Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][CH:3]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)[CH3:4]
Reactant: COc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(C)C/C=C/c1ccc(OC)nc1
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
Under a nitrogen atmosphere, a cold (0–5° C.), stirring solution of (4E)-N-methyl-N-(tert-butoxycarbonyl)-5-(6-methoxy-3-pyridyl)-4-penten-2-amine (2.90 g, 9.45 mmol) in dichloromethane (20 mL) was treated drop-wise over 15 min with trifluoroacetic acid (15 mL). After stirring for 30 min, the solution was concentrated to a yellow-orange oil. The residue was diluted with saturated aqueous NaCl solution (15 mL), cooled to 0–5° C., and basified with 10% aqueous NaOH solution (22 mL). The mixture was extracted with CHCl3 (5×25 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, and concentrated under vacuum to give a light-yellow oil (1.88 g). The crude product was purified by column chromatography on silica gel (70–230 mesh) (150 g), eluting with a CH3—OH-NH4OH step-wise gradient (100:1→15:1 in increments of 25:1). Fractions containing the product (Rf 0.28 in CHCl3—CH3OH-Et3N (50:1:1)) were kept separate from those containing an impurity (Rf 0.35) and were combined and concentrated to give 0.76 g of a light-yellow oil. Impure fractions were combined and concentrated to give 1.20 g of light-yellow oil. The latter material was re-chromatographed on a new silica gel column (75 g) using the same CH3—OH-NH4OH gradient elution protocol. Impure fractions were combined and concentrated to give 1.08 g of light-yellow oil. The latter material was re-chromatographed (6 times) on a new silica gel columns (45 g and 25 g) using CHCl3—CH3OH-Et3N step-wise gradient (16:1→1:1 in CHCl3—CH3OH, with each gradient step containing 1% Et3N). All fractions containing the product were combined and concentrated under vacuum to give 1.368 g (70.2%) of a light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([NH2:16])[C:4]=2[N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][C@H:26]2[CH2:31]N[CH2:29][CH2:28][NH:27]2)[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH2:24][CH2:25][C@@H:26]2[NH:27][CH2:28][CH2:29][N:16]([C:5]3[C:4]4[N:3]=[C:2]([CH3:1])[S:11][C:10]=4[NH:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[N:6]=3)[CH2:31]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(CC[C@H]2CNCCN2)c1
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2cccc(F)c2)C1
Yield: 46.4 %

Procedure:
By using a similar method to the method of Example 460, using 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.25 g, 5.42 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (1.13 g, 5.42 mmol) gives 1.06 g of the title compound as a tan solid: mass spectrum (ion spray): m/z=422 (M+1); Analysis for C23H24FN5S(0.2 H2O): calcd: C, 64.98; H, 5.78; N, 16.47; found: C, 65.18; H, 5.91; N, 16.17.
Reaction SMILES: Cl.Cl.Cl[CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:9]=1[CH3:22].[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:22][C:9]1[C:10]([CH2:14][S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:11][CH:12]=[CH:13][C:8]=1[S:7][CH2:6][CH2:5][CH2:4][N:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccccn1
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(SCCCN2CCc3ccccc3C2)ccnc1CSc1ccccn1
Yield: 46 %

Procedure:
According to the procedure described in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(2-pyridinylthio)methyl]pyridine dihydrochloride with 1,2,3,4-tetrahydroisoquinoline and potassium carbonate gives the title compound; m.p. hygroscopic; dec. from 58° C.; yield 46% of theory.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.O.C(=O)([O-])O.[Na+]>CN(C)C=O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)C(NC(=O)c1ccc(F)cc1)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1oc(-c2ccc(F)cc2)nc1-c1cccs1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 28.7 %

Procedure:
A mixture of ethyl 4-(4-fluorobenzoylamino)-4-(2-thienyl)-3-ketobutyrate (349 mg), and phosphorus oxychloride (0.12 ml) in N,N-dimethylformamide (5 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel flush column chromatography (solvent: hexane:ethyl acetate=20:1) to obtain ethyl 2-(4-fluorophenyl)-4-(2-thienyl)oxazol-5-ylacetate (95 mg) as pale yellowish powder.
Reaction SMILES: FC1C=CC(C=N[C@H](C(OC(C)(C)C)=O)CC(C)C)=CC=1.[C:22]([O:26][C:27]([C@@H:29]([N:34]1[C@H:37]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)[C@H:36]([N:45]=[N+:46]=[N-:47])[C:35]1=[O:48])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([C@@H:29]([N:34]1[C@@H:37]([C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)[C@@H:36]([N:45]=[N+:46]=[N-:47])[C:35]1=[O:48])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@H](N=[N+]=[N-])[C@H]1c1ccc(F)cc1
Agent: CC(C)C[C@H](N=Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Product: CC(C)C[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@H](N=[N+]=[N-])[C@@H]1c1ccc(F)cc1
Yield: 96.6 %

Procedure:
Using N-(4-fluorobenzylidene)-1(S)-t-butoxycarbonyl-3-methylbutylamine (10.09 g., 34.4 mmol) as a starting material, the reaction, separation and purification were carried out under the same conditions as in Referential example 7 to give a mixture of 1-(1(S)-t-butoxycarbonyl-3-methylbutyl)-3(S)-azido-4(R)-(4-fluorophenyl)azetidin-2-one and 1-(1(S)-t-butoxycarbonyl-3-methylbutyl)-3(R)-azido-4(S)-(4-fluorophenyl)azetidin-2-one (12.51 g., yield: 96.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[O:9][CH2:8][CH2:7][C:6]=2[CH:15]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH2:12][CH3:13])[C:10](=[O:14])[O:9][CH2:8][CH2:7][C:6]=3[CH:15]=2)=[N:18][CH:19]=1
Reactant: CCN1C(=O)OCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
Following a procedure analogous to Example 1742a, 2-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide. HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.41-7.30 (m, 3H), 7.12 (d, 1H), 7.04 (s, 2H), 4.27 (t, 2H), 3.66 (q, 2H), 2.68 (t, 2H), 2.66 (s, 3H), 0.98 (t, 3H); MS (m/e) 485 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH2:20].C(N(CC)CC)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:19][NH:20][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: COc1ccc(CN)cc1F
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
In DCM (50 mL) were dissolved ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (1.5 g, 6.46 mmol), 3-fluoro-4-methoxybenzylamine (1.0 g, 6.45 mmol) and triethylamine (1.3 g, 12.9 mmol). The reaction mixture was stirred at ambient temperature for 30 min, and washed with water. The organic phase was dried over sodium sulfate and concentrated to give ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylthio)pyrimidine-5-carboxylate as a yellow oil (2.2 g, yield: 97%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[CH:5]=[CH:4]1)[N:12]=[CH:11][CH:10]=[CH:9]3.[CH2:16]1[O:19][C@@H:17]1[CH3:18].[Cl-].[NH4+]>C1COCC1>[N:3]1([CH2:16][C@H:17]([OH:19])[CH3:18])[C:7]2=[C:8]3[C:13](=[CH:14][CH:15]=[C:6]2[CH:5]=[CH:4]1)[N:12]=[CH:11][CH:10]=[CH:9]3
Reactant: C[C@@H]1CO1
Reactant: c1cnc2ccc3cc[nH]c3c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2ccc3ncccc3c21
Temperature: 0 °C
Reaction time: 48 h
Yield: 18.2 %

Procedure:
A mixture of sodium hydride, 60% dispersion in mineral oil, (0.76 g, 18.5 mmol) and THF (30 mL) was cooled to 0° C. under Ar. A mixture of 1H-pyrrolo[2,3-f]quinoline (G. Bartoli, G. Palmieri, M. Bosco and R. Dalpozzo, Tetrahedron Letts., 1989, 30, 2129-2132) (2.5 g, 14.8 mmol) and THF (20 mL) was added and the mixture was left at 0° C. for 1 h. (R)-propylene oxide (2.1 mL, 30 mmol) was added and the mixture was left at room temperature for 48 h. Saturated ammonium chloride solution (100 mL) was added and the mixture was extracted with Et2O (3×100 mL), the extracts were combined, washed with brine (2×100 mL), dried (MgSO4), concentrated in vacuo and purified by column chromatography [SiO2; Et2O] to give the product (0.61 g, 18% yield) as a pale yellow oil: IRνmax(Nujol)/cm−1 3106, 1361, 1117, 826, 805, and 731; NMR δH (400 MHz, CDCl3) 1.35 (3H, d, J 6.5 Hz), 2.76 (1H, br), 4.33 (1H, m), 4.44 (1H, m), 4.56 (I1H, m), 6.64 (1H, d, J 3.0 Hz), 7.20 (1H, d, J 3.0 Hz), 7.30 (1H, dd, J8.5 and 4.5 Hz), 7.71 (1H, d, J 9.0 Hz), 7.87 (1H, d, J 9.0 Hz), 8.52 (1H, d, J 8.5 Hz) and 8.67 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:1][C:2]1[C:10]([NH2:11])=[C:9]([Cl:14])[C:8]([F:15])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(F)c(Cl)c(N)c1Cl
Reaction time: 3 h

Procedure:
A mixture of 2,4-dichloro-5-fluoro-3 nitro-benzamide (7.00 g, 27.7 mmol), Sn(II)Cl2×2H2O (28 g, 124 mmol) and EtOAc (250 mL) is stirred for 3 h at reflux and then carefully added to a sat. aq. NaHCO3-solution (250 mL). The resulting mixture is filtered through a pad of celite, the organic phase is separated and washed with brine, dried with MgSO4 and concentrated.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][C:27]([NH:31][C:32]([N:34]([CH2:47][CH2:48]O)[C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=3)=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1.N(C(OCC)=O)=NC(OCC)=O>C(#N)C>[O:20]=[C:21]1[C:30]2[C:25](=[CH:26][C:27]([N:31]3[CH2:48][CH2:47][N:34]([C:35]4[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45][CH3:46])=[O:44])=[CH:37][CH:36]=4)[C:32]3=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)CCc1ccc(N(CCO)C(=O)Nc2ccc3c(c2)CCCC3=O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)CCc1ccc(N2CCN(c3ccc4c(c3)CCCC4=O)C2=O)cc1

Procedure:
To a solution of 3.7 g of triphenylphosphine and 5.5 g of N-(1-oxo-1,2,3,4-tetrahydronaphthalin-6-yl)-N'-(2-hydroxyethyl)-N'-[4-[2-(methoxycarbonyl)ethyl]phenyl]-urea in 40 ml acetonitrile, are added, dropwise at 40°-45° C., 2.84 g of diethyl azodicarboxylate in 10 ml of acetonitrile. After 1.5 hours the mixture is cooled, the product is suction filtered and washed with a little acetone and diethylether.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[N+:12]([O-])=O)[CH:2]=[CH2:3].[NH4+].[Cl-].C(O)C>[Fe].O>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:6]=1[NH2:12])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: C=CCOc1ccc(Br)cc1N
Yield: 100.9 %

Procedure:
A mixture of Example 66A (5.06 g, 19.69 mmol), iron powder (11.02 g, 196.9 mmol), NH4Cl (0.53 g, 9.85 mmol), ethanol (160 mL), and water (40 mL) were heated at 80° C. for 6 hours. The solution was filtered, concentrated with silica gel powder (18 g), and purified by flash chromatography eluting with 10% ethyl acetate in hexanes (1 L) to give the title compound (4.53 g, 97%). MS (DCI) m/z 227.91 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 4.54 (d, J=5.43 Hz, 2 H) 5.29 (dd, J=10.51, 1.36 Hz, 1 H) 5.40 (dd, J=17.46, 1.53 Hz, 1 H) 6.09 (m, 1 H) 6.65 (d, J=8.48 Hz, 1 H) 6.84 (m, 1 H) 6.91 (d, J=2.37 Hz, 1 H).
Reaction SMILES: FC1C=C(F)C=CC=1C([O:6]/[C:7](/[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[CH:8]\[C:9]1[N:13](C(=O)C2C=CC(F)=CC=2F)[C:12]2[CH2:24][CH:25]([CH3:29])[CH2:26][CH:27]([CH3:28])[C:11]=2[N:10]=1)=O>O1CCOCC1.Cl>[F:37][C:31]1[CH:32]=[C:33]([F:36])[CH:34]=[CH:35][C:30]=1[C:7](=[O:6])[CH2:8][C:9]1[NH:13][C:12]2[CH2:24][CH:25]([CH3:29])[CH2:26][CH:27]([CH3:28])[C:11]=2[N:10]=1
Reactant: CC1Cc2c(nc(/C=C(\OC(=O)c3ccc(F)cc3F)c3ccc(F)cc3F)n2C(=O)c2ccc(F)cc2F)C(C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1Cc2[nH]c(CC(=O)c3ccc(F)cc3F)nc2C(C)C1
Temperature: 100 °C
Yield: 26.1 %

Procedure:
The compound of example X, step 4 is dissolved in 10 ml dioxane and 20 ml of hydrogen chloride solution (37%). The solution is heated at 100° C. for 20 h. The organic solvent is evaporated under vacuum. 30 ml water is added to the residue and the mixture is extracted with ethyl acetate. The water phase is reduced under vacuum. The residue is washed with sodium hydroxide solution to yield 150 mg (26.1% of th.) 1-(2,4-Difluoro-phenyl)-2-(4,6-dimethyl-4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)ethanone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH:82]1[CH2:87][CH2:86][S:85](=[O:89])(=[O:88])[CH2:84][CH2:83]1>O1CCOCC1.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:82]3[CH2:87][CH2:86][S:85](=[O:89])(=[O:88])[CH2:84][CH2:83]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[C:13]([C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[CH:14]=1
Reactant: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: O=S1(=O)CCNCC1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccncc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(N2CCS(=O)(=O)CC2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of heterocyclyl and heteroaryl substituted phenylsulfonyl derivatives previously described, using 4-Bromo-N-[4-chloro-2-(pyridine-4-carbonyl)-phenyl]-benzenesulfonamide 0.3 g (0.66 mmol), potassium phosphate tribasic monohydrate 0.91 g (3.96 mmol), rac-2,2′-bis (diphenylphosphino)-1,1′-binaphthyl 0.12 g (0.198 mmol), thiomorpholine 1,1-dioxide 0.44 g (3.3 mmol) and Pd (dba)3 60 mg (0.066 mmol) in 6 ml dioxane, followed by work up and HPLC purification: LC-MSD, m/z for C22H20ClN3O3S2 [M+H]+: 502
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[O:17])[C:29]=2[CH:36]=[N:35]1
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.4 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.398 mL, 1.40 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (315 mg, 1.40 mmol) in anhydrous THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (371 mg, 1.40 mmol) in dry THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography with EtOAc to afford (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (460 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:18]=2)[CH:14]=1.[Br:43]N1C(=O)CCC1=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[CH2:5][N:6]1[C:10]([Br:43])=[CH:9][N:8]=[C:7]1[CH:11]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])[CH2:12][C:13]1[CH:21]=[C:20]([CH3:22])[C:19]2[C:15](=[CH:16][N:17]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[N:18]=2)[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc(Br)n2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 1-(1-(3,5-difluorobenzyl)-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (72.0 mg, 0.12 mmol) was dissolved in methylene chloride (3.0 mL) and cooled to −78° C. To this was added N-bromosuccinimide (18.3 mg, 0.11 mmol) and the mixture allowed to stir at −78° C. for 30 min. After warming to room temperature, the solvent was removed and the residue purified by column chromatography to afford 30 mg (40%). 1H-NMR (CD3OD, 300 MHz) δ −0.06 (s, 9H), 0.89 (m, 2H), 1.33 (s, 9H), 2.44 (s, 3H), 3.15-3.25 (m, 1H), 3.57-3.66 (m, 2H), 4.80-5.09 (m, 2H), 6.26 (m, 2H), 6.47-6.66 (m, 2H), 7.12 (s, 1H), 7.20 (s, 1H), 7.91 (s, 1H). Mass spec.: 678.3 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:24])([CH3:23])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:28]2[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]2)=[O:27])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:1][C:2]1[CH:19]=[C:18]2[C:5]([C@@:6]3([CH3:25])[C@H:15]([CH2:16][S:17]2(=[O:21])=[O:20])[C@:14]2([CH3:22])[C@H:9]([C:10]([CH3:23])([CH3:24])[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]3)=[C:4]([C:26]([N:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]2)=[O:27])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(O)cc3c2[C@]2(C)CC[C@H]4C(C)(C)CCC[C@]4(C)[C@H]2CS3(=O)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCC[C@]2(C)[C@H]3CS(=O)(=O)c4cc(O)cc(C(=O)N5CCNCC5)c4[C@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
A mixture of tert-butyl 4-{[(1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-8,8-dioxo-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-trien-3-yl]-carbonyl}piperazine-1-carboxylate (99) (0.13 g, 0.23 mmol) and trifluoroacetic acid (1.0 mL, 13 mmol) in CH2Cl2 (10 mL) was stirred at room temperature under N2 for 18 h. The mixture was concentrated under reduced pressure, and basified with Et3N, dissolved in EtOAc and washed with water. The organic layer was separated and concentrated to dryness under reduced pressure to give (1R,10R,11S,16S)-5-hydroxy-1,11,15,15-tetramethyl-3-[(piperazin-1-yl)carbonyl]-8λ6-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene-8,8-dione (100) (0.06 g, 55%) as a brown solid. 1H NMR (CD3OD): δ 7.27 (d, 1H), 6.78 (d, 1H), 3.50 (m, 3H), 3.02 (m 2H), 2.90 (m, 2H), 2.53 (m, 1H), 2.16 (d, 1H), 1.88-1.14 (m, 14H), 1.00 (m, 5H), 0.90 (s, 3H), 0.86 (s, 3H). MS m/z 475 (C26H38N2O4S+H+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:27]([Cl:28])=[C:26]([O:29][CH:30]([F:32])[F:31])[N:25]([CH3:33])[N:24]=3)=[C:19]([F:34])[CH:18]=2)=[C:7]([CH:14]=1)[O:8][CH:9]([CH3:13])[C:10](Cl)=[O:11])[CH3:2].[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([NH:39][C:10](=[O:11])[CH:9]([O:8][C:7]1[CH:14]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:27]([Cl:28])=[C:26]([O:29][CH:30]([F:31])[F:32])[N:25]([CH3:33])[N:24]=2)=[C:19]([F:34])[CH:18]=1)[CH3:13])(=[O:38])=[O:37]
Reactant: CS(N)(=O)=O
Reactant: CCc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)c(F)c2)c(OC(C)C(=O)Cl)c1
Solvent: ClCCl
Product: CCc1ccc(COc2ccc(-c3nn(C)c(OC(F)F)c3Cl)c(F)c2)c(OC(C)C(=O)NS(C)(=O)=O)c1
Temperature: 120 °C

Procedure:
A stirring mixture of 2.6 0 grams (0.0050 mole) of 2-[5-ethyl-2-[3-fluoro-4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)phenoxymethyl]phenoxy]propanoic acid chloride and 0.52 gram (0.0055 mole) of methylsulfonylamine is heated at about 120° C. for two hours. The reaction mixture is then cooled and dissolved in about 35 mL of methylene chloride. The solution is washed with water, dried with magnesium sulfate, and filtered. The filtrate is concentrated under reduced pressure, yielding the title compound.
Reaction SMILES: O[CH:2]=[C:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.Cl.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1.Cl>C(O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:4]3[C:5]4[C:10]([CH2:11][C:3]=3[CH:2]=[N:23]2)=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:18][CH:17]=1
Reactant: O=C1C(=CO)Cc2ccccc21
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(-n2ncc3c2-c2ccccc2C3)cc1

Procedure:
2-Hydroxymethylene inden-l-one (Example 1(ii) (a) (4.0 g; 25 mmol), p-methoxyphenyl hydrazine hydrochloride (Aldrich) (4.41 g; 25.25 mmol), 10 M hydrochloric acid (1 cm3) and ethanol (30 cm3), were heated under reflux, for 21 hours. After cooling, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane, then washed with 2M NaOH, dried, filtered and concentrated in vacuo. Purification by column chromatography [Eluant: (dichloromethane: ethanol: ammonia (200:8:1)] Kugelrohr distillation (170° C.; 0.02 mmHg) and recrystallisation (ethanol) afforded needle shaped crystals, m.p. 102-103° C.