Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH2:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:37])[NH:35][OH:36])[N:33]=[C:29]4[N:28]=[C:27]([CH2:38][OH:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4cc(CO)nc5nc(C(=O)NO)nn45)CS[C@H]23)cs1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(C(=O)NO)nn34)CS[C@H]12)c1csc(N)n1)C(=O)NNC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (45 mg) (0.074 mmol) and 31 mg (0.096 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 3 ml of absolute dimethylacetamide. After stirring at room temperature for 24 hours the reddish solution is concentrated in a high vacuum. The residue is suspended in 6 ml of water and the product is filtered off under suction. After washing with water and diethyl ether and subsequently drying in a high vacuum there are obtained 50 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(hydroxycarbamoyl)-5-(hydroxymethyl)-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11](#[N:15])[CH:12]([CH3:14])[CH3:13].[F:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[C:21]([F:26])[C:18]=1[CH2:19]Br.O>C1COCC1>[CH3:13][C:12]([CH3:14])([CH2:19][C:18]1[C:21]([F:26])=[CH:22][CH:23]=[C:24]([F:25])[C:17]=1[F:16])[C:11]#[N:15]
Reactant: CC(C)C#N
Reactant: Fc1ccc(F)c(CBr)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C#N)Cc1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of lithium bis(trimethylsilyl)amide (LiHMDS) (1M in THF, 26.6 mL, 26.6 mmol) was added to a solution of isobutyronitrile (2.4 mL, 26.6 mmol) in THF at −78° C. and stirred for 25 minutes. 2,3,6-trifluorobenzyl bromide (2.3 mL, 17.8 mmol) was added and the reaction was warmed to room temperature and stirred for 1.5 h. Water was added to quench the reaction and it was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield 2,2-dimethyl-3-(2,3,6-trifluorophenyl)propanenitrile (34) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(OCC)(=O)C>COCCOC>[OH:16][CH:15]([CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:14][O:13][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:3]=1[O:2][CH3:1])[C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: C1CCNC1
Reactant: COc1cc2c(cc1OCC1CO1)CCC2=O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1cc2c(cc1OCC(O)CN1CCCC1)CCC2=O

Procedure:
A mixture of 6-methoxy-5-oxiranylmethoxy-indan-1-one (Intermediate M, 2.5 g, 0.0106 mole) and pyrrolidine (0.9 mL, 0.011 mole) was stirred in 50 mL of DME at 50° C. for 5 hrs under Argon. Then, 150 mL of ethyl acetate was added and the solution washed with water (2×). Following extraction with 2N HCl, the aqueous acidic layer was made basic with 3N NaOH and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over sodium sulfate and the solvent removed in vacuo. The resulting residue was triturated with diethyl ether to yield the title compound. MS m/z 306 (M+H)+.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[CH:11](=[O:15])[CH:12]([CH3:14])[CH3:13]>CCOCC.II>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:11]([OH:15])[CH:12]([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: CC(C)C=O
Reactant: Clc1ccc(CBr)cc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: CC(C)C(O)Cc1ccc(Cl)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
To a suspension of magnesium (2.98 g, 0.123 mol) in ether (30 mL) was added iodine (0.165 g, 0.000651 mol). To this was slowly added a solution of 4-chlorobenzyl bromide (24.00 g, 0.1168 mol) in ether (100 mL). Upon addition of approximately 1 mL of solution an exotherm was noted and the mixture reached reflux. The addition of solution was slowly continued to maintain a gentle reflux (˜90 min). On completion of addition, the reaction was heated for 30 minutes at 45° C. The reaction was then cooled to 0° C. Isobutyraldehyde (12.7 mL, 0.140 mol) in ether (10 mL) was then added slowly over 2 hours. On completion of the addition the reaction was allowed to warm to 23° C. and stirred overnight. The reaction was quenched with ice (˜200 g) and acidified with 2M HCl (˜100 ml). This was extracted twice with ether and the organic phase was evaporated. The residue was purified by flash chromatography (0 to 10% MeOH/CH2Cl2) to afford the title compound (9.89 g, 43%).
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.[CH2:17]([OH:20])[CH2:18][OH:19].N1C(C)=CC=CC=1C>O.[B-](F)(F)(F)F.[Ag+]>[OH:19][CH2:18][CH2:17][O:20][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: OCCO
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: Cc1cccc(C)n1
Product: O=C(O)CCCCCCC1=CC(OCCO)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 19.1 g. of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1-one (Example 93) in 310 ml. of ethylene glycol is added 15.6 g. (80 mmole) of silver fluoborate during 2 minutes. The exothermic reaction is controlled to give a temperature of 29° C., and after 1 minute the mixture is treated during 1 minute with 8.6 g. (80 mmole) of 2,6-lutidine. The mixture is stirred at ambient temperature for 2 hours, diluted with water, and filtered. The filtrate is diluted with saturated sodium chloride solution and extracted with ether. The extract is washed with half-saturated sodium chloride solution containing a little hydrochloric acid and saturated sodium chloride solution. The extract is dried over magnesium sulfate and concentrated. Column chromatograph of the residue on silica gel gives an oil, λ maxMeOH = 216 mμ (8350); ν max = 3340 (hydroxyl groups), 1700 (carbonyl groups), and 1620 cm -1 (olefin group).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH3:4].[CH2:6]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8].O>C1(C)C=CC=CC=1>[CH:1](/[N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:6][CH:7]([CH3:9])[CH3:8])=[CH:2]\[CH2:3][CH3:4]
Reactant: CC(C)CNCC(C)C
Reactant: CCCC=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC/C=C/N(CC(C)C)CC(C)C
Temperature: 130 °C
Yield: 73.8 %

Procedure:
Butanal (68 mL, 0.75 mol) was added dropwise over 20 minutes to a solution of diisobutylamine (87 mL, 0.50 mol) in toluene (100 mL) at room temperature under a nitrogen atmosphere. After installation of a Dean-Stark tube, the mixture was warmed to 130° C. and refluxed. 50 mL of distillate containing water was extracted twice. The reaction mixture was cooled to room temperature and then distilled under reduced pressure (0.25 mmHg, 51-55° C.) to obtain the title compound (67.67 g, yield: 74%) as a colorless oil substance.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH3:13])=[O:11])(OCC)=O)C.[Li]CCCC.[CH3:19][C:20]([CH3:24])([CH3:23])[CH:21]=O.O>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]=[CH:19][C:20]([CH3:24])([CH3:23])[CH3:21]
Reactant: CC(C)(C)C=O
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=CC(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Methyl diethylphosphonoacetate (13.35 mL, 73.6 mmol, 1.05 eq.) was dissolved in THF (30 mL) and cooled to −78° C. in an acetone-dry ice bath. n-BuLi (1.6M in hexanes) (45.8 mL, 73.2 mmol, 1.05 eq.) was added slowly over 20 min. Trimethylacetaldehyde (6.0 g, 69.6 mmol, 1.0 eq.), was added to the reaction and allowed to stir at −78° C. for 20 minutes and warmed to room temperature and stirred overnight. Water (30 mL) was added to quench and extracted with ethyl ether (3×100 mL). The combined organics were washed with brine and dried over MgSO4, filtered and evaporated to provide 4,4-Dimethyl-pent-2-enoic acid methyl ester, a colorless liquid (8.52 g, 60.0 mmol, 86%) and was used directly in the next reaction. 1H NMR (CDCl3, 400 MHz) δ 0.89 (s, 9H), 3.64 (s, 3H), 5.64 (d, 1H, J=16.0 Hz), 6.88 (d, 1H, J=16.0 Hz).
Reaction SMILES: CS(C)=O.[CH2:5]([OH:7])[CH3:6].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41](F)[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:49])[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:31]=[N:32][C:33]([NH2:48])=[C:34]([O:36][CH:37]([C:39]4[C:44]([Cl:45])=[CH:43][CH:42]=[C:41]([O:7][CH2:5][CH3:6])[C:40]=4[Cl:47])[CH3:38])[CH:35]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(Oc1cc(-c2ccc(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(Cl)c(C(C)Oc2cc(-c3ccc(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cnc2N)c1Cl
Temperature: 40 °C

Procedure:
To 4 mL of DMSO was added 0.124 ml ethanol followed by 32 mg NaH. After stirring for 30 minutes 250 mg of 250 mg 4-(4-{6-Amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction was heated to 40° C. After three hours the reaction was cooled and poured into water to precipitate. After neutralization to pH 6, 200 mg of a tan solid was isolated, 77%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[CH:26]=[CH:25][C:17]2[C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][O:20][C:16]=2[CH:15]=1)(=[O:12])=[O:11])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:31]O>>[CH3:31][O:23][C:22](=[O:24])[CH2:21][C:18]1[C:17]2[CH:25]=[CH:26][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])=[CH:15][C:16]=2[O:20][CH:19]=1
Reactant: CO
Reactant: O=C(O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1coc2cc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62 %

Procedure:
(6-{[(2-Nitrophenyl)sulfonyl]amino}-1-benzofuran-3-yl)acetic acid (2.84 g, 7.55 mmol) was suspended in methanol (8 mL), and thionyl chloride (2 mL, 27.4 mmol) was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-60% ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (1.82 g, yield 62%) as yellow prism crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=O)[NH:19][C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=2[NH2:27])[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N1C(C(=O)NC2C=CC(Br)=CC=2N)CC2(CC2)C1)=O)C1C=CC=CC=1>CC(O)=O>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]3[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=3[N:27]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Agent: Nc1cc(Br)ccc1NC(=O)C1CC2(CC2)CN1C(=O)OCc1ccccc1
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CC2(CC2)CC1c1nc2ccc(Br)cc2[nH]1
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of 6-(2-Amino-5-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester and 6-(2-Amino-4-bromo-phenylcarbamoyl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.446 g, 3.25 mmol) was dissolved in AcOH (20 mL) and the reaction mixture was stirred at 40° C. for 18 hours then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with saturated aqueous NaHCO3. The aqueous layer was extracted 2× with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated to provide 6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (1.385 g, 100%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:8][CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)CCO
Reactant: BrCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CC(C)CCOCCCCCCBr
Reaction time: 2 h

Procedure:
4.8 g (0.11 mol) of 55 % sodium hydride dispersion are added at 20°-40°C over the course of 1 hour, to 74 g (1.0 mol) of isopentyl alcohol. After stirring for 2 hours at 20°-25°C, 24.4 g (0.10 mol) of 1,6-dibromohexane are added dropwise over the course of 15 minutes. The mixture is stirred at 60°C for 16 hours, then filtered and the filtrate is taken up in ether. The ether solution is extracted with saturated sodium chloride slution, dried with sodium sulphate and evaporated at 40°C/18 mm Hg. After chromatography of the residue on silica gel with hexane/ethyl acetate (99:1) and subsequent distillation (B.P. 85°-87°/1 mm), 1-bromo-6-isopentyloxy-hexane is obtained as a slightly yellow clear liquid.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[CH3:20][CH2:21][CH:22]([OH:25])[CH2:23][CH3:24]>>[CH2:21]([CH:22]([O:25][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1)[CH2:23][CH3:24])[CH3:20]
Reactant: CCC(O)CC
Reactant: Cc1cc(C)c(Cc2nc(C)nc(Cl)c2C)c(C)c1
Product: CCC(CC)Oc1nc(C)nc(Cc2c(C)cc(C)cc2C)c1C

Procedure:
The title compound was prepared by the method analogous to that in Example 32 starting with 4-Chloro-2,5-dimethyl-6-(2,4,6-trimethyl-benzyl)-pyrimidine and 3-pentanol. White crystals, mp. 82–84° C.
Reaction SMILES: [H-].[Na+].O[CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[C:22]([O:25][CH2:26][CH3:27])(=[O:24])[CH3:23]>COCCOC>[CH2:14]([N:5]1[C:6](=[O:13])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]1[CH2:23][C:22]([O:25][CH2:26][CH3:27])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(C)=O
Reactant: O=C1c2ccccc2C(O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 20 °C

Procedure:
Ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate is prepared as described in Example 2, starting with 3.2 g of 60% sodium hydride in 200 cm3 of 1,2-dimethoxyethane, 16.4 cm3 of triethyl phosphonoacetate and 9.5 g of 3-hydroxy-2-benzyl-2,3-dihydroisoindol-1-one. The mixture is refluxed for 18 hours and is then cooled to a temperature in the region of 20° C. The reaction mixture is treated with 100 cm3 of water and then with 100 cm3 of ethyl acetate. After separation of the phases by settling, the aqueous phase is extracted twice with 100 cm3 of ethyl acetate. The organic extracts are combined, washed with 50 cm3 of brine, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is purified by chromatography under argon pressure (60 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of cyclohexane/ethyl acetate (75/25 and then 67/33 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 8.7 g of ethyl (2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate are thus obtained in the form of a viscous yellow oil. (Rf=0.35, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.C1(=O)O[CH2:14][CH2:13][O:12]1>>[OH:12][CH2:13][CH2:14][N:10]1[C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: O=C1OCCO1
Reactant: Cc1nc2cnccc2[nH]1
Product: Cc1nc2ccncc2n1CCO
Temperature: 150 °C
Yield: 8.6 %

Procedure:
2-Methylimidazo[4,5-c]pyridine (10.6 g) was mixed with ethylene carbonate (8.3 g) and heated as a melt at 150° C. for 1/2 hour. The crude black product was chromatographed on silica eluting with 40% methanol in ethyl acetate. The fraction with Rf 0.33 in methanol, ethyl acetate, (2:3) was evaporated and was identified as a mixture of the title compound and of the isomeric 1-(2-hydroxyethyl)-2-methylimidazo[4,5-c]pyridine. The mixture was chromatographed on silica eluting with 20% methanol in acetone. Fractions containing the more mobile isomer were combined and evaporated yielding the title compound (1.22 g, 9%) as a foam.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([NH:15][CH:16]=O)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:18]I>>[CH3:1][O:3][CH2:4][CH:5]([N:15]([CH3:16])[CH3:18])[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CI
Reactant: O=CNC(CCOc1ccccc1)COC=O
Product: COCC(CCOc1ccccc1)N(C)C

Procedure:
2-(formylamino)-4-phenoxy-1-butanol formate, described in Example 3, with methyl iodide, followed by reduction, gives 1-methoxy-N,N-dimethyl-4-phenoxy-2-butanamine,
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([C:37]3[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=3)[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: OB(O)c1cccnc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)N(c1cccnc1)CN2c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
8-(3,5-Bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one (253 mg) was dissolved in dichloromethane (5 mL), 3-pyridineboronic acid (246 mg), triethylamine (101 mg) and copper(II)-acetate (136 mg) were added. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (hexane/ethylacetate=2:1) to yield the desired product (120 mg, 41%), MS: m/e=583.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.[H][H]>CO.[Pd]>[NH2:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[F:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(C(=O)O)ccc1F

Procedure:
4-Fluoro-3-nitrobenzoic acid (270 mg, 2 mmol) and 10% Pd/C (80 mg) in MeOH (10 mL) was hydrogenated with a hydrogen balloon for 6.0 h. LC-MS indicated a completion of reaction. The mixture was filtered and the filtrate was concentrated to give 19A. 1H NMR (400 MHz, CDOD3) δ ppm 7.00 (dd, J=10.99, 8.79 Hz, 1H) 7.27-7.36 (m, 1H) 7.49 (dd, J=8.79, 2.20 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].[C:15]([Cu])#[N:16].[Li+].[Br-]>O1CCCC1.C1(C)C=CC=CC=1>[F:13][CH:12]([F:14])[O:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cccc(OC(F)F)c1Br
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1c(OC(F)F)cccc1[N+](=O)[O-]
Temperature: 200 °C
Yield: 84.6 %

Procedure:
A mixture of 2-bromo-1-difluoromethoxy-3-nitro-benzene (1 g, 3.7 mmol), CuCN (0.40 g, 4.5 mmol) and LiBr (0.32 g, 3.7 mmol) in tetrahydrofuran (10 ml) are heated in a microwave oven at 200° C. for 40 minutes. The reaction mixture is cooled to ambient temperature, diluted with toluene and washed with aqueous sodium bromide (1M) and aqueous sodium hydrogen sulfite (saturated). The organic phase is dried over sodium sulfate and concentrated. The residue is purified by HPLC to give 2-difluoromethoxy-6-nitrobenzonitrile (0.67 g, 84% yield). 1H-NMR (CDCl3, 400 MHz): 8.20 (d, 1H), 7.85 (t, 1H), 7.75 (d, 1H), 6.75 (t, 1H) ppm.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)[NH2:29]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:29]=[C:28]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=4)[N:27]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: COc1cccc(C(N)=NO)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(OC)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 37 mg (0.22 mmol, 1.2 eq.) of N′-hydroxy-3-methoxybenzenecarboximidamide were reacted according to the General Method 1. Yield: