Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:29][CH:30]=3)=[N:19][O:20]C(C)(OC)C)[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3].Cl>CC(C)=O>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:51])[C:18]([C:26]3[N:27]=[C:28]([NH:31][C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[S:29][CH:30]=3)=[N:19][OH:20])[C:14](=[O:52])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A mixture of the product of Step A, 10 ml of acetone and 3.5 ml of 2 N hydrochloric acid was stirred at room temperature for 50 minutes and the acetone was evaporated. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness. The residue was triturated with ether and was vacuum filtered to obtain 1.95 g of the syn isomer of 3-azidomethyl-7-[2-(2-tritylamino-4-thiazolyl)-2-hydroxyimino-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccc(CCc2nc(-c3ccccc3)c(C)s2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1sc(CCc2ccc(CO)cc2)nc1-c1ccccc1

Procedure:
Methyl 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]benzoate was reduced with lithium aluminum hydride in the same manner as in Reference Example 12 to yield 4-[2-(5-methyl-4-phenyl-2-thiazolyl)ethyl]benzyl alcohol, which was then recrystallized from ethyl acetate-hexane to yield colorless prisms having a melting point of 62°-63° C.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:11][CH2:10][CH2:9][O:8]1>C(O)(=O)C.[Pd]>[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[CH2:11][CH2:10][CH2:9][OH:8]
Reactant: Cc1ccccc1C1(c2ccccc2C)CCCO1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccccc1C(CCCO)c1ccccc1C
Reaction time: 5 h
Yield: 60.2 %

Procedure:
The crude 2,2-di-(2-tolyl)-tetrahydrofuran 33a (28 g) was dissolved in acetic acid (250 mL). 5% palladium on Carbon black (3 g) was added and the mixture was hydrogenated in a Parr apparatus at 3 ato at 55° C. for 5 hrs. The catalyst was filtered off and the solvent was evaporated in vacuo. The remaining oil was subjected to CC (n-heptane/ethyl acetate--15:1) to give 4,4-di-(2-tolyl)-1-butanol (17 g). A solution of 4,4-di-(2-tolyl)-1-butanol (19 g) in acetic acid (400 mL) was boiled under reflux for 3 hrs. The cooled solution was evaporated in vacuo to give 4,4-di-(2-tolyl)-1-butyl acetate (17 g) as an oil. A solution of 4,4-di-(2-tolyl)-1-butyl acetate (9.2 g) in 57% aqueous iodic acid (150 mL) was boiled under reflux for 3 hrs. The cooled solution was poured into a mixture of ice and water and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with water and a saturated aqueous solution of NaCl, dried (Na2SO4) and evaporated in vacuo to give the title compound 34a (11.7 g) as an oil, which was used without further purification. 1H NMR (CDCl3) δ1.80-2.10 (m,4H), 2.28 (s,6H), 3.17 (t,2H), 4.26 (t,1H), 7.12 (s,8H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](Br)[CH:7]=[CH:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20](P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)[CH2:21]CC>CN1C(=O)CCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:20]=[CH2:21])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: C=Cc1ccc2cc(OC)ccc2c1
Temperature: 130 °C
Yield: 92 %

Procedure:
50 mmol of 6-methoxy-2-bromonaphthalene and 60 mmol of potassium carbonate are dissolved in 40 ml of NMP, and 0.001 mol % of Pd(OAc)2 and 0.004 mol % of butyldiadamantyl-phosphine are added. The mixture is placed under an ethylene pressure of 20 bar and stirred at 130° C. until conversion is complete. After filtration of the insoluble constituents, washing with alkaline solution and distillation, 92% of 6-methoxy-2-vinylnaphthalene is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4]2([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]=1[CH2:12][OH:13])[O:8][CH2:7][CH2:6][O:5]2>[O-2].[O-2].[Mn+4].C(Cl)Cl>[CH3:1][C:2]1[CH2:3][C:4]2([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]=1[CH:12]=[O:13])[O:5][CH2:6][CH2:7][O:8]2
Reactant: CC1=C(CO)C(C)(C)CC2(C1)OCCO2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1=C(C=O)C(C)(C)CC2(C1)OCCO2

Procedure:
3 kg. of manganese dioxide was added in 4 portions over a period of 2 days to a solution of 150 g. of crystalline 7,9,9-trimethyl-1,4-dioxaspiro [4,5] dec-7-en-8-methanol in 3 l. of methylene chloride. After the mixture was stirred under nitrogen for an additional day, the oxidation was complete according to a determination by thin layer chromatagraphy. Filtration and evaporation of the solvent yielded the crude product which was used for the next step without further purification. A small portion of this product was purified by vacuum distillation. This product was identified as 7,9,9-trimethyl-1,4-dioxaspiro [4,5] dec-7-en-8-carboxaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].Cl[C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH3:39])=[O:37])=[N:34][CH:35]=1.C1N2CCN(CC2)C1>>[CH3:39][O:38][C:36]([C:33]1[CH:32]=[N:31][C:30]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:35][N:34]=1)=[O:37]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: C1CN2CCN1CC2
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cn1

Procedure:
In analogy to Example 62, step 1, 6-[(2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 56, Step 4) was reacted with methyl 5-chloro-2-pyrazine carboxylate and DABCO (1.5 h, r.t.) to give the title compound as a white solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1>O>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[O:2])=[CH:10][CH:9]=1
Reactant: COc1ccc(C)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 47.1 %

Procedure:
In this example an undivided cell was used, said cell being provided with a platinum anode and a lead cathode. A solution of 250 grams of water, 10 grams of sulfuric acid and 50 grams of manganous sulfate was placed in the cell and 50 grams of p-methoxytoluene slowly added thereto. The electrical energy which was used consisted of an E applied voltage of 5.5 volts along with about 4.0 amps while maintaining the current density at a rate of about 80 milliamps/cm2. The reaction was effected for a period of about 3.5 hours while maintaining the cell at ambient temperature and atmospheric pressure. A work-up of the results disclosed that there had been a 47.1% yield of anisaldehyde with a 50.5% selectivity to said aldehyde, a current efficiency of 93.3% being observed.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([N:20]2C(=O)C3C(=CC=CC=3)C2=O)[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@H:10]1[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].O.NN>CO>[NH2:20][C@H:17]1[C:12]2=[N:13][CH:14]=[CH:15][N:16]=[C:11]2[C@@H:10]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N2C(=O)c3ccccc3C2=O)CC[C@H]1c1cccc(F)c1F
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2[C@H](N)CC[C@H]1c1cccc(F)c1F
Temperature: 70 °C
Reaction time: 2 h

Procedure:
In a 100 mL round-bottomed flask was dissolved tert-butyl (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(1,3-dioxoisoindolin-2-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyrazin-5-ylcarbamate (46.8 mg, 0.090 mmol) in methanol (1 mL) to give a white suspension. Hydrazine hydrate (0.1 mL, 3.2 mmol) was added, and the mixture was stirred in a preheated oil bath at 70° C. under nitrogen for 2 h. LCMS indicated the desired product. Methanol was removed in vacuo and the residue was partitioned between 0.5N sodium hydroxide and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated. Flash column chromatography upto 10% methanol (with 2M ammonia) in methylene chloride afforded the desired product as a colorless oil (26.9 mg, 77% for two steps): 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.3 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 7.25 (t, J=6.4 Hz, 1H), 7.12-6.98 (m, 2H), 6.24 (d, J=8.6 Hz, 1H), 5.25 (t, J=9.5 Hz, 1H), 4.50 (d, J=10.2 Hz, 1H), 3.03 (t, J=10.7 Hz, 1H), 2.60-2.43 (m, 1H), 2.39-2.07 (m, 4H), 1.61-1.40 (m, 1H), 1.23 (s, 9H); 19F NMR (376 MHz, CDCl3) δ −138.95-−139.53 (m), −142.46 (d, J=18.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[CH3:12][NH2:13].CC([O-])(C)C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CC(O)(C)C>[CH3:12][NH:13][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Clc1ccc2ncccc2c1
Reactant: CN
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: CC(C)(C)O
Product: CNc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 94.8 %

Procedure:
Following general procedure A, a mixture of 6-chloroquinoline (164 mg, 1.0 mmol), 2M methylamine (1 mL, 2.0 mmol), NaOt-Bu (120 mg, 1.2 mmol), BrettPhos precatalyst 10 (8 mg, 0.01 mmol), and t-BuOH (1 mL) was stirred at room temperature for 17 h. The crude product was purified via column chromatography (99:1 to 97:3 CH2Cl2/MeOH gradient) to provide the title compound as a yellow oil (150 mg, 95%). 1H NMR (400 MHz, CDCl3) δ: 8.62 (dd, J=4.2, 1.7 Hz, 1H), 7.94 (d, J=8.3 Hz, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.26 (dd, J=8.3, 4.2 Hz, 1H), 7.09 (dd, J=9.1, 2.6 Hz, 1H), 6.68 (d, J=2.6 Hz, 1H), 4.19 (bs, 1H), 2.93 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 147.4, 146.1, 143.3, 133.9, 130.3, 130.2, 121.5, 102.4, 30.8 ppm.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:23]1[O:25][CH2:24]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH2:24][CH:23]([OH:25])[CH2:22][O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]([C:17]([CH3:20])([CH3:21])[CH2:18][CH3:19])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5]
Reactant: c1ccc(OCC2CO2)cc1
Reactant: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1O
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)c1cc(C(=O)c2ccccc2)c(O)cc1OCC(O)COc1ccccc1
Temperature: 135 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 10 g (35 mmol) of 2,4-dihydroxy-5-(1,1-dimethylpropyl)benzophenone, 5.8 g (38 mmol) of phenyl glycidyl ether, 1.3 g (3.5 mmol) of ethyltriphenylphosphonium bromide in 30 ml of xylene is stirred at 135° C. for 3 h. The reaction mixture is cooled and then filtered over Prolith rapid bleaching earth. The residue which remains after concentrating by evaporation is distilled in a bulb tube (250° C./0.1 mbar). 10.5 g (69%) of the compound are obtained as a viscous yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17].C(N(CC)CC)C>ClCCl>[CH3:13][O:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH:17][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccccc1N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)Nc2ccccc2OC)cc1
Reaction time: 16 h
Yield: 75.3 %

Procedure:
To a solution of 4-methoxybenzenesulfonyl chloride (5.0 g, 24 mmol) and 2-methoxyaniline (3.0 g, 24 mmol) in dichloromethane (24 mL) at 0° C. was added triethylamine (3.4 mL, 24 mmol) over 10 minutes. The ice bath was removed, and the mixture was stirred for 16 hr. The mixture was diluted with dichloromethane (100 mL) and the combined solution was washed with water (50 mL) and brine (50 mL). The organic solution was dried over MgSO4, filtered, and evaporated, and the crude product was purified by silica gel chromatography (15-60% EtOAc/Hex). Product-containing fractions were pooled, evaporated, and dried under high vacuum to yield 5.3 g (44%) of the product as a tan-colored oil: 1H-NMR (CDCl3) δ 7.70-7.67 (d, 2H), 7.53-7.50 (d, 1H), 7.05-6.99 (m, 2H), 6.91-6.83 (m, 3H), 6.73 (d, 1H), 3.80 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N:13]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>COCCOC.[Ag]=O>[CH2:22]([O:21][C:19]([N:13]1[CH2:14][CH2:15][N:16]([C:7]2[C:6](=[O:12])[C:5]3[CH:4]=[CH:3][CH:2]=[N:1][C:10]=3[C:9](=[O:11])[CH:8]=2)[CH2:17][CH2:18]1)=[O:20])[CH3:23]
Reactant: O=C1C=CC(=O)c2ncccc21
Reactant: CCOC(=O)N1CCNCC1
Agent: O=[Ag]
Solvent: COCCOC
Product: CCOC(=O)N1CCN(C2=CC(=O)c3ncccc3C2=O)CC1
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
A mixture of 1.1 g of 5,8-quinolinedione in 100 ml of 1,2-dimethoxyethane was added dropwise to a solution of 2.37 g of 1-piperazinecarboxylic acid, ethyl ester in 25 ml of 1,2-dimethyoxyethane with stirring. Stirring was continued for 30 minutes, then 1 g of silver oxide was added and this mixture was stirred overnight. The mixture was filtered and the solid washed with dichloromethane. The filtrate and wash were combined, evaporated, triturated with ethyl acetate and the solid collected. This solid was chromatographed, eluting with dichloromethane, then ethyl acetate. The active fractions were combined and evaporated, giving 817 mg of the desired product, mp 192°-194° C. (dec.).
Reaction SMILES: C([O:3][C:4](=[O:40])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[O:25])[CH:18]=3)[C:13]([C:34]#[N:35])=[CH:12]2)=[CH:7][C:6]=1[O:36]COC)C.C(O)C.O.[OH-].[Li+].Cl>O.O1CCCC1>[CH2:27]([O:26][C:24]([NH:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[C:19]2[C:14]([C:13]([C:34]#[N:35])=[CH:12][N:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:40])=[O:3])=[C:6]([OH:36])[CH:7]=2)=[CH:15][CH:16]=1)=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3ccc(OCCNC(=O)OCc4ccccc4)cc32)cc1OCOC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1cn(-c2ccc(C(=O)O)c(O)c2)c2cc(OCCNC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
To a solution of 4-[6-(2-benzyloxycarbonylaminoethyloxy)-3-cyanoindol-1-yl]-2-methoxymethoxybenzoic acid ethyl ester (0.14 g) in a mixed solvent of ethanol (2.5 mL), tetrahydrofuran (5 mL), and water (2.5 mL) was added lithium hydroxide mono hydrate (0.03 g), and this mixture was stirred at room temperature for 3 hours. To this reaction mixture was added 2 mol/L hydrochloric acid (0.75 mL), and this mixture was stirred at 50° C. for 5 hours. This reaction mixture was treated 1 mol/L hydrochloric acid (5 mL), and this mixture was concentrated under reduced pressure until this solvent volume became one-third. The precipitated solid was collected by filtration, and washed with water, methanol and ether to give the title compound (0.097 g)
Reaction SMILES: [H-].[Na+].CS(C)=O.[CH3:7][C:8]([CH3:14])([CH2:11][CH:12]=[CH2:13])[CH2:9][OH:10].[CH3:15]I>CCOCC.O>[CH3:15][O:10][CH2:9][C:8]([CH3:14])([CH3:7])[CH2:11][CH:12]=[CH2:13]
Reactant: C=CCC(C)(C)CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: C=CCC(C)(C)COC
Yield: 25.4 %

Procedure:
Under nitrogen, 2.211 g NaH was suspended in 50 mL dry ether in a three-necked round bottom flask. Anhydrous (CH3)2SO (5.0 mL ) was added. The flask was cooled with ice. 2,2-Dimethyl-4-penten-1-ol (7.0 g) in 13 mL anhydrous ether was added dropwise through an addition funnel. The solution was then refluxed overnight. Upon cooling in ice, 43.56 g CH3I (5 eq) was added through an addition funnel. Soon a white precipitate was seen. The slurry was refluxed for 4 h. Upon cooling, water and ether were added to the mixture. The ether layer was separated, washed with water twice and dried with Na2SO4. Careful evaporation of ether (the product has a low b.p.) gave 2.0 g pure product. 1H NMR (CDCl3): δ 0.86 (s, 6H, —CMe2—); 2.00 (d, 2H, CH2═CH—CH2—); 3.05 (s, 2H, —CH2OMe); 3.33 (s, 3H, —CH2OMe); 5.00 (m, 2H, CH2═CH—); 5.80 (m, 1H, CH2═CH—)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=4)[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C@H:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[NH2:42])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO.CN(C=O)C>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:37]2[CH2:41][CH2:40][CH2:39][C@H:38]2[NH:42][C:24]([C:23]2[CH:22]=[C:21]([C:18]3[CH:19]=[CH:20][C:10]4[O:9][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=4[CH:17]=3)[CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:35][CH:36]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)O)c3)cc12
Reactant: N[C@@H]1CCC[C@@H]1c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)N[C@@H]4CCC[C@@H]4c4ccc(Cl)cc4)c3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
In a 1 dram vial were combined 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (20 mg, 0.051 mmol), cis-2-(4-chlorophenyl)cyclopentanamine (14 mg, 0.072 mmol), and HATU (31 mg, 0.082 mmol). DMF (0.4 mL) and DIPEA (50 μL, 0.29 mmol) were added, and the vial was capped and stirred at r.t. for 2 h, then diluted with MeOH, filtered, and purify directly by prep HPLC. Concentration afforded the title compound (15 mg, 52% yield) as a fluffy white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.47-8.59 (m, 1H) 8.06 (d, J=8.85 Hz, 1H) 7.97-8.03 (m, 2H) 7.86 (d, J=1.83 Hz, 1H) 7.75-7.82 (m, 2H) 7.68 (s, 1H) 7.65 (dd, J=8.55, 1.83 Hz, 1H) 7.45-7.53 (m, 2H) 7.40 (t, J=8.85 Hz, 2H) 7.27 (s, 4H) 4.60-4.71 (m, J=7.67, 7.67, 7.55, 7.32 Hz, 1H) 3.33-3.41 (m, 1H) 2.87 (d, J=4.58 Hz, 3H) 1.99-2.15 (m, 3H) 1.89-1.98 (m, 1H) 1.72-1.82 (m, 1H) 1.57-1.71 (m, 1H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=10% CH3CN/90% H2O/0.1% TFA, solvent B=90% CH3CN/10% H2O/0.1% TFA, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=4 ml/min, column: Sunfire C18 5 μm 4.6×50 mm; HPLC Rt=2.02 min, (ES+) m/z (MH+)=567. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=15.42 min, purity=98%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=13.74 min, purity=97%.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[C:5]([F:16])=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, grey solid (42 mg, 51%), MS (ISP) m/z=333.1 [(M+H)+], mp 327° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: NCC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O

Procedure:
p-nitrophenyl ester of tert-butoxycarbonylphenylalanine is reacted with glycine to obtain tert-butoxycarbonylphenylalanylglycine;