Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[CH:10])=[CH:5][CH:4]=1.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1>C1COCC1.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:21][Si:20]([C:19]#[C:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][CH:14]=1)([CH3:22])[CH3:23]
Reactant: C[Si](C)(C)C#Cc1ccc(I)cc1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#Cc2ccc(C#C[Si](C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.5 %

Procedure:
Into a 50 ml round bottom flask was placed a mixture of 0.72 g (0.0054 mole) of p-methoxyphenylacetylene, 1.51 g (0.005 mole) of 4-iodophenyltrimethylsilylacetylene, 0.0102 g (0.0053 mmole) of CuI, 0.102 g (0.146 mmole) of bis(triphenylphosphine)palladium(II)dichloride in 10 ml of THF and 10 ml of triethylamine. The light orange brown mixture was stirred at room temperature under nitrogen for 3 days. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure. The residue was redissolved in 10 ml of chloroform and the solution was washed two times with water (10 ml each) and then dried over anhydrous MgSO4, filtered and concentrated. 1.5 g (98.7% yield) of solid was obtained. 1HNMR: 0.28 ppm (s, 9H); 3.85 ppm (s, 3H); 6.90 ppm (d, 2H); 7.45 ppm (s, 4H); 7.48 ppm (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH2:28])[C:22]2=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[N:24]=[C:23]2[C:25]([CH3:29])=[CH:26][N:27]([NH:28][C:14]([C:10]3[C:11]([CH3:13])=[N:12][C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][CH:9]=3)=[O:16])[C:22]2=[CH:21][CH:20]=1
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: COc1ccc2c(n1)c(C)cn2N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(n1)c(C)cn2NC(=O)c1cnc(-c2ccccn2)nc1C
Yield: 46.6 %

Procedure:
A solution of 2-pyridin-2-yl-4-methyl-pyrimidine-5-carboxylic acid (1.69 mmol), 5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-ylamine (1.69 mmol), DIPEA (5.01 mmol) and HATU (2.03 mmol) in anhydrous DMF (8 mL) is stirred at 90° C. for 16 h. DMF is evaporated in vacuo. The residue is dissolved in EtOAc (40 mL), and washed with water (3×10 mL) and brine (10 mL). The organic layer is dried (Na2SO4), filtered, and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with 0-15% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-methoxy-3-methyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (295 mg) as a solid. MS: 375 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.40 (s, 3H), 2.84 (s, 3H), 4.02 (s, 3H), 6.70 (d, H), 7.13 (s, H), 7.41 (m, H), 7.50 (d, H), 7.85 (t, H), 8.51 (m, 2H), 8.78 (s, 2H), 10.57 (br, N—H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[CH:7][C:6]=2[CH:11]=1.[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([I:1])=[CH:11][C:6]=2[CH:7]=1
Reactant: Cc1cc2cc(I)ccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2cc(I)ccc2o1
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a carbon tetrachloride (28 mL) solution of 5-iodo-2-methylbenzofuran (500 mg, 1.94 mmol) were added N-bromosuccinimide (410 mg, 2.3 mmol) and 2,2-azobis(isobutyronitrile) (47.8 mg, 0.291 mmol). This mixture was stirred for 2 hours and 45 minutes while heating under reflux. After allowing the reaction mixture to cool on standing, the reaction mixture was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 2-bromomethyl-5-iodo-benzofuran (320 mg, 49%).
Reaction SMILES: BrCC([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]1([NH2:18])C=CC=C[C:12]=1[NH2:17].CCN(C(C)C)C(C)C>C(O)C>[N:17]1[C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:18]=[CH:11][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: c1ccc2nccnc2c1

Procedure:
To a magnetically stirred solution of the appropriate α-bromoacetophenone (1 eq) in 5 ml of ethanol was added the appropriate 1,2-phenylenediamine (2.7 eq), followed by DIPEA (3.4 eq). The resultant solution was stirred at room temperature overnight with an air atmosphere. The reaction was concentrated, then purified by reverse phase chromatography on a C-18 column using a 0 to 90% gradient of CH3CN in water, with both containing 0.05% TFA. Product containing fractions were lyophilized to give a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([CH3:11])=[CH:7]2.[OH-].[K+].[Cl:14][CH2:15][CH2:16][CH2:17]Br>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH:15]([Cl:14])[CH2:16][CH3:17])[C:8]([CH3:11])=[CH:7]2
Reactant: Cc1cc2cccc(Cl)c2[nH]1
Reactant: ClCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(Cl)n1c(C)cc2cccc(Cl)c21
Yield: 52.3 %

Procedure:
40 g of 7-chloro-2-methyl-1H-indole are placed in 60 ml of toluene with 2.8 g of KOH under nitrogen. After stirring for 30 minutes at AT, 7.7 g of 3-chloro-1-bromopropane are added and then the mixture is heated to reflux for 3 hours. The medium is extracted with ether. The organic phase is washed with water, with a 10% HCl solution, with water and with a saturated NaCl solution. It is dried and evaporated and 6.19 g of the expected compound are obtained.
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:33]([O:35]C(C)(C)C)=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28]C(C)(C)C)=[O:27])=O)(C)(C)C.[ClH:40]>ClCCl>[ClH:40].[NH2:8][C@@:9]1([C:33]([OH:35])=[O:34])[C@H:14]([CH2:15][S:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1CSc1ccc(F)c(F)c1
Temperature: 70 °C
Yield: 19.9 %

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (0.58 g, 7.19 mmol) is weighed into a 100 mL round bottom with a stir bar. Hydrogen chloride (4N in dioxane, 33 mL, 132.0 mmol) is added. The mixture is warmed to 70° C. for 2 hours and then allowed to cool to ambient temperature. The solvent is removed under reduced pressure to give a residue. The residue is dissolve in dichloromethane (50 mL) and the solvent is removed under reduced pressure to give a residue. This is done three more times to give the title compound (567 mg, 1.43 mmol, 97% yield). MS (m/z): 360.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([O:21]C4C(F)=C(F)C(F)=C(F)C=4F)(=O)=[O:19])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:33]#[N:34])[CH:3]=1.[NH2:35][C:36]1[CH:41]=[CH:40][N:39]=[CH:38][N:37]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][C:10]3[CH:14]=[C:15]([S:18]([NH:35][C:36]4[CH:41]=[CH:40][N:39]=[CH:38][N:37]=4)(=[O:19])=[O:21])[CH:16]=[CH:17][C:9]2=3)=[C:4]([C:33]#[N:34])[CH:3]=1
Reactant: Nc1ccncn1
Reactant: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cc(Cl)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a solution of perfluorophenyl 4-(4-chloro-2-cyanophenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (370 mg, 0.717 mmol) and 4-amino pyrimidine (102 mg, 1.07 mmol) in THF (5 mL) was added LiHMDS (1M in THF, 1.43 mL, 1.43 mmol) at −78° C. The reaction mixture was stirred at −78° C. for 5 min and at 0° C. for 1 h. After completion, the reaction mixture was quenched with 2-3 drops of acetic acid and concentrated under reduced pressure. The crude mass was purified by combi flash column chromatography (12 g column; elution: 2.5% methanol in DCM) to provide 4-(4-chloro-2-cyanophenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (48 mg, 15.6%) as an off-white solid. 1H NMR (400 MHz, DMSO) δ 11.87 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H) 8.15 (d, J=2.4 Hz, 1H), 7.86 (dd, J=8.7, 2.5 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.12-6.96 (m, 1H), 7.43-7.24 (m, 2H), 6.56 (d, J=8.6 Hz, 1H), 4.34 (s, 2H), 3.77 (s, 2H); LCMS (ESI) m/z; 427.95 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH2:11][CH2:12][C:6]=2[C:5]([OH:19])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>CN(C1C=CN=CC=1)C>[C:26]([O:19][C:5]1[C:6]2[CH2:12][CH2:11][N:10]([C:13](=[O:18])[C:14]([F:16])([F:17])[F:15])[CH2:9][CH2:8][C:7]=2[C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:28])[CH3:27]
Reactant: O=C(N1CCc2c(O)ccc(Br)c2CC1)C(F)(F)F
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(Br)c2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Under nitrogen atmosphere, mix 9-bromo-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (6 g, 17.8 mmol), anhydrous pyridine (0.06 mL, 0.72 mmol), DMAP (222 mg, 1.8 mmol) and acetic anhydride (30 mL). Heat the mixture at reflux for 8 h and then stir at ambient temperature for another 8 h. Concentrate in vacuo, dilute the residue in EtOAc, wash with 1N aqueous HCl, and then with saturated aqueous NaHCO3. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the desired intermediate (5.64 g, 84%) that was used without further purification. MS (ES+) m/z: 380 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([O-:25])[CH3:24].[Na+].C(O)C>O>[CH2:23]([O:25][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:24]
Reactant: CC[O-]
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1cccc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 200 °C
Yield: 39 %

Procedure:
A solution of (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine (63 mg, 0.2 mmol) and 21% sodium ethanolate solution in ethanol (112 uL, 0.3 mmol) was heated to 200° C. for 30 minutes in a microwave oven. The same amount of sodium ethanolate solution was added and the reaction was again heated to 200° C. for 30 minutes in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound as a light brown solid (25 mg, 39%). MS ISP (m/e): 325.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.45 (t, 1H), 7.34 (s, 1H), 7.15 (d, 1H), 6.92 (d, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 6.37 (d, 1H), 6.24 (d, 1H), 4.35 (q, 2H), 3.83 (s, 3H), 2.30 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [OH:1][C:2]([C:4](F)(F)F)=O.[SH:8][CH2:9][CH:10]([CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:11]([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[C:2]([N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][CH:10]([CH2:9][SH:8])[C:11]([OH:13])=[O:12])[CH2:16][CH2:17]1)(=[O:1])[CH3:4]
Reactant: O=C(O)C(CS)CC1CCNCC1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(CC(CS)C(=O)O)CC1
Yield: 80.2 %

Procedure:
A solution of 2-Mercaptomethyl-3-piperidin-4-yl-propionic acid TFA salt (0.1 g, 0.32 mmol) in acetic anhydride (2 mL) was stirred over night under argon and then concentrated under reduced pressure. Purification by HPLC (10→50% acetonitrile, 0.1% TFA in water) gave the title compound (63 mg, 80%).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([C:22]([F:24])([F:25])[F:23])(=[O:21])=[O:20])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(S(=O)(=O)C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)sulfonyl]phenyl}propan-1-ol (260 mg, 0.69 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxybenzotriazdle hydrate (105 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (252 mg, 67%).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=2)[N:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:39]([C@H:44]1[CH2:49][CH2:48][C@H:47]([C:50](O)=[O:51])[CH2:46][CH2:45]1)[CH2:40][CH2:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:39]([C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([O:8][C:7]2[C:2]([F:1])=[N:3][C:4]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:11][CH:10]=3)=[CH:5][CH:6]=2)=[O:51])[CH2:48][CH2:49]1)[CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(OC(=O)[C@H]3CC[C@H](CCCCC)CC3)c(F)n2)cc1

Procedure:
0.29 g (0.91 mmol) of 2-fluoro-3-hydroxy-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 3), 0.19 g (0.91 mmol) of dicyclohexylcarbodiimide, 0.16 g (0.91 mmol) of trans-4-pentylcyclohexanecarboxylic acid and 0.01 g of 4-(N,N-dimethylamino)pyridine are stirred in 10 ml of methylene chloride at room temperature for 18 hours. Filtration, evaporation to dryness, purification by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallization from acetonitrile give 0.19 g of 2-fluoro-6-(4-octyloxyphenyl)pyridin-3-yl trans-4-pentylcyclohexanecarboxylate. ##STR40##
Reaction SMILES: CO[CH:3]1[CH2:7][CH2:6][CH:5](OC)O1.[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1.C(O)(=O)C.[OH-].[K+]>O>[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[CH:3]=[CH:7][CH:6]=[CH:5]2)=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-n2cccc2)c([N+](=O)[O-])c1

Procedure:
100 g (0.75 mole) of 2,5-dimethoxytetrahydrofuran are added to a solution of 84.1 g (0.5 mole) of 4-methoxy-2-nitroaniline in 500 ml. of glacial acetic acid. The solution is refluxed for 30 minutes, poured into 2500 ml. of water, and neutralized with potassium hydroxide. A solid precipitates and is filtered, dried, and recrystallized from ether to give 1-(4-methoxy-2-nitrophenyl)pyrrole, m.p. 75.5°-76.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[C:19]#N.[H-].C([Al+]CC(C)C)C(C)C.C[OH:32]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]2[CH3:18])=[CH:4][C:3]=1[CH:19]=[O:32]
Reactant: CO
Reactant: Cc1cn(-c2cc(C#N)c(N)c(C(F)(F)F)c2)c(C)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cn(-c2cc(C=O)c(N)c(C(F)(F)F)c2)c(C)n1
Temperature: 0 °C

Procedure:
To an ice-cooled stirred solution of 1-(4-amino-3-cyano-5-trifluoromethylphenyl)-2,4-dimethylimidazole (0.7 g) in tetrahydrofuran (10 cm3) was added 3.5 cm3 of a 1.5M solution of diisobutyl aluminium hydride in toluene. The mixture was heated at 40° for 2 hours, cooled in ice, treated with methanol (2 cm3), and evaporated in vacuo. The residue was treated with water (25 cm3) and 2M hydrochloric acid (5 cm3), and heated on a steam bath for five minutes. The solution was then cooled, basified to pH 8 with aqueous sodium carbonate solution, and extracted with chloroform:methanol, 20:1 (3×30 cm3). The combined organic extracts were dried (MgSO4), evaporated in vacuo, and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl acetate:methanol, 50:1, to afford 1-(4-amino-3-formyl-5-trifluoromethylphenyl)-2,4-dimethylimidazole, m.p. 200°-202°, (0.391 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[O:13].C(CN)O>O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:17]2[NH:11][C:12](=[O:13])[NH:14][C:15]2=[O:16])=[CH:5][CH:4]=1
Reactant: O=C1CNC(=O)N1
Reactant: COc1ccc(C=O)cc1
Solvent: O
Solvent: NCCO
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1
Yield: 85.5 %

Procedure:
A mixture of p-methoxybenzaldehyde (2.00 g., 14.7 mmoles) and hydantoin (1.47 g., 1 molar ratio) in water (12 ml) was heated to 70°; monoethanolamine (1.35 g., 1.5 molar ratio) was then added. The mixture was stirred magnetically and heated in an oil bath at 90°-92° for 4 hours. Usual workup furnished the title compound as a pale yellow solid (2.74 g.), m.p. 250°-252°.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][N:29]2[CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=2[O:43][CH3:44])=[CH:25][CH:24]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][C:7]([NH:22][C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[CH:28][N:29]3[CH2:32][C:33]3[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:34]=3[O:43][CH3:44])=[CH:25][CH:24]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)CC1CCCC1
Reactant: COC(=O)c1ccc(Cn2ccc3ccc(N)cc32)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Cn2ccc3ccc(NC(=O)CC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of cyclopentylacetic acid (0.24 ml) and 1,1'-carbonyldiimidazole (0.34 g) in methylene chloride (3 ml) was heated under reflux for 30 minutes and then treated with a solution of ester (B) (0.5 g) in methylene chloride (3 ml). The mixture was heated under reflux for 30 minutes, stirred at room temperature for 24 hours, and then diluted with ethyl acetate. This organic solution was washed sequentially with 10% v/v hydrochloric acid, water, and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on a 6×18 cm silica gel column using 99:1 v/v ethyl acetate:toluene as the eluent followed by recrystallization from hexane/ethyl acetate to give methyl 4-[6-(2-cyclopentylacetamido)indol-1-ylmethyl]-3-methoxybenzoate (P) as a solid; partial NMR: 2.0-2.5(br m, 3H, CH2CH), 3.9(s, 3H, OCH3), 4.0(s, 3H, OCH3), 5.3(s, 2H, NCH2).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]1[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7]1)[CH:2]=[CH2:3].Cl[CH2:14][C:15]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[O:16].[H-].[Na+].O>CS(C)=O>[CH2:18]([N:17]([CH2:21][CH2:22][CH3:23])[C:15](=[O:16])[CH2:14][O:12][CH2:11][CH:9]1[CH2:8][CH2:7][CH:6]([CH2:5][O:4][CH2:1][CH:2]=[CH2:3])[O:10]1)[CH2:19][CH3:20]
Reactant: CCCN(CCC)C(=O)CCl
Reactant: C=CCOCC1CCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCOCC1CCC(COCC(=O)N(CCC)CCC)O1
Temperature: 25 °C
Yield: 141 %

Procedure:
A mixture of 6.89 g of tetrahydro-5-[(2-propenyloxy)methyl]-2-furanmethanol (0.04 mole) and 7.12 g of 2-chloro-N,N-dipropylacetamide (0.02 mole) are dissolved in 200 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 0.50 g of sodium hydride (0.02 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour, the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl3 layer is separated and dried over anhydrous Na2SO4 overnight. The CHCl3 is removed in vacuo yielding a pale yellow oil which is vacuum distilled and the fraction distilling at 185°-188° @ 0.5 mm is collected yielding 8.84 g (70%) of the above compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[Br:13].[Sn].Cl>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[Br:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Agent: Cl
Agent: [Sn]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-bromo-4-nitro-benzoic acid methyl ester [100959-22-6] (350 mg, 1.35 mmol) in MeOH (60 mL) were subsequently added tin powder (1.6 g, 13.5 mmol) and 3N aqueous HCl (27.8 mL, 83 mmol). The mixture was stirred overnight at RT. The liquid phase was decanted from the excess tin and neutralized by adding a saturated aqueous NaHCO3 solution. An equal amount of water by volume was added and the water phase was extracted with EtOAc (3×). The combined organics were dried (Phase Separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane 1:4) to give the title compound as yellow solid. MS (LC/MS): 230 [M+H]+; tR (HPLC conditions b): 2.89 min.