Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C([N-]C(C)C)(C)C.[Li+].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[CH:28]=[CH2:29]>O1CCCC1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[C:12]([F:18])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:29][CH2:28][C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CCOC(=O)C(F)N1C(=O)c2ccccc2C1=O
Reactant: C=CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(CCC(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 2-(1,3-dioxoisoindolin-2-yl)-2-fluoroacetate (0.80 g, 3.2 mmol) in tetrahydrofuran (30 mL) is added lithium diisopropylamide (1.7 mL, 3.4 mmol, 2M) at -78° C. After 30 minutes, t-butyl acrylate (0.42 g, 3.2 mmol) is added to the mixture which is allowed to reach room temperature. The solvent is removed in vacuo and the residue stirred with methylene chloride (50 mL) and water (30 mL) for 10 min. The organic layer is washed with brine (30 mL), and dried over sodium sulfate. The solvent is removed in vacuo to give tert-butyl 4-(1,3-dioxoisoindolin-2-yl)-4-fluoro-4-ethoxycarbonylbutanoate which is further purified by column chromatography.
Reaction SMILES: C(OC([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])=[O:18])=[CH:9][C:8]=1[O:35][CH3:36])=O)C.O.C(=O)([O-])[O-].[Na+].[Na+].Cl>CO>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH:15]=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([CH2:24][CH2:25][CH:26]=[C:27]([CH2:29][CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH3:28])[CH3:23])=[O:18])=[CH:9][C:8]=1[O:35][CH3:36]
Reactant: CCOC(=O)Oc1ccc(C=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C)cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C=CC=CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)C)ccc1O
Reaction time: 3 h
Yield: 67.7 %

Procedure:
To a solution of 0.38 g of farnesyl 5-(4-ethoxycarbonyloxy-3-methoxyphenyl)-2,4-pentadienoate in 10 ml of methanol are added 2 ml of water and 0.08 g of sodium carbonate followed by stirring for 3 hours. To the reaction mixture is added 10 ml of water. The mixture is acidified with 1N hydrochloric acid and then extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure, and the residue is subjected to column chromatography on silica gel. From the fraction eluted with chloroform is obtained 0.22 g of farnesyl 5-(4-hydroxy-3-methoxyphenyl)-2,4-pentadienoate (10). Spectroscopic data of the product support the structure of the formula (10) below.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1)[CH2:7]2.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O.[BH4-].[Na+].[NH4+].[Cl-]>CO.O>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][NH:1][CH2:2][CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]1[N:10]=[CH:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1)[CH2:7]2
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1cnc(N2CC3C(CN)C3C2)nc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cnc(N2CC3C(CNCc4ccc5ccccc5c4)C3C2)nc1
Reaction time: 0.17 h

Procedure:
Ethyl 2-[6-(aminomethyl)-3-azabicyclo[3.1.0]hex-3-yl]pyrimidine-5-carboxylate (200 mg, 0.76 mmol) was stirred with 2-naphthaldehyde (119 mg, 0.76 mmol) in MeOH (10 ml) at r.t. under N2 for 16 h. NaBH4 (46 mg, 1.22 mmol) was then added and the mixture stirred for 10 min. Sat. aq. NH4Cl (20 ml) was added and the mixture stirred for 20 min. The reaction was then diluted with H2O (50 ml) and extracted with Et2O (2×100 ml). The combined organic layers were dried (MgSO4) and the solvent removed in vacuo to give the title compound as a yellow oil which was used in the next step without further purification. LCMS purity 92%, m/z 403 [M+H]+.
Reaction SMILES: Br.C([N:10]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]C1C#N)(=O)C1C=CC=CC=1.N.[C:25]([OH:28])(=[O:27])[CH3:26]>O>[C:25]([C:26]1[CH:12]=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:10]=1)([OH:28])=[O:27]
Reactant: COc1ccc2c(c1)C=CC(C#N)N2C(=O)c1ccccc1
Reactant: CC(=O)O
Agent: Br
Agent: N
Solvent: O
Product: COc1ccc2nc(C(=O)O)ccc2c1
Temperature: 90 °C

Procedure:
270 ml of 48% hydrobromic acid are added to a solution of 217 g (0,747 mol) of 1-benzoyl-2-cyano-6-methoxy-1,2-dihydroquinoline in 270 ml of acetic acid, and the mixture is heated at reflux for 30 min. It is filtered and rinsed with diethyl ether, and the solid obtained is then suspended in 2 l of water and heated to 90° C. Aqueous ammonia is then added until the pH=8-9 and the mixture is filtered while hot. The filtrate is acidified at 50° C., by adding acetic acid until the pH=4-5, and is then cooled. The crystallized product is filtered off, rinsed with water and then recrystallized from 250 ml of acetic acid and rinsed with diethyl ether. 129 g of product are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[CH:5]=[N:6][CH:7]=1.Br[C:12]1[CH:13]=[CH:14][C:15]([C:18]2([C:28]#[N:29])[CH2:27][CH2:26][C:21]3([O:25][CH2:24][CH2:23][O:22]3)[CH2:20][CH2:19]2)=[N:16][CH:17]=1.CN(CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I.O>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:3]=1)[C:8]([NH:10][C:12]1[CH:17]=[N:16][C:15]([C:18]2([C:28]#[N:29])[CH2:27][CH2:26][C:21]3([O:22][CH2:23][CH2:24][O:25]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:9]
Reactant: N#CC1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reactant: NC(=O)c1cncc(Br)c1
Agent: [Cu]I
Agent: CCN(C)C
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: N#CC1(c2ccc(NC(=O)c3cncc(Br)c3)cn2)CCC2(CC1)OCCO2
Temperature: 100 °C
Reaction time: 6 h
Yield: 13.2 %

Procedure:
A solution of 5-bromopyridine-3-carboxamide (734 mg), 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile (1.18 g) described in Reference Example 82, copper (I) iodide (35 mg), N,N-dimethylethylamine (33 mg) and potassium carbonate (1.01 g) in 1,4-dioxane (5 ml) was stirred at 100° C. for six hours. After completion of the reaction, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified with column chromatography to give 5-bromo-N-[6-(8-cyano-1,4-dioxaspiro[4.5]dec-8-yl)pyridin-3-yl]nicotinamide (213 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].Br[CH2:23][C:24]([CH:26]1[CH2:28][CH2:27]1)=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]1([C:24](=[O:25])[CH2:23][O:21][C:3]2[C:2]([F:1])=[CH:17][C:16]([N+:18]([O-:20])=[O:19])=[CH:15][C:4]=2[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[CH2:28][CH2:27]1
Reactant: O=C(CBr)C1CC1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCC(=O)C1CC1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 17D (1.15 g, 3.83 mmol) in DMF (10 mL) was added 21A (1.486 g, 3.69 mmol), K2CO3 (2.65 g, 19.15 mmol). The mixture was stirred 60° C. for 2 h, quenched with water, extracted with EtOAc (2×). The extract was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography to give 21B (1.486 g, 3.69 mmol, 96% yield). MS (ESI) m/z: 383.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:15]([C:17]1[C:29]([O:30][CH3:31])=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[C:19]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:18]=1)=O.C[O-].[Li+]>CN(C=O)C.CO.O>[CH3:14][S:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:15]/[C:17]2[C:29]([O:30][CH3:31])=[CH:28][C:20]([O:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[C:19]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[CH:18]=2)=[CH:9][CH:8]=1)(=[O:12])=[O:13]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1C=O
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1cc(OC(C)(C)C(=O)O)c(-c2cccs2)cc1/C=C/C(=O)c1ccc(NS(C)(=O)=O)cc1
Reaction time: 5 h
Yield: 15.5 %

Procedure:
A solution of N-(4-acetyl-phenyl)-methanesulfonamide (Ex-100A, 279.6 mg, 1.31 mmol) and 2-(4-formyl-5-methoxy-2-thiophen-2-yl-phenoxy)-2-methyl-propionic acid (Ex-47D, 400 mg, 1.20 mmol) in DMF (5.25 mL) and MeOH (2.25 mL) was treated with lithium methoxide (182.2 mg, 4.8 mmol) and stirred for 5 hours at room temp. under nitrogen atmosphere. The reaction mixture was diluted with water (25 mL) which was then extracted with isopropyl acetate (2×50 mL). The aqueous portion was collected and acidified to a pH of 3 with 3N HCl. The aqueous solution was then extracted with isopropyl acetate (2×50 mL). The organic was collected, dried over sodium sulfate, and concentrated to a green solid. Attempted to recrystallize crude material from ethanol/hexanes; however, this mixture was concentrated and stirred with ethyl acetate (3 mL) to give 95.6 mg (14%) of the title compound as a yellow solid, mp 181–183° C. 1H-NMR (DMSO-d6) δ 10.31 (br s, 1H), 8.24 (s, 1H), 8.12 (d, 2H), 7.95 (d, 1H), 7.87 (d, 1H), 7.67 (d, 1H), 7.50 (d, 1H), 7.30 (d, 2H), 7.09 (t, 1H), 6.45 (s, 1H), 3.81 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H). MS m/z=516 ([M+H]+, 100%). HRMS m/z: calc. 516.1150, found 516.1165.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[C:8](=[O:24])[C:9]2[C:14]([C:15](=[O:23])[C:16]=1[CH2:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:13][CH:12]=[CH:11][CH:10]=2)(=O)C>C1COCC1>[CH3:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]1[C:15](=[O:23])[C:14]2[C:9]([C:8](=[O:24])[C:7]=1[OH:6])=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(=O)OC1=C(CCC(C)(C)C)C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1=C(O)C(=O)c2ccccc2C1=O
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Sodium hydroxide solution (1M; 100 ml) was added to a solution of 2-ethanoyloxy-3-(3,3-dimethylbutyl)-naphthalene-1,4-dione (3.5 g)(see Example 44) in THF (100 ml) at room temperature and stirred for 4 hours. The THF was removed under vacuum and the resultant solution was washed with diethyl ether (3x). The aqueous layer was acidified then extracted with diethyl ether (x3), the combined extracts washed with water, dried over magnesium sulphate then evaporated to dryness under vacuum to yield 3 g title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[C:16]1([CH2:22][CH2:23][SH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:6][N:5]=[C:4]([CH3:15])[C:3]=2[CH2:2][S:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: SCCc1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Product: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 51, Step 1, using 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 2-phenylethanethiol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[F:13][CH2:14][C:15](O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:12]=[C:15]([CH2:14][F:13])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(O)CF
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)c2nc(CF)[nH]c2c1
Yield: 75.4 %

Procedure:
To a 250 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (6.75 g, 29.1 mmol) and 2-fluoroacetic acid (4.54 g, 58.2 mmol) in Toluene (100 mL). The solution was heated to reflux 48 h. The reaction was found to be incomplete so an additional equivalent of acid (2.25 g) was added and solution was heated 6 hours. The mixture was allowed to cool and was evaporated. The residue was dissolved in 20 ml of DCM and was filtered through a sintered glass funnel where a brown precipitate (5.5 g, 69%) was isolated to obtain 4-bromo-2-(fluoromethyl)-6-nitro-1H-benzo[d]imidazole (6.01 g, 21.93 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 5.69 (s, 1H) 5.81 (s, 1H) 8.33 (d, J=2.02 Hz, 1H) 8.49 (br. s., 1H); LC/MS: MS (ES+) m/e 275 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=NN(C)C.C(OCC)(=[O:25])C>O1CCCC1.P([O-])([O-])([O-])=O.O.O.[Cu](Cl)Cl>[CH3:1][O:2][CH:3]([O:21][CH3:22])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[C:6]1=[O:25]
Reactant: COc1ccc2c(c1)C(=NN(C)C)C(CC(OC)OC)CC2
Reactant: CCOC(C)=O
Agent: Cl[Cu]Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(CC(OC)OC)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1,2,3,4-Tetrahydro-1-(dimethylhydrazono)-7-methoxy-2-naphthaleneacetaldehyde dimethyl acetal (45.0 g) was dissolved under argon in a mixture of 1800 ml of tetrahydrofuran and 645 ml of 0.067M phosphate buffer of pH value 7. The solution was treated with 19.8 g of copper(II) chloride dihydrate and stirred at room temperature for 16 hours. 1000 ml of ethyl acetate were added to the reaction mixture and it was washed three times with 1500 ml of a mixture of 25% ammonia solution and saturated ammonium chloride solution (1:19) each time. The aqueous wash phases were extracted twice with 1000 ml of ethyl acetate, the organic phases were combined, dried over MgSO4 and freed from solvent. There were obtained 39.7 g of crude 1,2,3,4-tetrahydro-7-methoxy-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal which was processed without purification.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]([OH:16])=O)=[C:7]2[N:6]=[N:5]1.C(N=C=NCCCN(C)C)C.[C:28]([NH:36][NH2:37])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(#N)C>[C:28]([NH:36][NH:37][C:14]([C:13]1[N:12]=[CH:11][N:8]2[C:9](=[O:10])[N:4]([CH2:3][S:2][CH3:1])[N:5]=[N:6][C:7]=12)=[O:16])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CSCn1nnc2c(C(=O)O)ncn2c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CSCn1nnc2c(C(=O)NNC(=O)c3ccccc3)ncn2c1=O
Reaction time: 0.02 h
Yield: 65 %

Procedure:
3-(Methylthiomethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.73 mmol, 175 mg, 1 eq.), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (0.76 mmol, 146 mg, 1.05 eq.) and benzohydrazide (0.76 mmol, 104 mg, 1.05 eq.) were placed in a round bottom flask and dissolved in acetonitrile (3 mL). A suspension developed 1 minute after starting room temperature stirring and it was stirred for further 90 minutes. The reaction mixture was filtered and the obtained solid washed with water, acetonitrile and ether, and dried under vacuum. The filtrate was poured into ice/water and the filtration, washing and drying steps were repeated. Yield 65%. δH (DMSO-d6) 10.35 (1H, bs), 10.28 (1H, bs), 8.75 (1H, bs), 7.74 (2H, m), 7.37 (3H, m), 5.25 (2H, bs), 2.07 (3H, bs).
Reaction SMILES: [C:1]([C@@H:4]1[CH:9]2[CH2:10][CH2:11][CH:6]([CH2:7][CH2:8]2)[NH:5]1)(=[O:3])[NH2:2].[CH2:12]([O:14][C:15]([C@@H:17]([NH:21][C@H:22]([C:24](O)=[O:25])[CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C@@H:17]([NH:21][C@@H:22]([CH3:23])[C:24]([N:5]1[C@H:4]([C:1](=[O:3])[NH2:2])[CH:9]2[CH2:10][CH2:11][CH:6]1[CH2:7][CH2:8]2)=[O:25])[CH2:18][CH2:19][CH3:20])=[O:16])[CH3:13]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: NC(=O)[C@H]1NC2CCC1CC2
Product: CCC[C@H](N[C@@H](C)C(=O)N1C2CCC(CC2)[C@H]1C(N)=O)C(=O)OCC
Yield: 58 %

Procedure:
Using the (DCC/HOBT) peptide coupling method described by W. KONIG and R. GEIGER (Ber, 103, 788, 1970) the expected product is prepared from 0.02 mol of (3S)-3-carbamoyl-2-azabicyclo[2.2.2]octane, described in Patent FR 2,585,709, and 0.02 mol of (S)-N-[(S)-1-(ethoxycarbonyl)butyl]alanine, described by VINCENT et al (Tetrahedron Letters 23, (1982), 1677-1680), the product being purified by chromatography on silica gel (elution solvent: dichloromethane/ethanol, 90:10) and then lyophilized.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[F:26])=[C:6](\[C:9]1[CH:10]=[C:11]([CH:23]([CH3:25])[CH3:24])[CH:12]=[C:13]2[C:18]=1[N:17]([CH2:19][CH3:20])[CH2:16][CH2:15][C:14]2([CH3:22])[CH3:21])/[CH2:7][CH3:8])C.[H-]>>[CH2:19]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([CH:23]([CH3:25])[CH3:24])=[CH:10][C:9]=2/[C:6](/[CH2:7][CH3:8])=[C:5](/[F:26])\[CH2:4][OH:3])[C:14]([CH3:22])([CH3:21])[CH2:15][CH2:16]1)[CH3:20]
Reactant: CCOC(=O)/C(F)=C(/CC)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C
Agent: [H-]
Product: CC/C(=C(\F)CO)c1cc(C(C)C)cc2c1N(CC)CCC2(C)C

Procedure:
Following General Procedure F, (E)-3-(1-ethyl-6-isopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-8-yl)-2-fluoro-pent-2-enoic acid ethyl ester (Intermediate 16, 2.37 g, 9.08 mmol) and a 1 M solution of diisobutylalluminum hydride in hexanes (36.3 ml, 36.3 mmol) were reacted to give the title compound as light yellow oil after purification by flash chromatography (SiO2, first eluted with 5:95 ethyl acetate:hexane, followed by 1:9 ethyl acetate:hexane).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:2].FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4)=CC=2)=C(OC)C=1.C(OC(=O)CCBr)C>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][N:7]1[C:15]2[C:14](=[C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=4[O:32][CH3:33])=[CH:20][CH:19]=3)[CH:12]=[CH:11][CH:10]=2)[CH:9]=[CH:8]1)[CH3:2]
Reactant: CCOC(=O)CCn1ccc2ccc(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cc21
Agent: CCOC(=O)CCBr
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Product: CCOC(=O)CCn1ccc2c(COc3ccc(-c4cc(F)c(F)cc4OC)cc3)cccc21

Procedure:
3-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester was synthesized by a procedure similar to 3-[6-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-propionic acid ethyl ester from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and 3-bromo-propionic acid ethyl ester to yield the product as a clear to opaque oil/film (30 mg, 65%). LC-MS (ES) calculated for C27H25F2NO4, 465.2; found m/z 466 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH:12][C:13]2([CH3:16])[CH2:15][CH2:14]2)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:17]2[NH:21][C:20]3[CH2:22][NH:23][C:24](=[O:25])[C:19]=3[CH:18]=2)[N:3]=1.[Cl:26]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:26][C:18]1[C:19]2[C:24](=[O:25])[NH:23][CH2:22][C:20]=2[NH:21][C:17]=1[C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[N:10]=[C:11]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[C:2]([CH3:1])=[N:3]2
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CNC4=O)c2nc1NC1(C)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: Cc1nc2cccc(-c3[nH]c4c(c3Cl)C(=O)NC4)c2nc1NC1(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
To a 25-mL round-bottomed flask was added 2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (357) (68 mg, 0.20 mmol), N-chlorosuccinimide (33 mg, 0.24 mmol) (Alfa-Aesar, Ward Hill, Mass.), and CHCl3 (3 mL). The reaction mixture was stirred at RT for 16 h and partitioned between water (5 mL) and EtOAc (5 mL). The organic extract was washed with brine (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-3% MeOH in DCM to provide 3-chloro-2-(2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (358) (9 mg, 12% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.40 (dd, J=1.27, 7.73 Hz, 1H), 7.75 (s, 2H), 7.70 (dd, J=1.27, 8.12 Hz, 1H), 7.44 (t, J=7.82 Hz, 1H), 4.32 (s, 2H), 2.51 (s, 3H), 1.45 (s, 3H), 0.90-0.95 (m, 2H), 0.73-0.79 (m, 2H). m/z (ESI, +ve) 368.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:19][OH:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:23]([O-])([O-])=O.[K+].[K+]>[OH-].[K+].CC(C)=O.O>[CH3:23][O:20][CH2:19][C:10]1[N:11]=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Solvent: O
Product: COCc1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A solution of 5,6-diphenylpyridin-2-yl)methanol (Compound 90, 15 mg, 0.06 mmol), MeI (0.1 ml), K2CO3 (50 mg) and KOH (5N, 5 drops) in acetone was heated at 56° C. over night. The mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as a solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH2:6])=[NH:5].CC[O-].[Na+].[C:11]([OH:19])(=[O:18])/[C:12](=[C:14](\[CH:16]=O)/[Br:15])/Br>CCO>[Br:15][C:14]1[C:12]([C:11]([OH:19])=[O:18])=[N:5][C:4]([CH2:3][O:2][CH3:1])=[N:6][CH:16]=1
Reactant: COCC(=N)N
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCc1ncc(Br)c(C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 38.9 %

Procedure:
To a solution of 2-methoxy-acetamidine (7.21 g, 89.19 mmol) in EtOH (50 ml) was added sodium ethylate (26 ml, 22% solution in EtOH) and the reaction mixture was heated to 50° C. for 30 min. A solution of mucobromic acid (6.5 g, 38.77 mmol) in EtOH (50 ml) was added followed by sodium ethylate (14 ml, 22% solution in EtOH), and the reaction mixture was continued to stir at 50° C. for 1 h. After filtration and solvent evaporation, water (5 ml) was added, the reaction mixture was cooled to 0° C. and acidified with 2N HCl solution to pH ˜6. After evaporation of water, the residue was dissolved in MeOH, filtered, and the filtrate was evaporated. The crude material was purified by silica gel chromatography using a methanol/methylenechloride eluent as solvent to yield 3.73 g (60%) of the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][N:15](C=O)[CH2:14][CH2:13]2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[OH-].[Na+]>CO>[N:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: O=CN1CCN(c2ccccc2-n2cccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(-n2cccc2)c(N2CCNCC2)c1
Temperature: 50 °C
Yield: 77.3 %

Procedure:
A mixture of 4-(2-pyrrol-1-ylphenyl)piperazine-1-carbaldehyde (1.12 g, 4.4 mmol), sodium hydroxide (440 mg, 11 mmoL) and methanol (10 mL) was heated 14 hours at 50° C. The reaction mixture was allowed to cool to approximately 25° C. and then partitioned between water (20 mL) and dichloroethane (30 mL). The aqueous layer was separated and extracted with dichloroethane (3×30 mL). The combined dichloroethane was washed with brine and dried (K2CO3). The residue was purified by column chromatography on silica gel eluting with a gradient of 1 to 5% methanol/0.1% triethylamine/dichloroethane to give 1-(2-pyrrol-1-ylphenyl)piperazine (0.77 g, 3.4 mmol).