Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1nn2ccccc2c1I
Reactant: OB(O)c1cccnc1
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Product: CC(C)c1nn2ccccc2c1-c1cccnc1

Procedure:
2-Isopropyl-3-pyridin-3-yl-pyrazolo[1,5-a]pyridine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 3-pyridineboronic acid following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine (Example 59) (240 mg, 32%). 1H-NMR (250 MHz, DMSO-d6) δ 8.69 (d, J=7.3 Hz, 1H), 8.67 (s, 1H), 8.55 (d, J=4.0 Hz 1H), 7.85 (d, J=7.8 Hz, 2H); 7.56-7.47 (m, 1H), 7.20 (t, J=8.8 Hz, 1H), 6.89 (t, J=6.8 Hz, 1H), 3.24 (sept, J=7.0 Hz, 1H), 1.28 (d, J=6.8 Hz, 6H); LC/MS 237.9 m/z (M+H+). Compound 1111.
Reaction SMILES: N(=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])O.S(=O)(=O)(O)[OH:14]>C=O>[O:14]=[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)C(=NO)c1ccccc1
Agent: C=O
Product: O=C(O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3 Grams of α-oximinophenylacetic acid is dissolved in 9 ml of 37% formaldehyde containing a few drops of sulfuric acid. This is stirred overnight at RT, extracted with 3:1 ether:hexane, washed with brine, dried over sodium sulfate, stripped and distilled to yield the final product α-oxophenylacetic acid, b.p.=138°-141°/3.3 mm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:35][O:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[N:41][CH:42]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:39]5[CH:40]=[N:41][CH:42]=[C:37]([O:36][CH3:35])[CH:38]=5)[CH:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cncc(B(O)O)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)c4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cncc(OC)c5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(3-bromo-phenylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 5-methoxypyridine-3-boronic acid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.[CH2:17]([C:24]1[CH2:28][C:27]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:26][N:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:31]2[CH2:32][CH2:33][C:27]3([O:26][N:25]=[C:24]([CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:28]3)[CH2:29][CH2:30]2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: c1ccc(CC2=NOC3(CCNCC3)C2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(Cc2ccccc2)=NO3)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Tert-butylphenyl isocyanate (0.218 ml, 1.24 mmol), dissolved in abs. DCM (5 ml), was added dropwise to a solution of compound Y (286 mg, 1.24 mmol) in abs. DCM (10 ml) at RT within 20 min. After stirring for 3.5 h at RT, the solution was washed with 10% citric acid solution (1×10 ml) and water (1×10 ml), dried and concentrated. The colourless oil obtained (742 mg) contained few impurities. The oil was mixed with diethyl ether (10 ml) and stored at 5° C. The precipitated solid was removed by suction-filtration and washed with diethyl ether (5 ml). The desired product 3-benzyl-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylic acid-(4-tert-butylphenyl)amide was obtained in a yield of 73% (369 mg) having a melting point of 137-139° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12](=O)[NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>C1COCC1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(N)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a cold (0° C.) solution of (2S)-carbamoyl-azetidine-1-carboxylic acid tert-butyl ester (8 g) in dry THF (200 mL) was added dropwise 1M BH3 solution in THF (160 mL). The reaction mixture was stirred at RT under nitrogen for 20 h and cooled to 0° C. Then was added carefully 1M HCl solution (200 mL) and brine and the mixture was extracted with EA (3×). The aqueous phase was basified with 2M NaOH solution (pH 10), extracted with EA (3×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to yield the title compound light yellow oil (1.9 g, 25%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([NH:18][NH:19][C:20](=[O:35])[C:21]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([CH3:26])[C:22]([F:25])([F:24])[F:23])=O)=[N:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.C(N(CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[CH2:28]([O:27][C:21]([C:20]1[O:35][C:16]([C:3]2[C:2]([NH2:1])=[N:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([C:12]([F:13])([F:14])[F:15])[N:4]=2)=[N:18][N:19]=1)([CH3:26])[C:22]([F:25])([F:24])[F:23])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(OCc1ccccc1)(C(=O)NNC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)nc1N)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OCc1ccccc1)(c1nnc(-c2nc(C(F)(F)F)c(C(F)(F)F)nc2N)o1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-amino-W-(2-(benzyloxy)-3,3,3-trifluoro-2-methylpropanoyl)-5,6-bis(trifluoromethyl)pyrazine-2-carbohydrazide (step 1) (510 mg, 0.982 mmol) in DCM (20 ml) was treated with triethylamine (0.411 ml, 2.95 mmol) and stirred at RT. Tosyl chloride (562 mg, 2.95 mmol) was added and stirring continued for 30 minutes. The reaction mixture was partitioned between EtOAc (50 ml) and 1M HCl (50 ml), shaken and separated. The organic portion was washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by mass directed LC-MS eluting with MeCN/Water/0.1% TFA. The clean fractions were poured into EtOAc (50 ml) and washed with saturated NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:2]([C:14](O)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.[CH:24]1[CH:25]=[CH:26][C:27]2N(O)N=N[C:28]=2[CH:29]=1.CN([CH:37]=[O:38])C>>[NH:1]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@@H:2]([C:14]([NH:1][C@@H:2]([C:14]([O:38][CH3:37])=[O:15])[CH2:3][C:28]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:29]=1)=[O:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Boc-D-Trp(CH3)-OH (1.59 g), HCl·H-D-Phe-OCH3 (1.08 g) and HOBT (0.81 g) in DMF (20 ml) was added WSCD (0.93 g) under ice-bath cooling. After being stirred for 2 hours at room temperature, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 0.5N hydrochloric acid (20 ml), water (20 ml), saturated sodium bicarbonate (20 ml) and water (20 ml×2) successively, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with ether to give Boc-D-Trp(CH3)-D-Phe-OCH3 (1.45 g).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].Cl[C:12]1[S:16][N:15]=[C:14]([CH2:17][Cl:18])[N:13]=1.O>CN(C)C=O>[Cl:18][CH2:17][C:14]1[N:13]=[C:12]([NH:7][C:6]([NH2:8])=[NH:5])[S:16][N:15]=1
Reactant: N=C(N)N
Reactant: ClCc1nsc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Solvent: O
Product: N=C(N)Nc1nc(CCl)ns1
Reaction time: 0.5 h

Procedure:
Guanidine nitrate (244 g.) was slurried in dimethylformamide (500 ml., dried over molecular sieve) and sodium hydride paste (58 g. of a 63% w/w dispersion in oil) was added over 30 minutes with external cooling in an acetone/solid CO2 bath to maintain the internal temperature at 25°-30°. The mixture was stirred for 30 minutes at 25° then cooled to 20°. 5-Chloro-3-chloromethyl-1,2,4-thiadiazole (84.5 g.) was added at 20°-25° over 20 minutes with external cooling at 5°-10°. The mixture was stirred for 20 minutes at 25° then poured into water (5000 ml.) and extracted with ethyl acetate (2×5000 ml.). The combined upper layers were extracted with 2 N HCl (2×500 ml.) and the combined acid extracts were basified with 2 N NaOH. The product was filtered off, washed with water, sucked dry and then dried over P2O5 at 1 m.m. to give 3-chloromethyl-5-guanidino-1,2,4-thiadiazole.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]1([N:22]=[C:23]([Cl:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)=[O:33]>>[ClH:30].[N:1]1([CH2:6][CH2:7][S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23](=[N:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:33])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)=O
Reactant: Oc1ccccc1SCCN1CCCC1
Reactant: ClC(=Nc1ccccc1)c1ccccc1
Product: Cl
Product: OC(=Nc1ccccc1)c1ccccc1-c1ccccc1SCCN1CCCC1
Yield: 55 %

Procedure:
A solution of 5.5 gms (0.025 mole) of 2-[β-(1-pyrrolidinyl)ethylthio]phenol and 5.3 gms (0.025 mole) of N-phenylbenzimidoyl chloride in 50 ml acetone was stirred at room temperature for a period of two hours. The desired product crystallized out. It was filtered, washed with acetone and dried at room temperature. Recrystallization from isopropanol yielded 6.0 gms (55%) of product, M.P. 167°-9° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH:24](=O)[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:9]=[C:4]2[CH:3]=1
Reactant: COc1ccccc1C=O
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1cc(Br)cc(N)n1
Product: COc1ccccc1-c1nc2cc(Br)cc(N)n2n1

Procedure:
The title compound, MS m/e (%): 321 (M++2, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and o-anisaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: CN(C)C[C:4]#[C:5][C:6]1C=NC=C[C:11]=1[O:12][CH2:13][C:14]1N2N=C(C3C=CC=CC=3)C=CC2=NN=1.Br[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[CH:37]=[N:36][CH:35]=[CH:34]2.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:46].[OH-].[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.CCOCC>[CH:37]1[C:38]2[C:33](=[CH:32][C:31]([CH2:14][C:13]([O:12][CH2:11][CH2:6][CH2:5][CH3:4])=[O:46])=[CH:40][CH:39]=2)[CH:34]=[CH:35][N:36]=1
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CN(C)CC#Cc1cnccc1OCc1nnc2ccc(-c3ccccc3)nn12
Reactant: Brc1ccc2cnccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCOC(=O)Cc1ccc2cnccc2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A dry, 25 mL, 1 neck round bottom flask was charged with a 0.5 M Et2O solution of Zincate 2 (10.00 ml, 5.0 mmol, Reike Metals), and concentrated in vacuo. The vacuum was released with nitrogen, and the flask was charged with a stirbar, 5 mL dry THF, fitted with a reflux condenser and an Ar inlet. Upon dissolution of the solids, 6-bromoisoquinoline (0.516 g, 2.5 mmol) and tetrakis(triphenylphosphine)palladium (0.24 g, 0.21 mmol) was added. The solution was heated with an 80° C. oil bath for 5 h, and cooled. The solution was treated with 30 mL of 10% aqueous EDTA (pH adjusted to 6.1 with NaOH), and stirred for 1 h. A precipitate had formed that was removed by filtration of the biphasic solution through a sintered glass funnel and discarded. The filtrate was concentrated to ˜35 mL, and extracted with DCM (4×30 mL). The combined extracts were washed with water (1×30 mL), and the water was back-extracted with DCM (1×10 mL). The DCM layers were dried over MgSO4, and the resultant slurry filtered through a sintered glass funnel. The filtrate was concentrated in vacuo. The residue was dissolved in 10 mL DCM and treated with Si-carbonate (Silicycle, 5.5 g, 3.7 mmol). The slurry was swirled occasionally for 1 h, and filtered through a 0.22 uM PTFE membrane. The silica was washed with DCM (4×20 mL), and the combined filtrates were concentrated in vacuo. The residue was purified in three injections using a Waters Spherisorb S5 column (PN PSS830195, 20×250 mm, 60 Å pore, 5 μm particle size); flow=20 mL/min; A=DCE, B=EtOH; isocratic at 5% B. A band that eluted from 3.9 to 5.9 minutes was isolated. The solvent was removed in vacuo to afford ten-butyl 2-(isoquinolin-6-yl)acetate.
Reaction SMILES: [O:1]=[C:2]1[CH:11]2[CH2:12][CH2:13]O[C:10]2=[C:9]2[C:4]([C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8]2)=[N:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C1(O)C=CC=CC=1.O>[CH3:17][C:18]1[CH:19]=[C:20]([N:21]2[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[C:5]([O:15][CH3:16])[C:4]=4[NH:3][C:2](=[O:1])[C:11]=3[CH2:12][CH2:13]2)[CH:22]=[CH:23][CH:24]=1
Reactant: Cc1cccc(N)c1
Reactant: COc1cccc2c1=NC(=O)C1CCOC=21
Solvent: O
Solvent: Oc1ccccc1
Product: COc1cccc2c3c(c(=O)[nH]c12)CCN3c1cccc(C)c1
Temperature: 190 °C
Yield: 75.1 %

Procedure:
4-Oxo-6-methoxy-2,3-dihydrofuro[3,2-c]quinoline (217 mg, 1.0 mmol) was dissolved in 7 ml of phenol in a pressure tube and 3-methylaniline (268 μl, 2.5 mmol) was added under nitrogen. The reaction mixture was heated at 190° C. for 15 hours. The reaction mixture was diluted with 20 ml of salt water and the aqueous layer was extracted with methylene chloride (15 ml×3). After washing with water (15 ml×3), the organic layer was dried by anhydrous magnesium sulfate and filtered, and concentrated under reduced pressure. The residue was purified with ethyl acetate as eluent by silica gel chromatography to obtain 230 mg of desired compound as solid in 76% of yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4](Cl)[N:3]=1.[NH3:19]>CC(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:4]([NH2:19])[N:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2ncn(CC3CCOCC3)c2n1
Solvent: CC(C)O
Product: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1

Procedure:
2,6-dichloro-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine (3.08 g, containing triphenylphosphine oxide) was heated with 2M ammonia in IPA (50 mL) at 50° C., overnight. The reaction mixture was then evaporated to dryness to give a yellow solid. This material (3.2089 g) was recrystallised using methanol (50 mL) and after cooling the resultant solid was filtered and washed with methanol (5 mL) to give the title compound (1.5554 g). The filtrate was evaporated and recrystallised from methanol (25 mL) and after cooling the resultant solid was filtered to give a second crop (0.2324 g) and was consistent with first batch by NMR and LCMS.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[O:6]=[S:7]1(=[O:22])[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH:16][C:17](=[O:21])/[CH:18]=N/O)[CH:14]=[CH:15][C:8]1=2>C(OCC)(=O)C>[O:6]=[S:7]1(=[O:22])[C:8]2[C:9](=[C:12]3[C:13](=[CH:14][CH:15]=2)[NH:16][C:17](=[O:21])[C:18]3=[O:2])[CH2:10][CH2:11]1
Reactant: O=C(/C=N/O)Nc1ccc2c(c1)CCS2(=O)=O
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc3c(c2C1=O)CCS3(=O)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
6.74 ml (126.38 mmol) of conc. sulphuric acid were introduced into a three-neck round-bottom flask with thermometer and high-efficiency condenser and heated to 70° C. 3.06 g (12.04 mmol) of N-(1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-5-yl)-2-[(E)-hydroxyimino]acetamide were then added in portions over the course of half an hour, during which the mixture became dark reddish brown in colour. After the addition was complete, the reaction mixture was heated to 90° C. and stirred at this temperature for one hour. For working up, the reaction mixture was allowed to cool to RT and was then added to a mixture of ice-water (110 ml) and ethyl acetate (25 ml) and briefly stirred. After separation of the phases, the solid which formed was filtered off with suction, washed with diethyl ether and dried in a drying oven at 50° C. overnight. 1.50 g of the desired compound were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CO>O1CCCC1.ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(-c2cccs2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc(-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 4-(2-thienyl)benzonitrile (0.086 g, 0.464 mmol) was dissolved in dry tetrahydrofuran (1.6 ml) before lithium aluminum hydride (0.46 ml, 0.464 mmol, 1 M in THF) was added dropwise. The reaction was allowed to stir at room temperature overnight. TLC (5% methanol in dichloromethane) still showed starting material remaining. Another 1 eq of LAH was added. After an additional hour, the reaction was quenched by the Fieser and Fieser method using wager (17.46 μl), aqueous sodium hydroxide solution (17.46 μl, 15% soln.), and water (52.37 μl) added sequentially to the reaction. The reaction was then diluted with diethyl ether and water and extracted twice with diethyl ether before drying over sodium sulfate and concentrating in vacuo. The residue was carried on crude without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.28 mmol) in 50 mL of THF (distilled from Na-benzophenone) is cooled to 0° C. and sodium borohydride (1.9 g, 51.4 mmol) is added portionwise. The reaction is stirred at 0° C. for 2 h, then warmed to RT, and after 2 h, quenched with water (5 mL). The solvent is evaporated and the aqueous residue is acidified by addition of aqueous 6N HCl. The product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-fluorobenzenesulfinic acid: NMR (DMSO-d6) 7.12 (app t, 2H, J=8.3), 7.5 (dd, 2H, J=8.3, 6); ESI-MS 159 [M−1]−.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Li].[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)=[O:18].[NH4+].[Cl-]>O1CCCC1>[CH3:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:9]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH:27]([CH3:29])[CH3:28])[CH:20]=1)([OH:18])[CH3:5]
Reactant: COc1cc(C)c(C(=O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Reactant: [Li]C
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C)c(C(C)(O)c2ccc(OC)c(C(C)C)c2)c(C)c1
Reaction time: 2 h
Yield: 43 %

Procedure:
To anhydrous cerium chloride (1.185 g, 4.80 mmol) dry tetrahydrofuran (15 mL) was added with stirring under argon and stirring was continued for 2 hours at room temperature. The resultant suspension was then cooled at -78° C., and 3.43 mL of methyllithium (1.4M in diethylether) was added with stirring, whereupon the color of the suspension turned from white to yellow. After maintaining the same temperature for 30 minutes, (2,6-dimethyl-4-methoxyphenyl)-(3-isopropyl-4-methoxyphenyl) methanone (10) (1 g, 3.20 mmol) in tetrahydrofuran (5 mL) was added and the mixture was stirred for 3 hours at -78° C. and for 2 hours at 0° C. The reaction mixture was treated with sat. NH4Cl solution, filtered through Celite, and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), evaporated, and the residue was purified by flash column chromatography (silica gel, 97:3 hexane/ethylacetate) to give 1-(2,6-dimethyl-4-methoxyphenyl)-1-(3-isopropyl-4-methoxyphenyl) ethanol (12) (450 mg, 1.37 mmol, 43%); 1HNMR (CDCl3) δ 1.20 (dd, 6H), 1.58 (s, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 3.30 (heptet, 1H), 3.82 (s, 3H), 3.88 (s, 3H), 6.50 (s, 1H), 6.60 (s, 2H), 6.80 (d, 1H), 7.06 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
With stirring 96.47 g (0.467 m) of the 4-methoxybenzenesulfonyl chloride obtained in part A above was slowly added to a slurry of 175.0 ml of concentrated ammonium hydroxide and 175.0 g of ice keeping the temperature under -5° C. during the addition. Slowly the resulting mixture was heated to approximately 70° C. over approximately two and one half hours. The resulting slurry was cooled and maintained at approximately 10° C. for about forty minutes. The solid was collected by filtration, washed three times with 50.0 ml of ice water and dried on the filter to obtain 97.37 g of water-wet 4-methoxybenzenesulfonamide. This product was suspended in 664.0 ml of water and 22.0 ml of 50 percent aqueous sodium hydroxide and 3.75 g of decolorizing carbon was added. After approximately forty-five minutes, the carbon was collected by filtration and washed twice with 50.0 ml of water. The filtrate and 50.0 ml or rinse water was adjusted to approximately pH 3 with the addition of approximately 33.0 ml of concentrated hydrochloric acid. The resulting slurry was cooled to approximately 5° C., stirred approximately two hours and the solid was collected by filtration, washed three times each with 50.0 ml of ice water and dried in vacuo to obtain 70.93 g of 4-methoxybenzenesulfonamide, a shiny white solid which melted at 111.5°-112.50° C. The nuclear magnetic resonance spectrum was concordant with the assisgned structure.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[C:2]=[S:3].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].O>O1CCCC1>[CH2:14]([N:16]([CH2:17][CH3:18])[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: CCNCC
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=S)Nc1ccccc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Methyl 2-isothiocyanatobenzoate (Acros) (20.0 g, 104 mmol) was dissolved in tetrahydrofuran (300 mL), followed by addition of diethylamine (35.9 mL, 349 mmol). The reaction mixture was stirred at room temperature. After 1 hour, the mixture was poured into water (800 mL). The precipitate was collected by filtration, washed with water and dried under vacuum to give the title compound (26.2 g, yield 94.2%).