Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2c(Cl)cccc12
Yield: 49.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 7-chloro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 6) (30 mg, 0.10 mmol) and 5-(3-amino-phenyl)tetrazole (34 mg, 0.21 mmol) giving 20.2 mg (50%) of the title compound. MS (ESI+) calcd for C16H12ClN5O2S2 405.012094, found 405.012294.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19](Cl)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][CH:44]=1.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]3[C:21](=[O:32])[N:20]([CH2:33][CH2:34][CH3:35])[C:19]([C:43]4[CH:42]=[CH:41][CH:40]=[C:39]([C:38]([F:49])([F:48])[F:37])[CH:44]=4)=[N:18][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCCn1c(Cl)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
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: C1CCOC1
Solvent: O
Product: CCCn1c(-c2cccc(C(F)(F)F)c2)nc2nc(-c3ccc(OCc4ccccc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Temperature: 85 °C
Reaction time: 28 h
Yield: 11.2 %

Procedure:
A mixture of 8-(4-benzyloxy-phenyl)-2-chloro-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (50.0 mg, 0.96 mmol), 3-Trifluoromethyl phenyl boronic acid (31.0 mg, 1.4 mmol) were taken in THF (5 ml) and degassed for 10 minutes. To above degassed solution NaHCO3 (20.0 mg, 0.24 mmol) in water (1 ml) and Pd(PPh3)4 were added and degassed for another 20 minutes. The reaction mixture was stirred for 28 hours at 80-90° C. The mixture was cooled to 25-27° C. and diluted with water (5 ml). The aqueous layer was extracted with DCM (3×5 ml). The organic layer was washed with brine (2×10 ml), dried over Na2SO4, and the solvent was evaporated. The residue obtained was purified by preparative TLC (35% Ethyl acetate in hexane) to obtain pure 8-(4-Benzyloxy-phenyl)-1-propyl-2-(3-trifluoromethyl-phenyl)-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (68 mg, quantitative) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10](=O)[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]=2[N:13]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:13]=[C:12]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]=12
Reactant: Cc1nn(C)c2nc(-c3ccccc3F)[nH]c(=O)c12
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nn(C)c2nc(-c3ccccc3F)nc(Cl)c12
Yield: 51 %

Procedure:
6-(2-Fluoro-phenyl)-1,3-dimethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (2.0 g, 7.74 mmole) was treated with 40 ml phosphorous oxychloride and heated to reflux overnight. The excess phosphorous oxychloride was removed under vacuum and ice water was added to the residue. The product was extracted with ethyl acetate, washed with 10% sodium carbonate, water, dried over sodium sulfate (anh) and the solvent was removed to give crude product. Crude product was chromatographed on silica gel column eluting with chloroform to give 1.10 g of pure product (yield: 51%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:14])=[C:7]([CH:15]([CH3:17])[CH3:16])[CH:6]=1)=[O:4].[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=1[O:27][CH3:28].C(OCC)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH:15]([C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][C:20]=2[O:27][CH3:28])[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[C:8]=1[OH:14])([CH3:17])[CH3:16]
Reactant: CC(C)c1cc(C(=O)CBr)cc(C(C)C)c1O
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C=O)ccc1OCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6.00 g (18.3 mmol) of 2-bromo-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone and 2.78 g (18.3 mmol) of 4-hydroxy-3-methoxy-benzaldehyde in 20 ml of ethyl acetate 5.00 g (36.7 mmol) of potassium carbonate is added and the mixture is stirred for 18 hours at room temperature. After addition of water and adjusting the pH to 5-6 by adding 32% HCl, the mixture is extracted with ethyl acetate. The combined extracts are washed with water, dried and evaporated to give compound 102. 1H-NMR (300 MHz, CDCl3), δ (ppm): 7.79 (s, 2H), 7.46-7.45 (d, 1H), 7.41-7.38 (dd, 1H), 6.90-6.87 (d, 1H), 5.43 (s, 2H), 3.97 (s, 3H), 3.24-3.15 (sept., 2H), 1.32-1.29 (d, 12H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][N:6]=[C:5]([NH:12][CH3:13])[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH:27]1[CH:32]2[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]2)[CH2:28]1>>[N:29]12[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30]1)[CH:27]([NH:26][C:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([NH:12][CH3:13])=[N:6][CH:7]=1)=[O:11])[CH2:28]2
Reactant: CNc1ncc(C(=O)O)c(OC)n1
Reactant: NC1CN2CCC1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Product: CNc1ncc(C(=O)NC2CN3CCC2CC3)c(OC)n1

Procedure:
Following the procedure of Example 22, 4-methoxy-2-(methylamino)-5-pyrimidinecarboxylic acid, 1,1'-carbonyldiimidazole and 3-aminoquinuclidine are reacted to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.C>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:14])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1ccc(Br)cc1
Temperature: 50 °C

Procedure:
4-Bromophenylacetic acid (100 g, 0.465 mol), thionyl chloride (300 mL) and DMF (about 2 mL) are charged to a 1-liter round bottom 3-necked flask equipped with a reflux condenser and a mechanical stirrer. The reaction mixture is heated under nitrogen to 50° C. for 2 hours, using a charcoal scrubber for escaping gases. The thionyl chloride is evaporated and the product, 4-bromophenylacetyl chloride, is put into an addition funnel with benzene (30 mL).
Reaction SMILES: COC(=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[C:13](OC)=[O:14])Br.[OH:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C(N(CC)CC)C>CC#N>[Cl:12][C:9]1[CH:8]=[C:7]2[C:6]([C:4]3[O:18][C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]=3[N:22]=[C:13]2[OH:14])=[CH:11][CH:10]=1
Reactant: N#Cc1ccccc1O
Reactant: COC(=O)c1cc(Cl)ccc1C(Br)C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Oc1nc2c3ccccc3oc2c2ccc(Cl)cc12
Temperature: 25 °C
Yield: 56.7 %

Procedure:
A mixture of 19A (crude, 20.29 mmol) and 2-hydroxy-benzonitrile (20.29 mmol) in MeCN (100 mL) was stirred at room temperature. To the solution was added triethylamine (TEA, 20.44 g, 202.9 mmol) dropwise. After addition completed, the reaction was refluxed for 24 hours, then cooled. The precipitated solids were collected by filtration, washed with a small amount of MeCN, then washed with water several times until there was no TEA salt, dried to give pure product 19B (3.1 g).
Reaction SMILES: [CH2:1]1[CH2:11]CN2[C:4](=[N:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][CH2:2]1.[CH3:12][N:13]([CH:15]=[O:16])[CH3:14]>CC(=O)OCC.O>[CH2:11]=[C:1]1[C:2]2=[CH:3][CH:4]=[N:5][C:6]3[CH:7]=[CH:8][C:15](=[O:16])[N:13]([C:14]=32)[CH2:12]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C1Cn2c(=O)ccc3nccc1c32
Yield: 72 %

Procedure:
A solution of intermediate BD.v (1.03 g) in DMF (10 mL) was stirred at rt in the presence of DBU (1.12 mL) for 2 h. The reaction mixture was diluted with EA and water. The aq. layer was extracted with EA (2×100 mL) and DCM/MeOH (3×50 mL; 9:1). The combined org. layers were sequentially washed with water and brine and dried over MgSO4. The solvent was evaporated under reduced pressure, affording a yellow solid (490 mg; 72% yield).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:20](=[O:22])[CH3:21])=[C:6]([CH3:19])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:17][CH3:18])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH3:31]>>[C:20]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:8]([CH3:9])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:30][CH3:31])=[CH:12][C:11]=2[O:17][CH3:18])[C:6]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: COc1cc(O)ccc1-n1c(C)c(C(C)=O)c(C(C)=O)c1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(OC)c1

Procedure:
Utilizing the general procedure outlined in Example 65, 1-[4-acetyl-1-(4-hydroxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (70 mg, 2.3 mmol) reacted with bromoethane (300 μL, excess), in the presence of K2CO3 (50 mg), to afford 1-[4-acetyl-1-(4-ethoxy-2-methoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 330 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH2:24][C:25](Cl)=[O:26]>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:26])[CH2:24][C:20]1[S:19][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1cccs1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 52.9 %

Procedure:
To a solution of (S)-(−)-4-benzyl-2-oxazolidinone (350 mg, 2.00 mmol) in dry THF (10 mL) at −30° C. was added dropwise n-butyllithium (2.59 M in hexanes, 0.8 mL). The mixture was cooled to −78° C. and treated with 2-thiopheneacetyl chloride (0.25 mL, 2 mmol). After stirring at −78° C. for 45 minutes, the mixture was allowed to warm to ambient temperature and stir for 1 hour. The mixture was diluted with hexanes (10 mL), quenched with 1M pH7 phosphate buffer, and stirred for 45 minutes. The layers of the resultant biphasic mixture were separated and the aqueousueous phase extracted with EtOAc. The combined organic layers were washed with 0.5N aqueous HCl two times, saturated aqueous NaHCO3 two times, and brine, dried over Na2SO4, and concentrated to provide a crude residue which was purified via flash column chromatography with 20% EtOAc/hex as eluant to yield 319 mg(53%) of 4(S)-benzyl-3-(2-thien-2-yl-acetyl)-2-oxazolidinone as a tan solid, mp 56-9° C. 1H NMR: δ 7.34-7.26 (m, 5H), 7.17-7.14 (m, 2H), 7.02-6.98 (m, 1H), 4.72-4.67 (m, 1H), 4.57, 4.48 (AB quartet, 2H, J=16.8 Hz), 4.26-4.17 (m, 2H), 3.29 (dd, 1H, J=3.2, 13.4 Hz), 2.78 (dd, 1H, J=9.5, 13.4 Hz). Anal. Calculated for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65; S, 10.64. Found: C, 63.87; H, 5.04; N, 4.71; S, 10.74.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:62][CH:63]1[CH2:68][CH2:67][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:65][CH2:64]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([NH:62][CH:63]5[CH2:64][CH2:65][N:66]([C:69]([O:71][C:72]([CH3:75])([CH3:74])[CH3:73])=[O:70])[CH2:67][CH2:68]5)=[O:26])=[CH:22][C:21]=4[O:29][CH3:30])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 8) (0.49 g, 1.2 mmol, 1 eq), TBTU (0.42 g, 1.3 mmol, 1.1 eq) and DIPEA (0.40 mL, 2.4 mmol, 2 eq) were stirred together in DCM (25 mL) for 30 min before addition of 4-amino-1-BOC-piperidine (0.29 g, 1.4 mmol, 1.2 eq). The RM was stirred at rt for 20 hours before diluting with DCM (30 mL) and washing sequentially with water (2×15 mL), 50% saturated aqueous sodium hydrogen carbonate (1×20 mL), saturated aqueous potassium carbonate (1×20 mL) and saturated brine (1×20 mL). Concentrated in vacuo to isolate 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-BOC-piperidin-4-yl)benzamide that was used without further purification (0.71 g). Rt=3.58 min (Analytical—1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].[CH3:11]O>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(=O)O)cc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)s1
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 4-bromo-5-methyl-2-thiophenecarboxylic acid (3 g, 13.6 mmol) in MeOH (67 mL) and H2SO4 (3 mL) was stirred at 50° C. After 12 h, the solution was added to ice-H2O and the pH was adjusted to ˜11. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding the title compound (3 g, 94%) as an orange solid: LCMS (ES) m/z 236 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[CH:12]=1.[N:13]([O-])=[O:14].[Na+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:13]=[O:14])[C:6]=2[CH:12]=1
Reactant: Fc1ccc2c(c1)NCCCS2
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCSc2ccc(F)cc21
Yield: 92 %

Procedure:
7-fluoro-2,3,4,5-tetrahydro-1,5-benzothiazepine (423 mg, 2.3 mmol) was dissolved in acetic acid (1.15 mL)at 0° C. in an ice bath. 2.7 M aqueous sodium nitrite (1 mL) was added and this was stirred over night. Water was added (100 mL) and extracted with dichloromethane (3×50 mL), the organics were combined and concentrated to give 7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 92%). 1H NMR (CDCl3, 300 MHz): δ 7.43 (t, 1H, J=7.1 Hz), 7.30 (dd, 1H, J=9.1 Hz, J=9.2 MHz), 7.26–7.00 (m, 1H), 4.18 (t, 2H, J=5.8 Hz), 2.86 (t, 2H, J=7.2 Hz), 2.17–2.04 (m, 2H) ppm.
Reaction SMILES: [Cl-].Cl[CH2:3][C:4]1[NH+:5]([CH2:9][CH3:10])[CH:6]=[CH:7][N:8]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:9]([N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH2:3][S:18][C:16]1[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=1)[CH3:10]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC[NH+]1C=CN=C1CCl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccnc1CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
A mixture of 2-(chloromethyl)-1-ethyl-1H-imidazol-1-ium chloride (1.0 g, 5.5 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (650 mg, 4.6 mmol), and potassium carbonate (2.0 g, 14.4 mmol) in anhydrous DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The solid residue was treated with dichloromethane (20 mL) and brine (60 mL). The aqueous layer was recovered and evaporated. The residue was purified by flash chromatography (0-20% MeOH/CH2Cl2), affording 2-{[(1-ethyl-1H-imidazol-2-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (244 mg, 21% yield); 1H NMR (400 MHz, DMSO-d6): δ 1.27 (t, 3H, J=7.2 Hz), 2.17 (s, 3H), 4.00 (m, 2H), 4.50 (s, 2H), 6.00 (s, 1H), 6.81 (s, 1H), 7.15 (s, 1H); M+251. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1CCNC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(O)CC1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution containing 4 (5.9 g, 12.5 mmol) in anhydrous THF (100 mL) was cooled to 0° C. TBAF (1M/THF, 14 mL, 14.0 mmol) was added in one portion. After 5 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 to 1:3 hexanes/EtOAc) to afford 4.1 g (91%) of 5. 1H NMR (CDCl3, 300 MHz): δ7.31 (m, 5H), 5.93 (m, 1H), 5.07 (m, 2H), 4.37 (m, 1H), 4.03 (m, 1H) 3.51-3.06 (m, 4H), 2.05 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H) ppm. Mass spectrum, m/z [365.2] (M+H)+.
Reaction SMILES: ClC1C=C([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:13])=[O:12])C=CC=1C(O)=O.[Cl:22][C:23]1[CH:31]=[C:30](S(Cl)(=O)=O)[CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]>>[Cl:22][C:23]1[CH:31]=[CH:30][C:29]([S:11]([N:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([CH3:21])[CH2:15]2)(=[O:12])=[O:13])=[CH:28][C:24]=1[C:25]([OH:27])=[O:26]
Reactant: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(C(=O)O)c(Cl)c2)C1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1Cl
Product: C[C@@H]1C[C@H](C)CN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)C1

Procedure:
In the same way, 2-chloro-4-(cis-3,5-dimethylpiperidinosulfonyl)benzoic acid, m.p. 233°-234° C., is prepared from 2-chloro-4-chlorosulfonylbenzoic acid.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([C:11]3(O)[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([OH:32])[C:9]([CH:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH2:20][C:21]4[O:22][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:25]=4)[C:12]3=[O:30])=[CH:10][C:4]=2[O:3]1
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2ccccc2C1(O)c1cc2c(cc1O)OC(F)(F)O2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1C(c2cc3c(cc2O)OC(F)(F)O3)c2ccccc2N1Cc1ccc(C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.1 %

Procedure:
To a solution of 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (2.50 g, 5.32 mmol) in anhydrous dichloromethane (10 mL) at 0° C. was added triethylsilane (4.2 mL, 26 mmol) and trifluoroacetic acid (12 mL). The reaction mixture was allowed to warm to ambient temperature and was stirred for 72 h and was concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 0% to 30% gradient of ethyl acetate in hexanes afforded 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (1.81 g, 75%) as a colorless amorphous solid: MS (ES+) m/z 454.2 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([CH3:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([C:24](=[O:31])[N:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)[CH3:26])[CH:18]=1)=[C:10]([CH3:32])[CH:9]=2)=[O:5])C.[OH-].[K+]>CO.O>[CH:27]1([N:25]([CH3:26])[C:24]([C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=2[OH:23])[O:16][C:11]2[C:12]([CH3:15])=[C:13]3[C:8](=[CH:9][C:10]=2[CH3:32])[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:31])[CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)c1cc2c(C)c(Oc3ccc(O)c(C(=O)N(C)C4CCC4)c3)c(C)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2[nH]c(C(=O)O)cc2c(C)c1Oc1ccc(O)c(C(=O)N(C)C2CCC2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a solution of 5-[3-(Cyclobutyl-methyl-carbamoyl)-4-hydroxy-phenoxy]-4,6-dimethyl-1H-indole-2-carboxylic acid ethyl ester (102 mg, 0.23 mmol) in methanol (2 mL) at room temperature was added 3N potassium hydroxide (0.44 mL) and the mixture was stirred at room temperature for 7 hours. The reaction mixture was diluted with water (10 mL) and washed with EtOAc/Et2O (1/1, 3 times 5 mL). The aqueous solution was acidified with hydrochloric acid and then extracted with ethyl acetate (3 times 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to afford the title compound (81 mg) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ11.08 (s, 1H), 7.15-7.14 (d, 2H), 6.76 (s+m, 2H), 6.33 (br s, 1H), 4.25-4.16 (m, 1H), 2.90 (s, 3H), 2.25 (s, 3H), 2.22-2.19 (m, 2H), 2.15 (s, 3H), 1.95-1.85 (m, 2H), 1.60-1.48 (m, 2H). MS (APCI+) Calc: 408.2, Found: 409.2 (M+1).
Reaction SMILES: [CH:1](/[S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6])=[CH:2]\[C:3]#[CH:4].[NH2:20][OH:21]>C1COCC1>[OH:21][NH:20][CH:2]([C:3]#[CH:4])[CH2:1][S:5]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:6])=[O:7]
Reactant: C#C/C=C/S(=O)(=O)N1CCN(c2ccccn2)CC1
Reactant: NO
Solvent: C1CCOC1
Product: C#CC(CS(=O)(=O)N1CCN(c2ccccn2)CC1)NO
Temperature: 60 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of 1-[(1E)-1-buten-3-ynylsulfonyl]-4-(2-pyridinyl)piperazine (30 mg; 0.11 mmol; 1.00 eq.) in THF (3 mL) was added an aq. solution of hydroxylamine (50%, 0.10 mL; 1.62 mmol; 15.0 eq.) and the resulting reaction mixture was stirred at 60° C. for 4 h. Evaporation of the solvents (rotavap gave an oil). Purification on silicagel (50/50 up to 70/30 AcOEt-c-Hex) a colorless oil (15 mg, 44% yield). LC/MS, M+ (ESI): 311.1, M−(ESI): 311.1, M− (ESI): 309.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=12.[OH-].[Na+].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:11])[N:8]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:7]=12
Reactant: Cc1cc2cnnc(Cl)c2n1CC(C)C
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])c2cnnc(Cl)c2n1CC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16.0 g (71.5 mmol) of 7-chloro-1-isobutyl-2-methylpyrrolo[2,3-d]pyridazine are dissolved in portions at 0° C. with vigorous stirring in a mixture of 100 ml of fuming nitric acid and 50 ml of conc. sulfuric acid. The solution is stirred at room temperature for a further 4 h and subsequently introduced into 400 ml of ice-water. The mixture is then neutralized with 10 N sodium hydroxide solution and extracted with 3×250 ml of ethyl acetate. The organic extracts are dried over magnesium sulfate and concentrated. After crystallization from diisopropyl ether/ethyl acetate, 15.9 g (82%) of the title compound are isolated. M.p.: 96° C. (dec.).