Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[CH2:13][C@@H:12]([CH2:16][OH:17])[O:11][C@H:10]1[N:18]1[C:30]2[C:29]3[NH:31][C:32]4[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=4[C:28]=3[C:27]3[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=3[C:25]=2[C:24]2[C:19]1=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:47](Cl)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:47]([O:17][CH2:16][C@H:12]1[O:11][C@@H:10]([N:18]2[C:30]3[C:29]4[NH:31][C:32]5[CH:33]=[C:34]([F:39])[C:35]([F:38])=[CH:36][C:37]=5[C:28]=4[C:27]4[C:40](=[O:44])[NH:41][C:42](=[O:43])[C:26]=4[C:25]=3[C:24]3[C:19]2=[CH:20][C:21]([F:46])=[C:22]([F:45])[CH:23]=3)[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@@H:14]([OH:15])[CH2:13]1)([C:60]([CH3:63])([CH3:62])[CH3:61])([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=C1NC(=O)c2c1c1c3cc(F)c(F)cc3[nH]c1c1c2c2cc(F)c(F)cc2n1[C@@H]1O[C@H](CO)C[C@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H](O)[C@@H](OCc2ccccc2)[C@H](n2c3cc(F)c(F)cc3c3c4c(c5c6cc(F)c(F)cc6[nH]c5c32)C(=O)NC4=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.8 %

Procedure:
To a solution of 12-[4-deoxy-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo-[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.500 g, 0.79 mmol) in 6 mL of dry DMF, at 5° C. under Ar, was added tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol). After stirring this mixture at room temperature for 20 h it was re-cooled at 5° C. and more tert-butyldiphenylsilyl chloride (0.205 mL, 0.79 mmol) and imidazole (0.161 g, 2.37 mmol) were added. The resulting mixture was stirred at room temperature for 2.5 h and then it was diluted with ethyl acetate, washed (1M NaHCO3, brine), dried (MgSO4) and evaporated. Chromatography (SiO2/20-35% ethyl acetate-hexane) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo [3,4-c]carbazole-5,7(6H)-dione (0.474 g, 69%); MS (ESI−) m/e 870 (M−H)−. To a solution of a portion (0.050 g, 0.057 mmol) of this material in 2 mL of dichloromethane was added a suspension of Dess-Martin periodinane (0.048 g, 0.114 mmol) in 3 mL of dichloromethane and the mixture was stirred for 30 min. The mixture was then diluted with ethyl acetate, washed (cold 30% aq. Na2S2O3,1M NaHCO3, H2O, brine), dried (MgSO4) and evaporated. Prep tlc (SiO2/ethyl acetate-hexane, 2:3) of the residue afforded 12-[4-deoxy-6-O-(tert-butyldiphenylsilyl)-2-O-benzyl-3-oxo-β-D-glucopyranosyl]-2,3,9,10-tetrafluoro-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione (0.035 g, 70%) as a gum which solidified on standing; MS (ESI−) m/e 868 (M−H)−.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][C:33](O)=[O:34]>CN(C=O)C>[Br:31][CH2:32][C:33]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:34]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
WSC (2.1 g, 11 mmols) and HOBt (1.49 g, 11 mmols) were added to a DMF (30 ml) solution of 2,4-difluroaniline (1.29g, 10 mmols) an bromoacetic acid (2.08 g, 15 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 1.7 g (yield: 68%) of 2-bromo-N-(2,4-difluorophenyl)acetamide as colorless needle-like crystals.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:43][CH2:44][C:45](=O)[CH3:46])=[CH:42][C:37]=2[O:36][CH2:35]1>>[CH3:46][C:45](=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:44][CH2:43][C:41]1[CH:40]=[CH:39][C:38]2[O:34][CH2:35][O:36][C:37]=2[CH:42]=1
Reactant: CC(=O)CCc1ccc2c(c1)OCO2
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(=CCc1ccccc1)CCc1ccc2c(c1)OCO2
Yield: 30.7 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (1.82 g, 4.07 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 2.6 mL, 4.07 mmol, 1.0 equiv.) and 4-(benzo[d][1,3]dioxol-5-yl)butan-2-one (1.17 g, 6.10 mmol, 1.5 equiv.), 0.35 g (30%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1).
Reaction SMILES: C(OC([NH:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=O)C1C=CC=CC=1.[H][H]>O1CCCC1.[C].[Pd]>[NH2:11][C:12]12[CH2:19][CH2:18][C:15]([C:20]([NH:22][CH:23]3[CH2:28][CH2:27][C:26]([F:29])([F:30])[CH2:25][CH2:24]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2
Reactant: O=C(NC12CCC(C(=O)NC3CCC(F)(F)CC3)(CC1)CC2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: NC12CCC(C(=O)NC3CCC(F)(F)CC3)(CC1)CC2
Yield: 101 %

Procedure:
4-Benzyloxycarbonylamino-N-(4,4-difluorocyclohexyl)bicyclo[2.2.2]octane-1-carboxamide (55.4 mg) was dissolved in tetrahydrofuran (6 mL). To this solution, 10% palladium carbon (20.0 mg) was added and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column (eluant:ethyl acetate:methanol=10:1) to give 4-amino-N-(4,4-difluorocyclohexyl)bicyclo[2.2.2]octane-1-carboxamide (38.1 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12](=O)[CH2:13][C:14](OCC)=[O:15].C(=O)([O-])O.[Na+]>P(=O)(O)(O)O>[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([OH:15])[C:8]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:9]=2)[N:7]=1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])O
Agent: O=P(O)(O)O
Agent: [Na+]
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 4.6 %

Procedure:
4-Methoxyaniline (5.00 g) was dissolved in 75% phosphoric acid (20 mL) and ethyl trifluoroacetoacetate (7.48 g) was dropwise added thereto at 110° C. The mixture was stirred at 110° C. for 4 hr with heating. After allowing to cool, the reaction mixture was added to saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (0.450 g).
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CN=C1.[C:16]1(=[O:21])[CH2:20][CH2:19][CH:18]=[CH:17]1>CO.O>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:17]2[C:16](=[O:21])[CH2:20][CH2:19][CH:18]=2)=[CH:6][C:7]([CH3:10])=[CH:8][N:9]=1
Reactant: O=C1C=CCC1
Reactant: Cc1cnc(Cl)c(C=O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Product: Cc1cnc(Cl)c(C(O)C2=CCCC2=O)c1
Yield: 98 %

Procedure:
The clear solution of 2-Chloro-5-methylnicotinaldehyde (10 mmol, 1.55 g) and imidazole (10 mmol, 0.68 g) in 50 ml. of MeOH was slowly charged with 50 ml. of deionized water. To a stirred homogeneous reaction mixture was added 2-cyclopenten-1-one (10.2 mmol., 0.88 g) at room temperature and reaction progress was monitored by TLC. Upon completion of the reaction, excess MeOH was removed under reduced pressure, washed with water and extracted with CHCl3 thrice. Combined organic layers were washed with brine solution twice. The organic layer was concentrated and column chromatography of the crude product on silica gel, using 30% EtOAC in hexane as eluent, gave pure Baylis-Hillman adduct in 98% yield (2.32 g)
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[C:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:17][C:18]2([C:19](=[O:20])[O:21][CH2:22][CH2:23]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCOC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A stirred solution of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D8, 160 g of 75% purity, assume 0.51 mole) and α-methylene-γ-butyrolactone (D10, 50 g, 0.51 mole) in dichloromethane (1 liter) under nitrogen was cooled to 0° C. and then treated with a 1 M solution of trifluoroacetic acid in dichloromethane (50 ml, 0.05 mole), keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature over 2 h, then washed with saturated sodium bicarbonate solution. The aqueous wash was extracted with dichloromethane and the organic solutions then combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow oil. This was distilled in vacuo to give the title compound (D11) as a colourless oil (96 g, 81%) b.p. 160°-170° C. at 1 mmHg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]O)=[CH:23][C:22]=1[I:29].C(Br)(Br)(Br)[Br:31]>ClCCl>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Br:31])=[CH:23][C:22]=1[I:29]
Reactant: OCc1ccc(Cl)c(I)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CBr)cc1I
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 139.9 %

Procedure:
Triphenylphosphine (1.1 g) was added in portions to a solution of 4-chloro-3-iodobenzyl alcohol (1.1 g) in dichloromethane (40 ml) at 0° C. and stirring was continued for 10 minutes. Carbon tetrabromide (1.5 g) was then added in portions over 2 minutes, the reaction mixture was allowed to warm to ambient temperature and was stirred for 15 hours. The solution was added directly to a silica charged chromatography column and was eluted with dichloromethane to give 4-chloro-3-iodobenzyl bromide (1.9 g). NMR (CD3SOCD3): d 4.6 (s, 2H), 7.5 (m, 2H), 7.6 (s, 1H), 8.0 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[C:19]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: Cc1nc2ccc(O)cc2o1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(C)oc2c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A slurry of 2-methyl-1,3-benzoxazol-6-ol (7.1 g, 47.8 mmol) in tetrahydrofuran was cooled to 10° C. and triethylamine (5.8 mL, 81.3 mmol) was added in one portion, followed by the addition of acetyl chloride (11.3 mL, 81.6 mmol) in small portions. After stirring at room temperature over night the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed twice with water and concentrated to give the titled compound (8.2 g, 90%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[CH:4]1[CH:9]3[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Clc1ccc2c3c1c1c(n3CCNCC2)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Clc1ccc2c3c1C1CCCCC1N3CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
To a solution of 8-chloro-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (2.2 g, 8.00 mmole) in acetic acid (200 mL) was added sodium cyanoborohydride (95 wt. %, 2.5 g, 40.0 mmole) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was diluted with methylene chloride (400 mL) and washed with aqueous sodium hydroxide (1N, 300 mL), saturated sodium chloride (300 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 1.67 g of the title compound. 0.116 g of the compound was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 199-200° C. MS (ES) m/z 277.1 ([M+H]+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20](Cl)[N:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:23]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Cl)nc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.74 g (3.4 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 1.0 g (3.2 mmol) (2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was mixed with water and stirred for 30 min at RT. The precipitated solid was suction filtered, stirred with diisopropylether and isopropanol and suction filtered again. After drying the crude product was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[CH:8][C:7]=1[N+:18]([O-])=O>[Fe].C(OCC)(=O)C>[NH2:18][C:7]1[CH:8]=[C:9]([NH:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: CCS(=O)(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(F)c(N)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
A mixture of 63.1 g (1.13 mol) of iron powder and 120 ml of an aqueous solution of 5% acetic acid was heated to 80° C., and a mixed solution of 28.0 g (0.113 mol) of N-(4-fluoro-3-nitrophenyl)ethanesulfonamide, 116 ml of acetic acid and 116 ml of ethyl acetate was slowly added dropwise to the resultant mixture. After the reaction was continued for 3 hours, the insolubles were filtered out and washed with ethyl acetate. Thereafter the filtrate was distilled to remove the solvent, and the product was dissolved in ethyl acetate and washed with saturated sodium hydrogencarbonate, water and saturated saline solution. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude product (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 22.0 g of the objective product (yield: 89%) in the form of light yellow crystals.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[CH:7]=[C:8]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])[CH:9]=[CH:10][C:11]=1[Cl:12])([OH:3])=[O:2].[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:24]1([O:2][C:1]([CH2:4][S:5][C:6]2[CH:7]=[C:8]([N:13]3[C:21](=[O:22])[C:20]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=4[C:14]3=[O:23])[CH:9]=[CH:10][C:11]=2[Cl:12])=[O:3])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCC1
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl)OC1CCCC1
Yield: 44.3 %

Procedure:
2-(3-Carboxymethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (3.61 g), cyclopentanol (1.24 g) and p-toluenesulfonic acid monohydrate (0.18 g) were suspended in toluene (10 ml), molecular sieve 3A (0.2 g) was added thereto, and the resultant mixture was heated under reflux for 6 hours. The reaction mixture was allowed to cool, admixed with water and extracted with toluene. The extract was washed with water, dried, and concentrated. The precipitated crystals were washed with methanol to give 1.91 g of 2-(3-cyclopentyloxycarbonylmethylthio-4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione. m.p., 57°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[CH:6]2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([CH3:14])[N:8]=1
Reactant: COc1ccc2c(=O)[nH]c(C)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(C)cc2c1

Procedure:
Isoquinoline-1-one 43 was dissolved in POCl3 (2.5 mL) and heated at reflux for 1 h. The excess POCl3 was removed in vacuo and the residue was dissolved in CHCl3. The resulting solution was washed with 1N aq. NaOH, water and saturated ag. NaCl. Evaporation of the solvent gave crude 44 which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:3]#[C:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:8][CH:6]([CH2:5][C:4]#[C:3][C:2]([CH3:1])([OH:20])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH3:7])(=[O:23])[CH3:22]
Reactant: CC(C)CCCC(C)CCCC(C)(O)C#CCC(C)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CC#CC(C)(O)CCCC(C)CCCC(C)C
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A solution of 230 mg (0.814 mmole) of 6,10,14-trimethyl-4-pentadecyne-2,6-diol (produced in accordance with Example XVI) and 0.25 mL (2.65 mmoles) of acetic anhydride in 0.25 mL of pyridine (A.C.S. reagent-grade, purchased from Aldrich Chemical Co., Milwaukee, Wis.) was stirred, while being maintained under a nitrogen atmosphere, at room temperature for 8 hours. After destroying excess acetic anhydride by addition of 10 mL of ice-cold 1M aqueous sodium hydroxide, the mixture was diluted with 20 mL of hexane and 25 mL of 10% aqueous sodium chloride. The layers were then separated, and the organic layer washed in successive order with 1:1 (v/v) 1M aqueous sodium hydroxide: 10% aqueous sodium chloride (1×10 mL), 1:1 (v/v) 2M aqueous hydrochloric acid: saturated brine (2×20 mL), saturated aqueous sodium bicarbonate (1×10 mL), and saturated brine (1×10 mL). The washed organic layer was subsequently dried over anhydrous magnesium sulfate and filtered. Removal of the volatile organic material by evaporation at reduced pressure afforded 249 mg (94% yield) of 2-acetoxy-6,10,14-trimethyl-4-pentadecyn-6-ol (i.e., the product derived by selective acetylation of the 2° alcohol functionality in the starting alkynediol).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[C:8]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([F:26])[F:25])=[CH:20][CH:19]=3)[C:6]=2[CH:7]=1.CS(C)=[O:29]>>[F:25][CH:24]([F:26])[C:21]1[CH:22]=[CH:23][C:18]([O:17][C:8]2[C:6]3[CH:7]=[C:3]([CH:2]=[O:29])[O:4][C:5]=3[CH:11]=[C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=2)=[CH:19][CH:20]=1
Reactant: CS(C)=O
Reactant: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(CBr)oc2c1
Product: CCOC(=O)c1cc(Oc2ccc(C(F)F)cc2)c2cc(C=O)oc2c1
Yield: 81 %

Procedure:
A solution of ethyl 2-(bromomethyl)-4-[4-(difluoromethyl)phenoxy]-1-benzofuran-6-carboxylate (440 mg, 1.03 mmol) and IBX (579 mg, 2.07 mmol) in DMSO (2 mL) was heated at 65° C. for 3 h. The reaction was quenched with water and the product was extracted with CHCl3 (3×). The combined organic layers was washed with water (2×), dried over MgSO4 and concentrated. The product was purified via gradient silica gel chromatography using hexanes/EtOAc (100/0 to 50/50) to give the title compound (300 mg, 81%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 6.67 (t, J=56.42 Hz, 1 H) 7.11-7.18 (m, J=8.67 Hz, 2 H) 7.48 (d, J=0.94 Hz, 1 H) 7.51 (d, J=0.94 Hz, 1 H) 7.55 (d, J=8.67 Hz, 2 H) 8.08 (d, J=0.94 Hz, 1 H) 9.87 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:18][C:11]3[N:12]=[C:13]([CH3:17])[NH:14][C:15](=O)[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:15]1[C:10]2[CH:9]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:18][C:11]=2[N:12]=[C:13]([CH3:17])[N:14]=1
Reactant: Cc1nc2sc(C3CCC(C)(C)CC3)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 130 °C

Procedure:
To a mixture of 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4(3H)-one (30.0 g) and toluene (240 mL) were added phosphorous oxychloride (40 mL) and DMF (1.0 mL), followed by heating to reflux at 130° C. for 2 hours. The reaction mixture was left to be cooled to room temperature and concentrated under reduced pressure. To the residue were added chloroform and saturated aqueous sodium bicarbonate, followed by stirring. The organic layer was washed sequentially with water and brine. To the organic layer were added MgSO4, activated carbon (10 g), and silica gel (100 mL), followed by stirring. The mixture was filtered through Celite and then concentrated under reduced pressure to obtain 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (31.3 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)O
Product: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Yield: 54 %

Procedure:
(S)-4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylic acid (11.2 g, 42.5 mmol) was reacted with benzyl bromide (8.72 g, 51 mmol) according to the procedure as described in Example 34, Step A to give the title compound as a white solid (8.11 g, 54%). The compound was characterized by the following spectroscopic data: