2cc(NS(C)(=O)=O)ccc2C=Cc2ncc(-c3ccccc3)cc21
Temperature: 120 °C

Procedure:
To a stirred solution of N-(5-hydroxy-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (50 mg, 0.13 mmol) in AcOH (1 mL) was added Ac2O (0.5 mL). The reaction mixture was heated to 120° C. for 1 d, concentrated, and purified by flash chromatography to afford the title compound. 1H NMR (600 MHz, CDCl3) δ 8.83 (s, 1H); 8.11 (s, 1H); 7.18-7.63 (m, 10H); 6.75 (s, 1H); 3.03 (s, 3H); 2.23 (br s, 3H). LRMS (APCI) calc'd for (C23H21N2O4S) [M+H]+, 421.1; found 421.1.
Reaction SMILES: [CH2:1]([CH:8]([CH2:14][C:15]#[C:16]C)[C:9]([O:11]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](C(CC#CC)C(O)=O)C1C=CC=CC=1>>[CH2:1]([C:8]([CH3:18])([CH2:14][C:15]#[CH:16])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CCC(Cc1ccccc1)C(=O)OCC
Reactant: CC#CCC(Cc1ccccc1)C(=O)O
Product: C#CCC(C)(Cc1ccccc1)C(=O)O

Procedure:
By replacing ethyl 2-benzyl-2-methyl-5-trimethylsilylpent-4-ynoate with ethyl 2-benzylhex-4-ynoate, 2-benzylhex-4-ynoic acid was prepared; IR: 3300-2500, 1710 cm-1.
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][C@@H:24]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:25][C@H:26](O)[C@@H:27]([NH:35][C:36]([O:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][CH:41]=3)=[O:37])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N[C@@H](CC1C=CC=CC=1)C[C@H](O)[C@@H](NC(OCC1SC=NC=1)=[O:67])CC1C=CC=CC=1.N[C@H]([C@@H](O)C[C@@H](NC(OCC1SC=NC=1)=O)CC1C=CC=CC=1)CC1C=CC=CC=1.CO>C(Cl)(Cl)Cl>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][C@H:24]([C@@H:25]([OH:67])[CH2:26][C@@H:27]([NH:35][C:36]([O:38][CH2:39][C:40]3[S:44][CH:43]=[N:42][CH:41]=3)=[O:37])[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[N:11]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reactant: CC(C)[C@H](NC(=O)OCc1csc(N2CCOCC2)n1)C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)[C@H](NC(=O)OCc1csc(N2CCOCC2)n1)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1

Procedure:
Using the procedure of Example 1 U but replacing N-((N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine with the resultant compound of Example 11 E and replacing (2S,3S,5S)-5-amino-2-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane with (2S,3S,5S)-2-amino-5-(N-((5-thiazolyl)methoxycarbonyl)amino)-1,6-diphenyl-3-hydroxyhexane provided, after silica gel chromatography using 2% methanol in chloroform, 196 mg (90%) of the desired compound (Rf 0.19, 4% methanol in chloroform), mp. 146°-148° C. Mass spectrum: (M+H)+ =751.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3I)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH2:38]([O:41][CH3:42])[C:39]#[CH:40]>ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13]4=[C:14]([CH:40]=[C:39]([CH2:38][O:41][CH3:42])[N:12]4[CH:11]=2)[CH:15]=[C:16]([CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:17]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: C#CCOC
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CN3CCOCC3)cc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1cc2cc(CN3CCOCC3)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4)cn1c23
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a flame-dried flask under a nitrogen atmosphere is added N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(4-morpholinylmethyl)-3-quinolinecarboxamide (269 mg) of Preparation 26, PdCl2(PPh3)2 (18 mg), and CuI (10 mg). The flask is back-filled with nitrogen gas and charged with dichloromethane (10 mL), Et3N (0.14 mL), and methyl propargyl ether (0.046 mL). The reaction is stirred at room temperature for 4 days. The reaction mixture is diluted with dichloromethane and partitioned against dilute aqueous sodium carbonate. The aqueous phase is extracted with two portions of dichloromethane. The combined organic layers are washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue is flash column chromatographed on silica gel eluting with 1% to 4% methanol in dichloromethane. The product containing fractions are combined and concentrated under reduced pressure to give a yellow solid which is crystallized from toluene to afford 0.13 g of the title compound as tan needles.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:3][Mg]Cl.[F:13][C:14]([F:23])([F:22])[C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(OCC)C.C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[C:15]([OH:21])([C:14]([F:13])([F:22])[F:23])[CH2:3][C:2]([CH3:1])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[CH3:20]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)C(F)(F)F
Reaction time: 2 h

Procedure:
To a room temperature solution of 45 mL (22.5 mmol) of a 0.5 M solution of 2-methyl-2-phenylpropylmagnesium chloride in diethyl ether was added 38 g (22.5 mmol) of ethyl trifluoropyruvate in 10 mL of anhydrous THF. The reaction became slightly warm to the touch and a white precipitate quickly developed. After 2 hours, the reaction was diluted with diethyl ether and quenched with 1 N aqueous HCl. The aqueous layer was separated and extracted with ether. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a brown oil. Chromatography on silica gel eluting with hexanes-EtOAc (98:2), afforded the title compound as a clear, colorless oil (4.6 g, 67%).