Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH:13]3[O:18][CH2:17][CH2:16][N:15]([C:19](OC(C)(C)C)=O)[CH2:14]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C=O.O.C([BH3-])#N.[Na+]>Cl.O1CCOCC1>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:12][CH:13]3[O:18][CH2:17][CH2:16][N:15]([CH3:19])[CH2:14]3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1oc2ccc(OCC3CN(C(=O)OC(C)(C)C)CCO3)cc2c1C
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1oc2ccc(OCC3CN(C)CCO3)cc2c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 3-methyl-5-(4-Boc-morpholin-2-ylmethoxy)-benzofuran-2-carboxylate (1.05 mmol) was dissolved in 30 ml of a 4.0 M solution of hydrochloric acid in dioxan and stirred at room temperature for 1 hour. After removing the solvent under vacuo the resulting amine was dissolved in 20 ml of a mixture 2 to 1 of methanol and a buffered solution of acetic acid and sodium acetate at pH=5.3. A 37% solution of formaldehyde in water (1.16 mmol) was added and the mixture was stirred at room temperature for 1 hour. Then sodium cyanoborohydride (1.16 mmol) was added and the mixture was stirred over night at room temperature. The methanol was removed under vacuo and the water was eliminated by liophylisation. The solid obtained was purified by flash chromatography to yield ethyl 3-methyl-5-(4-methyl-morpholin-2-ylmethoxy)-benzofuran-2-carboxylate: m/z=334 in MS ES+, as a white solid.
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])=[C:14]([F:34])[CH:13]=1>>[CH3:32][C:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([N:5]4[C@@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][C:14]=3[F:34])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: CC(C)[C@H]1CCS(=O)(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@@H](C(C)C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 11.8 %

Procedure:
Using (R)-3-isopropylisothiazolidine 1,1-dioxide (300 mg) described in Preparation Example 8 and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (440 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 4, the title compound (63 mg) was obtained.
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Ni]>[C:16]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [O-][n+]1ccc(OC(c2ccccc2)c2ccccc2)cc1
Agent: [Ni]
Solvent: CCO
Product: c1ccc(C(Oc2ccncc2)c2ccccc2)cc1
Yield: 64.7 %

Procedure:
4-Diphenylmethoxypyridine-1-oxide (5.0 g; 0.018 m) was hydrogenated in ethanol (100 ml) at a pressure of 2 atmospheres using 5 g, of freshly alcohol washed Crosfield Raney nickel. After two hours at room temperature the mixture was filtered, and the solvent removed, leaving an oil that crystallised from petrol (60-80) to give 3.05 g of 4-diphenylmethoxypyridine as white crystals, m.pt. 68°-70° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=[O:24].C(O)(=O)C>CCO>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][C:12](=[N:26][NH:25][C:23](=[O:24])[C:22]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=1[F:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NNC(=O)c1cc(F)ccc1F
Reactant: CC(C)(C)[Si](C)(C)OCCCC(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCC(=NNC(=O)c1cc(F)ccc1F)c1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(tert-butyldimethylsilanyloxy)-1-phenylbutan-1-one (420 mg, 1.5 mmol) in EtOH (4 mL) was added 2,5-difluorobenzoic acid hydrazide (260 mg, 1.5 mmol) and acetic acid (0.07 mL, 1.2 mmol). After stirring the reaction mixture at 90° C. for 5 hours, more acetic acid (0.1 mL) was added. The mixture was stirred at 90° C. for 40 hours and then concentrated under reduced pressure. The mixture of starting material and product was carried forward without further purification.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]>>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1[CH2:67][CH:68]1[NH:72][C:71](=[O:73])[NH:70][C:69]1=[O:74])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC1NC(=O)NC1=O
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3NC(=O)NC3=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 31 %

Procedure:
The same procedure as in Example 8-1 was carried out by using allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (220 mg, 0.440 mmol) and (2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)-4-tritylthiopyrrolidine diastereomer B (220 mg, 0.406 mmol, compound of Reference Example 29) to obtain allyl (1R,5S,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2,4-dioxoimidazolidin-5-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (70 mg, yield: 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][C:12]=2[CH2:20][CH:21]=[CH2:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:47][C@@H:48]([NH2:58])[CH2:49][CH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([NH:58][C@H:48]([CH3:47])[CH2:49][CH2:50][CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)=[O:19])=[CH:13][C:12]=2[CH2:20][CH:21]=[CH2:22])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=CCc1cc(C(=O)O)ccc1-c1ccc(OC)c(OC)c1
Reactant: C[C@@H](N)CCCc1cccnc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCc1cc(C(=O)N[C@H](C)CCCc2cccnc2)ccc1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A solution of 379 mg of 3',4'-dimethoxy-2-(2-propenyl)[1,1'-biphenyl]-4-carboxylic acid in 8 mL of dimethylformamide was cooled in an ice bath and 0.19 mL of triethylamine and 0.30 mL of diphenylphosphorylazide were added. After 1 hour. 0.223 g of (R)-alpha-methyl-3-pyridinebutanamine was added and the reaction mixture was allowed to warm to room temperature over 48 hours. The mixture was diluted with ethyl acetate and washed with water and saturated potassium carbonate, dried. and concentrated. The residue was chromatographed over 50 g of silica gel, eluting with ethyl acetate to afford 527 mg of (R)-3',4'-dimethoxy-2-(2-propenyl)-N-[1-methyl-4-(3-pyridinyl)butyl][1,1'-biphenyl]-4-carboxamide as a water white oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(trans-3-hydroxycyclobutyl)carbamate (0.93 g, 4.97 mmol) was dissolved in dry THF (20 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.2 g, 4.97 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at RT for 30 min then benzyl bromide (0.88 mL, 7.45 mmol) added dropwise and the resulting dark brown suspension stirred at rt for 16 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and partitioned between saturated aqueous NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a off-white solid (0.99 g, 72%). 1H NMR (CDCl3, 400 MHz): δ 7.35-7.31 (5H, m), 4.65 (1H, br, NH), 4.40 (2H, s), 4.24-4.12 (2H, m), 2.50-2.35 (2H, m), 2.18-2.06 (2H, m), 1.43 (9H, s).
Reaction SMILES: [H-].[K+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12].[CH2:13]([Sn:17]([CH2:26]I)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>O1CCCC1.CCOCC>[CH2:13]([Sn:17]([CH2:26][O:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: OCCCc1ccccn1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)COCCCc1ccccn1
Reaction time: 0.5 h

Procedure:
Potassium hydride (52 mg, 1.30 mmol) was added to a solution of 3-(2-pyridyl)propan-1-ol (161.8 mg, 1.18 mmol) in tetrahydrofuran (3 ml) at room temperature under argon. After 30 minutes, a solution of tributylstannylmethyl iodide (510 mg, 1.18 mmol) in tetrahydrofuran (0.5 ml) was added. After stirring was continued at room temperature for 9 days, the mixture was diluted with ether and washed thoroughly with water. Evaporation of the dried (magnesium sulphate) organic layer gave an oil, which was flash chromatographed on silica using 60% ethyl ether/hexane. Fractions with Rf of about 0.53 on evaporation gave the title ether as a bright yellow oil.
Reaction SMILES: C(O[CH2:10]/[CH:11]=[C:12](\[CH3:26])/[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([OH:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=1[OH:25])(=O)C1C=CC=CC=1>C1COCC1>[CH3:26][C@@:12]1([CH:11]=[CH2:10])[CH2:13][CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([OH:22])[C:18]([CH3:23])=[C:17]([CH3:24])[C:16]=2[O:25]1
Reactant: C/C(=C\COC(=O)c1ccccc1)CCc1c(C)c(O)c(C)c(C)c1O
Solvent: C1CCOC1
Product: C=C[C@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Yield: 56 %

Procedure:
A solution of 106 mg (0.3 mmol) of (E)-5-(2,5-dihydroxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl benzoate, 5 mg (3%) of (R)-6,6'-dimethyl-2,2'-bis-(diphenylphosphino)-1,1'-biphenyl and 1.7 mg (1.5%) of π-allylpalladium chloride dimer in 5 ml of THF was heated to 70° C. for 24 hours. After cooling the solvent was removed and the residue was Purified as described in Experiment 1, yielding 39 mg of (S)-3,4-dihydro-2,5,7,8-tetramethyl-2-vinyl-2H-[1]-benzopyran-6-ol. O.P. 56%.
Reaction SMILES: C[O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([NH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[O:17])([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].O1CCCC1.O.[OH-].[Li+]>O>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:7]12[CH2:13][CH:11]3[CH2:10][CH:9]([CH2:14][C:5]([C:3]([OH:4])=[O:2])([CH2:12]3)[CH2:6]1)[CH2:8]2)=[O:17]
Reactant: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC12CC3CC(C1)CC(C(=O)O)(C3)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 25 h
Yield: 93.3 %

Procedure:
To a round bottom flask was added 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester (24.8 g, 78.9 mmol), tetrahydrofuran (250 mL), water (250 mL) and lithium hydroxide monohydrate (14.9 g, 355 mmol) and the mixture was stirred vigorously at room temperature for 25 hours. The crude mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran, then the aqueous solution was diluted with water (200 mL) and the pH was adjusted to about 3-4 by adding solid citric acid monohydrate. A voluminous white precipitate appeared which was filtered, washed with water and dried under high vacuum at 50° C. to afford 22.1 g (93%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid, as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.55-8.50 (m, 1H), 8.18 (d, J=7.7 Hz, 1H), 7.97 (br s, 1H), 7.85 (td, J=7.8, 1.8 Hz, 1H), 7.42 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 2.35-2.31 (m, 2H), 2.31-2.25 (m, 2H), 2.25-2.09 (m, 4H), 2.00-1.86 (m, 4H), 1.80-1.64 (m, 2H). ESI-MS m/z: 301.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH2:12]([OH:14])[CH3:13]>>[CH2:12]([O:14][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=1)[CH3:13]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCO
Product: CCOC(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 42 g (0.2 mol) 3,4-dichlorobenzoyl chloride and 200 ml ethanol was heated to boiling for 2 hours, evaporated, the residue taken up in ether, the solution washed with NaHCO3 -solution and water, dried and evaporated. The distillation yielded 32 g (73% theor.) ethyl-3,4-dichlorobenzoate with a BP of 84° C./0.13 mbar and a mp of 33° to 35° C.
Reaction SMILES: [Cl:1][C@@H:2]1[CH2:15][C@@H:14]([O:16]C2CCCCO2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33]C2CCCCO2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>C(O)(=O)C.O.O1CCCC1>[Cl:1][C@@H:2]1[CH2:15][C@@H:14]([OH:16])[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([OH:33])[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:30])[CH3:31])[C@H:3]1[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)=CCC(C)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@H](Cl)C[C@H]1O
Yield: 14.6 %

Procedure:
Under argon, 915 mg of (5Z,13E)-(8R,9R,11R,12R,-15S,16RS)-9-chloro-11,15-bis(tetrahydropyran-2-yloxy)-16,19-dimethyl-5,13,18-prostatrienoic acid was stirred at room temperature for 17 hours with 19 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture was evaporated thereafter under vacuum and the residue purified by column chromatography on silanized silica gel with ethanol/water (1:1), thus obtaining 94 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:18][CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: Cc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C)ccc1Cl
Yield: 100 %

Procedure:
To a suspension of 2-chloro-5-methylphenol (10.0 g, 0.07 mol) and potassium carbonate (11.7 g, 0.08 mol) in acetonitrile (200 mL) at 82° C., was dropwise added a solution of allyl bromide (9.6 mL, 0.11 mol) in acetonitrile (50 mL). The mixture was reflux overnight. Once at room temperature, the mixture was filtered and the precipitate rinsed with diethyl ether. The filtrate was then concentrated in vacuo. The residue was dissolved in diethyl ether (250 mL) and washed with a 2N sodium hydroxide solution (150 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 1-chloro-4-methyl-2-(prop-2-en-1-yloxy)benzene (7a) (12.72 g, 0.07 mol, 99%) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.P(Br)(Br)[Br:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][Br:14])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCCO)cc1
Reactant: BrP(Br)Br
Product: COc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol) in 250 mL of tolune, cooled to 0° C., was added dropwise 26 mL of phosphorus tribromide (0.27 mol). Following completion of the addition the reaction was stirred at room temperature for 1 hour, then refluxed for an additional hour. The reaction was cooled and poured onto ice, the layers were separated, and the organic phase washed with saturated sodium bicarbonate (3×) and brine (3×). The crude material obtained upon drying and evaporation of the solvent was chromatographed, eluting with 10%, EtOAc/hexane, to obtain 14 g (61%) of 3-(p-methoxyphenyl)-1-propylbromide.
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=1)[CH:21]=[CH:20]2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([CH2:27][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:2]3[C:3](=[O:15])[C:4]([CH3:14])([CH3:13])[O:5][C:6]=3[C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)=[CH:33][CH:34]=1)[CH:21]=[CH:20]2
Reactant: CC1(C)OC(c2ccncc2)=C(Br)C1=O
Reactant: CC1(C)OB(c2ccc(OCc3ccc4cc(F)ccc4n3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(c2ccncc2)=C(c2ccc(OCc3ccc4cc(F)ccc4n3)cc2)C1=O
Yield: 24.8 %

Procedure:
A mixture of 4-bromo-2,2-dimethyl-5-(pyridin-4-yl) furan-3(2H)-one (0.085 g, 0.32 mmol), 6-Fluoro-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)quinoline (0.12 g, 0.32 mmol), and Cs2CO3 (0.52 g, 1.58 mmol) in toluene (5 mL) and water (2 mL) was degassed, added Pd(dppf)Cl2 (0.052 g, 0.06 mmol) under an inert atmosphere and degassed again. Then the reaction was refluxed for 2 h. The reaction mixture was filtered through a pad of Celite®, the filtrate was diluted with EtOAc (30 mL), washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 4-(4-((6-fluoroquinolin-2-yl)methoxy)phenyl)-2,2-dimethyl-5-(pyridin-4-yl)furan-3(2H)-one (35 mg, 25%) as a pale yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.71 (d, J=8.5 Hz, 2H), 8.42 (t, J=7.9 Hz, 1H), 8.1 (t, J=8.4 Hz, 1H), 7.70-7.61 (m, 3H), 7.44 (d, J=8.5 Hz, 2H), 7.18 (d, J=7.4 Hz, 2H), 7.11 (d, J=7.5 Hz, 2H), 5.40 (s, 2H), 1.44 (s, 6H). MS: [M+H]: m/z=441.1. HPLC: 90.1% (RT-2.39 min), Column: Acquity BEH-C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]2[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12]2>C(Cl)(Cl)(Cl)Cl>[OH:6][C:7]1[C:8]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][C:10]([CH3:17])=[C:11]2[C:15]=1[C:14](=[O:16])[CH2:13][CH2:12]2
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(O)c2c1CCC2=O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(S(=O)(=O)Cl)c(O)c2c1CCC2=O
Temperature: 0 °C

Procedure:
Into a solution of 90 ml of chlorosulfonic acid in 150 ml of carbon tetrachloride was added 30 g of 7-hydroxy-4-methyl-1-indanone gradually under an ice-cooling condition. The carbon tetrachloride layer was removed by separation, and one liter of ice-water was added into the residual layer then the mixture was stirred vigorously. The solid matter precipitated was collected by filtration, then washed with water to obtain 8.7 g of 7-hydroxy-6-chlorosulfonyl-4-methyl-1-indanone. This product was added, without purified, to a solution consisting of 31.4 g of stannous chloride dihydrate and 100 ml of concentrated hydrochloric acid, and the mixture was stirred at a room temperature for 4 hours. The reaction mixture was poured into 500 ml of ice-water, the crystals precipitated were collected by filtration, washed with water, dried to obtain 7.86 g of 7-hydroxy-6-mercapto-4-methyl-1-indanone. Next, this product was suspended, without purified, in 100 ml of methanol, then to this suspension was added 3.9 ml of methyl iodide and a solution of 5.1 g of sodium bicarbonate in 20 ml of water, the whole mixture was stirred at a room temperature for 1 hour. The mixture was concentrated under a reduced pressure to remove the solvent to dryness. The residue was purified by means of a silica gel column chromatography (eluent: chloroform) and recrystallized from ethanol to obtain 1.52 g of 7-hydroxy-4-methyl-6-methylthio-1-indanone.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O>>[NH:1]([C:8]1[N:13]=[C:12]([CH2:14][N:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2=[O:24])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCN
Reactant: O=Cc1ccnc(Nc2ccccc2)n1
Agent: Cl
Product: O=C1CCCCN1Cc1ccnc(Nc2ccccc2)n1
Yield: 48.8 %

Procedure:
By an analogous process to Method 4, 2-anilinopyrimidin-4-carbaldehyde (Method 3; 3.24, 16.2 mmol) was treated with methyl 5-aminopentanoate hydrochloride (3.0 g, 17.9 mmol) to give the title compound (2.23 g, 51%) as a pale yellow solid. NMR: 1.85 (m, 4H), 2.5 (s, 2H), 3.4 (s, 2H), 4.58 (s, 2H), 6.63 (d, 1H), 7.05 (t, 1H), 7.3 (m, 3H), 7.62 (d, 2H), 8.34 (d, 1H); m/z 305.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].O1CCCC1.[CH2:20]([S:24]([CH2:27][Li])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23].[Cl-].[NH4+]>[Hg].CCCCCC.O1CCCC1>[CH2:20]([S:24]([CH2:27][Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:26])=[O:25])[CH2:21][CH2:22][CH3:23]
Reactant: [Li]CS(=O)(=O)CCCC
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Hg]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)C[Sn](CCCC)(CCCC)CCCC

Procedure:
A 250-ml, three-necked flask fitted with a stirrer, a dropping funnel, and a thermometer was swept thoroughly with argon and maintained in an air-free condition by a mercury-filled trap. The flask was charged with 27 ml. of tri-n-butyltin chloride dissolved in 50 ml. of tetrahydrofuran (THF). To the solution of tributyltin chloride was added dropwise with stirring 100 ml. of an approximately one-molar solution of (butylsulfonyl-methyl)lithium in a hexane-THF mixture. The temperature was held at -10° C to 10° C during the addition which required 15 minutes. The reaction mixture was then agitated by stirring at room temperature for 2 hours. The reaction mixture was hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by distillation yielded the desired product (butylsulfonylmethyl)-tributyltin. The product, a colorless liquid, had a boiling point of 161°-165° C/0.1 mm. Hg. Analysis gave 48.4% Carbon and 9.2% Hydrogen compared to the calculated values, respectively, of 48.0% and 9.0%. Infrared and proton nuclear magnetic resonance spectral analyses confirmed the assigned structure.