Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CN=C1.[CH3:6][CH:7]([O:9][C:10]1[C:11]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29]CC3C=CC=CC=3)=[CH:23][C:12]=2[S:13][C:14]=1[C:15]([NH:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[O:16])[CH3:8]>[Pd].C(O)(=O)C>[CH3:8][CH:7]([O:9][C:10]1[C:11]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([OH:29])=[CH:23][C:12]=2[S:13][C:14]=1[C:15]([NH:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1)=[O:16])[CH3:6]
Reactant: COc1cc2c(OC(C)C)c(C(=O)Nc3nnn[nH]3)sc2cc1OCc1ccccc1
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CC(=O)O
Product: COc1cc2c(OC(C)C)c(C(=O)Nc3nnn[nH]3)sc2cc1O
Reaction time: 33 h
Yield: 28.6 %

Procedure:
A slurry of 3-(1-methylethoxy)-5-methoxy-6(phenylmethoxy)-N-1H-tetrazol-5-yl-benzo[b]thiophene2-carboxamide imidazole salt (1.55 g, 3 mmoles) and 20% palladium on carbon (0.5 g) in acetic acid (250 mls) is shaken under hydrogen (50 psig) in a Parr apparatus at 40° C. After 19 hours an additional 0.5 g of catalyst and acetic acid (250 mls) are added and shaking continued at 50° C. for 33 hours. The catalyst is filtered from the cooled mixture and rinsed with acetic acid. The filtrate is stripped of solvent under reduced pressure to leave the crystalline product. Recrystallization from methanol gave the pure 3-(1-methylethoxy)-5-methoxy-6-hydroxy-N-lH-tetrazol-5-yl-benzo[b]thiophene-2-carboxamide (0.3 g): mp=245° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][Cl:36]>CN(C=O)C>[Cl:36][CH2:35][CH2:34][CH2:33][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(OCCCCl)cc13
Temperature: 50 °C
Yield: 73.9 %

Procedure:
To a stirred solution of 3-hydroxy-N-(tert-butyloxycarbonyl)morphinan (20 mg, 0.058 mmol) in dry DMF (0.3 mL) was added potassium carbonate (24 mg, 0.174 mmol), 1-bromo-3-chloropropane (17.3 μL, 0.174 mmol) sequentially and the mixture was stirred at 50° C. After starting material disappeared on TLC, solvent was removed and column chromatography gave 18 mg (74%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.05 (1H, m); 6.83 (1H, d); 6.75 (1H, d.d.); 4.28 (1H, d); 4.05 (2H, t); 3.90 (1H, m); 3.83 (3H, t); 3.15 (1H, m); 2.60 (2H, m); 2.30 (1H, m); 2.15 (1H, m); 1.30 (9H, s); 1.00˜1.80 (10H, m).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[CH2:7]([P:9]([CH2:15][O:16][S:17]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])(=[O:19])=[O:18])(=O)[O:10]C(C)C)[CH3:8]>ClCCCl>[CH2:7]([P:9]([Cl:2])([CH2:15][O:16][S:17]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27])(=[O:19])=[O:18])=[O:10])[CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCP(=O)(COS(=O)(=O)c1c(C)cccc1Cl)OC(C)C
Solvent: ClCCCl
Product: CCP(=O)(Cl)COS(=O)(=O)c1c(C)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Phosphorus pentachloride, 8.32 g, was added in approximately three equal portions over 15 minutes to a mixture at 20° C. of 11.4 g of O-isopropyl P-ethyl[[(2-chloro-6-methylphenyl)-sulfonyloxy]methyl]phosphinate (Compound 119) and 30 ml of 1,2-dichloroethane. Each addition of the phosphorus pentachloride caused a mild exotherm, but the reaction temperature did not exceed 32° C. The reaction slowly cooled to room temperature and was allowed to stir for 72 hours. A 3 ml aliquot of the reaction mixture was concentrated and analyzed by 31P NMR. The 31P NMR indicated that the reaction was complete. The remainder of the reaction mixture was concentrated, 100 ml of toluene was added, the mixture reconcentrated and then high vacuum was pulled on the sample at 55° C. for one hour to yield 10.5 g of the crude desired product.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]([C:19]#N)(C)[C:15](N)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+]>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH3:19])[C:15]([OH:16])=[O:21])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C#N)(C(N)=O)c1cccc(Oc2ccccc2)c1
Reactant: [OH-]
Agent: [Na+]
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 106.4 g. of 2-(3-phenoxy-phenyl)-2-cyano-propionic acid amide, 200 ml. of 40% aqueous sodium hydroxide and 400 ml. of alcohol is boiled under stirring for 20 hours. The alcohol is then distilled off and the residue is diluted with 200 ml. of water. The aqueous solution is acidified to pH=1 by adding concentrated hydrochloric acid. The separating oil is extracted with 3×500 ml of benzene. The benzene solution is evaporated after drying above sodium sulphate. Thus 96 g. (98.5%) 2-(3-phenoxy-phenyl)-propionic acid are obtained; the product is suitable for the preparation of salts without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1>C(O)C>[O:1]=[C:2]1[CH:7]=[CH:6][C:5](=[N:8][C:9]2[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=2[C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:12])[CH:4]=[CH:3]1
Reactant: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1C=CC(=Nc2ccccc2C(=O)N2CCCCC2)C=C1
Yield: 35.1 %

Procedure:
A mixture of 8.9 g (0.03 mole) 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, 6.4 g (0.03 mole) of mercuric oxide, 80 ml of toluene and 20 ml of ethanol was heated at reflux for three hours. The reaction mixture was filtered through an alumina column and eluted with ethyl acetate. The solvent was removed in vacuo and the residue subjected to high pressure liquid chromatography, eluting with 20% ethyl acetate in hexane. The resulting 5.4 g of oil was partitioned between water and ether, the ether fraction dried over anhydrous sodium sulfate and concentrated, and the residue recrystallized from hexane to give 3.1 g of 1-{2-[(4-oxo-2,5-cyclohexadien-1-ylidene)amino]benzoyl}piperidine, orange powder, m.p. 74°-76° C.
Reaction SMILES: [C:1]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8])([O:3][CH2:4][CH3:5])=[O:2].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[C:1]([C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:14]=[O:16])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccccc1N=C=O

Procedure:
2-Carboethoxy-phenylisocyanate (0.20 g, 1.0 mmol) was prepared by the reaction of 2-carboethoxyaniline and triphosgene in toluene at reflux, followed by removing the solvent in vacuo. The isocyanate and the compound resulting from Example 1B (0.24 g, 1.0 mmol) were combined in 40 mL of toluene and heated at reflux for 3 hours. The product was then partitioned between 5% NaHCO3 and hot ethyl acetate, and the organic phase was dried (K2CO3) and evaporated. The resulting product was converted to its hydrochloride salt and recrystallized from ethanol-ether to yield 0.12 g of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.92 (d, 1H), 7.65 (t, 1H), 7.12-7.27 (m, 2H), 7.08 (t, 1H), 6.72 (dd, 2H), 4.02 (t, 2H), 3.73 (s, 3H), 3.12-3.3 (m, 3H), 2.52-2.65 (m, 3H), 2.38-2.48 (m, 2H), 2.1-2.3 (m, 2H), 1.57-1.68 (m, 1H), 1.37-1.5 (m, 1H). Anal calcd for C23H25N3O3 ·HCl·H2O: C, 61.95; H, 6.33; N, 9.42. Found: C, 61.94; H, 6.10; N, 9.18.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:14][O:15][C:16](=[O:28])[C@@H:17]([OH:27])[C@@H:18]([NH:26][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ncc2[nH]1

Procedure:
5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 170 mg, 0.86 mmol) and (3S,2S)-3-amino-2-hydroxy-4-phenylbutyric acid methyl ester (Preparation 21A, 174 mg, 0.83 mmol) were coupled under similar conditions to EXAMPLE 43 using HOBt (142 mg, 0.93 mmol), EDCI (200 mg, 1.04 mmol), DIPEA (0.32 ml, 1.87 mmol) in DMF (10 ml). The crude product was purified by chromatography on silica gel eluting with hexane/ethyl acetate (25:75) to give the title compound as a colourless oil. δH (CDCl3): 3.04 (4H, 2dd), 3.74 (3H, s), 4.36 (1H, br s), 4.63 (1H, m), 4.98 (1H, ddd), 6.66 (1H, s), 6.96 (1H, d), 7.18–7.35 (5H, m), 7.48 (1H, s), 8.63 (1H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[C:7]=2[N:8]=1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1.CCN(CC)CC>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Ag+2]>[CH:16]1([CH2:15][O:13][C:9]2[C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[CH:12]=[CH:11][N:10]=2)[CH2:18][CH2:17]1
Reactant: BrCC1CC1
Reactant: CSc1ncc2cc[nH]c(=O)c2n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CSc1ncc2ccnc(OCC3CC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.4 %

Procedure:
A suspension of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one (Preparation 32, 502 mg, 2.60 mmol) and silver carbonate (988 mg, 3.58 mmol) in CHCl3 (25 mL) was treated with bromomethyl cyclopropane (310 μl, 3.19 mmol) and stirred at room temperature for 18 hours. The mixture was stirred at reflux for 4 hours and additional bromomethyl cyclopropane (310 μl, 3.19 mmol) was added. The reaction was stirred for 18 hours at 6° C. Further bromomethyl cyclopropane (310 μl, 3.19 mmol) was added and heated continued for 2 hours. Et3N was added (6 mL), the mixture filtered through celite washing with DCM and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with 0 to 80% EtOAc in cyclohexane to give the title compound (112 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22].BrC1C=[C:28]2[C:33](=CC=1)[NH:32][C:31](=O)[C:30](OC1C=CC=CC=1)=C2O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:32]([CH2:33][CH3:28])[CH2:31][CH3:30])[C:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:5]2[C:21]([F:24])([F:23])[F:22]
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1Oc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Product: CCN(CC)c1nc2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
The title compound was prepared using 6-bromo-2-chloro-3-(4-chlorophenoxy)-4-(trifluoromethyl)quinoline (Intermediate 7, step d) in place of 6-bromo-2,4-dichloro-3-phenoxyquinoline (Intermediate 5, step c) according to the procedure described in Intermediate 5, step d except the reaction mixture was heated at 60° C. under reflux condenser for 12 hours.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CC(=O)CC>[C:1]1([O:11][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CBr
Reactant: Oc1cccc2c1CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)COc1cccc2c1CCCC2

Procedure:
10 g 5,6,7,8-tetrahyro-1-naphthol are dissolved in 150 ml 2-butanone and then 18.5 g potassium carbonate and 12.3 g methyl bromoacetate are introduced into the mixture. After having been refluxed for 24 hours, the mixture is filtered, the solvent evaporated under reduced pressure and after removal of the starting phenol soluble in aqueous basic medium, 13.1 g of final product are distilled.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[O:12][C:13](=[O:14])[C:3]1=2.[CH3:16][OH:17]>>[CH3:16][O:17][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[C:13]([OH:12])=[O:14])=[O:15]
Reactant: CO
Reactant: Cn1c2c(c3ccccc31)C(=O)OC2=O
Product: COC(=O)c1c(C(=O)O)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
An ice cold solution of dimethyl 1H-indole-2,3-dicarboxylate (3 g, 12.86 mmol) in N,N-dimethylformamide (DMF) (31.5 ml) was treated with NaH (0.617 g, 15.44 mmol) and methyl iodide (0.881 ml, 14.15 mmol) and warmed to 75° C. After 8 h, the reaction mixture was partitioned between EtOAc and sat. aq. NH4Cl. The combined organics were washed with water (3×), brine, dried (MgSO4), filtered and concentrated. The residue was treated with a solution of KOH (8.66 g, 154 mmol) in EtOH (200 mL) and heated to reflux (95° C. bath temp). After 8 h, the reaction mixture was cooled to ambient temperature, diluted with EtOAc and the layers partitioned. The aqueous layer was extracted with EtOAc (2×) and acidified with 1 M HCl to pH 3. The aqueous layer was then extracted with EtOAc and the organics were washed with brine, dried (MgSO4), filtered and concentrated to afford 1-methyl-1H-indole-2,3-dicarboxylic acid (2.82 g, 12.87 mmol, 100% yield) as a white solid. The acid was suspended in DCM (30 mL) and treated dropwise with TFAA (4.39 ml, 32.2 mmol). After 2 h, the reaction mixture was concentrated in vacuo to afford 4-methyl-1H-furo[3,4-b]indole-1,3(4H)-dione as a purple solid. The anhydride was suspended in MeOH (100 mL) and stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo to afford 3-(methoxycarbonyl)-1-methyl-1H-indole-2-carboxylic acid (2.95 g, 12.65 mmol, 98% yield) as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ=8.00 (s, 1 H), 7.64 (d, J=8.4 Hz, 1 H), 7.40-7.33 (m, 1 H), 7.28 (s, 1 H), 3.82 (d, J=5.7 Hz, 6 H); LCMS (m/z) ES+=234 (M+1).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Si:23]([O:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]#[CH:43])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>[Cu]I.C(#N)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:43]#[C:42][CH2:41][N:33]([CH2:32][CH2:31][O:30][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:37])[CH3:38])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCO[Si](C)(C)C(C)(C)C
Yield: 47.1 %

Procedure:
The sub-titled compound was prepared from N-(1 adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.37 g), tert-butyl (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)prop-2-yn-1-ylcarbamate (Example 11(i)) (0.54 g), copper (I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (6 ml) and anhydrous acetonitrile (6 ml) by the method of Example 2(iii). The crude product was purified by chromatography on silica gel eluting with, iso-hexane:ethyl acetate (8:1 to 4:1) to afford the sub-titled compound (0.28 g) as a yellow gum.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[CH:29](=O)/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>CN(P(N(C)C)(N(C)C)=O)C.C1COCC1>[C:2]([OH:4])(=[O:3])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:29][CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCC/C=C/C=O
Reactant: O=C(O)CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCCCCC=CC=CCCCCC(=O)O
Yield: 42.6 %

Procedure:
This compound was synthesized from 5-carboxypentyltriphenylphosphonium bromide (9.50 g, 20 mmol) and 2-trans-octenal (2.52 g, 20 mmol) in 10% HMPA-THF (100 mL) by Wittig reaction. Kugelrohr distillation yielded the product (1.91 g, 43%) as a pale yellow oil (bp 122-125° C./0.01 torr). IR: 3500-2500, 1730 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.40 (m, 10H), 2.30 (m, 6H), 6.00 (m, 4H), 11.30 (bs, 1H). Anal. Calcd. for C14H24O2 : C, 74.95, H, 10.78%; Found: C, 75.04, H, 10.80%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]=1[C:16]#[N:17])(=O)=O.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[N+:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]=1[C:16]#[N:17])([O-:15])=[O:14]
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cccc1[N+](=O)[O-]
Reactant: OB(O)c1ccccc1
Product: N#Cc1c(-c2ccccc2)cccc1[N+](=O)[O-]

Procedure:
Prepared as in Example 129c from 2-cyano-3-nitrophenyl trifluoromethanesulfonate (Example 129d) and phenylboronic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N:12]=[CH:13][N:14](C)C.Cl.[CH3:18][O:19]N>C(O)C>[CH3:18][O:19][N:14]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1
Reactant: CN(C)C=Nc1cnc2ccccc2c1Cl
Reactant: CON
Agent: Cl
Solvent: CCO
Product: COn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A solution of N′-(4-chloroquinolin-3-yl)-N,N-dimethylimidoformamide (10.9 g, 46.6 mmol) and O-methylhydroxylamine hydrochloride (3.9 g, 47 mmol) in ethanol (100 mL) was heated at reflux for 4.5 hours. An analysis by LC/MS indicated the reaction was incomplete, and additional O-methylhydroxylamine hydrochloride (2.0 g, 24 mmol) was added. The reaction was heated at reflux overnight, allowed to cool to room temperature, and concentrated under reduced pressure. The work-up and purification procedures described in Part C of Example 19 were followed with the modification that chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent. 1-Methoxy-1H-imidazo[4,5-c]quinoline (approximately 3.7 g) was obtained as a red solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:17]2[N:35](CC(=O)C3C=CC=CC=3)[CH2:36][NH:37][C:16]=2[CH2:15]1)=[O:13].C(#N)C>CCOCC>[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C:17]2[N:35]=[CH:36][N:37]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[CH2:15]1)=[O:13]
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Reactant: Cc1cccc(CBr)c1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.7 mL 3-methylbenzyl bromide, 5.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenylethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 50 mL acetonitrile is heated at reflux 4 hr. The cooled solution is added dropwise to 750 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 75 mL methanol and treated with 16 g zinc dust and 75 mL acetic acid. The resulting suspension is sonicated 6 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 650 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 4.97 (s, 2H, NCH2Ar).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCc1ccc(OCc2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(OCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-benzyloxy-pyridin-2-yl)-methanol described in Preparation Example 183 (2.00 g, 9.29 mmol) in tetrahydrofuran (40 mL) were added phthalimide (1.50 g, 10.2 mmol), triphenylphosphine (2.92 g, 11.1 mmol) and diethyl azodicarboxylate (5.08 mL, 11.1 mmol, 40% toluene solution) at 0° C., and the solution was stirred at room temperature for 2 hours. The reaction solution was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (heptane/ethyl acetate=2/1), and the title compound (4.1 g, quantitatively) was obtained as a white solid.
Reaction SMILES: C(=O)(O)[O-].[K+].[CH3:6][O:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][CH:14]2[NH:18][CH2:17][CH2:16][S:15]2)=[CH:10][CH:9]=1.[Cl:21][CH2:22][C:23](Cl)=[O:24]>O.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH:14]2[N:18]([C:23](=[O:24])[CH2:22][Cl:21])[CH2:17][CH2:16][S:15]2)=[CH:19][CH:20]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(OCC2NCCS2)cc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(OCC2SCCN2C(=O)CCl)cc1

Procedure:
A solution of 26 g of potassium bicarbonate in 55 ml of water was added under storing stirring to a solution of 2-(4-methoxy-phenoxymethyl)thiazolidine (54,5 g) in 550 ml of ethyl acetate cooled at 0°-5° C. The mixture was added with a solution of α-chloro-acetylchloride (19,2 ml) in ethyl acetate (50 ml) for 1 hour, under strong stirring and external cooling. Stirring was continued for 2 more hours, then the phases were separated. After washing of the organic phase with water, 5% aqueous NaHCO3 and water, and drying over Na2SO4, the mixture was evaporated to dryness to give 54,5 g of 2-(4-methoxy-phenoxymethyl)-3-α-chloroacetyl-thiazolidine, m.p. 51°-53° C. (from isopropyl alcohol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]>[Fe].CC(O)=O.CCOC(C)=O>[NH2:11][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: COc1cc([N+](=O)[O-])ccc1C#N
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cc(N)ccc1C#N
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
2-Methoxy-4-nitro-benzonitrile (500 mg, 2.81 mmol) was suspended into 4 mL AcOH/EtOAc (1:1) and the resulting mixture was heated to 75° C. to give a clear solution. Fe powder (313 mg, 5.61 mmol, 325 Mesh) was added and the mixture was stirred for 30 min, after which additional Fe powder (313 mg, 5.61 mmol, 325 Mesh) was introduced. The mixture was stirred at 75° C. for an additonal 30 min, and then cooled to rt and filtered, eluting with EtOAc. The filtrate was concentrated in vacuo, re-dissolved in EtOAc, filtered (eluting with EtOAc) and concentrated. Purification was achieved by silica gel flash chromatography with 0 to 10% MeOH in CH2Cl2 to give compound 848A as a tan solid.