Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[CH3:12][C:13](=[CH2:15])[CH3:14]>[Hg](Cl)Cl.[Al]>[C:13]([CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][CH2:11][CH:2]1[OH:1])([CH3:15])([CH3:14])[CH3:12]
Reactant: C=C(C)C
Reactant: OC1CCc2ccccc2C1
Agent: Cl[Hg]Cl
Agent: [Al]
Product: CC(C)(C)C1c2ccccc2CCC1O
Temperature: 100 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
In an autoclave 222 g of 2-hydroxytetraline, 2.5 g of aluminium grit and 0.2 g of mercury(II) chloride are heated at 180° C for 1 h. After cooling 85 g of isobutylene are added and the mixture is stirred at 100° C for 3 h. In order to eliminate the catalyst the reaction product is washed with diluted hydrochloric acid. A subsequent distillation yields 212 g of 1-t-butyl-2-hydroxytetraline. Boiling point (13 mm Hg): 171° C. Melting point: 104° C.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4=[CH:23][S:24][CH:25]=[C:19]4[N:18]([CH2:31][CH2:30][C:29]([O:33][CH3:34])=[O:32])[C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Reactant: C=CC(=O)OC
Product: COC(=O)CCn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 59.8 %

Procedure:
The title compound was prepared by starting with 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (9.0 g, 22.4 mmol) was reacted with methyl acrylate as described in Example 1 to produce 6.54 g (59.8%) of methyl 3-[3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as an orange oil after chromatography. A portion of this material was crystallized from CH2Cl2 /hexane to afford a peach-colored solid, mp 122°-123° C.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].C(OC([N:37]1[CH:41]=[CH:40][CH:39]=[C:38]1B(O)O)=O)(C)(C)C>>[NH:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:25])[CH3:26])[C:3]=1[CH3:29]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc[nH]1)OCC2c1ccc(C(C)C)cc1
Yield: 19 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl) boronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 19%. Melting point: 188-190° C. (ethyl acetate).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[N:16](C(OC(C)(C)C)=O)[N:15]=[C:14]([CH2:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=2)[CH:13]=1.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[N:48]=[CH:47][C:46]([C:49](OC)=[O:50])=[CH:45][N:44]=2)[CH2:39][CH2:38]1>C1COCC1>[CH3:33][O:32][C:30]1[CH:31]=[C:26]([CH2:25][CH2:24][C:14]2[CH:13]=[C:12]([NH:11][C:49]([C:46]3[CH:47]=[N:48][C:43]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[N:44][CH:45]=3)=[O:50])[NH:16][N:15]=2)[CH:27]=[C:28]([O:34][CH3:35])[CH:29]=1
Reactant: COc1cc(CCc2cc(N)n(C(=O)OC(C)(C)C)n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)CC2)nc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 0.6 %

Procedure:
A solution of NaHMDS (2.100 ml, 2.10 mmol) in THF (1.0M) was added to a stirred solution of tert-butyl 5-amino-3-[2-(3,5-dimethoxyphenyl)ethyl]-1H-pyrazole-1-carboxylate (0.486 g, 1.4 mmol) and methyl 2-(4-methylpiperazin-1-yl)pyrimidine-5-carboxylate (0.397 g, 1.68 mmol) in THF (7.00 ml, cooled to −20° C.), over a period of 5 mins under nitrogen. The resulting solution was stirred at room temperature for 18 h. The mixture was heated to reflux for 90 min, then cooled to room temperature. More NaHMDS (2.100 ml, 2.10 mmol) was added and the mixture stirred for 70 mins. The mixture was allowed to stand for 96 h and then partitioned between ethyl acetate and 2.0M aqueous hydrochloric acid. The aqueous layer was separated and basified with 50% aqueous sodium hydroxide solution and then extracted with ethyl acetate (75 mL). The organic layer was washed with saturated brine (50 mL) and then dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by preparative LCMS using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (4.00 mg, 0.633%) as a white solid;
Reaction SMILES: [OH:1][C:2]1[C:6]([CH3:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].[C:13](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:7][C:6]1[C:2]([O:1][CH3:13])=[C:3]([C:9]([O:11][CH3:12])=[O:10])[S:4][C:5]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(C)c(C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1sc(C)c(C)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-hydroxy-4,5-dimethylthiophene-2-carboxylate (Preparation 1) (29.7 g, 160 mmol) in anhydrous acetone (500 ml) was added anhydrous potassium carbonate (24.5 g, 178 mmol) and the mixture stirred for 1 hour at room temperature. Dimethyl sulphate (22.4 g, 178 mmol) was added and the mixture stirred under reflux for 2.5 hours. The solvent was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic phase was washed with brine, dried with sodium sulphate and evaporated to give crude product which was used in the following preparation.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]2=[C:4]([N:13]2[CH2:19][CH:18]3[O:20][CH:15]([CH2:16][CH2:17]3)[CH2:14]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:15]12[O:20][CH:18]([CH2:17][CH2:16]1)[CH2:19][N:13]([C:4]1[N:3]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)[N:7]=[C:6]3[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:5]=13)[CH2:14]2
Reactant: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Temperature: 120 °C

Procedure:
A mixture of 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (0.55 g, 1.9 mmol), 4-aminophenylboronic acid pinacol ester (0.62 g, 2.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.22 g, 10 mol %) in toluene/ethanol (1:1, 12 mL) and 2 M aqueous sodium carbonate solution (2 mL) was heated in a 10-20 mL Smith process vial in the microwave reactor for one hour at 120° C. The cooled mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude residue was purified via automated flash chromatography (methanol/chloroform) to provide 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline. MS (ES+): 351.0 (M+H)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.CC1C=CC(S(O[CH2:55][CH2:56][N:57]2[CH2:61][CH2:60][O:59][C:58]2=[O:62])(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:62]=[C:58]1[N:57]([CH2:56][CH2:55][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([CH2:13][O:12][C:11]4[CH:14]=[C:15]5[C:19](=[CH:20][C:10]3=4)[CH2:18][CH2:17][O:16]5)[C:2]2=[O:21])[CH2:61][CH2:60][O:59]1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: Cc1ccc(S(=O)(=O)OCCN2CCOC2=O)cc1
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1OCCN1CCN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(2-oxooxazolidin-3-yl)ethyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[2-(2-oxo-1,3-oxazolidin-3-yl)ethyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (46%) as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.08 (dd, J=7.3, 7.3 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.50 (s, 1H), 6.40 (s, 1H), 4.78 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.33-4.22 (m, 1H), 4.21-4.00 (m, 2H), 3.93-3.58 (m, 4H), 3.57-3.43 (m, 1H), 3.05-2.91 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 178.8, 161.8, 161.3, 158.7, 141.7, 132.4, 129.0, 124.1, 123.7, 120.0, 119.0, 108.3, 93.2, 80.5, 72.5, 62.1, 57.7, 44.3, 41.7, 37.3, 29.0; MS (ES+) m/z 393.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[NH:6]2.[H-].[Na+].I[CH3:18].O>CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH3:14])=[O:12])[N:6]2[CH3:18]
Reactant: COC(=O)c1cc2c(F)cccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(F)cccc2n1C
Yield: 105.2 %

Procedure:
To methyl 4-fluoro-1h-indole-2-carboxylate (1.211 mmol, 234 mg) in N,N-dimethylformamide (10 ml) at 0° C. was added sodium hydride (1.817 mmol, 72.7 mg). The reaction mixture was stirred for one hour at room temperature before iodomethane (1.817 mmol, 0.113 ml, 258 mg) was added. After stirring for three hours water was added and the product was extracted with dichloromethane and concentrated in vacuo to give methyl 4-fluoro-1-methyl-1H-indole-2-carboxylate (264 mg). The latter compound was dissolved in ethanol (5 ml). Then 2 N aqueous sodium hydroxide (5.84 mmol, 2.92 ml) and potassium hydroxide (1.168 mmol, 65.5 mg) were added and the reaction mixture was stirred at 80° C. over night. 2N Hydrochloric acid was added to the reaction mixture and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to give 4-fluoro-1-methyl-1H-indole-2-carboxylic acid (189 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([CH3:12])=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:3]=1[CH:4]=O.[SH:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]1[O:26][N:25]=[C:24]([CH3:27])[N:23]=1>>[OH:1][C:2]1[C:3]([CH2:4][S:19][CH2:20][C@H:21]([NH:28][C:29](=[O:31])[CH3:30])[C:22]2[O:26][N:25]=[C:24]([CH3:27])[N:23]=2)=[C:6]([C:13]2[O:17][N:16]=[C:15]([CH3:18])[N:14]=2)[C:7]([CH3:12])=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(O)c(C=O)c(-c2nc(C)no2)c1C
Reactant: CC(=O)N[C@@H](CS)c1nc(C)no1
Product: COc1cc(O)c(CSC[C@H](NC(C)=O)c2nc(C)no2)c(-c2nc(C)no2)c1C

Procedure:
2-Hydroxy-4-methoxy-5-methyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)-benzaldehyde and (R)-N-[2-mercapto-1-(3-methyl-1,2,4-oxadiazol-5-yl) -ethyl]-acetamide were subjected in an analogous manner to the procedure described in Example 1(g) to yield (R)-N-[2-[6-hydroxy-4-methoxy-3-methyl-2-(3-methyl -1,2,4-oxadiazol-5-yl)benzylsulfanyl]-1-(3-methyl-1,2,4-oxadiazol-5-yl)-ethyl]-acetamide as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[C:10]=1[CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25](OCCC(C)C)=O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[C:16]([N:15]1[C:11]2[C:10](=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:14]=[CH:13][CH:12]=2)[C:19]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[N:25]1)(=[O:18])[CH3:17]
Reactant: CC(C)CCON=O
Reactant: CC(=O)Nc1cccc(OCc2ccccc2)c1CCOC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)OCc1nn(C(C)=O)c2cccc(OCc3ccccc3)c12

Procedure:
This is obtained by nitrosation and subsequent ring closure by treating 2-(2-acetoxyethyl)-3-acetamidophenyl benzyl ether with isoamyl nitrite, sodium acetate and acetic anhydride in toluene at 80° C. It is obtained in the form of colorless crystals; m.p. 99°-100° C.
Reaction SMILES: ClC1C=CC(C2N(CC3C=CC(CCC(O)=O)=CC=3)C3C=C(F)C(F)=CC=3N=2)=C(OCC2CCCC2)C=1.C1([CH2:44][N:45]2[C:49]3[CH:50]=[C:51]([F:55])[C:52]([F:54])=[CH:53][C:48]=3[N:47]=[C:46]2[C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[O:62][CH2:63]C2C=CC(C3NN=NN=3)=CC=2F)CCCCC1.BrC[C:78]1[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=1[F:86]>>[F:54][C:52]1[C:51]([F:55])=[CH:50][C:49]2[N:45]([CH2:44][C:78]3[CH:85]=[CH:84][C:81]([C:82]#[N:83])=[CH:80][C:79]=3[F:86])[C:46]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=3[O:62][CH3:63])=[N:47][C:48]=2[CH:53]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: Fc1cc2nc(-c3ccccc3OCc3ccc(-c4nnn[nH]4)cc3F)n(CC3CCCCC3)c2cc1F
Agent: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Product: COc1ccccc1-c1nc2cc(F)c(F)cc2n1Cc1ccc(C#N)cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 5,6-difluoro-2-(2-methoxy-phenyl)-1H-benzoimidazole (Example 34, intermediate d) and 4-bromomethyl-3-fluoro-benzonitrile (CAS Reg. No. 105942-09-4). Blue solid (32%). MS (Turbo Spray): m/z=394.4 (M+H).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27](OCC)=O)[CH2:20][CH2:19]1>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]2[O:9][N:8]=[C:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=23)[CH2:20][CH2:19]1
Reactant: CCOC(=O)CCCN1CCC(c2cccc(Cl)c2Cl)CC1
Reactant: ON=C1CCCCCC1
Product: Clc1cccc(C2CCN(CCCc3onc4c3CCCCC4)CC2)c1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(2,3-dichlorophenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(2,3-dichlorophenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:18]=3)[NH:13][N:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:2]1([S:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][NH2:1])[CH:18]=3)[NH:13][N:12]=2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4ccccc4)c3c2)cc1
Reactant: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NCCOc1ccc2[nH]nc(S(=O)(=O)c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
Over five different reactions, liquid ammonia (about 10 mL) was added to a −78° C. solution of toluene-4-sulfonic acid 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethyl ester (1.72 g, 3.63 mmol) in THF (48 mL). This was usually allowed to warm to ambient temperature. This was heated in sealed tube for about 16-35 hours at 70-100° C. After cooling to about ambient temperature, the combined reaction mixtures were then poured into excess sodium bicarbonate solution and extracted with chloroform or methylene chloride. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chlormatography with 0.75% ammonium hydroxide/7.5% methanol in chloroform. The residue was further purified by HPLC using 30-80% (chloroform/methanol(8:2)/TEA) in heptane/TEA. Concentrating and drying yielded 2-(3-benzenesulfonyl-1H-indazol-5-yloxy)-ethylamine as a white solid to which was added methanol and ethereal hydrochloride. Concentration and drying for 30 hours in vacuo at 83° C. yielded the hydrochloride as a cream-colored solid (0.0951 g, 7.4%): MP: >300° C.; Mass Spectrum (−EI, [M−H]−) m/z 316. 1HNMR (500 MHz, DMSO-d6): δ14.24(s, 1H), 8.09 (br,s, 3H), 7.96-7.98 (m, 2H), 7.56-7.68 (m, 4H), 7.39 (d, 1H, J=2.20 Hz), 7.17 (dd, 1H, J=9.15 Hz and 2.32 Hz), 4.22-4.25 (m, 2H), 3.20-3.24 ppm (m, 2H). Elemental Analysis for C15H15N3O3S.1.00 mol HCl.0.85 mol H2O: Calcd: C, 48.81; H, 4.83; N, 11.38; Found: C, 48.65; H, 4.77; N, 11.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>C(O)(=O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=1
Reactant: [NH-]c1ccc(Br)cc1N
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Br)cc2[nH]1

Procedure:
A mixture of 1.61 g of (2-amino-4-bromophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid in 80 ml of glacial acetic acid is refluxed for 2.5 hours. Allow to return to ambient temperature and evaporate the reaction medium to dryness under vacuum. The residue is taken up with 50 ml of dichloromethane, and the organic phase is washed with twice 50 ml of a saturated solution of sodium bicarbonate and 50 ml of a saturated solution of sodium chloride. After drying over magnesium sulphate, the organic phase is evaporated to dryness under vacuum. The residue is chromatographed on silica gel, eluting with a mixture of methanol and dichloromethane (5/95 by volume). In this way, we obtain 1.5 g of 4-(6-bromo-1H-benzimidazol-2-yl)-9H-fluoren-9-one, with the following characteristics:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH:11]C(=O)OCC)[S:8][C:6]=2[N:7]=1.[CH3:17][O-:18].[Na+].O>CO>[CH3:17][O:18][C:2]1[N:3]=[CH:4][C:5]2[N:10]=[C:9]([NH2:11])[S:8][C:6]=2[N:7]=1
Reactant: C[O-]
Reactant: CCOC(=O)Nc1nc2cnc(Cl)nc2s1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc2nc(N)sc2n1
Temperature: 25 °C
Yield: 82 %

Procedure:
Ethyl 5-chlorothiazolo[5,4-d]pyrimidin-2-ylcarbamate (250 mg, 0.966 mmol) was suspended in MeOH (10 mL) and a 25% (w/w) solution of sodium methoxide in methanol was added (10 mL, 46.3 mmol). The resulting solution was refluxed overnight, cooled to ambient temperature, poured into an equal volume of water and extracted with chloroform (4×). A significant amount of compound was still present in the aqueous phase, so this was concentrated to residue, and then dissolved in a small amount of 1N HCl (not enough to make the resulting solution acidic) and extracted again with EtOAc (5×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. 5-Methoxythiazolo[5,4-d]pyrimidin-2-amine (144 mg, 0.790 mmol, 82% yield) was thus obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (s, 1H) 7.81 (s, 2H) 3.90 (s, 3H). MS (LC/MS) R.T.=0.73; [M+H]+=183.03.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:13])[CH3:12]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A stirred, 0° C. solution of 4-hydroxybenzonitrile (50.7 g, 426 mmol) in 1400 mL of dichloromethane and 75 mL anhydrous ethanol is treated with anhydrous hydrogen chloride gas (110 g) over 1.5 hours. This solution is stirred a room temperature for 64 hours and the resulting solids collected and washed with 500 mL diethyl ether and 2×1000 mL of ethyl acetate. The remaining solids (60.4 g) are dissolved in 1200 mL of water and the residual solids filtered. To the filtrate is added a solution of sodium hydroxide (12.57 g) in 150 mL water. The resulting white solid is filtered and washed with water to afford ethyl 4-hydroxybenzenecarboximidoate.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:6]=2[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:4]=2[N:3]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[CH2:23]([O:20][C:18]1[CH:17]=[CH:16][C:5]2[C:6]3[C:7]4[CH:8]=[CH:9][N:10]=[CH:11][C:12]=4[C:13](=[O:15])[C:14]=3[C:2]([Cl:1])=[N:3][C:4]=2[CH:19]=1)[CH:22]=[CH2:21]
Reactant: O=C1c2cnccc2-c2c1c(Cl)nc1cc(O)ccc21
Reactant: C=CCBr
Product: C=CCOc1ccc2c3c(c(Cl)nc2c1)C(=O)c1cnccc1-3

Procedure:
This compound was prepared from 6-chloro-3-hydroxy-5,9-diaza-benzo[c]fluoren-7-one (Example 34a) and allyl bromide in a similar manner to Example 34b. The desired product was obtained as a yellow powder. ESI−MS: m/z 323 (MH+); 1H-NMR (CDCl3): δ4.75 (2H, dt, J=5 Hz, 1 Hz), 5.41 (1H, dq, J=11 Hz, 1 Hz), 5.52 (1H, dq, J=17 Hz, 1 Hz), 6.12 (1H, ddt, J=17 Hz, 11 Hz, 5 Hz), 7.43 (1H, dd, J=8 Hz, 1.5 Hz), 7.45 (1H, s), 8.01 (1H, dd, J=5 Hz, 1 Hz), 8.36 (1H, dd, J=8 Hz, 1.5 Hz), 8.96 (1H, d, J=5 Hz), 9.04 (1H, d, J=1 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.S(Cl)([Cl:30])(=O)=O>ClCCl>[Cl:30][C:13]1[C:14](=[O:16])[O:15][C:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([Cl:1])[C:3]([O:25][CH3:26])=[CH:4][C:5]=2[O:23][CH3:24])([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][C:12]=1[OH:17]
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cl)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared by chlorination of 6-[2-(5-chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from step 6 of example B(15) with sulfuryl chloride in dichloromethane at room temperature. 1H NMR (CDCl3) δ 1.51 (m, 8H), 1.79 (m, 1H), 2.06, (m, 2H), 2.45 (m, 2H), 2.60 (m, 1H), 2.67 (d, J=17.75, 1H), 2.92 (d, J=17.75, 1H), 3.82 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 7.06 (s, 1H). HRMS calcd for C20H24O5Cl2 (M+H+) 415.1079, found 415.1063.