Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:31])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:31])[CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:19]=[CH:20][C:21]([O:24][C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:22][CH:23]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(Oc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-(4-phenoxy-phenyl)-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>O1CCCC1>[CH:1]1([NH:6][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC1CCCC1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Cyclopentylamine (85.2 g, 1.0 mol) and triethylamine (101.2 g, 1.0 mol) were dissolved in tetrahydrofuran (750 mL) and cooled to 0°-5° C. by means of an ice-water bath. Ethyl bromoacetate (167 g, 1.0 mol) was added dropwise at 0°-5° C. to the solution. After addition the mixture was allowed to warm up to room temperature and then stirred over night at ambient temperature. The precipitated white triethylamine hydrochloride was filtered off and the filtrate concentrated to an oil which was purified over silica gel using hexane/ethyl acetate (8.2) as the eluent. The collected product was dissolved in ether and cooled by means of an ice water bath. Dry hydrogen chloride was bubbled into the solution whereby the HCL salt of the product precipitated. Filtration yielded 138 g of product as a white solid melting at 174°-176° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][CH3:6].Cl[C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17]>CS(C)=O.O>[CH2:3]([O:7][C:9]1[CH:14]=[CH:13][N+:12]([O-:15])=[C:11]([CH3:16])[C:10]=1[CH3:17])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydride with 200 mL of dimethylsulfoxide, 16.0 g (2.0 eq.) of 1-butanol was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and was concentrated to dryness under reduced pressure. The obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-butoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1.[CH2:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N#N>C(Cl)Cl>[CH2:32]([NH:39][C:40]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:11][N:12]([CH2:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=2)[CH:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH2:9][OH:10])[CH:8]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cc1cnc(CN(Cc2ccc(CN)cc2CO)C2CCCc3cccnc32)c(C)c1
Agent: N#N
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ccc(CNC(=O)NCc3ccccc3)cc2CO)C2CCCc3cccnc32)c(C)c1
Temperature: 0 °C
Yield: 91 %

Procedure:
A solution (5-aminomethyl-2-{[(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-phenyl)-methanol (0.12 g, 0.26 mmol) dissolved in CH2Cl2 (10 mL) was cooled down to a temperature of 0° C. Benzyl isocyanate (0.03 g, 0.26 mmol) was added and the solution was stirred at 0° C. for 16 hours under a positive pressure of N2. The reaction was quenched using a saturated NaHCO3 solution (25 mL). Extract with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to afford a light yellow oil. Purification via column chromatography on silica gel (CH2Cl2:MeOH, 99:1, v/v) afforded the product as a white solid (0.13 g, 91%). 1H NMR (CDCl3) δ 1.38 (m, 1H), 1.89 (m, 2H), 2.04 (m, 1H), 2.09 (s, 3H), 2.19 (s, 3H), 2.47 (m, 1H), 2.67 (m, 1H), 3.49 (d, 2H, J=11.8 Hz), 3.65 (d, 2H, J=12.7 Hz), 4.06 (m, 7H), 5.94 (m, 2H), 7.04 (m, 11H), 8.10 (s, 1H), 8.17 (d, 1H, J=3.9 Hz); 13C NMR (CDCl3) δ 18.28, 18.48, 21.06, 21.90, 29.63, 44.07, 44.23, 53.89, 54.05, 54.33, 57.51, 62.87, 122.05, 127.01, 127.57, 128.60, 130.86, 131.33, 132.27, 133.57, 134.94, 136.03, 137.01, 139.35, 140.11, 140.30, 142.03, 146.55, 146.87, 153.54, 156.99, 159.26; HPLC (98.05%); ES-MS m/z 550 (M+H). Anal. Calcd. for (C34H39N5O2) 0.1(CH2Cl2): C, 73.37H, 7.08 N, 12.55. Found: C, 72.95H, 7.07 N, 12.43.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@@:12]23[CH2:27][CH2:26][C:25](=O)[CH2:24][C@H:13]2[CH2:14][O:15][C:16]2[C:21]3=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[CH3:32][O:33][NH2:34].CCN(CC)CC>CCO>[CH3:32][O:33][N:34]=[C:25]1[CH2:24][CH:13]2[CH2:14][O:15][C:16]3[C:21]([C:12]2([S:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:29])([F:1])[F:30])=[CH:8][CH:7]=2)(=[O:10])=[O:11])[CH2:27][CH2:26]1)=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[F:23]
Reactant: O=C1CC[C@@]2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OC[C@@H]2C1
Reactant: CON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CON=C1CCC2(S(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c(F)ccc(F)c3OCC2C1
Reaction time: 8 h

Procedure:
To a solution of trans-10a-(4-trifluoromethyl-benzenesulfonyl)-1,4-difluoro-6a,9,10,10a-tetrahydro-6H,7H-benzo[c]chromen-8-one (40 mg, 0.10 mmol) in EtOH (2 mL) was added O-methyl hydroxylamine hydrochloride (20 mg, 0.23 mmol), and NEt3 (20 uL, 0.14 mmol). The reaction mixture was stirred overnight and then PS-dimethylaminoethyl resin was added, the stirring was continued for 2 h and then the resin removed by filtration. The solvent was removed under a stream of N2 and the residue purified by preparative TLC eluting with 25% ethyl acetate in hexanes (22 mg, 47%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12].Cl.[C:14]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]([NH2:30])=[NH:29])=[NH:26])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C(O)C>[ClH:12].[NH2:26][C:25]1[N:24]([C:21]2[CH:22]=[CH:23][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=2)[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[N:29]=[C:28]([NH2:30])[N:27]=1
Reactant: CCCCCCCCCC=O
Reactant: CC(C)(C)c1ccc(NC(=N)NC(=N)N)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(C(C)(C)C)cc1

Procedure:
100 ml of ethanol, 5.2 g (33.3 mmol) of 1-decanal and 0.9 ml of concentrated hydrochloric acid were added to 6.0 g (22.2 mmol) of N1-(4-tert-butylphenyl)-biguanide hydrochloride, and the mixture was refluxed for 7 hours. The solvent was concentrated under reduced pressure, and the residue was cooled. The resulting precipitated crystals were filtered, and recrystallized from 80% aqueous ethanol to obtain 3.1 g of colorless crystals having a melting point of 238 to 240° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:12]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:13]=2[S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O>[O:7]([C:11]1[C:12]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:13]=2[S:14][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Oc1ccccc1
Temperature: 75 °C
Yield: 17 %

Procedure:
Phenol (108 mg, 1.15 mmol) was added to a stirred suspension of sodium hydride (46 mg of 60% dispersion in mineral oil, 1.15 mmol) in anhydrous dimethylformamide (1 ml), under a nitrogen atmosphere. Ethyl 3-chloro-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Preparation 4, 200 mg, 0.58 mmol) was added to the mixture after 30 minutes, and the mixture was then heated to 75° C. for 48 hours. The reaction was partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using diethyl ether as eluant. The isolated product was crystallised from hexane to give the title compound as a colourless solid (40 mg).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2].C(=O)([O-])[O-].[K+].[K+].[SH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]>CN(C)C=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[O:6])#[N:2]
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CS(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(S(=O)(=O)C[C@@H]2CCCC[C@H]2C(=O)NCC#N)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
trans-N-Cyanomethyl-2-(4-fluorobenzenesulfonylmethyl)cyclohexanecarboxamide (3.384 g, 10 mmol) and potassium carbonate (2.34 g, 17 mmol) were weighed into a 100 mL round bottom flask fitted with a stir bar and a cap. Ethyl 2-mercaptoacetate (1.86 mL) was added, followed by the addition of dimethylformamide (30 mL). The reaction vessel was flushed with nitrogen and then sealed with a cap. After stirring the reaction mixture at 100° C. for 2 h, the reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was diluted with ethyl acetate (300 mL), filtered, and washed with brine. The organic layer was dried over magnesium sulfate, filtered and evaporated on a rotavap. The residue was chromatographed on 500 cm3 of silica gel in a 5×25 cm column with 50:50 dichloromethane:ethyl acetate eluent to give the title compound as a white solid. 1H NMR (DMSO-d6): =8.59 (1H, t), 7.69 (2H,dd), 7.49 (2H,dd), 4.44-4.04 (6H, m), 3.37 (1H, q), 2.95 (1H, dd), 2.2-1.8(3H, m), 1.62 (3H, m), 1.30 (1H, m), 1.16 (6H, m) MS [ESI, (M−H)−] m/z=437.2 amu
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]23[CH2:15][CH:14]2[CH2:13][O:12][C:11]3=[O:16])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH3:17]>>[OH:12][CH2:13][CH:14]1[CH2:15][C:10]1([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:11]([NH2:17])=[O:16]
Reactant: N
Reactant: O=C1OCC2CC12c1cccc([N+](=O)[O-])c1
Product: NC(=O)C1(c2cccc([N+](=O)[O-])c2)CC1CO
Temperature: 60 °C
Reaction time: 84 h
Yield: 85.9 %

Procedure:
A mixture of (1SR,5RS)-1-(3-nitrophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (intermediate B5a) (11.47 g, 52.3 mmol, Eq: 1.00) in ammonia (7 M in MeOH) (140 ml, 980 mmol, Eq: 18.7) was stirred in 10 sealed tubes at 60° C. for 3.5 days, but still not complete (ca. 75% conversion). Evaporated all volatiles, coated on silica gel and the crude material was purified by flash chromatography (silica gel, 200 g, 70% to 100% EtOAc in heptane to EtOH/THF 3:1->2:1) to give recovered (1SR,5RS)-1-(3-nitrophenyl)-3-oxabicyclo[3.1.0]hexan-2-one (1.957 g, 16%, which was converted under the same conditions to product) and (1SR,2RS)-2-(hydroxymethyl)-1-(3-nitrophenyl)cyclopropanecarboxamide (10.61 g, 44.9 mmol, 85.8% yield) as a light brown solid. MS (ISN): m/z=235.1 [(M−H)−].
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31]C(=O)C(F)(F)F)=[N:4][C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)=[N:6][CH:7]=1.[OH-].[K+]>CO.O>[NH2:31][C@@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]2[CH:23]=[CH:22][C:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][CH3:21])[CH2:16][CH2:17][C:11]=3[CH:10]=2)[N:4]=1
Reactant: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4N)n3)cc2CC1
Temperature: 60 °C

Procedure:
N-((1R,2R)-2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-cyclohexyl)-2,2,2-trifluoro-acetamide (313 mg, 0.578 mmol) was dissolved in Methanol (10 mL) and 1.0 M of Potassium hydroxide in water (3.0 mL) was added. The reaction was heated at 60° C. for 7 h, at which time the reaction had reached completion by HPLC. The reaction was cooled then was poured into 30 mL satd. sodium bicarbonate-20 mL water, then extracted 4×50 mL DCM, dried over sodium sulfate and concentrated in vacuo to afford the amine as a off-white film (260 mg, 100%). LCMS (m/e) 445 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.89 (s, 1H), 7.28 (m, 2H), 7.01 (d, 1H, J=7.9 Hz), 6.79 (s, 1H), 5.14 (d, 1H, J=8.0 Hz), 3.75 (m, 1H), 3.53 (m, 2H), 3.37 (s, 3H), 2.91 (m, 4H), 2.75 (m, 6H), 2.58 (m, 1H), 2.16 (m, 1H), 2.04 (m, 1H), 1.78 (m, 2H), 1.32 (m, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=2[CH3:22])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc([N+](=O)[O-])ccc2C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
To a solution of 5-methyl-3-(2-methyl-5-nitrophenylsulfonyloxy)phenol (1.46 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.6 g, 8.0 mmol) and 1,3-propanediol (2.3 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.0 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (80 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (1:1 hexane/ethyl acetate) to give the title compound as a yellow oil (920 mg, 48%). 1H-NMR (300 MHz, CDCl3) δ 8.72 (s, 1H), 8.37 (d, J=8.3 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 6.63 (s, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.81 (t, J=6.0 Hz, 2H), 2.89 (s, 3H), 2.25 (s, 3H), 1.99 (m, 2H), 1.58 (s, 1H).
Reaction SMILES: [H-].[Na+].CN(C=O)C.[CH2:8]([O:10][C:11]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][CH:25]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12])[CH3:9].[Br:34][C:35]1[C:40]([CH2:41]Br)=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]>O>[Br:34][C:35]1[C:40]([CH2:41][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:29]=2)[C:11]([O:10][CH2:8][CH3:9])=[O:12])=[C:39]([O:43][CH3:44])[C:38]([O:45][CH3:46])=[C:37]([O:47][CH3:48])[C:36]=1[O:49][CH3:50]
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCOc1ccc(C(=O)OC)cc1)(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Sodium hydride (60% oily, 1.02 g, 25.6 mmols) was added to a DMF (80 ml) solution of ethyl 2-ethoxycarbonyl-6-(4-methoxycarbonylphenoxy)hexanoate (8.55 g, 23.3 mmols), with cooling with ice, then allowed to warm to room temperature, and stirred for 30 minutes. Next, a DMF (10 ml) solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (9.47 g, 25.6 mmols) was dropwise added thereto at room temperature, and stirred for 6 hours. Water was added to the reaction mixture, which was then extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) to obtain the entitled compound (15.0 g) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+].[Br-]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1)[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
To a solution of ethyl-3,5-dihydroxy benzoate, 3 (16.8 g, 92 mmol) in acetone (350 mL) were added potassium carbonate (27.6 g, 200 mmol) and benzyl bromide (23.8 mL, 200 mmol) and stirred at room temperature for 9 h. Reaction mixture was filtered, concentrated on rotavapor and the crude product purified by column chromatography to afford 8. Yield 24.7 g (74%); mp 63-65° C.; MS (FAB) 363 (M++1); IR (KBr) 1824, 1708; 1H NMR (200 MHz, CDCl3) δ 7.34-7.35 (m, 10H), 7.30 (d, J=2.3 Hz, 2H), 6.79 (t, J=2.2 Hz, 1H), 5.07 (s, 4H), 4.36 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].O.C[N:17]([CH:19]=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:4]([C:19]#[N:17])[C:3]=1[C:19]#[N:17]
Reactant: CN(C)C=O
Reactant: Sc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: N#Cc1c(Sc2ccccc2Cl)ccc(Sc2ccccc2Cl)c1C#N
Reaction time: 1 h

Procedure:
2-Chlorothiophenol (12.50 g, 86.5 mmol), potassium carbonate (11.94 g, 86.5 mmol) and ditosylated dicyanohydroquinone (20.36 g, 43.5 mmol) in DMF (80 mL) were reacted as described above. Water (100 mL) was added and the mixture stirred for 1 hour then filtered. The filter cake was purified by flash column chromatography (eluting 30% ethyl acetate:isohexane) to give the title compound as a yellow solid (5.53 g, 13.4 mmol, 31%) [Found: C, 58.1%; H, 2.7%; N, 6.9%; S, 15.4%; Cl 16.6%; C20H10N2S2Cl2 requires C, 58.1%; H, 2.4%; N, 6.8%; S, 15.5%; Cl 17.2%]; MS (EI+) 412 (M+, 100%)
Reaction SMILES: [F:1][C:2]1([F:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](O)[C:3]1([CH3:13])[CH3:12].[NH:15]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.O1CCOCC1>C1COCC1>[CH3:23][O:22][C:20]([C:18]1[N:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2]([F:14])([F:1])[C:3]2([CH3:13])[CH3:12])[CH:16]=[N:15][CH:19]=1)=[O:21]
Reactant: CC1(C)C(O)c2ccccc2C1(F)F
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COC(=O)c1cncn1C1c2ccccc2C(F)(F)C1(C)C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a solution of 3,3-difluoro-2,2-dimethyl-indan-1-ol (388 mg, 1.96 mmol) in THF (16 mL) is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 370 mg, 2.94 mmol), and triphenylphosphine (770 mg, 2.94 mmol). The reaction is cooled to 0° C. and di-t-butyl azodicarboxylate (670 mg, 2.94 mmol) is added. The reaction is placed at room temperature and permitted to stir for six hours and then is heated to 40° C. overnight. The next day the reaction mixture is cooled to 0° C. and quenched with 4 N HCl in dioxane (5 mL, 20 mmol) and stirred for 30 minutes. The reaction is concentrated to near dryness and diluted with ethyl acetate. The organic layer is extracted three times with 1 N aqueous HCl. The aqueous extracts are combined, neutralized with Na2CO3, and extracted three times with ethyl acetate. The combined organic layers are dried with Na2SO4 filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:5) to furnish 3-(3,3-difluoro-2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester. MS: (ESI) m/z 307.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (d, J=2.5 Hz, 3 H), 1.33 (d, J=3.0 Hz, 3 H), 3.96 (s, 3 H), 6.43 (d, J=2.8 Hz, 1 H), 7.17 (s, 1 H), 7.30-7.37 (m, 1 H), 7.56-7.64 (m, 2 H), 7.69-7.76 (m, 1 H), 7.85 (s, 1 H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].Cl.[NH2:13][OH:14].[OH-].[Na+].Cl>>[OH:1][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:13][OH:14])=[O:5]
Reactant: NO
Reactant: COC(=O)c1ccncc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(NO)c1ccncc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.5 %

Procedure:
To a stirred suspension of methyl 3-hydroxy-isonicotinate (176 g; 1.15 mol) in water/ice (50/50, 1700 mL), was added hydroxylamine hydrochloride (127.9 g; 1.84 mol). The temperature fell to −5° C. and then aqueous NaOH solution (454 mL, 28% w/v) was added dropwise keeping the temperature below 5° C. during the addition. Hereafter the reaction mixture was stirred at ambient temperature for 1.5 h followed by heating to 60° C. At this temperature the pH was adjusted to 5.4 by the addition of aqueous hydrochloric acid (10 M) at which point a heavy precipitate forms. The reaction mixture was then stirred at ambient temperature followed by cooling to 5° C. The pH was then adjusted to 4.0 by the addition of aqueous hydrochloric acid (10 M), and then was stirred whilst cold for 1.5 h. The crystals were filtered off, rinsed with water (3×100 mL), dried on the filter and then dried further at reduced pressure and 40° C. overnight to give 3,N-dihydroxy-isonicotinamide (169.3 g, 96%; HPLC purity 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH3:19][NH2:20]>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:20][CH3:19])=[O:14]
Reactant: CN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1Cl
Product: CNC(=O)c1ccncc1Nc1ccc(I)cc1Cl

Procedure:
3-[(2-chloro-4-iodophenyl)amino]-N-methylisonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-chloro-4-iodophenyl)amino]isonicotinic acid (intermediate 2) and 0.43 mmol of monomethylamine LC/MS [9.23 min; 389 (M+1)]