Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25].C([O-])(O)=O.[Na+]>C(O)C>[N:1]1([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:24]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[NH:25])[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC(=N)c1cccs1
Reactant: Nc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(CCN3CCCC3)c2c1)c1cccs1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-amine (0.59 g, 2.57 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (1.467 g, 5.15 mmol) at room temperature and the resulting mixture was stirred overnight. The reaction was basified with saturated NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.39 g, 1.152 mmol, 44.8% yield) as a solid. 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 7.70 (d, 1H, J=2.7 Hz), 7.58 (d, 1H, J=3.9 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.10-7.08 (m, 2H), 6.92 (s, 1H), 6.62 (d, 1H, J=6.3 Hz), 6.23 (s, 2H), 2.80 (t, 2H, J=6.0 Hz), 2.65 (t, 2H, J=5.4 Hz), 2.52-2.48 (m, 4H, merged with DMSO peak), 1.68 (s, 4H); ESI-MS (m/z, %): 339 (MH+, 100).
Reaction SMILES: [C:1]([C:4]1[NH:20][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:6]=2[CH:5]=1)([OH:3])=O.[B-](F)(F)(F)F.[CH3:26][N:27](C(ON1C(=O)C=CC=C1)=[N+](C)C)[CH3:28].CNC>CN(C=O)C>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[NH:12][C:11]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[N:27]([CH3:28])[CH3:26])[NH:20][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc2c(Nc3cccc(Cl)c3)ncnc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under a N2 atmosphere, 97.6 mg (0.338 mmol) of 6-carboxy-4-(3-chloro-anilino)-7H-pyrrolo[2,3-d]pyrimidine are introduced into 7 ml of DMF, and 119 mg (0.40 mmol) of TPTU and a solution of 164 mg (33% in ethanol; 1.2 mmol) of dimethylamine in 1 ml of DMF are added thereto. After 2 hours, a further 30 mg of TPTU is added to the reaction solution, which is then stirred at RT for 2 days, then poured into 30 ml of ice-water, stirred, filtered and washed with water to yield the title compound; HPLC: tRet (Grad20)=9.5; TLC-Rf =0.38 (CH2Cl2 /methanol [10:1]); FAB-MS: (M+H)+ =316.
Reaction SMILES: [C:1]([O:5][C:6](=[O:54])[NH:7][C@H:8]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[OH:53])[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[C:13]([CH3:33])[N:12]([CH2:34][C:35]2[C:40]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:11]1=[O:46])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:61]([O:65][C:66](=[O:69])[CH2:67]Br)([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.ClCCl>[C:61]([O:65][C:66](=[O:69])[CH2:67][O:53][C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:54])[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]3[O:25][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)=[C:13]([CH3:33])[N:12]([CH2:34][C:35]2[C:40]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:38]=[CH:37][C:36]=2[F:45])[C:11]1=[O:46])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2O)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2OCC(=O)OC(C)(C)C)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A solution of [(R)-2-{3-(2-fluoro-6-trifluoromethyl-benzyl)-4-methyl-2,6-dioxo-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-3,6-dihydro-2H-pyrimidin-1-yl}-1-(2-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester (100 mg, 0.13 mmol), potassium carbonate (36 mg, 0.26 mmol), and bromo-acetic acid tert-butyl ester (38 μl, 0.26 mmol) were dissolved at 70° C. for 4 hrs in DMF (1 mL) with stirring, and then chilled to room temperature. The solution was diluted in dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate, 2/1) and dried in a vacuum to afford 51 mg of the compound as a white oil (yield 44%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[CH3:27]CN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1

Procedure:
The product (0.867 g) obtained in the above (2) is dissolved in dichloromethane (15 ml), and thereto are added methanol (1.5 ml), 4-dimethylaminopyridine (34 mg) and WSC.HCl (0.633 g) under ice-cooling. The mixture is stirred under ice-cooling for two hours, and then stirred at room temperature for 12 hours. The mixture is concentrated under reduced pressure to the volume of about 5 ml, and the residue is poured into water.
Reaction SMILES: O[CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]([CH3:18])[C:6]1=O)[CH:3]=O.[NH2:20][NH2:21]>C1C=CC=CC=1>[CH3:18][CH:7]1[C:6]2[N:20]=[N:21][CH:3]=[CH:2][C:5]=2[CH2:10][CH2:9][N:8]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: NN
Reactant: CC1C(=O)C(C(O)C=O)CCN1C(=O)OC(C)(C)C
Solvent: c1ccccc1
Product: CC1c2nnccc2CCN1C(=O)OC(C)(C)C

Procedure:
To a solution of 70.0 mg (0.258 mmol) of tert-butyl 4-(1-hydroxyl-2-oxoethyl)-2-methyl-3-oxopiperidine-1-carboxylate (Step E) in 12 mL of benzene was added hydrazine. The reaction was heated to reflux for 3.5 h and concentrated to afford the title compound. LC/MS 194 (M+1-56).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Si:12](OC(CCC)CC(OCC)=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[Si:12]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCOC(=O)CCCCCO
Reactant: CCCC(CC(=O)OCC)O[Si](C)(C)C(C)(C)C
Product: CCOC(=O)CCCCCO[Si](C)(C)C(C)(C)C
Yield: 90 %

Procedure:
Ethyl 6-((tert-butyldimethylsilyl)oxy)hexanoate 8 (3.08 g) was prepared in 90% yield using ethyl 6-hydroxyhexanoate 7 according to the procedures described for compound 2 in above (see Schemes 1-3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1.[CH3:20][O:21][CH2:22][CH2:23][CH2:24]OS(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[CH3:20][O:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: CCCCC(CC(=O)OC)c1ccc(O)cc1OC
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCOCC
Product: CCCCC(CC(=O)O)c1ccc(OCCCOC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 58A), and 3-methoxy-1-tosyloxypropane, the corresponding ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[CH:12]1([C:15]2[CH:16]=[C:17]([CH3:27])[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:20]=2)[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:18]3[C:17]([CH3:27])=[CH:16][C:15]([CH:12]4[CH2:13][CH2:14]4)=[CH:20][N:19]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C)CC1
Yield: 54 %

Procedure:
Using 4-bromo-2-methylbenzoic acid (1.00 g) and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (1.52 g) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (1.04 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].N1C=CC=CC=1.[C:23](Cl)(=[O:25])[CH3:24]>O>[C:23]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])(=[O:25])[CH3:24]
Reactant: NC(=O)c1cc(-c2ccc(F)cc2)sc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1sc(-c2ccc(F)cc2)cc1C(N)=O
Reaction time: 0.5 h

Procedure:
A vigorously stirred mixture of 2-amino-5-(4-fluorophenyl)- 3-thiophenecarboxamide (0.01 mole) and pyridine (20 ml) at 0° was treated dropwise with acetyl chloride (0.011 mole). The resulting solution was stirred a further 30 minutes at 0° and then poured on to cold water. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from ethanol yielded 2-acetamido-5-(4-fluorophenyl)- 3-thiophenecarboxamide (90°/o, m.p. 230°-3°).
Reaction SMILES: [C:1]1([CH:7]2[NH:11][N:10]=[CH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>C(Cl)(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([N:11]2[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH:9]=[N:10]2)=[O:27])[CH:22]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C1=NNC(c2ccccc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(c1cccnc1)N1N=CCC1c1ccccc1
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
A mixture of 5-phenyl-2-pyrazoline (2.9 g) and triethylamine (4 g) was added dropwise with ice cooling to a suspension of nicotinoyl chloride hydrochloride (4 g) in 20 ml chloroform, the resulting mixture was stirred for 15 minutes, washed with water and concentrated, and the concentrate was purified by silica gel chromatography (chloroform/methanol=100/1), giving 4.3 g (yield: 86%) of pure product. M.p. 100°-102° C.; NMR (CDCl3): 2.9-3.8 (2H, m), 5.61 (1H, dd, J=5, 12 Hz), 7.03 (1H, t, J=2 Hz), 7.31 (5H, s), 7.28 (1H, m), 8.15 (1H, dt, J=8, 2 Hz), 8.68 (1H, dd, J=2, 6 Hz), 9.13(1H, d, J=2 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:13])=[CH:5][CH:6]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cccc(Nc2ccncc2)c1
Product: O=C(c1cccc(Nc2ccncc2)c1)N1CCCCC1

Procedure:
1-[3-(4-Pyridinylamino)benzoyl]piperidine was prepared from 3-(4-pyridinylamino)benzoic acid and piperidine according to a procedure analogous to that of Example 48(b), and was obtained in the form of its hydrochloride salt, colorless powder, m.p. 224°-226° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]([S-:5])([CH3:4])[CH3:3].[Na+].[CH3:7][S:8](Cl)(=[O:10])=[O:9]>O1CCCC1.ClCCl>[CH3:7][S:8](=[O:10])([S:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[S-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)SS(C)(=O)=O
Temperature: -60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Tetrahydrofuran (100 ml) was added to sodium 2-methyl-2-propanethiolate (7.83 g, 69.8 mmol), and the mixture was cooled to −60° C. or lower. A solution of methanesulfonyl chloride (6.77 ml, 87.0 mmol) in tetrahydrofuran (50 ml) was added dropwise to this suspension over 25 minutes. The reaction solution was gradually warmed to room temperature over 2 hours and stirred at room temperature for additional 1 hour. The reaction solution was diluted with dichloromethane (300 ml) and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford S-tert-butyl methanesulfonothioate (Compound SP684) (11.17 g, 76%). The obtained compound was confirmed based on the compound data described in Non patent literature (Inorganic Chemistry, 2010, 49, 8637-8644).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=O.C(N(CC)CC)C.C1C=CC(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([N:34]=[N+:35]=[N-:36])=[O:12]
Reactant: O=C(O)/C=C/c1ccccc1Cl
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NC(=O)/C=C/c1ccccc1Cl
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of (E)-3-(2-chlorophenyl)acrylic acid (13 g, 71.2 mmol) in benzene (100 ml) was added triethylamine (14.4 g, 141 mmol) followed by DPPA (19.5 g, 71.2 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The solvent was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated to get crude compound. The crude compound was purified by conventional column chromatography (Silica gel, 60-120 mesh) using 10% ethyl acetate in pet ether as mobile phase to get the desire compound as pale yellow solid (14 g, 95%). 1H NMR (400 MHz, CDCl3): δ ppm 8.19-8.15 (d, J=16 Hz, 1H), 7.63-7.61 (d, J=8 Hz, 1H), 7.44-7.42 (m, 1H), 7.36-7.26 (m, 2H), 6.44-6.40 (d, J=16 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C@@H:6]1([O:37][P:38]([OH:41])([OH:40])=[O:39])[C@@H:11]([O:12][P:13]([OH:16])([OH:15])=[O:14])[C@H:10]([O:17][P:18]([OH:21])([OH:20])=[O:19])[C@@H:9]([O:22][P:23]([OH:26])([OH:25])=[O:24])[C@@H:8]([O:27][P:28]([OH:31])([OH:30])=[O:29])[C@H:7]1[O:32][P:33]([OH:36])([OH:35])=[O:34]>>[CH:8]1([O:27][P:28]([OH:31])([OH:30])=[O:29])[CH:9]([O:22][P:23]([OH:25])([OH:26])=[O:24])[CH:10]([O:17][P:18]([OH:20])([OH:21])=[O:19])[CH:11]([O:12][P:13]([OH:16])([OH:15])=[O:14])[CH:6]([O:37][P:38]([OH:41])([OH:40])=[O:39])[CH:7]1[O:32][P:33]([OH:35])([OH:36])=[O:34]
Reactant: O=P(O)(O)O[C@H]1[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H](OP(=O)(O)O)[C@@H](OP(=O)(O)O)[C@H]1OP(=O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P(O)(O)OC1C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C(OP(=O)(O)O)C1OP(=O)(O)O
Temperature: 90 °C
Reaction time: 24 h
Yield: 137.9 %

Procedure:
Alternatively, the phytic hexa-citrate compound was produced by the following method: First, 0.33 kg of calcium carbonate was slowly added, in increments of 0.1 kg, to 0.87 kg of phytic acid liquid. The mixture was heated and refluxed for about one hour at about 90° C. The two solids were separated and filtered. The white solid, which was calcium phytate, was collected. About 1 kg of the calcium phytate was dissolved into 2.0 liters of water and heated to about 89° C. for about 10-15 minutes until calcium phytate was completely dissolved in the water solution. About 0.9 kg of citric acid was then added to and stirred in the calcium phytate soluttion until the citric acid was completely dissolved. The heat source was removed and the resulting mixture was left sat at no more than 40° C. or in a refrigerated environment at a temperature of about 5-10° C. to allow the newly formed phytic hexa-citrate to crystallize for approximately 6 to 8 hours or until crystallization has ceased. The mixture was allowed to dry out at room temperature until no liquid was visible. The crystals were spread in a drying pan for approximately 24 hours at a temperature of no more than 40° C., which yielded approximately 1.2 kg of hexa-citrated phytate.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[O:11][C:10]=2[CH:20](O)[CH3:21])[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:25]>C(Cl)Cl>[Br:25][CH:20]([C:10]1[O:11][C:12](=[O:19])[C:13]2[C:18]([C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:23])[CH3:1])[CH:4]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:21]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(N(C)C)c1
Yield: 125.9 %

Procedure:
The title compound was made in a similar way as that of the intermediate C6, using 4-(3-(dimethylamino)phenyl)-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate B8, 200 mg, 0.64 mmol), 1M PBr3 (1.1 ml, 1.1 mmol) in DCM (2 ml) at RT. The crude was purified with Biotage Silica SNAP 50 g with a gradient of DCM and MeOH to give the title compound (300 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21]>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[C:20]([F:21])([F:22])[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
18 g (166.67 mmol) of benzylalcohol was slowly added to a solution of 6.7 g (167.50 mmol) of sodium hydride in 148 mL NMP. The reaction mixture was stirred for 30 min at RT, then a solution of 27 g (139.09 mmol) of 1-fluoro-4-methoxy-2-trifluoromethyl-benzene in 515 mL NMP was added, and this was stirred for 30 min at RT and for 2 h at 100° C. After cooling to RT the mixture was diluted with water and extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated down. The residue was purified by chromatography (silica gel, petroleum ether/ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:13]=[O:14])=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].CC(=CC)C.[Cl-].[Na+].[O:22]1CCOCC1>O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:22])=[O:14])=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(C=O)cc1C(C)C
Reactant: C1COCCO1
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1sc(C(=O)O)cc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 5-Formyl-3-isopropyl-thiophene-2-carboxylic acid methyl ester (0.51 g, 2.40 mmol) in dioxane (12 ml) was added 2-methyl-2-butene (3 ml) and a solution of Na2ClO2 (0.65 g, 7.21 mmol) and NaH2PO4 (0.79 g) in water (3 ml). The mixture was stirred at rt for 2 h. The solution was saturated with sodium chloride, then successively extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (0.45 g, 82% yield).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:11]([O:12]C(=O)C)[C@:10]2([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24](=[O:34])[C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)[CH:18]=3)[O:16][C@@:7]([CH2:35][O:36]C(=O)C)([CH2:8][O:9]2)[C@H:6]1[O:40]C(=O)C)(=O)C.C[O-].[Na+]>CO.O1CCCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C@@:10]23[O:16][C@@:7]([CH2:35][OH:36])([CH2:8][O:9]2)[C@@H:6]([OH:40])[C@H:5]([OH:4])[C@H:11]3[OH:12])=[CH:18][C:19]=1[C:24]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:32][CH3:33])=[CH:29][CH:30]=1)=[O:34]
Reactant: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc2Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(C(=O)c2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.7 %

Procedure:
To a solution of acetic acid (1R,2S,3S,4R,5S)-3,4-diacetoxy-1-acetoxymethyl-5-[4-chloro-3-(4-ethoxy-benzoyl)-phenyl]-6,8-dioxa-bicyclo[3.2.1]oct-2-yl ester (see Example 11 for preparation; 65 mg, 0.10 mmol) in methanol (3 mL) and tetrahydrofuran (2 mL) was added sodium methoxide in methanol (25% wt) until pH 12 was obtained and the resulting mixture was stirred at room temperature. After 16 hours, the reaction mixture was neutralized by the addition of Dowex Monosphere 650C (H) cation exchange resin until the pH of the solution was <7, filtered and concentrated under reduced pressure. The resulting material was precipitated from ethyl acetate and heptanes and the resulting white solid was washed with heptane 2 times and dried under reduced pressure to yield the desired product (44.5 mg, 94% yield). MS (LCMS) 451.1 (M+H+; positive mode)1H NMR (400 MHz, METHANOL-d4) delta ppm 1.40 (t, J=6.9 Hz, 3 H), 3.55 (d, J=8.0 Hz, 1 H), 3.60 (d, J=7.4 Hz, 1 H), 3.65 (t, J=8.1 Hz, 1 H), 3.67 (d, J=12.5 Hz, 1 H), 3.77 (d, J=8.0 Hz, 1 H), 3.83 (d, J=12.5 Hz, 1 H), 4.12 (q, J=7.0 Hz, 2 H), 4.14 (d, J=7.6 Hz, 1 H), 6.98 (d, J=8.8 Hz, 2 H), 7.48 (d, J=8.4 Hz, 1 H), 7.52 (d, J=2.0 Hz, 1 H), 7.65 (dd, J=8.4, 2.0 Hz, 1 H), 7.73 (d, J=8.8 Hz, 2 H). HRMS calculated for C22H23O8Cl (M) 450.1081. found 450.1079.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:17][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 250 mL round bottomed flask were placed ethyl 4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) and methylene chloride (100 mL). To the solution was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred for 3 h at rt. To the mixture was added a freshly prepared 10% aqueous solution of NaHSO3 (5 g NaHSO3 dissolved in 50 mL water) and the resulting biphasic mixture was vigorously stirred for 15 min at rt. The organic phase was separated and the aqueous phase was extracted with DCM (30 mL). The organic phases were combined and washed with a saturated aqueous solution of NaHCO3 (50 mL) and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residual yellow oil was essentially pure and was used in the next step without further purification. LC/MS (FA) ES− 319.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1
Reactant: c1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2ccnc2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methylpyridine (example A.51) (0.5 g, 0.8 mmol) and commercially available imidazole (0.112 g, 1.6 mmol) according to the general procedure IVa. Obtained as a white solid (0.060 g, 24%). MS (ISP) 304.0 [(M+H)+], 306 [(M+2+H)+] and 308 [(M+4+H)+]; mp 227° C.