Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCCC2)C1
Reaction time: 1 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-cyclopentyl]-(3-hydroxymethyl-piperidin-1-yl)-methanone (0.5 g, 1.55 mmol) in dichloromethane (9.5 mL) at room temperature was added iPr2NEt (0.5 g, 3.9 mmol) followed by MsCl (0.214 g, 1.86 mmol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (gradient 2.5-100% EtOAc in hexane). The desired compound was obtained as an oil (0.345 g, 56%). 13C (100 MHz, CDCl3, partial) δ 174.0, 144.0, 131.8, 128.8, 126.5, 70.8, 58.1, 35.3, 26.5, 24.9. 1H (300 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 7.13-7.10 (m, 2H), 4.61-1.86 (m, 19H), 1.67 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[OH-].[Li+].O.Cl>C1COCC1.CO>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]2[N:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=[C:15]2[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2n(n1)CCCN(S(=O)(=O)c1ccccc1[N+](=O)[O-])C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Ethyl 5-[(2-nitrophenyl)sulfonyl]-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.143 g, 0.362 mmol) was dissolved in a mixture of THF (4 mL) and methanol (1 mL) and to the solution was added 1.0 M of lithium hydroxide in water (1.5 mL, 1.5 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated, and the residue was dissolved in water (5 mL) and neutralized with 1.0 M hydrochloric acid in water (1.5 mL, 1.5 mmol). The resulting precipitate was collected via vacuum filtration to afford Intermediate 20 as a white solid (0.1166 g, 88%). LC-MS: (FA) ES+395.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([N:43]=[C:44]=[O:45])[CH:40]=[CH:41][CH:42]=1.C(N(CC)CC)C>CS(C)=O>[CH3:34][N:31]1[CH2:32][CH2:33][N:28]([C:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]4[C:11]([C:8]5[CH:7]=[CH:6][C:5]([CH2:4][NH:3][C:44]([NH:43][C:39]6[CH:40]=[CH:41][CH:42]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=6)=[O:45])=[CH:10][CH:9]=5)=[CH:12][N:13]=[C:14]4[CH:19]=3)=[CH:25][CH:24]=2)=[O:27])[CH2:29][CH2:30]1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cccc(C(F)(F)F)c6)cc5)cnc4c3)cc2)CC1
Yield: 52.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), 3-trifluoromethylphenyl isocyanate (0.1 mL, 0.73 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.18 g, 52%). MS(ES), m/z 613 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8](O)=[O:9].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH:6]=[CH:7][C:8]([Cl:16])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(C=CC(=O)O)c1
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][N:18]=1>O>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[N:18][CH:19]=1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(OCCN2CCCC2)nc1
Reaction time: 1 h

Procedure:
To a stirred DMF solution (25 mL) containing N-(2-hydroxyethyl)pyrrolidine (2.18 g, 18.9 mmol) under N2 was added 60% NaH in mineral oil (0.76 g, 18.9 mmol). The mixture was stirred for 1 hr while gas evolution ceased. Subsequently 2-chloro-5-nitropyridine (2.0 g, 12.6 mmol) was added. After stirring overnight, the dark solution was poured into H2O (100 mL) and extracted 3× with EtOAc. The combined organic layers were washed 2× with H2O prior to drying over Na2SO4, Concentration under vacuum yielded an orange oil which was chromatographed on silica gel employing ˜10% MeOH/CH2Cl2 to elute 1.62 g of 5-nitro-2-(pyrrolidin-1-yl)-ethoxy)pyridine (54%). The above product reduced, to the corresponding substituted aminopyridine by hydrogenation in an EtOH solution (20 mL) containing 10% Pd/C (0.1 g) under 60 psi of H2 for 4 hr. Upon completion the reaction was filtered prior to concentration under vacuum. The resulting dark oil was chromatographed on silica. Gradient elution (CH2CL2 to 20% MeOH/CH2Cl2) eluted 1.03 g of the title compound as a broad peak.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](F)[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[F:14].[CH3:16][O-:17].[Na+]>CO>[F:14][C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:17][CH3:16])=[CH:9][C:4]=1[C:3]([OH:2])=[O:15]
Reactant: C[O-]
Reactant: COC(=O)c1cc(F)c([N+](=O)[O-])cc1F
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
To a solution of methyl-2,5-difluoro-4-nitrobenzoate (1 g, 4.6 mmol) in methanol (10 mL) was added sodium methoxide (95%, 393 mg, 6.9 mmol). The reaction mixture was stirred at room temperature overnight. It was then concentrated, acidified with HCl. Solid was filtered and dried to give the product as light yellow powder (728 mg, 70%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3 H) 7.66 (d, J=4 Hz, 1 H) 8.01 (d, J=8 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:9]([CH2:14][NH:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36]Br.CCN(C(C)C)C(C)C>CC#N>[CH3:25][O:26][C:27](=[O:38])[C:28]1[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[CH:30][C:29]=1[CH2:36][N:15]([CH2:14][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: COC(=O)c1cc(C#N)ccc1CBr
Reactant: Cc1cccnc1CNCc1ncccc1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C#N)ccc1CN(Cc1ncccc1C)Cc1ncccc1NC(=O)OC(C)(C)C
Yield: 90.2 %

Procedure:
Using General Procedure A: A solution (2-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-carbamic acid tert-butyl ester (0.220 g, 0.65 mmol), 2-bromomethyl-5-cyano-benzoic acid methyl ester (0.245 g, 0.97 mmol), and DIPEA (0.23 mL, 1.32 mmol) in CH3CN (7 mL) was stirred at room temperature for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 0.294 g (88%) of 2-{[(3-tert-Butoxycarbonylamino-pyridin-2-ylmethyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3) δ 1.58 (s, 9H), 2.20 (s, 3H), 3.76 (s, 2H), 3.86 (s, 3H), 4.05 (s, 2H), 4.09 (s, 2H), 7.09-7.16 (m, 2H), 7.44 (d, 1H, J=7.8 Hz), 7.55 (dd, 1H, J=8.1, 1.5 Hz), 7.89 (d, 1H, J=8.1 Hz), 8.04 (d, 1H, J=1.5 Hz), 8.09 (dd, 1H, J=1.5, 4.8 Hz), 8.51 (d, 1H, J=7.8 Hz), 8.63 (d, 1H, J=4.8 Hz).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:19])[CH:14](Cl)[C:15](=O)[CH3:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[S:8][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:15]=1[CH3:16])=[O:19])[CH3:11]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cccnc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccnc2)nc1C
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of thionicotinamide (10 g, 0.07 mol) and 2-chloro-3-oxo-butyric acid ethyl ester (10 mL, 0.07 mol) in ethanol (100 mL) was heated at refluxed for 20 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (12.2 g): MS: (+) m/z 249.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCCC1>[C:26]([O:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][C:16]([OH:18])=[O:17])([CH3:14])[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 66.1 g. (0.25 mol.) of (±)-(6-hydroxy-2,5, 7,8-tetramethylchroman-2-yl) acetic acid and 250 ml. each of pyridine and acetic anhydride was stirred at 25° C. under N 2 for 20 hours and stripped of solvent at 40° C. to give an orangebrown oil. To a suspension of this material in 500 ml. of H 2 O and 100 ml. of tetrahydrofuran was added 166 g. (2.0 mol.) of NaHCO 3. the suspension was stirred at 25° C. for 4.0 hours, washed with ether, acidified with 2N-aqueous HCl and extracted with ether. The ether solutions were washed with saturated brine, dried over sodium sulfate and stripped of solvent to give (±)-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl) acetic acid as and orangeish resin. Crystallization from diethyl ether petroleum ether (b.p. 30°-60° C.) gave (±)-(6-acetoxy-2,5,7,8 -tetramethylchroman-2-yl) acetic acid as a granular white solid.
Reaction SMILES: [NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[OH-].[Na+].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>O1CCCC1>[NH:1]([C:8]1([C:14]([OH:16])=[O:15])[CH2:9][CH2:10][N:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(O)C1(Nc2ccccc2)CCNCC1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2ccccc2)(C(=O)O)CC1
Reaction time: 3 h

Procedure:
To a stirred and cooled (ice-salt bath) mixture of 12.1 parts of 4-anilinoisonipecotic acid, sodium salt, 200 parts of sodium hydroxide solution 1 N and 20 parts of tetrahydrofuran are added dropwise 6.45 parts of ethyl chloroformate in 25 parts of tetrahydrofuran over 15 minutes and at a temperature between 2° and 5° C. Upon completion, stirring is continued for 3 hours in the cool-bath. The whole is extracted with ether. The aqueous phase is separated and degassed on a rotavapor without heating. The mixture is acidified with glacial acetic acid, whereupon an oil is separated. The latter is stirred in fresh water and extracted with chloroform. The extract is washed three times with water, dried, filtered and evaporated. The residue is crystallized from a mixture of ethyl acetate and petroleumether, yielding 4-anilino-1-(ethoxycarbonyl)isonipecotic acid; mp. 149°-156° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([OH:26])=[O:25])=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[C:1]([O:5][C:6]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:15]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:16][C:17]3[C:22]([N:23]=2)=[CH:21][C:20]([C:24]([O:26][CH3:33])=[O:25])=[CH:19][CH:18]=3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)C1CCN(c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(C(=O)OC(C)(C)C)CC3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylic acid (509.7 mg, 1.10 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), potassium carbonate (762.3 mg, 5.52 mmol, 5.00 equiv). The resulting solution was stirred 30 min at room temperature. Then CH3I (783.3 mg, 5.52 mmol, 5.00 equiv) was added dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at room temperature. The reaction was then quenched by the addition of water. The resulting aqueous solution was extracted with 6×20 mL of dichloromethane. The organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 285.5 mg (54%) of methyl 3-(4-(tert-butoxycarbonyl)piperidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)(C)(C)C.[OH:17][C:18]1[CH:23]=[C:22]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])[C:21]([CH:34]=O)=[CH:20][C:19]=1[O:36][CH3:37].[CH2:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39]1.[O-]S(C(F)(F)F)(=O)=O.[In+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][CH:34]([C:21]1[C:22]([C:24]3[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=3[O:32][CH3:33])=[CH:23][C:18]([OH:17])=[C:19]([O:36][CH3:37])[CH:20]=1)[CH:39]1[CH2:40][C:41]3[C:46]([CH:38]21)=[CH:45][CH:44]=[CH:43][CH:42]=3
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: C1=Cc2ccccc2C1
Reactant: COc1cc(C=O)c(-c2c(OC)cccc2OC)cc1O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [In+3]
Solvent: CC#N
Product: COc1cc(C2Nc3ccc(CN)cc3C3c4ccccc4CC23)c(-c2c(OC)cccc2OC)cc1O
Temperature: 70 °C

Procedure:
(4-Amino-benzyl)-carbamic acid tert-butyl ester (307 mg, 1.4 mmole) was dissolved in acetonitrile (approx. 5 mL). The solution was treated with 5-hydroxy-4,2′,6′-trimethoxy-biphenyl-2-carbaldehyde (390 mg, 1.4 mmole) and indene (157 mg, 1.4 mmole). Indium triflate (1.2 g, 2.2 mmole) was added and the reaction was heated at 70° C. for 18 hours to give 6-(2-Aminomethyl-5,6a,7,11b-tetrahydro-6H-indeno[2,1-c]quinolin-6-yl)-4,2′,6′-trimethoxy-biphenyl-3-ol which was then purified using reverse phase HPLC. Mass spectrum 491 (M−17); in the presence of 0.1M ammonium acetate 507 (M−1) observed for negative ion mode.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11](I)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>O1CCOCC1.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([B:19]2[O:20][C:21]([CH3:23])([CH3:22])[C:17]([CH3:24])([CH3:16])[O:18]2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)(C)OC(=O)c1c(F)cccc1I
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1c(F)cccc1B1OC(C)(C)C(C)(C)O1
Temperature: 165 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a degassed mixture of tert-butyl 2-fluoro-6-iodobenzoate (161 mg, 0.5 mmol), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.1 mL, 0.6 mmol) and TEA (0.25 mL, 1.5 mmol) in 2 mL dioxane, was added Pd(PPh3)2Cl2 (7 mg, 0.01 mmol). The mixture was stirred at 165° C. for 10 min in a microwave oven. The mixture was diluted with EtOAc, washed with sat. NH4C1, H2O and brine, dried over (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0-10% EtOAc/hexanes gradient) to afford 50 mg (45%) of Intermediate 436.2.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
α-Hydroxypalmitic acid (3.2 g) was dissolved in pyridine (15 ml), and palmitoyl chloride (3.3 g) was added thereto at 0° C. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water and the aqueous solution was stirred at room temperature for 1 hour, followed by acidification with 1N hydrochloric acid, and extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give a residue which was recrystallized from petroleum ether to afford crystals of 2-hexadecanoyloxyhexadecanoic acid (5.4 g). M.p. 55°-56° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=1)[CH2:7][CH:8]=[CH2:9])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:15][CH:14]=1
Reactant: C=CCN(CCN(CC)CCCCC(C)C)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: C=CCN(CCN(CC)CCCCC(C)C)c1ccc(N)cc1

Procedure:
In a manner similar to Preparation 4 react N-ethyl-N-(5-methylhexyl)-N'-(4-nitrophenyl)-N'-(2-propenyl)1,2-ethanediamine with tin(II) chloride dihydrate in ethanol to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[Br:11]Br.[O-]S([O-])=O.[Na+].[Na+]>ClCCl.C(OCC)(=O)C.[Fe]>[Br:11][C:5]1[C:6]2[C:10](=[N:9][O:8][N:7]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Clc1cccc2nonc12
Reactant: BrBr
Agent: [Fe]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Clc1ccc(Br)c2nonc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
4-Chlorobenzo[c][1,2,5]oxadiazole (1.0 g, 6.5 mmol) was treated with iron powder (14 mg, 0.2 mmol), stirred and heated to 50° C. and then treated in portions with bromine (1.1 g, 7.1 mmol) to produce a homogeneous red melt solution. The flask was fitted with a reflux condenser and the temperature was raised to 85° C. and stirred for 60 min. An additional 450 mg of bromine were added, heating was continued for 1 h more and then the mixture was allowed to stand for 18 h at 20° C. The solid contents of the flask were dissolved in 15 mL dichloromethane and stirred for 30 min with 15 mL saturated Na2SO3 solution. The mixture was diluted with 30 mL ethyl acetate and the organic phase was washed with 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-7% ethyl acetate-hexane gradient to give the title compound as a white solid (1.4 g; 93%): mp 81-83° C.; 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.5 Hz, 1H), 7.33 (d, J=7.5 Hz, 1H); EIMS m/z 232.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]1([P:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:16][NH2:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:17][CH2:16][CH2:15][P:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NCCP(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc[nH]1
Product: C(=NCCP(c1ccccc1)c1ccccc1)c1ccc[nH]1
Yield: 99.3 %

Procedure:
Replicate the preparation of the ligand used in Ex. 7 except use 0.2 g (2.103 mmol) of pyrrole-2-carbaldehyde and use 0.506 g (2.208 mmol) of 2-(diphenylphosphino)ethanamine instead of N1,N1-dimethylethane-1,2-diamine to give 0.640 g (99%) of N-((1H-pyrrol-2-yl)methylene)-2-(diphenylphosphino)ethanamine as a white solid, which is analytically pure by GC-MS and 1H-NMR: 1H NMR (400 MHz, C6D6) δ 9.49 (s, 1H), 7.62 (s, 1H), 7.49-7.32 (m, 5H), 7.11-6.92 (m, 5H), 6.44-6.29 (m, 2H), 6.22-6.14 (m, 1H), 3.58 (td, J=8.8, 1.0 Hz, 2H), 2.37 (dd, J=8.4, 7.1 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:22]NC.C=O.C(O)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:20])[C:17](=[CH2:22])[CH2:18][CH3:19])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CCCC(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CC)C(=O)c1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
A mixture of 2-(2,3-dichloro-4-butyrylphenoxy)-2-methylpropionic acid (10 g, 0.031 mole), dimethylamine hydrochloride (15 g, 0.18 mole), paraformaldehyde (3 g, 0.10 equiv.) and acetic acid (0.6 ml) was stirred and heated on a steam bath for two hours. N,N-dimethylformamide (30 ml) was added and stirring and heating was continued for another two hours. The mixture was poured into ice water which was then extracted with ether. The ether extract was washed with water, then brine and finally dried over MgSO4. The ether was evaporated in vacuo and the residue recrystallized from cyclohexane to give 6.3 g 2-[2,3-dichloro-4-(2-methylenebutyryl)phenoxy]-2-methylpropionic acid, m.p. 88°-89° C.