Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:9]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:4].Cl.[CH3:32][NH:33][O:34][CH3:35].C([Mg]Cl)(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:35][O:34][N:33]([CH3:32])[C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:16][C:17]2[CH:18]=[C:19]([C:27]([F:28])([F:30])[F:29])[CH:20]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:22]=2)[C:9]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CNOC
Reactant: COC(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Combine 1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazole-4-carboxylic acid methyl ester (0.46 g, 1.1 mmol) and N,O-dimethyl-hydroxylamine-HCl (0.16 g, 1.6 mmol) in THF (5.5 mL). Chill to 0° C., then slowly add isopropyl magnesium chloride (2M/THF, 1.6 mL, 3.2 mmol). After 45 min., warm to RT. Add 70% sat. aq. NH4Cl, and extract with EtOAc. Dry over MgSO4, filter, and concentrate. Purify by flash chromatography on silica gel to give the title compound: MS (ES) 459.2 (M+1); 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=4.8 Hz, 1H), 8.52 (app d, 1H), 7.79 (s, 1H), 7.73 (s, 1H), 7.63 (app d, J=8.1 Hz, 1H), 7.35–7.31 (m, 1H), 7.30 (s, 2H), 5.21 (s, 2H), 3.79 (s, 3H), 3.37 (br s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl.CN(C1C=CC=CN=1)C>[CH2:24]([O:23][C:21]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 67.8 %

Procedure:
A solution of 6-nitroindoline (10.0 g, 0.061 mol), triethylamine (22.7 mL, 0.16 mol) and dimethylaminopyridine (50 mg, cat.) in dichloromethane (130 mL) was stirred at 0° C. and benzyl chloroformate (18 mL, 0.12 mol) was added slowly. The mixture was allowed to warm to room temperature overnight. The mixture was washed with water (50 mL), 5% aqueous HCl (100 mL), saturated aqueous NaHCO3 (50 mL) and water (50 mL). The dichloromethane was dried (MgSO4) and evaporated under reduced pressure to give an orange solid. This was triturated in diethyl ether (150 ml) to give a yellow solid (12.34 g, 68%).
Reaction SMILES: [ClH:1].O1CCOCC1.[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[O:12][CH2:13][CH:14]1[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16][N:15]1[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28]>CO>[ClH:36].[ClH:1].[F:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[O:12][CH2:13][CH:14]1[CH2:19][NH:18][CH2:17][CH2:16][N:15]1[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc(Cl)cc2)C(COc2cccc(F)c2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Oc1ccc(Cl)cc1)N1CCNCC1COc1cccc(F)c1
Reaction time: 1 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 4-tert-butyl 1-(4-chlorophenyl) 2-((3-fluorophenoxy)methyl)piperazine-1,4-dicarboxylate (38.3 mg, 0.082 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 32.9 mg (99%) of the desired product as a white solid. LC-MS: RT=5.83 min, [M+H]+=365.1.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:3]1[C:4]2[CH:20]=[CH:19][CH:18]=[CH:17][C:5]=2[N:6]([CH2:7][CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NCCn1c(=O)[nH]c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50 %

Procedure:
To a solution of tert-butyl (2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)carbamate (190 mg, 0.69 mmol) in THF (10 mL) was added sodium hydride (34.5 mg, 0.86 mmol, 60% in mineral oil) at 0° C. under nitrogen in a sealed tube. After the resulting reaction mixture was stirred at room temperature for 20 min, iodomethane (112 mg, 0.79 mmol) in THF (2 mL) was added at 0° C. under nitrogen. The reaction was stirred at room temperature for 4 h. The reaction was quenched with saturated aqueous ammonium chloride solution and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Concentration under vacuum gave the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (100 mg, 0.345 mmol, 50% yield). MS (ESI) m/z 292.1 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[CH:5][C:4]=1[CH3:11])=[O:2].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)=[O:10])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)O)[nH]c1C=O
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O

Procedure:
5-Formyl-4-methyl-1H-pyrrole-2-carboxylic acid was amidated with 1-methylpiperazine using General Amidation Procedure 1 to give 3-Methyl-5-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde. MS m/z 236 [M+1].
Reaction SMILES: C1(C2C=CC(CNCCC3C=CC(F)=C(C(F)(F)F)C=3)=CC=2)CC1.[CH3:25][C:26]([C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1)([CH3:29])[CH2:27][CH3:28].[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH2:48])[CH:42]=[CH:43][C:44]=1[Cl:45].[BH4-].[Na+]>>[Cl:38][C:39]1[CH:40]=[C:41]([CH2:46][CH2:47][NH:48][CH2:34][C:33]2[CH:36]=[CH:37][C:30]([C:26]([CH3:29])([CH3:25])[CH2:27][CH3:28])=[CH:31][CH:32]=2)[CH:42]=[CH:43][C:44]=1[Cl:45]
Reactant: NCCc1ccc(Cl)c(Cl)c1
Reactant: CCC(C)(C)c1ccc(C=O)cc1
Agent: Fc1ccc(CCNCc2ccc(C3CC3)cc2)cc1C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Product: CCC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 96.5 %

Procedure:
The title compound was synthesized in analogy to (4-cyclopropylbenzyl)-[2-(4-fluoro-3-trifluoromethylphenyl)-ethyl]-amine (described in example S53) using 4-(1,1-dimethylpropyl)-benzaldehyde (87.5 mg, 0.50 mmol), 2-(3,4-dichlorophenyl)-ethylamine (94 mg, 0.50 mmol) and sodium borohydride (28 mg, 0.75 mmol). The desired product (169 mg, 97%) was isolated without further purification as a colorless oil. MS (ISP) 350.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6].[Si:14]([OH:18])([OH:17])([OH:16])[OH:15].[CH2:19](O)[CH2:20][CH2:21][CH2:22][OH:23]>>[Si:14]([OH:18])([OH:17])([OH:16])[OH:15].[CH:22]([OH:23])([OH:6])[CH2:21][CH2:20][CH3:19].[CH3:1][C:2]1[C:3](=[CH:7][C:8](=[CH:12][CH:13]=1)[N:9]=[C:10]=[O:11])[N:4]=[C:5]=[O:6]
Reactant: OCCCCO
Agent: Cc1ccc(N=C=O)cc1N=C=O
Agent: O[Si](O)(O)O
Product: CCCC(O)O

Procedure:
30 parts by weight of toluene diisocyanate are slowly added and mixed with the said 1,4-butanediol silicate powder, thereby rapidly forming a light tan, solid polymer, poly(toluene diisocyanate butanediol silicate).
Reaction SMILES: Br[C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:23]5[C:10](=[C:11]([C:25]([OH:27])=[O:26])[CH:12]=[C:13]([Cl:24])[C:14]=5[C:15]=3[C:16]([Cl:22])=[CH:17][C:18]=2Br)[C:9]([C:28](O)=[O:29])=[CH:8][C:7]=4[Cl:31])=[C:4]([Cl:32])[CH:3]=1.[C:33]1([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[Cl:24][C:13]1[CH:12]=[C:11]2[C:25](=[O:26])[O:27][C:28](=[O:29])[C:9]3[CH:8]=[C:7]([Cl:31])[C:6]4[C:5]5[C:4]([Cl:32])=[CH:3][C:2]6[C:45]7[C:40]([N:39]([C:33]8[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=8)[C:18]8[C:19]=6[C:20]=5[C:15]([C:14]=1[C:23]=4[C:10]2=3)=[C:16]([Cl:22])[CH:17]=8)=[CH:41][CH:42]=[CH:43][CH:44]=7
Reactant: O=C(O)c1cc(Cl)c2c3c(Cl)cc(Br)c4c(Br)cc(Cl)c(c5c(Cl)cc(C(=O)O)c1c25)c43
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1oc(=O)c2cc(Cl)c3c4c(Cl)cc5c6c(cc(Cl)c(c7c(Cl)cc1c2c73)c46)c1ccccc1n5-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A suspension of 9,10-dibromo-1,6,7,12-tetrachloroperylene-3,4-dicarboxylic acid anhidride (1.24 g, 2.0 mmol), diphenylamine (0.40 g, 2.40 mmol), Pd(AcO)2 (10 mmol %), sodium-tert-butoxide (0.48 g, 5.0 mmol), tricyclohexylphosphine (20 mol %) in 70 ml toluene was stirred at 100° C. under argon atmosphere for 24 h. The solvent was removed under reduced pressure. The solid was dissolved in dichloromethane and acetic acid and stirred overnight at 70° C. The solvent was removed under reduced pressure. The crude product was purified by column chromatography using dichloromethane as eluent on silica. Yield 0.50 g (40%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[C:17]([F:26])[CH:16]=1.N>C(O)C>[F:21][C:19]1[CH:20]=[C:15]([NH:14][C:2]2[N:7]3[N:8]=[C:9]([S:11][CH3:12])[N:10]=[C:6]3[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:16]=[C:17]([F:26])[C:18]=1[C:22]([F:24])([F:25])[F:23]
Reactant: CSc1nc2nc(C)cc(Cl)n2n1
Reactant: Nc1cc(F)c(C(F)(F)F)c(F)c1
Agent: N
Solvent: CCO
Product: CSc1nc2nc(C)cc(Nc3cc(F)c(C(F)(F)F)c(F)c3)n2n1
Temperature: 25 °C

Procedure:
To a suspension of 7-chloro-5-methyl-2-(methylthio)[1,2,4]triazolo[1,5-a]pyrimidine (Intermediate 8 (0.286 g, 1.332 mmol)) in ethanol (5 mL), 4-amino-2,6-difluorobenzotrifluoride (FLUOROCHEM, 0.263 g, 1.332 mmol) was added and the mixture was stirred at room temperature until reaching completion. Anhydrous ammonia (0.190 mL, 1.332 mmol) was added and solvent was removed in vacuo. The residue was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 95:5 to 40:60%). Upon collection of the appropriate fractions, the title compound was obtained as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=1.[F:20][C:21]([F:33])([F:32])[O:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[F:20][C:21]([F:32])([F:33])[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([C@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(I)cc1
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Yield: 43.6 %

Procedure:
The Suzuki coupling of (+,−) Cis propane-2-sulfonic acid [2-(4-iodo-phenyl)-cyclopentyl]-amide (203 mg, 0.52 mmol, prepared in example 17) and 4-trifluoromethoxyphenylboronic acid (128 mg, 0.62 mmol) was accomplished in a manner analogous to the procedure described in example 27. The reaction was worked up in a manner analogous to example 3. Purification by silica chromatography using a Chromatotron® was achieved eluting with methylene chloride, followed by a second chromatography eluting with 0.2% MeOH/methylene chloride to afford 97 mg (44%) of the title compound.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O.O.C(OCC)(=O)C>[OH:15][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=N[O-]
Reactant: CCOC(=O)c1cc(N)ccc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.2 %

Procedure:
A mixture of ethyl 5-amino-2-methylbenzoate (14.4 g, 80.3 mmol) in aqueous 5% sulfuric acid (300 mL) was cooled with an ice-bath for 15 min. Sodium nitrite (6.09 g, 88.3 mmol) was then added dropwise as a solution in water (50 mL), and the resulting mixture stirred for at 0° C. for 30 min. After this time, the resulting mixture was heated to 60° C. for 18 h. The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (150 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 0-40%, hexanes/ethyl acetate) afforded 12.48 g (86%) of ethyl 5-hydroxy-2-methylbenzoate as red-brown solid: 1H NMR (300 MHz, CDCl3) δ 7.44 (d, J=2.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 1H), 6.91 (dd, J=8.3, 2.8 Hz, 1H), 5.44 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); ESI MS m/z 181 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20][CH2:21][O:22][CH3:23]>C(#N)C>[CH3:23][O:22][CH2:21][CH2:20][CH2:19][N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCCOC)CC1
Temperature: 25 °C
Yield: 96.6 %

Procedure:
To a stirred solution of ethyl isonipecotate (22.0 grams, 140 mmol) in acetonitrile (250 mL) at room temperature was added cesium carbonate (97 grams, 298 mmol) followed by 1-bromo-3-methoxypropane (20 mL, 154 mmol) and the reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature and filtered through a small pad of celite. The volatiles were removed under reduced pressure to obtain ethyl 1-(3-methoxy propyl)piperidin-4-carboxylate (31.0 grams).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[O:14].[O:24]([CH2:31][CH2:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]1[CH3:42])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(OC(=O)C)(=O)C.[OH-].[NH4+]>C1(C)C=CC=CC=1.C(O)(C)C>[O:24]([CH2:31][CH2:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([C:13]2([C:3]3[CH:4]=[CH:5][C:6]([N:8]([CH2:9][CH3:10])[CH2:11][CH3:12])=[CH:7][C:2]=3[CH3:1])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[O:14]2)=[C:34]1[CH3:42])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc2ccccc2n1CCOc1ccccc1
Reactant: CCN(CC)c1ccc(C(=O)c2ccccc2C(=O)O)c(C)c1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCN(CC)c1ccc(C2(c3c(C)n(CCOc4ccccc4)c4ccccc34)OC(=O)c3ccccc32)c(C)c1
Temperature: 70 °C
Yield: 93.2 %

Procedure:
A mixture of 14.0 g of 2-(2-methyl-4-diethylaminophenyl)carbonylbenzoic acid, 10.0 g of 1-(2-phenoxyethyl)-2-methylindole and 500.0 ml of acetic anhydride was maintained at approximately 70° C. for approximately four hours. The reaction solution was cooled to ambient temperature and 25.0 ml of isopropyl alcohol was added. The resulting solution was poured slowly into a mixture of 500.0 ml of toluene and 50.0 ml of 5 percent aqueous ammonium hydroxide. The toluene layer was separated, washed with water and then with saturated aqueous sodium chloride solution. The toluene layer was evaporated to dryness. The residue was recrystallized in 150.0 ml of isopropyl alcohol and dried to obtain 20.2 g of 3-[1-(2-phenoxyethyl)-2-methylindol-3-yl]-3-(2-methyl-4-diethylaminophenyl)phthalide (Formula I: R=C6H5OC2H4 ; R1 =R2 =CH3 ; R3 =R4 =C2H5 ; X=Y=H), a white-colored solid which melted at 182°-183° C. Significant infrared maxima appeared at 1750 (C=O; s) and 1130 (C--O; s)cm-1. The nuclear magnetic resonance spectrum was in accord with the assigned structure. A toluene solution of the product spotted on an acidic clay or a phenolic resin coated paper developed a cyan-colored image.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[C:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)[CH3:6]>>[CH:6]([P:1]([OH:4])(=[O:3])[OH:2])=[CH:5][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)c1ccccc1
Reactant: OP(O)O
Product: O=P(O)(O)C=Cc1ccccc1

Procedure:
In this Example, an acid catalyst (ZSM-5-40 zeolite) was used for both the reaction of phosphorous acid (24.6 gm) with 36 gm of acetophenone (at 75° C.) and the subsequent reaction (at 80° C.) to crack the acyl derivative to form SPA. The amount of catalyst used in the first reaction was 12 gm. It was determined that the product contained 77 wt % styrene phosphonic acid (SPA), 17 wt % unreacted phosphorous acid, and 6 wt % Diels-Alder dimer phosphorus compound. The yield of SPA in this reaction was therefore 65% of theory.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[O:21]1[CH2:22][CH2:23][CH:18]([O:17][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH2:9][NH:8][CH2:16]3)[CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OC3CCOCC3)cc2C1
Solvent: O=C(O)C(F)(F)F
Product: c1cc2c(cc1OC1CCOCC1)CNC2

Procedure:
Prepared in analogy to Example A2(c) from 5-(tetrahydro-pyran-4-yloxy)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and trifluoroacetic acid. Yellow oil. MS (m/e): 220.3 ([M+H]+, 100%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1.[OH-].[Na+]>CO>[CH3:1][N:2]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13]([NH:15]2)=[O:14])[CH2:10][S:9]1
Reactant: COC(=O)CCCCCN(C)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCCCC(=O)O)C(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 2.5 h
Yield: 90.4 %

Procedure:
To a 1 liter round bottom flask, charged with 11.58 g (30.0 mmol) of 13 in 100 mL of methanol was added 50 mL of 1 N aqueous sodium hydroxide. The mixture was stirred for 2-3 h and then concentrated via rotary evaporation. The residue was transferred to a 250 mL round bottom flask in a total of 75 mL of de-ionized water. With vigorous stirring, the pH of the solution was adjusted to 1.5-2 by addition of 1 N aqueous HCl, the product precipitating out as a white solid in the process. The mixture was vacuum filtered. The collected solids were rinsed with 3×50 mL aliquots of ice cold de-ionized water. The solids were air dried for 3 h and then under full vacuum pump pressure (<0.5 mm Hg) for 21 h to afford 10.07 g of the product (14) as a white solid (90%): 1H NMR (d6-DMSO) d 6.43 (1H, s), 6.35 (1H, s), 4.30 (1H, m), 4.12 (1H, m), 3.23 (2H, t), 3.10 (1H, m), 2.91 and 2.78 (3H, 2 s), 2.81 (1H, dd), 2.57 (1H, d), 2.30-2.13 (4H, m) and 1.79-1.10 (12H, m) ppm; 1H NMR (CD3OD) d 4.48 (1H, dd), 4.29 (1H, dd), 3.35 (2H, t), 3.19 (1H, m), 3.02 and 2.88 (3H, 2 s), 2.91 (1H, dd), 2.68 (1H, d), 2.43-2.23 (4H, m) and 1.83-1.21 (12H, m) ppm; Thin Layer Chromatography (Visualization with p-aminocinnimaldehyde spray); RP-18 Silica Gel, Rf=0.50 (60/40 methanol/water).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]([CH2:11][CH2:12][CH2:13][C:14]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:18][CH2:17][CH2:16][O:15]1)C)C1C=CC=CC=1.Cl.[H][H]>[Pd].CO>[ClH:1].[CH3:2][NH:9][CH2:11][CH2:12][CH2:13][C:14]1([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[O:15][CH2:16][CH2:17][O:18]1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCC1(c2ccc(F)cc2)OCCO1
Temperature: 25 °C
Yield: 93 %

Procedure:
A suspension of 12 g of 5% palladium on carbon, 135 g (0.369 mol) of 2-[3-(N-benzyl-N-methylamino)propyl]-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride, 0.1 ml of a saturated solution of hydrogen chloride in methanol and 1 liter of methanol was shaken at 40° for 5 hours under 50 psi hydrogen. The suspension was allowed to cool to room temperature, filtered and the solvent evaporated. Trituration with anhydrous ether, followed by filtration provided 94.6 g (0.343 mol, 93%) of 2-(3-[methylamino]propyl)-2-(4-fluorophenyl)-1,3-dioxolane hydrochloride. Crystallization from isopropyl alcohol provided analytically pure material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28](I)[CH:27]=1>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[C:30]([C:3]2[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:31]=1
Reactant: OB(O)c1c(O)cccc1Cl
Reactant: Fc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Oc1cccc(Cl)c1-c1cc(Br)ccc1F
Temperature: 105 °C
Yield: 91.5 %

Procedure:
(2-Chloro-6-hydroxyphenyl)boronic acid (250 mg, 1.450 mmol, 1.0 equiv), Pd(PPh3)4 (168 mg, 0.145 mmol, 0.1 equiv) and aqueous Na2CO3 (2 M, 1.8 mL, 3.63 mmol, 2.5 equiv) were mixed with toluene (3 mL) in a sealed microwave tube. 4-Bromo-1-fluoro-2-iodobenzene (436 mg, 1.450 mmol) in MeOH (1.50 mL) was added to the above mixture. The mixture was heated at 105° C. overnight. Then, the reaction mixture was loaded on 12 g column and purified using 30% EtOAc/Hex to afford 5′-bromo-6-chloro-2′-fluoro-[1,1′-biphenyl]-2-ol (400 mg, 91% yield). 1H NMR (400 MHz, CDCl3) δ 7.57 (ddd, J=8.8, 4.5, 2.5 Hz, 1H), 7.47 (dd, J=6.3, 2.5 Hz, 1H), 7.24 (t, J=8.2 Hz, 1H), 7.17-7.06 (m, 2H), 6.90 (d, J=8.0 Hz, 1H). LCMS (M+1)=302.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24][OH:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylate (14 g, 34 mmol) in MeOH (200 mL) was added NaBH4 (10.35 g, 272 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at rt for 2-3 hr. The solvent was removed in vacuo to provide a residue which was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4 and evaporated to give the crude (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (12.50 g), which was used in the next step without purification.