Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23](O)=[O:24].C([N:28](CC)CC)C.C(OC(Cl)=O)C(C)C>C1COCC1>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH2:28])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(N)=O)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Indomethacin (10 g; 0.028 mol) in 150 mL THF was treated with triethylamine (4.8 mL; 0.035 mol) and cooled to -10° C. Isobutylchloroformate (4.4 mL; 0.033 mol) was added and the reaction was stirred at -10° C. for 10 min. The ice bath was removed and NH3 was bubbled through the solution for 15 min. The resulting pale yellow solid was collected, slurried in CH2Cl2 and filtered again. The product was used with no further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Br[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[CH:22][CH:21]=2)[CH:16]=[CH:17][C:18]=1[NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2ccccc2c1
Reactant: Nc1ccc2ncccc2c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc2cc(Nc3ccc4c(c3)CCCN4)ccc2c1
Temperature: 25 °C
Yield: 70.9 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condensor, and nitrogen inlet was added 6-aminoquinoline (6.69 grams, 46.4 mmoles), 2-bromonapthalene (9.15 grams, 44.2 mmoles), tris(dibenzylideneacetone)dipalladium (0) (0.80 grams, 0.87 mmoles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (1.10 grams, 1.77 mmoles), sodium tert-butoxide (8.49 grams, 88.3 mmoles) and anhydrous toluene (90 mL). The contents of the flask were refluxed for five hours; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with tetrahydrofuran (135 mL). The combined organic layers were concentrated in vacuo to yield a brown solid. The solid was recrystallized from ethanol to afford 8.6 grams of the desired product as a yellow solid. 1H NMR (DMSO-d6/D2O) δ 8.9 (d, 1H), 8.65 (d, 1H), 8.2 (d, 1H), 7.25-8.05 (m, 10H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[O:18][CH2:17]4)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OCC1CC1
Reactant: COCC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC)c2OCC2CC2)COC1
Temperature: 70 °C
Yield: 27.7 %

Procedure:
To a stirring solution of 5-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (15 mL), was added potassium carbonate (101 mg, 0.736 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (95 mg, 0.490 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a solid (30 mg, 28%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CS(O[CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:25][CH:26]=2)=[C:16]([O:35][CH3:36])[CH:15]=1)(=O)=O>>[N:1]1([CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:27]=[CH:28]/[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:25][CH:26]=3)=[C:16]([O:35][CH3:36])[CH:15]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1cc(CCCOS(C)(=O)=O)ccc1OCc1coc(/C=C/c2ccccc2)n1
Reactant: c1c[nH]cn1
Product: COc1cc(CCCn2ccnc2)ccc1OCc1coc(/C=C/c2ccccc2)n1
Yield: 60 %

Procedure:
In substantially the same manner as in Working Example 8, imidazole was allowed to react with 3-[3-methoxy-4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate to give 4-[4-[3-(1-imidazolyl)propyl]-2-methoxyphenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 60%. Recrystallization from ethyl acetate-hexane gave colorless prisms, m,p.95-96° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][SH:6].[O-]CC.[Na+].Cl.[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][Cl:22])[N:20]=1)[C:13]([NH2:15])=[NH:14]>C(O)C>[ClH:22].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:6][CH2:5][CH2:4][CH2:3][NH2:2])[N:20]=1)[C:13]([NH2:15])=[NH:14]
Reactant: NCCCS
Reactant: N=C(N)Nc1nc(CCl)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCCN)cs1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-Aminopropanethiol hydrochloride (2.54 g.) in ethanol (20 ml.) was added to a solution of sodium ethoxide (1 g. Na in 25 ml. ethanol) at 0° C. under a nitrogen atmosphere. The suspension was stirred at 0° C. for 2 hours and a solution of 2-guanidino-4-chloromethylthiazole hydrochloride (2.27 g.) in ethanol (25 ml.) was then added. The suspension was allowed to reach room temperature and stirred for 16 hours. Filtration of the suspension and acidification of the filtrate with concentrated hydrochloric acid gave a precipitate of 2-guanidino-4-[(3-aminopropyl)thiomethyl]thiazole hydrochloride, m.p. >350° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:20])[C:14]([CH3:19])=[CH:15][C:16]([OH:18])=[O:17]>O.C(O)(=O)C.[Zn]>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:20])[CH:14]([CH3:19])[CH2:15][C:16]([OH:18])=[O:17]
Reactant: CC(=CC(=O)O)C(=O)c1ccccc1N1CCCC1=O
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: CC(CC(=O)O)C(=O)c1ccccc1N1CCCC1=O

Procedure:
27.3 g (0.1 mole) of the compound obtained in Example 1 are dissolved in 200 ml of water and 15 ml of acetic acid. After addition of 15 g (0.23 mole) of zinc dust, the mixture is heated under reflux for 30 minutes and filtered. The aqueous phase is rendered alkaline and extracted, the extract is acidified and the resulting oil is separated off.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=1)=[O:9].[NH2:27][C:28]1[S:32][N:31]=[CH:30][N:29]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([S:23]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([Cl:22])[CH:13]=1)=[O:9]
Reactant: Nc1ncns1
Reactant: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Cl)cc1Cl
Agent: Cl
Product: O=C(NCc1ccc(C(F)(F)F)c(Cl)c1)c1ccc(S(=O)(=O)Nc2ncns2)cc1Cl

Procedure:
The title compound was prepared from 3-chloro-4-({[3-chloro-4-(trifluoromethyl)benzyl]amino}carbonyl)benzenesulfonyl chloride (Preparation 38) and 5-amino-1,2,4-thiadiazole in following Method H described for Example 6. The reaction mixture was added to 2M HCl, extracted into ethyl acetate, dried over sodium sulphate, filtered and evaporated. The crude material was purified by column chromatography eluting with DCM:MeOH:AcOH (95:5:0.5) to yield the title compound.
Reaction SMILES: [C:1]([CH2:3][N:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:5][C:6]([O:8]CC)=[O:7])#[N:2].[Li+].[OH-].FC(F)(F)C(O)=O.Cl.O1CCOCC1>C1COCC1.O.CC#N.O>[C:1]([CH2:3][N:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=1)[CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)CN(CC#N)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: N#CCN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 96.6 %

Procedure:
Ethyl N-(cyanomethyl)-N-(3,4-dichlorophenyl)glycinate (1.00 g, 3.48 mmol) was dissolved in 10 mL of THF and treated with LiOH (83.4 mg, 3.48 mmol) dissolved in 2 mL of water. After 2 h, HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid) showed that all of the starting material (Rt=7.6 min) was gone and that a single new peak (Rt=6.2 min) had formed. The reaction mixture was treated with a solution of 4.0M HCl in dioxane (1.74 mL, 6.96 mmol) and then the solvent was removed by rotary evaporation followed by high vacuum to give 870 mg (3.36 mmol, 96%) of N-(cyanomethyl)-N-(3,4-dichlorophenyl)glycine as a white solid which was used in subsequent chemistry without further purification. LC/MS (APCI) m/e 232 [M−CN]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1.C(N(C(C)C)C(C)C)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl.CN(C)C=O>[C:31]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:2]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1ccc(NCC2CNCCO2)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCOC(CNc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of EXAMPLE 415B (145 mg) and N-ethyl-N-isopropylpropan-2-amine (120 μl) in anhydrous dichloromethane (5 mL) and N,N-dimethylformamide (2 mL) was cooled with an ice bath and acetic anhydride (56 μl) was added dropwise. The mixture was stirred at room temperature for 3 hours and concentrated to dryness. The residue was triturated with water. The resulting solid was dried under vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([C:25]#[N:26])(C)[C:19](OCC)=O)[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[C:13]([CH:18]([CH3:19])[C:25]#[N:26])[CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C#N)c1cccc2c(-c3ccc(Cl)cc3)nccc12
Yield: 62.3 %

Procedure:
Ethyl 2-[1-(4-chlorophenyl)isoquinolin-5-yl]-2-cyanopropionate (1.0 g) was heated under reflux together with 40 ml of ethanol, 0.20 g of sodium hydroxide and 2 ml of water. After the reaction, the reaction mixture was concentrated under reduced pressure. The resulting oily product was extracted with ether, and dried. The solvent was distilled off, and the residue was recrystallized from ether-hexane to afford 0.5 g of 2-[1-(4-chlorophenyl)isoquinolin-5-yl]propionitrile as colorless needles having a melting point of 127.5° to 130° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].[CH:18]([O:21]C)(Cl)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:1][C:2]([F:16])([F:17])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([CH:9]=1)[CH:18]=[O:21])[C:4]([F:6])([F:5])[F:7]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C=O
Yield: 90.9 %

Procedure:
To a stirred and ice-cooled solution of Compound 8 (650 mg, 2.5 mmol) in dry CH2Cl2 (15 ml) was added neat TiCl4 (950 mg, 5.0 mmol) followed by Cl2CHOMe (600 mg, 5.0 mmol). After the addition was complete, the mixture was stirred at room temperature for 5 hr, poured into H2O (60 ml), and extracted with CH2Cl2. The combined extracts were dried (Na2SO4), and concentrated in vacuo to give a yellow oil, which was purified by a column chromatography on silica gel to give Compound 9 (650 mg, 90%)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O>C(#N)C>[Br:21][C:16]1[C:17]([CH3:19])=[CH:18][C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)c2c(c1)OCC2c1ccc(C(C)C)cc1
Solvent: CC#N
Product: Cc1cc2c(c(C)c1Br)C(c1ccc(C(C)C)cc1)CO2
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran synthesized in Reference Example 15 (5.62 g, 21.1 mmol) in acetonitrile (60 mL) was added N-bromosuccinimide (3.76 g, 21.1 mmol) at 0° C., and the mixture was stirred at the same temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 5.95 g (yield 82%) of the title compound. Melting point: 90-91° C. (methanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([Br:28])=[CH:4][N:3]=1.[CH3:29]C(C)([O-])C.[K+].IC.C(OCC)(=O)C>O1CCOCC1>[C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[C:2]([NH:1][CH3:29])=[N:3][CH:4]=[C:5]([Br:28])[N:6]=2)[CH2:9][C@@H:10]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CI
Product: CNc1ncc(Br)nc1N1CCN(C(=O)OC(C)(C)C)[C@@H](Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 309.9 %

Procedure:
To a solution of 2-amino-5-bromo-3-[(S)4-Boc-3-benzylpiperazinyl]pyrazine 108 (140 mg, 0.313 mmol) in anhydrous dioxane (3 mL) was added a 1 M solution of potassium t-butoxide (0.34 mL, 0.34 mmol). The reaction mixture was stirred at room temperature for 10 minutes and iodomethane (89 mg, 0.627 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 3-[(S)-4-Boc-3-benzylpiperazinyl]-5-bromo-2-methylaminopyrazine 111 (45 mg, 0.97 mmol).
Reaction SMILES: C([O:4][CH:5]1[C:11](=[O:12])[NH:10][C:9]2=[CH:13][N:14]([CH3:17])[C:15]([CH3:16])=[C:8]2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1)(=O)C.[OH-].[Na+].C(=O)=O>C(O)C>[OH:4][CH:5]1[C:11](=[O:12])[NH:10][C:9]2=[CH:13][N:14]([CH3:17])[C:15]([CH3:16])=[C:8]2[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:6]1
Reactant: CC(=O)OC1N=C(c2ccccc2)c2c(cn(C)c2C)NC1=O
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c2c(cn1C)NC(=O)C(O)N=C2c1ccccc1
Temperature: 5 °C

Procedure:
To a suspension of 3-acetoxy-1,7-dihydro-6,7-dimethyl-5-phenyl-pyrrolo[3,4-e][1,4]-diazepin-2(3H)-one (40 g) in ethanol (2000 ml), cooled to 5° C., 1N NaOH (128 ml) was added with stirring. After 10 minutes the reaction mixture was cooled to about 4° C. and allowed to stand at this temperature for one night. Then CO2 was gradually added to the solution to lower the pH to about 8. Ethanol was evaporated at the pump and the obtained residue was washed first with water and then with methanol, and crystallized from ethanol yielding 30 g of the compound of the title. M.p. 243° C. with decompostion.
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH:10]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:11]([CH3:17])[C:12]([O:14]CC)=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:3].[OH-].[Ba+2].[OH-].O>O1CCCC1>[CH3:17][CH:11]([CH:10]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:2]([OH:1])[CH3:3])[C:12]([OH:14])=[O:13]
Reactant: CCOC(=O)C(C)C(NCc1ccccc1)C(C(=O)OCC)C(C)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)O

Procedure:
A mixture (140 mg) of the isomers (10a) and (10b) of diethyl 2-(1-hydroxyethyl)-3-benzylamino-4-methylpentanedioate (10a:10b=5:2) as obtained in Example 14 (2.15 g) was dissolved in tetrahydrofuran (4 ml), barium hydroxide (250 mg) and water (2 ml) were added thereto, and the resultant mixture was stirred vigorously at room temperature of 45 minutes. Insoluble materials were collected by filtration and washed with ethanol. The washing and the filtrate were combined together and concentrated under reduced pressure. The residue was subjected to thin layer chromatography, whereupon a new spot was revealed in addition to the spots corresponding to the starting material and the original point. The product as the new spot was collected and fractionally purified to give (2RS,3RS,4SR,5SR)-2-methyl-3-benzylamino-4-ethoxycarbonyl-5-hydroxyhexanoic acid (70 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[C:8]([CH2:11][CH2:12][CH2:13][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:10])=[O:9].[Br:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>O1CCCC1.CS(C)=O>[Br:33][C:34]1[CH:35]=[C:36](/[CH:37]=[CH:13]/[CH2:12][CH2:11][C:8]([OH:10])=[O:9])[CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: O=C(O)CC/C=C/c1cccc(Br)c1
Reaction time: 18 h

Procedure:
A 1M solution of potassium tert-butoxide in tetrahydrofuran (80 mL) was added dropwise to (3-carboxypropyl)triphenylphosphonium bromide (17 g, 40 mol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and the solution was stirred 30 min. before addition of 3-bromobenzaldehyde (4.7 mL, 40 mmol). After several minutes a precipitate was observed and an additional 20 mL of DMSO was added to aid solvation, and the reaction was stirred 18 h. The solution was poured onto water (120 mL) and washed with chloroform. The aqueous layer was acidified with conc. HCl and extracted with chloroform (3×250 mL). The organic phase was concentrated and applied to a 65i Biotage silica gel column, gradient elution from 15-65% B (A=Hexanes; B=ethyl acetate) over 2 L to give J.1, (E)-5-(3-bromophenyl)pent-4-enoic acid, 8.2 g (82%). 1H NMR (300 MHz, CDCl3) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H), 2.52 (s, 4H). LC (Cond.-J1): RT=2.0 min; LRMS: Anal. Calcd. for [M−H]− C11H11BrO2: 252.97; found: 252.98.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Naphthalene-2-boronic acid (0.119 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) in DME (2 mL) were combined in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.063 g in 63% yield.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C[O:8][C:9](=[O:34])[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[CH:28]=[C:27]([Cl:32])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[CH:12][C:11]=1Br>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.C(OCC)(=O)C>[CH:1]1([C:11]2[CH:12]=[C:13]([C:16]3[CH2:20][C:19]([C:25]4[CH:26]=[C:27]([Cl:32])[CH:28]=[C:29]([Cl:31])[CH:30]=4)([C:21]([F:24])([F:22])[F:23])[O:18][N:17]=3)[CH:14]=[CH:15][C:10]=2[C:9]([OH:34])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reactant: OB(O)C1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
A solution of cyclopropyl boronic acid (0.67 g), 2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoic acid methyl ester (3 g) and Bis(triphenylphosphine)palladium(II) chloride (210 mg) were sequentially added to degassed toluene (38 ml). The reaction mixture was stirred for 30 min at room temperature then a degassed aqueous 2N solution of potassium phosphate (7 ml) was added and the resulting mixture was heated at 110° C. overnight. The reaction mixture was filtered over Hyflo and the resulting solution was concentrated in vacuo to give a yellow oil, which was poured into ethyl acetate. The organic phase was washed with water, dried over sodium sulfate, and the solvents were evaporated in vacuo. The product was used as such for the saponification step, as described in Example 17, Step E to afford the title acid compound (2.5 g) as a yellow solid. LCMS (Method F) 2.15 min M−H 442/444.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1.[CH3:25][NH:26][CH3:27]>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[C:13]([S:15]([N:26]([CH3:27])[CH3:25])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=3[Cl:19])[N:7]=[CH:6][C:5]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:3][CH2:2]1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)Cl)ccc2Cl)c1C1CC1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cc(S(=O)(=O)N(C)C)ccc2Cl)c1C1CC1
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A solution of ethyl 5-cyclopropyl-1-(2-chloro-5-{chlorosulfonyl}phenyl)-1H-pyrazole-4-carboxylate (0.315 g, 0.812 mmol) in CH2Cl2 (3 mL) was treated at 23° C. with dimethylamine (2 M in THF, 3 mL, 6 mmol). The resulting mixture was stirred for 15 min and concentrated in vacuo. The residue was partitioned between EtOAc and HCl (0.1 M aq). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Flash 40S™ chromatography (65:35 hexanes-EtOAc) to afford 0.276 g (86% yield) of desired product as a colorless oil.