Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[C:14](=O)([O:18]CC)[O:15][CH2:16][CH3:17].[H-].[Na+].Cl>C(O)C>[CH3:13][S:10]([C:7]1[CH:6]=[CH:5][C:4]([C:2](=[O:3])[CH2:1][C:14]([O:15][CH2:16][CH3:17])=[O:18])=[CH:9][CH:8]=1)(=[O:12])=[O:11]
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 2 h

Procedure:
To a mixed solution of 4-(methylsulfonyl)acetophenone (10 g, 42.2 mmol), ethanol (0.2 ml) and diethyl carbonate (50 ml) was added sodium hydride (3.37 g, 60% in oil, 84.4 mmol) by small portions at room and the mixture was stirred temperature for 2 hrs. and at 60° C. for 1 hr. The reaction solution was cooled, 1N hydrochloric acid (30 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the objective substance (3.76 g, 33%) as crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].Cl.[CH2:11](O)[CH3:12]>>[NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCO
Reactant: O=C(O)C1COCCN1
Agent: Cl
Product: CCOC(=O)C1COCCN1

Procedure:
A solution of morpholine-3-carboxylic acid (4.035 g; 30.8 mmol) in ethanol (250 ml) was saturated with gaseous HCl, then stirred for a week. The solvent was evaporated and the residue taken up in water and made basic (pH ˜10) with sodium hydrogen carbonate and sodium carbonate. The mixture was then extracted with dichloromethane (7×), the combined extracts dried (Na2SO4) and the solvent evaporated to give ethyl morpholine-3-carboxylate (746 mg). EIMS: m/z=160.4 [M+H]+. This ester derivative and lithium aluminium hydride (1 M in THF, 9.4 ml, 9.4 mmol) were carefully combined under a nitrogen atmosphere and following addition were heated to reflux. After 5 h the reaction was cooled to room temperature and carefully quenched using dropwise water addition with ice cooling, then filtered and washed with dichloromethane. The solvent was evaporated to give 3-(hydroxymethyl)morpholine (409 mg). EIMS: m/z=118.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](Cl)=[O:13].[OH-].[Na+]>ClCCl>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9])=[O:13]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C(Cl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
To a solution of 2-amino-5-fluorophenol (1.0 g, 7.87 mmol) in dichloromethane (50 mL) at 0° C. was added 2-Chloroacetyl chloride (978 mg, 8.66 mmol). The reaction mixture was stirred at rt for 2 h, followed by addition of aqueous saturated NaOH solution. The organic layer was washed with brine, dried over Na2SO4 and solvent was removed under reduced pressure to afford 550 mg (35%) of 2-chloro-N-(4-fluoro-2-hydroxyphenyl)acetamide (I-21) as a brown solid. ESI-LC/MS (m/z): (M−H)− 201.6, RT 2.65 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:40][C:41](O)=[O:42])[CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:41](=[O:42])[CH2:40][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2)c(OC)c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)benzoate (424 mg, 1.52 mmol) in DMF (8 mL) was added pentafluorophenyl ester of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (728 mg, 1.52 mmol) and Et3N (0.26 mL, 1.87 mmol). And the resulting mixture was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo and the residue was purified by column chromatography on silica-gel with CHCl3—MeOH (50:1, v/v) as eluent to give 830 mg (95%) ethyl (S)-3-methoxy-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl methoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ1.38 (t, 3 H, J=7.3 Hz), 1.88-2.20 (m, 4 H, m), 2.24 (m, 3 H), 3.44-3.50 (m, 1 H), 3.53-3.58 (m, 7 H), 3.82 (s, 3 H); 4.09-4.17 (m, 1 H), 4.22-4.25 (m, 1 H), 4.35 (q, 2 H, J=7.3 Hz), 4.38-4.49 (m, 1 H), 6.71-4.78 (m, 1 H), 6.99 (d, 1 H, J=8.3 Hz), 7.04-7.07 (m, 1H), 7.16-7.19 (m, 2 H), 7.49-7.66 (m, 3 H), 8.06 (d, 1 H, J=8.3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]2[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=2)[C:11]=1[CH:12]=O)=[O:5])[CH3:2].Cl.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][NH2:38])=[CH:33][CH:32]=1.C([O-])(=O)C.[Na+]>C(Cl)Cl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][N:38]=[CH:12][C:11]2[C:14]([O:18][C:19]3[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=3)=[CH:15][CH:16]=[CH:17][C:10]=2[O:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:33][CH:32]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CCOC(=O)CCCOc1cccc(Oc2nc(OC)cc(OC)n2)c1C=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CCCOc1cccc(Oc2nc(OC)cc(OC)n2)c1C=NNc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
A mixture of 2.93 g (7.5 mmol) of 2-(3-ethoxycarbonyl-propoxy)-6-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-benzaldehyde (cf. Example 1), 1.5 g (8.3 mmol) of 4-chloro-phenylhydrazine-hydrochloride, 0.76 g(9.3 mmol) of sodium acetate and 150 ml of methylene chloride is stirred at 20° C. for 15 hours, then washed with saturated disodium hydrogen phosphate solution, dried with sodium sulphate and filtered. The filtrate is concentrated, the residue is stirred with methanol and the crystalline product is isolated by filtering off with suction. 2.6 g (67% of theory) of 2-(3-ethoxycarbonyl-propoxy)-6-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-benzaldehyde-4-chloro-phenylhydrazone of melting point 139° C. are obtained.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Br[C:44]1[CH:49]=[N:48][C:47]([Br:50])=[CH:46][N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:57][C:58]([F:67])([F:66])[C:59]1[N:64]=[CH:63][C:62]([NH2:65])=[CH:61][CH:60]=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:50][C:47]1[N:48]=[CH:49][C:44]([NH:65][C:62]2[CH:63]=[N:64][C:59]([C:58]([F:67])([F:57])[F:66])=[CH:60][CH:61]=2)=[N:45][CH:46]=1
Reactant: Brc1cnc(Br)cn1
Reactant: Nc1ccc(C(F)(F)F)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 36.3 %

Procedure:
Pd(OAc)2 (0.097 g, 0.432 mmol) and Xantphos (0.25 g, 0.432 mmol) were added to a solution of 2,5-dibromopyrazine (2.05 g, 8.64 mmol) in 15 mL of toluene under argon atmosphere, followed by cesium carbonate (8.44 g, 25.9 mmol) and 6-(trifluoromethyl)pyridin-3-amine (1.4 g, 8.64 mmol). The mixture was degassed for 10 min. The reaction mixture was stirred at 100° C. for 4 h, allowed to warm to room temperature, and diluted with ethyl acetate and water. The separated organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography using 20% ethyl acetate in hexane to afford the title compound (1 g, 36%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.88 (d, J=2.5 Hz, 1H), 8.47-8.35 (m, 2H), 8.17 (d, J=1.4 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H). ESI-MS m/z: 319 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[C:22]([C:30]#[N:31])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+].Cl>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH3:29])[CH:27]=5)[C:22]([C:30]5[NH:34][N:33]=[N:32][N:31]=5)=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(C#N)cn(Cc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3nnn[nH]3)cn(Cc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Temperature: 120 °C
Reaction time: 72 h
Yield: 19.1 %

Procedure:
The mixture of 4-tert-butyl-2-{5-[(3-cyano-6-methylindol-1-yl)methyl]benzofuran-2-yl}thiazole (0.19 g), sodium azide (0.32 g) and ammonium chloride (0.30 g) in N,N-dimethylformamide (2 ml) was stirred at 120° C. for 72 hours. After being cooled to room temperature, the reaction mixture was poured into ice-water and the mixture was acidified with diluted hydrochloric acid. The resulting precipitates were collected by filtration and air-dried. The precipitates were subjected to column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 5-{1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-6-methylindol-3-yl}-1H-tetrazole (0.04 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[C:9]1[C:11](=[CH:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:8]=1[CH:7]=[CH:6]2>CO.[C].[Pd]>[CH3:1][C:2]1[N:3]([CH3:20])[N:4]=[C:5]2[C:10]=1[C:9]1[CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[CH2:12][CH2:13][C:8]=1[CH:7]=[CH:6]2
Reactant: CC(=O)NCC=C1CCc2ccc3nn(C)c(C)c3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nn(C)c(C)c3c21
Temperature: 25 °C
Reaction time: 7 h
Yield: 68 %

Procedure:
To a solution of N-[2-(1,2-dimethyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]acetamide (55.7 mg, 0.207 mmol) in methanol (2 mL) was added palladium-carbon powder (10 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography (methanol/ethyl acetate=13/87) to give the title compound (38.2 mg, yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:14][N:13]([C:15](OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:26].CC(O)=O.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](C=O)=[CH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:23](=[CH:24][CH:25]=1)[O:22][C:11]1([CH2:12][N:13]([CH2:15][C:35]3[C:36]4[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]([CH3:32])[CH:34]=3)[CH2:14]1)[CH2:10][C:9]2=[O:26]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(C(=O)OC(C)(C)C)C1)O2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CN(Cc3cn(C)c4ccccc34)C1)O2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
TEA (0.11 ml, 0.77 mmol) was added to a suspension of Intermediate 4 (240 mg, 0.77 mmol) in DCM (10 ml). The mixture was stirred at RT for 10 min and then the pH value was adjusted to 5 with AcOH. The mixture was treated with N-methyl-indol-3-carbaldehyde (148 mg, 0.93 mmol) and NaBH(OAc)3 (197 mg, 0.93 mmol) following the procedure described in Example 31, Step A, giving (E)-3-[1′-(1-methyl-1H-indol-3-ylmethyl)-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid methyl ester (220 mg) as a light orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]2[CH2:13][CH2:12][CH:11](Cl)[CH2:10]2)=[CH:4][C:3]=1[F:15].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[Br:1][C:2]1[C:3]([F:15])=[CH:4][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([N:20]3[C:16](=[O:26])[C:17]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:19]3=[O:21])[CH2:10]2)=[C:6]([F:8])[CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1cc(C2CCC(Cl)C2)c(F)cc1Br
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C1CCC(c2cc(F)c(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of 29.6 g (0.1 mol) of 1-bromo-4-(3-chlorocyclopentyl)-2,5-difluorobenzene in 150 ml of dry dimethylformamide was treated with 19.4 g (0.105 mol) of potassium phthalimide and the resulting suspension stirred at 100° for 8 hours and room temperature overnight. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and water. The aqueous layer was reextracted with methylene chloride and the combined organic layers were washed with water, dried (MgSO4), filtered, and evaporated in vacuo to give 36.8 g of the title compound as a viscous oil which crystallized on standing and had mp 44°-47°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:18][C:17]([F:20])([F:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31]Br)=[C:27]([F:33])[CH:26]=1>>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[C@@H:12]2[CH2:18][C:17]([F:19])([F:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])=[C:27]([F:33])[CH:26]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Product: COC(=O)c1ccc(CN([C@@H]2CC(F)(F)CCNC2=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-benzenesulfonamide was alkylated using 4-bromomethyl-3-fluoro-benzoic acid methyl ester analogous to Example 1 to afford 4-{[(4-chloro-benzenesulfonyl)-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester: MS: m/e=504.9 (MH+), 522.1(MNH4+).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:16]=[CH:15][C:5]([O:6][CH:7]4[CH2:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:8]4)=[CH:4][CH:3]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CCN1CCCC(Oc2ccc(Br)cc2)C1
Product: CCN1CCCC(Oc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)C1

Procedure:
Prepared according to general working method I from 3-(4-bromo-phenoxy)-1-ethyl-piperidine (90 mg, 0.32 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (68 mg, 0.32 mmol).
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH2:3].N1C=CC=CC=1.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](Cl)=[O:20]>CCOCC>[CH3:1][N:2]([C:4]([NH:6][CH3:7])=[S:5])[NH:3][C:19]([C:15]1[S:14][CH:18]=[CH:17][CH:16]=1)=[O:20]
Reactant: O=C(Cl)c1cccs1
Reactant: CNC(=S)N(C)N
Solvent: c1ccncc1
Solvent: CCOCC
Product: CNC(=S)N(C)NC(=O)c1cccs1

Procedure:
To a stirred, room temperature, solution of 2,4-dimethylthiosemicarbazide (3.75 g, 3.15×10-2 mole) and pyridine (30 ml) was added dropwise 2-thiophenecarbonyl chloride (3.20 ml, 2.99×10-2 mole). After stirring overnight the pyridine was evaporated at reduced pressure and the concentrate was treated with H2O. The resulting semi-solid was extracted into ethyl acetate. The ethyl acetate extract was washed with saturated NaCl and subsequently dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure, leaving a slightly yellowish solid. This was treated with Et2O and the solid was collected by filtration affording a colorless powder: 4.7 g (68%), mp 176°-178° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@H:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)COCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
tert-Butyl N-[(1R)-2-(benzyloxy)-1-(hydroxymethyl)ethyl]carbamate (1.2 g, 4.3 mmole) was dissolved in CH2Cl2 (40 mL). Dess-Martin periodinane (2.4 g, 5.5 mmole) was added. The solution was stirred for 2 h at room temperature and then quenched with Na2S2O3 and saturated bicarbonate solution. After extracting with CH2Cl2, the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by chromatography (silica, 4/1: Hexane/EtOAc, Rf=0.4) afforded (S)-tert-butyl 1-(benzyloxy)-3-oxopropan-2-ylcarbamate as a white solid (1.1 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[C:4]([CH3:10])[C:5]([CH3:9])=[C:6]([CH:8]=1)[OH:7].C(OC)(OC)OC.OS(O)(=O)=O.C(C(C)=O)=C.[CH3:29][O:30][C:31]([CH:33]=[CH2:34])=[CH2:32].O=C(C)CCO.COC(OC)(C)C=C.COCCC(=O)C>CO>[OH:11][C:3]1[C:2]([CH3:1])=[C:8]2[C:6](=[C:5]([CH3:9])[C:4]=1[CH3:10])[O:7][C:31]([O:30][CH3:29])([CH3:32])[CH2:33][CH2:34]2
Reactant: C=CC(=C)OC
Reactant: Cc1cc(O)c(C)c(C)c1O
Agent: C=CC(C)(OC)OC
Agent: C=CC(C)=O
Agent: CC(=O)CCO
Solvent: COC(OC)OC
Solvent: CO
Product: COC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 24 h

Procedure:
In the manner described in Example 1, 3.80 g (25 mmol) samples of trimethylhydroquinone were treated in 25 ml of methanol, 5.0 ml of trimethyl orthoformate, and 0.10 ml of 36 N aqueous H2SO4 with 50 mmole portions of the following methyl vinyl ketone substitutes: a, 2-methoxybutadiene; b, 3-ketobutanol; c, 3,3-dimethoxybutene (contaminated with about 20 percent 2-methoxybutadiene); and d, 4-methoxy-2-butanone. The reactions were monitored by tlc. Reactions a,c and d were complete after 24 hr and were worked up and dried in the manner of Example 1 to give (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman. In reaction b, a>50 percent conversion to (±)-6-hydroxy-2-methoxy-2,5,7,8-tetramethylchroman was indicated by tlc.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4].CC1C=C(C)[N:11]([C:15]([NH:17][C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[S:19])=N)N=1>CS(C)=O>[NH2:11][C:15]1[N:17]=[C:18]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[S:19][C:2]=1[C:3]([CH:5]1[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(CBr)C1CC1
Reactant: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCNc1nc(N)c(C(=O)C2CC2)s1
Temperature: 100 °C

Procedure:
A solution of 404 mg (2.48 mmol) of 2-bromo-1-cyclopropylethanone in 15 ml of DMSO is added dropwise to 845 mg (2.48 mmol) of the crude mixture from Example 72A while cooling in ice, and the mixture is then heated at 100° C. for 1 h. The crude mixture is poured into ice-water and extracted three times with ethyl acetate. After the combined organic phases have been dried, the solvent is completely removed and the residue is purified by subsequent purification by preparative HPLC. 428 mg (48% of theory) of the product are obtained as a solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>O1CCCC1>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][O:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Yield: 118.5 %

Procedure:
Under an argon atmosphere, the tert-butyl-4-hydroxymethylpiperidine-1-carboxylate obtained in Step 1 (12.9 g, crude) was dissolved in anhydrous tetrahydrofuran (100 mL), triethylamine (17 mL, 120 mmol) was added, thereafter methanesulfonyl chloride (3.5 mL, 44 mmol) was added dropwise under ice-cooling over about 10 minutes, and stirring was further conducted under ice-cooling for 30 minutes. Water was added to the reaction liquid to quench the reaction, and the reaction liquid was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give tert-butyl-4-{[(methylsulfonyl)oxy]methyl}piperidine-1-carboxylate (15.3 g) as a crude purified product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Cl.Cl[CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[N:6]=[C:5]2[I:11]
Reactant: ClCCN1CCCC1
Reactant: Clc1ccc2[nH]nc(I)c2c1
Agent: Cl
Product: Clc1ccc2c(c1)c(I)nn2CCN1CCCC1
Yield: 60 %

Procedure:
The title compound was prepared from 5-chloro-3-iodo-indazole and 1-(2-chloroethyl)pyrrolidine hydrochloride in 60% yield according to the procedure for Preparation 50A. 1H NMR (400 MHz, CDCl3): δ 1.75-1.80 (4H, m), 2.54-2.59 (4H, m), 2.99 (2H, t, J=7.3 Hz), 4.52 (2H, t, J=7.1 Hz), 7.35-7.39 (2H, m), 7.45 (1H, s). [M+H] Calc'd for C13H15ClN3, 376; Found, 376.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])C.Cl[O-].[Na+].[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)([OH:19])=[O:18].B#B>COCCOCCOC.CCOCC>[C:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)([OH:19])=[O:18].[OH:3][CH2:1][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: B#B
Agent: O=C(O)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOCCOC
Product: OCc1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodium acetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.