Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=O
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 5.00 g of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate was slowly added dropwise to a solution of 9.60 g (0.072 mol) of lithium iodide and 70 ml of dry pyridine at reflux temperature. After the reaction mixture had been stirred for 2 hours under reflux it was cooled, and the solvent was removed in vacuo. The residue was subsequently taken up in water and brought to pH 1-2 using dilute hydrochloric acid. After the aqueous phase had been extracted with ethyl acetate, the combined organic phases were washed to neutrality with water, dried and concentrated. This gave 4.00 g of 2-chloro-3-formyl-4-methylsulfonylbenzoic acid (85% yield).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([C:11](=[CH:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>>[CH:1]1([S:4]([C:5]2[CH:6]=[CH:7][C:8]([C:11](=[CH:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:10]=2)=[O:32])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(=CC1CCOCC1)c1ccc(SC2CC2)cc1
Product: CCOC(=O)C(=CC1CCOCC1)c1ccc(S(=O)C2CC2)cc1

Procedure:
Partial oxidation of ethyl 2-(4-cyclopropylsulfanylphenyl)-3-(tetrahydropyran-4-yl)acrylate (see Preparation 22, 3.14 g, 9.44 mmol) with mCPBA, employing the protocol described above in Preparation 18, furnished ethyl 2-(4-cyclopropanesulfinylphenyl)-3-(tetrahydropyran-4-yl)acrylate: m/z (ES+)=349.2 [M+H]+. Sanctification of this ester (1.15 g, 3.3 mmol), using the procedure described in Preparation 25, afforded the title compound: m/z (ES+)=641.4 [2M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:25]([F:28])([F:27])[F:26])([OH:24])[CH:4]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[CH:6]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCl>[Br:1][CH2:2][C:3]([C:25]([F:26])([F:27])[F:28])([OH:24])[CH:4]([NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1
Reactant: COc1cccc(C(Nc2cccc3ccccc23)C(O)(CBr)C(F)(F)F)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cccc(C(Nc2cccc3ccccc23)C(O)(CBr)C(F)(F)F)c1
Reaction time: 16 h
Yield: 36.9 %

Procedure:
To 20 mg (0.04 mmol) of α-Bromomethyl-3-methoxy-β-[(naphth-1-yl)amino]-α-(trifluoromethyl)benzeneethanol in 2 ml dichloromethane at −20° C. are added 0.44 ml of a 1 M solution of boron tribromide in dichloromethane under argon. The reaction mixture is stirred for 16 hours in a temperature range of between 0° C. and 25° C. The reaction mixture is mixed at 0° C. with saturated sodium bicarbonate solution. After dilution with ethyl acetate the batch is allowed to come to room temperature, stirred for 10 minutes and extracted twice with ethyl acetate. The combined organic extracts are washed with saturated NaCl solution and dried over sodium sulfate. The solvent is evaporated and the residue purified by preparative thin layer chromatography on silica gel (ethyl acetate in hexane 33%). 6.5 mg of the desired compound are isolated.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:16])[C:7](=[O:15])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N+:17]([O-])([OH:19])=[O:18].O>C(O)(=O)C>[C:11]([C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6](=[O:16])[C:7](=[O:15])[C:8]=1[N+:17]([O-:19])=[O:18])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)C1=CC(=O)C(=O)C(C(C)(C)C)=C1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C1=CC(C(C)(C)C)=C([N+](=O)[O-])C(=O)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g, 19.1 mmol) in acetic acid (115 mL) was slowly added HNO3 (15 mL). The mixture was heated at 60° C. for 40 min before it was poured into H2O (50 mL). The mixture was allowed to stand at room temperature for 2 h, then was placed in an ice bath for 1 h. The solid was collected and washed with water to provide 4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24%). 1H NMR (400 MHz, DMSO-d6) δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH2:15])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[CH3:20][O:21][C:22]1[C:23](=O)[C:24](=[O:28])[C:25]=1[O:26]C.C(N(CC)C(C)C)(C)C>CO>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:23]3[C:24](=[O:28])[C:25](=[O:26])[C:22]=3[O:21][CH3:20])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: COc1c(OC)c(=O)c1=O
Reactant: Nc1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
A vial containing a solution of 7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamine (Example #F.8.1, 0.020 g, 0.075 mmol), 3,4-dimethoxy-3-cyclobutene-1,2-dione (0.011 g, 0.077 mmol), N,N-diisopropylethylamine (14 μL, 0.080 mmol) and MeOH (1.5 mL) was shaken at ambient temperature for about 16 hours then filtered to give 3-(7-benzo[b]thiophen-2-yl-1H-indazol-5-ylamino)-4-methoxy-cyclobut-3-ene-1,2-dione (0.022 g, 78%) as a tan solid; RP-HPLC (Table 1, Method e) Rt 1.80 min, m/z (ESI+) 375.9 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 55 %

Procedure:
A solution of 20.0 g of 6-methoxy-1-indanone, 31.3 ml of 3-buten-2-ol, 53.5 ml of 2,2-dimethoxypropane and 200 mg of p-toluenesulfonic acid in 200 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux overnight. After cooling, the solution was washed with 50 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 50 ml of ethyl acetate, the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 13.6 g (55%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH3:14])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].FC(F)(F)C(O)=[O:18].ClC1C=CC=C(C(OO)=O)C=1.C(Cl)(Cl)Cl>C(Cl)Cl>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([S:11]([CH2:12][CH2:13][CH3:14])=[O:18])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: CCCSc1ccc([N+](=O)[O-])c(N)c1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCS(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cool to 0°-5° C. a stirred solution of 2-nitro-5-propylthioaniline (21.2 g) in methylene chloride (350 ml) and add trifluoroacetic acid (11.40 g), followed by the dropwise addition of 85% m-chloroperbenzoic acid (22.34 g) in methylene chloride (450 ml). Stir 30 minutes at 0° C., then warm to room temperature and stir 3.5 hours. Add chloroform to dissolve the solids, and extract the mixture with 10% sodium carbonate solution three times, extract with water once, filter over magnesium sulfate, then evaporate the organic solvent in vacuo. Recrystallize the residue from methanol to obtain 2-nitro-5-propylsulfinylaniline, m.p. 128°-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1)[C:8]([OH:10])=[O:9].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][C:43](Cl)=[O:44])[CH:37]=[C:38]([O:40][CH3:41])[CH:39]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[O:6][C@@H:7]([C@:11]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][N:12]1[C:43](=[O:44])[CH2:42][C:36]1[CH:35]=[C:34]([O:33][CH3:32])[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=1)[C:8]([OH:10])=[O:9]
Reactant: COc1cc(OC)cc(O[C@H](C(=O)O)[C@@]2(c3ccccc3)NCCc3ccccc32)c1
Reactant: COc1cc(CC(=O)Cl)cc(OC)c1
Product: COc1cc(CC(=O)N2CCc3ccccc3[C@@]2(c2ccccc2)[C@H](Oc2cc(OC)cc(OC)c2)C(=O)O)cc(OC)c1
Yield: 60.2 %

Procedure:
(±)-(S*)-(3,5-dimethoxy-phenoxy)-{(1S*)-2-[2-(3,5-dimethoxy-phenyl)-acetyl]-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl}-acetic acid (77 mg) is prepared in analogy to Example 5 starting from (±)-(S*)-(3,5-dimethoxy-phenoxy)-((1S*)-1-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-acetic acid (90 mg, 0.214 mmol, Example 1) and 3,5-dimethoxyphenylacetyl chloride (83 mg, 0.385 mmol). LC-MS2: tR=5.23 min, [M+1]+=598.35, [M−1]−=596.29.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:25]1[C:34]2[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][C:26]=1[OH:35]>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:35][C:26]1[CH:27]=[CH:28][C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:25]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(Br)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Reactant: Oc1ccc2c(c1)CCCC2
Product: COC(=O)C(Oc1ccc2c(c1)CCCC2)c1ccc(OCCCOc2ccc(Cl)cc2)cc1
Yield: 95.6 %

Procedure:
As described in Example 44, 8.28 g of methyl bromo{p-[3-(p-chlorophenoxy)propoxy]phenyl}acetate is reacted with 3.4 g of 5,6,7,8-tetrahydro-2-naphthol to give 9.2 g of product as a viscous oil.
Reaction SMILES: C([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:24]=[C:23]([C@H:25]4[C@H:30]([O:31]CC5C=CC=CC=5)[C@@H:29]([O:39]CC5C=CC=CC=5)[C@H:28]([O:47]CC5C=CC=CC=5)[C@@H:27]([CH2:55][O:56]CC5C=CC=CC=5)[O:26]4)[CH:22]=[CH:21][C:20]=3[CH:64]3[CH2:66][CH2:65]3)[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.CO>C1COCC1.[Pd]>[CH:64]1([C:20]2[CH:21]=[CH:22][C:23]([C@H:25]3[C@H:30]([OH:31])[C@@H:29]([OH:39])[C@H:28]([OH:47])[C@@H:27]([CH2:55][OH:56])[O:26]3)=[CH:24][C:19]=2[CH2:18][C:15]2[CH:16]=[CH:17][C:12]3[O:11][CH2:10][CH2:9][NH:8][C:13]=3[CH:14]=2)[CH2:66][CH2:65]1
Reactant: c1ccc(COC[C@H]2O[C@@H](c3ccc(C4CC4)c(Cc4ccc5c(c4)N(Cc4ccccc4)CCO5)c3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)NCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 18 h
Yield: 16.6 %

Procedure:
To a solution of 4-benzyl-6-[2-cyclopropyl-5-((2S,3S,4R,5R,6R)-3,4,5-tris-benzyloxy-6-benzyloxymethyl-tetrahydro-pyran-2-yl)-benzyl]-3,4-dihydro-2H-benzo[1,4]oxazine (0.42 g, 0.4783 mmol) in THF (4.7 mL) was added 10% palladium on charcoal (80 mg), 0.1 mL conc. HCl followed by methanol (4.7 mL) and the mixture was stirred under hydrogen atmosphere for 18 h. The reaction mixture was filtered through a celite bed, washed with methanol and concentrated. The resulting residue was purified by preparative HPLC to furnish (2S,3R,4R,5S,6R)-2-[4-cyclopropyl-3-(3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (34 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]([CH2:14][C:15]2[CH:34]=[CH:33][C:18](/[CH:19]=[CH:20]/[C@@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:37]([O:41][C:42]([N:44]1[CH2:48][CH2:47][CH2:46][C@H:45]1[C:49](O)=[O:50])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[C:29]([O:28][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1/[CH:20]=[CH:19]/[C:18]1[CH:33]=[CH:34][C:15]([CH2:14][N:7]([CH2:6][C:5]2[CH:35]=[CH:36][C:2]([NH:1][C:49]([C@@H:45]3[CH2:46][CH2:47][CH2:48][N:44]3[C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])=[O:50])=[CH:3][CH:4]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(N)cc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1/C=C/c1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)OC(C)(C)C)cc2)c2ccccc2)cc1
Yield: 24.3 %

Procedure:
The product from Example 149F (700 mg, 1.45 mmol) and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (374 mg, 1.74 mmol) were processed using the method described in Example 43 to afford 240 mg (23%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.92 (s, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.18 (m, 4H), 7.07 (m, 2H), 6.64 (d, J=8.1 Hz, 2H), 6.55 (t, J=7.7 Hz, 1H), 6.31 (d, J=15.6 Hz, 1H), 6.14 (dd, J=15.5, 6.5 Hz, 1H), 4.63 (s, 2H), 4.60 (s, 2H), 4.22 (m, 1H), 4.17 (m, 1H), 3.38 (m, 2H), 3.28 (m, 2H), 1.85 (m, 8H), 1.38 (s, 9H), 1.30 (s, 9H).
Reaction SMILES: CO.[CH3:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([O:19]CC)=[O:18])=[CH:11]2.[Li+].[OH-]>C1COCC1>[CH3:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([OH:19])=[O:18])=[CH:11]2
Reactant: CCOC(=O)c1cc2cc(OCCSC)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CSCCOc1ccc2[nH]c(C(=O)O)cc2c1
Temperature: 70 °C
Yield: 41.4 %

Procedure:
A methanol solution of ethyl 5-{[2-(methylthio)ethyl]oxy}-1H-indole-2-carboxylate (0.099 g, 0.356 mmol) was treated with 1 N LiOH (4 mL). The reaction mixture turned cloudy and THF was added until the cloudiness disappeared. The reaction was heated to 70° C. until TLC showed consumption of the starting material. The reaction mixture was partitioned between EtOAc and water and the basic layer was separated. The basic layer was acidified with conc. HCl and extracted with EtOAc, the layers were separated and the EtOAc was evaporated to afford the title compound (0.037 g, 41%) as a white solid. 1H NMR (400 MHz, Acetone-d6) δ ppm 10.74 (br. s., 1H), 7.44 (d, 1H), 7.17 (d, 1H), 7.11 (s, 1H), 6.96 (dd, 1H), 4.19 (t, 2 H), 2.88 (t, 2H), 2.20 (s, 3H). LCMS: m/z=251.9 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([NH2:9])[CH:6]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: OB(O)c1cc(Cl)ccc1Cl
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: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (4.1 g, 14.5 mmol), 2,5-dichlorophenylboronic acid (3.3 g, 17.4 mmol), Pd(PPh3)4 (500 mg, 1.45 mmol) and Na2CO3 (4.7 g, 43.5 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to room temperature, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (3.3 g, 75.8% yield) as an off-white solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[O:9]=[S:10]1(=[O:21])[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([CH3:20])([CH3:19])[C:16](=[O:18])[CH3:17]>CS(C)=O>[CH3:17][C:16]1([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][S:10]2(=[O:21])=[O:9])([CH3:20])[CH3:19])[CH2:4][O:18]1
Reactant: C[S+](C)(C)=O
Reactant: CC(=O)C(C)(C)N1CCCS1(=O)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C(C)(C)N2CCCS2(=O)=O)CO1
Temperature: 70 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a stirred suspension of 60% sodium hydride in mineral oil (0.039 g, 1.0 mmol) in anhydrous dimethyl sulfoxide (5 mL), under nitrogen, was added trimethylsulfoxonium iodide (0.214 g, 1.0 mmol). The mixture was stirred at 70° C. for 1 hr and then cooled to room temperature. 3-(1,1-Dioxidoisothiazolidin-2-yl)-3-methylbutan-2-one (0.100 g, 0.5 mmol) was added and the reaction mixture was stirred at room temperature for 16 hrs and then heated at 70° C. for 4 hrs. The mixture was cooled to 0° C. and quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes) to afford the product as a thick oil (0.065 g, 61%). 1H NMR (300 MHz, CDCl3) δ 3.52-3.12 (m, 4H), 2.76 (d, 1H, J=4.5 Hz), 2.54 (d, 1H, J=4.5 Hz), 2.42-2.20 (m, 2H), 1.60 (s, 3H), 1.43 (s, 3H), 1.35 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]([N:7]=[C:8]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[C:37]4=[N:38][CH:39]=[C:40]([Br:42])[CH:41]=[C:36]4[CH2:35][CH2:34][C:33]4[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:32]3=4)[CH2:27][CH2:26]2)=[O:24])[CH2:18][CH2:17]1)OC1C=CC=CC=1)=[O:6])=[O:3].[NH3:48]>C1COCC1>[NH2:1][C:2]([NH:4][C:5]([NH:7][C:8]([N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH:31]3[C:37]4=[N:38][CH:39]=[C:40]([Br:42])[CH:41]=[C:36]4[CH2:35][CH2:34][C:33]4[CH:43]=[C:44]([Cl:47])[CH:45]=[CH:46][C:32]3=4)[CH2:27][CH2:26]2)=[O:24])[CH2:20][CH2:21]1)=[NH:48])=[O:6])=[O:3]
Reactant: NC(=O)NC(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Reactant: N
Solvent: C1CCOC1
Product: N=C(NC(=O)NC(N)=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 40 %

Procedure:
Phenyl N-[[(aminocarbonyl)amino]carbonyl]-4-[2-[4-(3-bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperazinyl]-2-oxoethyl]-1-piperidine-carboximidate (Formula 16.1) (0.2943 g, 0.462 mmoles) was dissolved in a saturated solution of ammonia in anhydrous THF (80 ml) and the mixture was stirred at 25° C. for 19 h in a sealed vessel. The solution was evaporated to dryness and the residue was chromatographed on silica gel using 3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give the title compound (Formula 17.1) (0.2663 g, 40%), ESIMS: m/z 645.2 (MH+).
Reaction SMILES: [NH:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH2:4][S:3]1.[C:17](Cl)(=[O:23])[O:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[CH2:19]([O:18][C:17]([N:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:8]=2)[CH2:5][CH2:4][S:3]1)=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: N=C1SCCN1c1cccc(C(F)(F)F)c1
Reactant: CCCCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Yield: 40.5 %

Procedure:
A solution of N-(3-trifluoromethylphenyl)thiourea (6.1 g), dibromoethane (5.7 g) and anhydrous potassium carbonate (11.5 g) in acetone (60 ml) was refluxed for 1 day. The solvent was removed by distillation therefrom, and the residue was extracted with ethyl ether, washed with water, dried over anhydrous magnesium sulfate and subjected to column chromatography to give 7.5 g of 2-imino-3-(3-trifluoromethylphenyl)thiazolidine. The thus obtained 2-imino-3-(3-trifluoromethylphenyl)thiazolidine (1.0 g), n-butyl chlorocarbonate (0.61 g) and triethylamine (1.2 g) were dissolved in tetrahydrofuran, and the resultant solution was stirred at room temperature for 5 hours. The solvent was removed, and the residue was extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was subjected to column chromatography to give 0.57 g of 2-butoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][O:46][CH3:47])[CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:35][CH:34]=1.N1CCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2([CH2:45][O:46][CH3:47])[CH2:41][CH2:42][CH2:43][CH2:44]2)=[CH:35][CH:34]=1
Reactant: COCC1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]4OC(C)=O)ccc3Cl)cc2)CCCC1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: COCC1(Oc2ccc(Cc3cc([C@@]4(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)cc2)CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-methoxymethyl-cyclopent-1-yloxy)-benzyl]-benzene (0.39 g) in tetrahydrofuran (3 mL) is added pyrrolidine (0.22 mL). The solution is stirred at ambient temperature for 16 h. After dilution with ethyl acetate, the resulting solution is washed with aqueous hydrochloric acid (1 mol/l), dried (Na2SO4) and the solvent is removed under reduced pressure. The residue is purified by HPLC on reversed phase (YMC C18; water/acetonitrile 95:5→2:98).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH:9]1([NH:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:16][C:17]1[O:18][CH:19]=[CH:20][C:21]=1[C:22](Cl)=[O:23]>C1C=CC=CC=1>[CH:9]1([N:14]([C:22]([C:21]2[CH:20]=[CH:19][O:18][C:17]=2[CH3:16])=[O:23])[OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1occc1C(=O)Cl
Reactant: ONC1CCCC1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1occc1C(=O)N(O)C1CCCC1
Reaction time: 1 h

Procedure:
30 Parts of triethylamine is added to a suspension of 20 parts of N-cyclopentylhydroxylamine hydrochloride in 300 parts of benzene and the whole is stirred for 1 hour. At room temperature, 10 parts of 2-methylfuran-3-carboxylic chloride is dripped in. After the mixture has been stirred for a further 3 hours it is suction filtered, the residue is washed with benzene, and the organic phase is washed with water, dried with sodium sulfate and evaporated. There is obtained 25 parts of N-cyclopentyl-2-methylfuran-3-hydroxamic acid in the form of an oil. This oil is dissolved in 300 parts of dichloromethane; while stirring and at room temperature, 16 parts of sodium hydroxide in 70 parts of water, and 26 parts of dimethyl sulfate are added to the solution. After the mixture has been stirred for 2 hours the organic phase is separated, washed with water until neutral and dried with anhydrous sodium sulfate. Distillation gives 21 parts of O-methyl-N-cyclopentyl-2-methylfuran- 3-hydroxamic acid having a boiling point at 0.01 mm Hg of 104° to 108° C and the refractive index nD25 : 1.5073. ##SPC14##