Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:11](=[O:14])[N:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=2[N:6]=1.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][N:13]2[C:12]3[C:11](=[O:14])[N:10]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:9](=[O:24])[N:8]([CH3:25])[C:7]=3[N:6]=[C:5]2[CH2:4][C:3]2[CH:26]=[C:27]([O:30][C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:29][C:2]=2[F:1])=[CH:38][CH:39]=1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cc(OC(F)(F)F)ccc4F)nc3n(C)c2=O)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cc(OC(F)(F)F)ccc4F)n3Cc3ccc(Cl)cc3)n(C)c2=O)cc1
Temperature: 60 °C
Yield: 84.3 %

Procedure:
To a solution of 8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (67 mg, 0.14 mmol) in DMF (3 mL) was added 1-(bromomethyl)-4-chlorobenzene (43.2 mg, 0.21 mmol) followed by potassium carbonate (38.7 mg, 0.28 mmol). The reaction was heated to 60° C. for 3 h. The reaction was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give a crude product, which was purified by silica gel chromatography eluting with DCM/methanol (60:1) to give 7-(4-chlorobenzyl)-8-(2-fluoro-5-(trifluoromethoxy)benzyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (71.2 mg, 84.3% yield) as a white solid. LCMS retention time 2.375 min; LCMS MH+ 603.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH:9]([OH:11])[CH2:8][CH2:7][N:6]1[C:12](=[O:21])[N:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[CH3:14])=[O:4].[Li+].[OH-].Cl>O1CCCC1.O>[CH2:15]([N:13]([CH3:14])[C:12]([N:6]1[CH2:7][CH2:8][CH:9]([OH:11])[CH2:10][CH:5]1[C:3]([OH:4])=[O:2])=[O:21])[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCCCCN(C)C(=O)N1CCC(O)CC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCN(C)C(=O)N1CCC(O)CC1C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of compound 32 (2.03 g, 1 eq.) and LiOH (0.815 g, 5 eq.) in a mixture of tetrahydrofuran (30 mL) and water (30 mL) was stirred at room temperature until completion by TLC. HCl (1N, 50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). Dried organics were evaporated in vacuo to give compound 33 as a yellow gum in 100% yield. MS (ESI, EI+) m/z=285 (MH+).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH2:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[CH:17]=[CH:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=2[CH3:27])=[N:14]1>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]2[CH:17]=[CH:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])=[N:14]2)=[O:9])[N:6]=1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: Nc1nc(C(=O)O)co1
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(N)n3)n2)ccc(C#N)c1Cl
Yield: 29 %

Procedure:
(S)-2-amino-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-amino-1,3-oxazole-4-carboxylic acid (0.196 g, 1.527 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.437 g, 1.272 mmol). The product was purified by Flash-chromatography. Yield 29.0%. 1H-NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 2.58 (s, 3H), 4.29 (dd, 1H), 4.39 (dd, 1H), 4.54 (m, 1H), 4.59 (s, 2H), 6.44 (d, 1H), 7.31 (d, 1H), 7.50 (d, 1H), 7.53 (dd, 1H), 7.58 (dd, 1H), 7.68 (s, 1H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CN(C)C1C=CN=CC=1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([O:4][C:3]([CH3:5])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:2]=[CH2:1])=[O:16]
Reactant: C=C1CC(=O)O1
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: CN(C)c1ccncc1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Temperature: 55 °C
Yield: 92 %

Procedure:
A mixture of linalool (100 g, 0.648 mol) and 4-dimethylaminopyridine (0.40 g, 3.20 mmol) in a 500 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer is heated to 55° C. Diketene (54.50 g, 0.648 mol) is added dropwise in the course of 30 min. The mixture has a slight exotherm and turns from yellow to red during this time. After stirring an additional hour at 50° C., the mixture is cooled to room temperature. At this point, NMR analysis indicates the reaction is complete. The material from this lot is carried onto the next step. Purification of an earlier sample from this route by flash chromtography (elution with dichloromethane) yields the desired product in 92% yield and nearly colorless.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH:14]=[O:15].[Br:16]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:16][C:12]1[CH:11]=[C:10]([CH:14]=[O:15])[N:9]([C:3]2[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:13]=1
Reactant: O=Cc1cccn1-c1c(Cl)cccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc(Br)cn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 0.65 g of 1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde, and then 0.53 g of N-bromosuccinimide was added thereto. The mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, a deposited precipitate was collected by filtration to obtain 0.85 g of 4-bromo-1-(2,6-dichlorophenyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]12[CH2:18][CH:17]1[CH2:16][CH2:15][S:14][C:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:12]2.[H][H]>CO.[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]23[CH2:18][CH:17]2[CH2:16][CH2:15][S:14][C:13]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[N:12]3)[CH:4]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc([N+](=O)[O-])ccc3F)CC2CCS1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(N)ccc3F)CC2CCS1
Reaction time: 3 h
Yield: 83.8 %

Procedure:
tert-Butyl (1SR,7SR)-1-(2-fluoro-5-nitrophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (intermediate rac-A7a) (68 mg; 0.18 mmol) was dissolved in 20 ml methanol under argon and 10% palladium on carbon (Pd/C) (28 mg, 15 mol %) was added. The atmosphere of the reaction system was replaced with hydrogen, followed by stiffing at 23° C. for 3 hours. More 10% Pd/C (67 mg) was added and stiffing was continued under hydrogen atmosphere for 20 hours. The reaction mixture was filtered and evaporated to give the tert-butyl (1SR,7SR)-1-(5-amino-2-fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-ylcarbamate (53 mg; 85%) as a grey foam which was used in the next step without further purification. MS (ISP): m/z=352.3 [(M+H)+].
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[H][H]>CCOC(C)=O.CCO.[Pd]>[NH2:12][C:11]1[C:3]([NH:2][CH3:1])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CNc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNc1c(N)cccc1C(=O)O

Procedure:
A mixture of 2-methylamino-3-nitro-benzoic acid and 10% Pd/C (300 mg) in EtOAc (5 mL) and EtOH (5 mL) was stirred in an atmosphere of hydrogen over night. The mixture was filtered though a pad of Celite and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to provide 3-amino-2-methylamino-benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[C:8]([CH2:10][CH2:11][CH3:12])=[N:9][C:5]=2[N:4]=[C:3]1[CH3:50]>CC(O)=O>[CH3:1][N:2]1[C:6]2[N:7]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:18][CH:19]=3)[C:8]([CH2:10][CH2:11][CH3:12])=[N:9][C:5]=2[N:4]=[C:3]1[CH3:50]
Reactant: CCCc1nc2nc(C)n(C)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc2nc(C)n(C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
1,6-Dihydro-1.2-dimethyl-5-propyl-6-[(2'-{N-triphenylmethyltetrazol-5-yl}{1,1'-biphenyl}-4-yl)-methyl]imidazo[4,5-d]imidazole prepared as described above in Step F can be deblocked with aqueous HOAc at 50° C. as described for a related procedure (see Example 11, Step F) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][N:13]=[C:12]3[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:21][C:11]=23)[CH2:5][CH2:4]1.[CH3:30]OC(OC)N(C)C>>[CH3:1][O:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([N:9]2[C:10]3[C:15](=[CH:14][N:13]=[C:12]4[N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:20]=[CH:21][C:11]4=3)[C:16](=[O:18])[CH:17]=[CH:30]2)[CH2:7][CH2:8]1
Reactant: COC(OC)N(C)C
Reactant: CO[C@H]1CC[C@H](Nc2c(C(C)=O)cnc3c2ccn3COCC[Si](C)(C)C)CC1
Product: CO[C@H]1CC[C@H](n2ccc(=O)c3cnc4c(ccn4COCC[Si](C)(C)C)c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-[(trans-4-Methoxycyclohexyl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-5-yl)ethanone (179 mg, 0.428 mmol) in N,N-dimethylformamide dimethyl acetal (3 mL) was stirred at 170° C. for 6 hours under microwave irradiation. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (3 mL) and stirred with 1 M hydrochloric acid (3 mL) at 80° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1 (v/v)) to give the title compound (141 mg, yield 77%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:15])=O>>[Cl:1][C:2]([Cl:12])=[CH:3][C@@H:4]1[C@H:6]([C:7]([Cl:15])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 98 %

Procedure:
In a flask were placed 400 g (1.913 moles) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid and sufficient thionyl chloride to create a slurry. The remainder of the thionyl chloride (total used was 412.6 g (5.74 moles)) was added dropwise with stirring under a nitrogen blanket, and the reaction mixture was stirred at room temperature overnight. The crude product was distilled at 66°-67° C. at 66.7 Pa (0.5 mm of Hg) to produce 426.4 g of 98% (cis)-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:20][CH:21]1[CH2:30][CH2:29][C:28]2[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=2[CH2:22]1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=[CH:24][C:23]=3[CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)Cc1ccc2c(c1)CCC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 1.94 g of 4-chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added to a mixture of 30 ml of ethyl acetate, 20 ml of water, 3.46 g of potassium carbonate and 2.25 g of ethyl 6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride under stirring at room temperature. After the mixture is stirred at room temperature for 45 minutes, the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.84 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as oil.
Reaction SMILES: C(C1OC(C(C2OC(CC)=CC=2)[C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11](O)=[O:12])=CC=1)C.C1([N:33]=C=NC2CCCCC2)CCCCC1.N>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][CH:9]=[C:10]([CH:14]=1)[C:11]([NH2:33])=[O:12]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCc1ccc(C(c2ccc(CC)o2)c2ccc(OC)cc2C(=O)O)o1
Agent: N
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Under argon, 2-formyl-5-methoxybenzoic acid (10 mmol) and 2-ethylfuran (40 mmol) were dissolved in abs. dioxane (20 ml), and after 10 minutes of stirring at room temperature, conc. perchloric acid (0.3 ml) was added. The resulting reaction mixture was subsequently stirred at 60° C. for 1 h, then poured into water and stirred. Filtration and drying of the resulting precipitate gave 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid in the form of a colourless solid (60% of theory). 2-[Bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid (10 mmol), dicyclohexylcarbodiimide (2.27 g, 11 mmol) were dissolved in abs. dichloromethane (90 ml) and stirred at room temperature for 10 min. Aqueous ammonia (4 ml) was then added, and the resulting reaction mixture was then stirred at room temperature for 1 h. Filtration, concentration under reduced pressure and subsequent purification by column chromatography (gradient ethyl acetate/n-heptane) of the residue that remained gave 2-[bis(5-ethyl-2-fury))methyl]-5-methoxybenzamide (982 mg, 28% of theory) in the form of a colourless solid. Under argon, abs. 1,2-dichloroethane (10 ml) was added to 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzamide (706 mg, 2 mmol) and p-toluenesulphonic acid bound to macroporous polystyrene resin (2 mmol). The resulting reaction mixture was stirred at a temperature of 100° C. for 1 h, after cooling to room temperature filtered off through Celite and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 2,4-diethyl-10-methoxy-6,7-dihydro-8H-furo[2′,3′:3,4]cyclohepta[1,2-c]isoquinolin-8-one (51 mg, 8% of theory) in the form of a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.66 (br. s, 1H, NH), 8.31 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 6.47 (s, 1H), 5.35 (t, 1H), 3.87 (s, 3H), 2.79 (q, 2H), 2.68 (m, 2H), 2.33 (q, 2H), 1.30 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2.C[Si]([C:22]#[CH:23])(C)C.C(N(CC)CC)C.C(#N)C>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.O>[C:22]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH:6]=[CH:5]2)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: Fc1ccc(-n2ccc3cc(Br)ccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A mixture of 5-bromo-1-(4-fluorphenyl)-1H-indole (40 g) (prepared as described by Perregaard et al. J. Med. Chem. 1992 35, 1092-1101), (trimethylsilyl)acetylen (21.4 g), bis(triphenylphospine)palladium(II) dichloride (2.9 g) copper(I) iodide (1.3 g), triethylamine (40 mL) and acetonitrile (150 mL) was boiled under reflux for 8 hours. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate (4×300 mL). The combined organic phases were washed with brine (2×800 mL), dried (Na2SO4) and the solvents evaporated in vacuo. A solution of the remaining oil and potassium hydroxide (12.1 g) in a mixture of methanol (500 mL) and water (200 mL) was boiled at reflux for 3 h. The volatile solvents were evaporated in vacuo and a mixture of water (200 mL) and ethyl acetate (1000 mL) was added. The phases were separated and the aqueous phase extracted with ethyl acetate (250 mL). The combined organic phases were dried (Na2SO4) and the volatile solvents evaporated in vacuo. Purification of the remaining oil by column chromatography on silica gel (dichloromethane/heptane 1:6) afforded crystalline pure title compound 18a (11.4 g): Sp 99-100° C.; 1H NMR (CDCl3) δ 3.00 (s, 1H), 6.55 (d, 1H), 7.20 (t, 2H), 7.25 (d, 1H), 7.35 (m, 2H), 7.40 (dd, 2H), 7.85 (broad s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11](=O)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([C:10]1[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:23][C:11]=1[CH2:12][CH3:13])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCc1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A mixture of 2-benzoylamino-4-methyl-3-oxo-butanoic acid benzyl ester (1.26 g, 3.88 mmol), triphenylphosphine (2.64 g, 10.09 mmol), and iodine (1.04 g, 8.225 mmol) in tetrahydrofuran (60 mL) was cooled to −78° C., followed by addition of triethylamine (2.18 mL, 15.52 mmol). The resulting solution was stirred at −78° C. for about 10 min, and then was warmed up to room temperature for about 1 hr. The solvent was removed and the residue was triturated with dichloromethane and filtered. The filtrate was evaporated and the residue dissolved in 70 mL of ethyl acetate, washed with 0.5 M citric acid (2×50 mL), saturated sodium bicarbonate (2×50 mL), and brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-10% ethyl acetate in hexane) gave 5-ethyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (1 g) as a light yellow solid. LCMS calcd for C19H17NO3 (m/e) 321, obsd 322 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:20]([F:23])=[CH:21][CH:22]=1)[CH2:5][C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8].[CH3:24][Si:25]([CH3:68])([CH3:67])[CH2:26][CH2:27][O:28][C:29](=[O:66])[C@H:30]([CH2:42][C:43]1[CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=[CH:45][C:44]=1[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.ClCCl>[CH2:59]([O:58][C:44]1[CH:45]=[CH:46][C:47]([C:2]2[CH:22]=[CH:21][C:20]([F:23])=[C:4]([CH2:5][C@H:6]([N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=2)=[CH:48][C:43]=1[CH2:42][C@H:30]([NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C:29](=[O:66])[O:28][CH2:27][CH2:26][Si:25]([CH3:68])([CH3:67])[CH3:24])[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: COC(=O)[C@H](Cc1cc(Br)ccc1F)N(C)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)OCC[Si](C)(C)C)c2)ccc1F)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.68 g (4.09 mmol) of methyl 3-bromo-N-(tert-butoxycarbonyl)-6-fluoro-N-methyl-L-phenylalaninate (Example 14O) in 8 ml of 1-methyl-2-pyrrolidone is rendered inert and saturated with argon (pass argon through for about 30 min). Then 334 mg (0.41 mmol) of bis(diphenylphosphino)ferrocenepalladium(II)chloride (PdCI2(dppf)) are added, and the mixture is stirred at RT for 10 min. Thereafter, 3.45 g (4.92 mmol) of 2-(trimethylsilyl)ethyl-2-(benzyloxy)-N-[(benzyloxy)carbonyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-L-phenylalaninate (Example 16A) in 8 ml of 1-methyl-2-pyrrolidone and 2.67 g (8.19 mmol) of cesium carbonate are added. A gentle stream of argon is passed over the reaction mixture, which is stirred at 50° C. for 20 h. The mixture is cooled, taken up in dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, and the solvent is concentrated in vacuo. The residue is purified by column chromatography on silica gel (cyclohexane:ethyl acetate 7:3).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([O:16]C)=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:2]([C:10]([N:12]1[CH2:20][CH2:19][CH2:18][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 86.3 %

Procedure:
Boc-D-Phe-Pro-OMe (8.3 g) was dissolved in dioxane/water=6/4 v/v (150 ml) and treated with 2M sodium hydroxide solution (16.5 ml) portionwise over 1 h at room temperature, keeping the pH at 12.5. 2M hydrogen chloride solution was added to the reaction mixture until pH 3.0 and the water layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to yield Boc-D-Phe-Pro-OH (6.9 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)[CH2:16][CH2:15][N:14]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:41](I)[CH3:42].[Cl-].[NH4+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH2:41][CH3:42])[C@@H:12]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:19]=2)[CH2:16][CH2:15][N:14]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cccc(OCc3ccccc3)c2)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: CCI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OCc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(OCc2ccccc2)c1
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (rac.)-(3R,4R)-3-{[(benzyloxy)carbonyl]amino}-4-[3-(benzyloxy)-phenyl]piperidine-1-carboxylate (3.70 g) in DMF (16 ml) was added at 0° C. sodium hydride (573 mg), and the mixture was stirred for 15 minutes. To the mixture was added ethyl iodide (1.48 ml), and the mixture was stirred at 60° C. for 5 hours. The reaction solution was cooled, and a saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution (×2) and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (2.59 g).