Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:32]=[CH:31][C:12]2[NH:13][C:14]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[C:21](=[N:29]O)[C:20]=4[CH:19]=[CH:18][CH:17]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].O.[C:35]([OH:38])(=O)[CH3:36].[CH2:39](O)C>[Zn]>[CH:35]([O:38][CH:32]([CH3:31])[CH3:9])([CH3:36])[CH3:39].[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:32]=[CH:31][C:12]2[NH:13][C:14]([C:16]3[C:28]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]([NH2:29])[C:20]=4[CH:19]=[CH:18][CH:17]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8]
Reactant: CCO
Reactant: CC(=O)O
Reactant: CN(C)CCCNC(=O)c1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4=NO)nc2c1
Agent: [Zn]
Solvent: O
Product: CC(C)OC(C)C
Product: CN(C)CCCNC(=O)c1ccc2[nH]c(-c3cccc4c3-c3ccccc3C4N)nc2c1

Procedure:
The procedure used in Example 216 is followed. In a 10 ml round-bottomed flask under an argon atmosphere, dissolve 229 mg of 4-{5-[(3-dimethylaminopropyl)aminocarbonyl]-1H-benzimidazol-2-yl}-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 1.2 ml of ethanol, 1.2 ml of water and 1.2 ml of acetic acid. At room temperature, add 136 mg of zinc in three stages. Between each addition, stir for approximately one hour to two hours. Add Celite and filter. The filtrate is concentrated under pressure. The crude product is purified by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and ammonia as a 7N solution in methanol (9/1 by volume). After formation of the paste with diisopropyl ether, in this way we obtain 150 mg of 4-{5-[(3-dimethylaminopropyl)aminocarbonyl]-1H-benzimidazol-2-yl}-9H-fluorene-9(R,S)-amine, in the form of an off-white powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [NH2:1][CH:2]([CH:6]1[CH2:8][CH2:7]1)[CH2:3][CH2:4][OH:5].[CH:9]([C:11]1[C:19]2[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=2[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=1)=O.C([BH3-])#N.[Na+]>CO.CC(O)=O>[CH:6]1([CH:2]([NH:1][CH2:9][C:11]2[C:19]3[C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:16]=[N:15][C:14]=3[N:13]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:12]=2)[CH2:3][CH2:4][OH:5])[CH2:8][CH2:7]1
Reactant: NC(CCO)C1CC1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccnc2c1c(CNC(CCO)C1CC1)cn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
3-Amino-3-cyclopropylpropan-1-ol (30 mg, 0.26 mmol) was added to a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (39.6 mg, 0.13 mmol) in MeOH (3 mL) with AcOH (2 drops). After stirring for 90 min at rt, sodium cyanoborohydride (33 mg, 0.53 mmol) was added, and the reaction was stirred for an additional 3 h. The mixture was quenched with sat. NaHCO3 solution and extracted with ethyl acetate. The organics were dried over MgSO4 and concentrated in vacuo to give 50 mg of crude 1-tert-butyl 4-methyl 3-((1-cyclopropyl-3-hydroxypropylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate as a yellow oil which was used without further purification. [M+H] found 404.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([S:12][CH2:13][CH:14]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:11])=O)(C)(C)C.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([S:12][CH2:13][CH:14]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:15]([NH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)SCC(Cc1ccccc1)C(=O)Nc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
3-[[2-[N-(t-butyloxycarbonyl)glycylthiomethyl]-3-phenylpropionyl]amino]benzoic acid (compound of Example 165) (0.43 g) is dissolved in trifluoroacetic acid (3 ml), and the mixture is stirred at room temperature for 30 minutes and adjusted to pH 4.0 with aqueous sodium hydrogen carbonate solution, and then is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected and concentrated under reduced pressure, and thereto is added dioxane, and the solution is lyophilized to give the title compound (0.22 g).
Reaction SMILES: C(Cl)(Cl)=O.[C:5]1([OH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>C.[Ti]>[C:13](=[O:14])([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Oc1ccccc1
Agent: [Ti]
Agent: O=C(Cl)Cl
Product: O=C(Oc1ccccc1)Oc1ccccc1
Yield: 52440.5 %

Procedure:
0.42 mol/h of phosgene were continuously passed through 141 g (1.50 mol) of phenol in the presence of 14.1 g (10 wt. % relative to the phenol) of a powdered titanium carbide from H. C. Starck at 140° C. in a plane ground joint flask equipped with flow spoilers, a gas-dispersion stirrer and reflux condenser. After approximately 2 hours' reaction time, phenol conversion was 18.2%, wherein 0.04 g of phenyl chloroformate and 28.7 g of diphenyl carbonate were formed. Selectivity for carbonates was approximately 99%.
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH:5]=[CH:4][N:3]=[N:2]1.[Cl:10][C:11]1[CH:39]=[CH:38][C:14]([CH2:15][C@H:16]2[CH2:20][NH:19][C@H:18]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)=[O:22])[CH2:17]2)=[CH:13][CH:12]=1>>[N:1]1([CH2:6][C:7]([N:19]2[CH2:20][C@H:16]([CH2:15][C:14]3[CH:38]=[CH:39][C:11]([Cl:10])=[CH:12][CH:13]=3)[CH2:17][C@H:18]2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[CH:26][CH:25]=2)=[O:22])=[O:9])[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1
Reactant: O=C(O)Cn1ccnn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccc(Cl)cc2)CN1C(=O)Cn1ccnn1

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid and (2S,4R)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 228, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-4-(4-chlorobenzyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide. 1H-NMR (400 MHz, CDCl3): δ 8.94 (s, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.43 (d, 2H), 7.30 (d, 2H), 7.14 (d, 2H), 7.00 (t, 2H), 6.94-6.89 (m, 4H), 5.28 (d, 1H), 5.14 (d, 1H), 4.78 (d, 1H), 3.68 (dd, 1H), 3.26 (t, 1H), 3.04-2.91 (m, 1H), 2.88 (dd, 1H), 2.71-2.59 (m, 2H), 1.73-1.65 (m, 1H). MS (EI) for C28H25ClFN5O3 found 534.2 (MH+).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=3[Cl:24])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[N:4]([CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:5]2[CH:11]=[C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=3[Cl:24])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:1]([C:3]1[N:7]([CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:6]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[C:18]([F:19])=[CH:17][C:16]([C:20]([F:22])([F:23])[F:21])=[CH:15][C:14]=3[Cl:24])=[CH:11][C:5]=2[N:4]=1)#[N:2]
Reactant: CCOC(=O)C(C)Br
Reactant: N#Cc1nc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)n1c(C#N)nc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Product: CCOC(=O)C(C)n1c(C#N)nc2ccc(Oc3c(F)cc(C(F)(F)F)cc3Cl)cc21
Reaction time: 8 h

Procedure:
2-Cyano-5-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)benzimidazole (0.325 g), ethyl 2-bromopropionate (0.13cm3) and anhydrous potassium carbonate (1 g) were heated under reflux in acetonitrile (30cm3) for 2 hours and left at room temperature overnight. The mixture was filtered and the solvent removed from the filtrate under vacuum. The residue was purified by preparative plate chromatography (SiO2 ; hexane:ether,1:1) to yield ethyl 2-[2-cyano-6-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)benzimidazol-1-yl]-propionate (0.14 g) as the faster component (compound 101) and ethyl 2-[2-cyano-5-(2-chloro-4-trifluoromethyl-6-fluorophenoxy)benzimidazol-1-yl]propionate (0.15 g) as the slower component (compound 100).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=1[F:18])(=O)=O.[C-:19]#[N:20].[Na+].O>CS(C)=O>[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:17])[CH3:16])=[C:8]([F:18])[C:7]=1[CH2:6][C:19]#[N:20]
Reactant: CC(=O)Nc1ccc(Cl)c(COS(C)(=O)=O)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c(CC#N)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 3-acetamido-6-chloro-2-fluorobenzyl methanesulfonate (1.31 g, 3.54 mmol) in DMSO (10 mL) was treated with sodium cyanide (0.868 g, 17.72 mmol), stirred at RT overnight, treated with water and extracted with EtOAc (2×). The combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-chloro-3-(cyanomethyl)-2-fluorophenyl)acetamide (630 mg, 78% yield) as a yellow solid. MS (ESI) m/z: 227.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[N:17]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1C=CC=CC=1>[Cu].C1(C)C=CC=CC=1>[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[C:10]([NH:17][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(Cc1ccccc1)c1ccccc1
Reactant: c1ccncc1
Agent: [Cu]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccncc2)c(NCc2ccccc2)c1
Reaction time: 5 h

Procedure:
158 parts of pyridine and 155 parts of benzoyl chloride are heated with 4 parts of copper powder for an hour at 100° to 105° C. At 70° to 80° C there is then added 197 parts of methylbenzylaniline and heating is continued for another five hours at 100° to 105° C. When the reaction is over 800 parts of toluene is added at 70° to 80° C, and the precipitate is suction filtered and dissolved in 1,000 parts of 5% hydrochloric acid. The product is clarified with animal charcoal and reprecipitated in the cold with ammonia and recrystalized from a mixture of ethanol and water for further purification. 50 parts of 4-(4'-methylbenzylaminophenyl)-pyridine is obtained as practically colorless crystals which melt at 118° to 119° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C.[OH-].[Na+]>[CH2:31]([O:30][C@@H:16]1[C@@H:15]([CH2:14][NH:13][C:10](=[O:11])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 173 mg of 5'-amino-3'-O-benzyl-2',5'-dideoxy-5-ethyluridine in 4.5 ml of 0.11M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was recrystallized from ethanol to give 120 mg of 3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 174°-177° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15]O)[CH:13]=2)[CH:8]=[N:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:43])C(=O)C1>C(Cl)Cl>[Br:43][CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[N:7][N:6]2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCn1ncc2ccc(CO)cc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COCCCn1ncc2ccc(CBr)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To a solution of (1-(3-methoxypropyl)-1H-indazol-6-yl)methanol (660 mg, 3 mmol) in dry CH2Cl2 (15 mL) at 0° C., Ph3P (943 mg, 3.6 mmol) and NBS (640 mg, 3.6 mmol) were added in portions. After stirring for 12 h at rt, the mixture was evaporated and the residue was purified by flash chromatography on silica gel to give 6-(bromomethyl)-1-(3-methoxypropyl)-1H-indazole (420 mg, 50%). 1H NMR (400 MHz, CDCl3): 2.18 (m, 2H), 3.26 (m, 2H), 3.31 (s, 3H), 4.49 (m, 2H), 4.65 (s, 2H), 7.18 (m, 1H), 7.48 (s,1H), 7.79 (m,1H), 7.99 (m,1H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:42][C@@H:43]2[O:45][CH2:44]2)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:42][C@H:43]1[CH2:44][O:45]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (1.35 g, 4.2 mmol), (prepared as described for the starting material in Example 271), potassium carbonate (1.74 g, 12.6 μmmol) and (2R)-(−)-glycidyl tosylate (1.92 g, 8.4 mmol) in DMF (25 ml) was stirred at 60° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the solvent removed in vacuo. The residue was dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate solution. The organic layer was then dried (MgSO4), filtered and solvent removed in vacuo to give a solid. This was triturated with ether and the solid filtered off and dried to give (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (842 mg, 53%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH3:28][C:29](N=C(N(C)C)N(C)C)([CH3:31])[CH3:30].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][N:20]=3)[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:27])[O:4][N:3]=1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC(C)CBr
Solvent: CC#N
Product: Cc1cnc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a solution of 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}-N-(3,5-dimethyl-2-pyridinyl)benzenesulfonamide (56 mg, 0.145 mmol) in acetonitrile (1 mL) was added N″-(1,1-dimethylethyl)-N,N,N′,N′-tetramethylguanidine (25 mg, 0.145 mmol) and the mixture was stirred at room temperature for 1 hour, 1-bromo-2-methylpropane (0.031 mL, 0.289 mmol) was then added and the mixture was stirred at 70° C. for 125 hours. The mixture was concentrated in vacuo and partitioned between dichloromethane (5 mL) and water (5 mL). The organic layer was then purified by mass directed autoprep (formic acid modifier) to give the title compound (30 mg) as a white solid. LCMS (2 min, formic) Rt 1.31 min, m/z (ES+) 444 (M+H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([O:18][CH:19]([F:21])[F:20])[N:15]([CH3:22])[N:14]=2)=[CH:9][CH:8]=1>C(Cl)(Cl)(Cl)Cl>[Cl:4][C:17]1[C:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)=[N:14][N:15]([CH3:22])[C:16]=1[O:18][CH:19]([F:21])[F:20]
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(-c2ccc(Cl)cc2)c(Cl)c1OC(F)F
Reaction time: 2 h

Procedure:
A solution of 74.0 g (0,549 mol) of sulfuryl chloride in 200 ml of carbon tetrachloride was added slowly to a solution of 128.9 g (0.5 mol) of 3-(4-chlorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole in 500 ml of carbon tetrachloride. After the exothermic reaction with evolution of gas had subsided, the reaction mixture was stirred at 20°-25° C.for 2 hours more. The reaction solution was then washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloridesolution, and finally dried and concentrated. Yield: 139.3 g; 1H-NMR (270 MHz, in CDCl3): δ [ppm]=7,79 (d,2H), 7,43 (d,2H), 6,70 (t,1H), 3,85 (s,3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[C:6]([Cl:13])[C:5]=1[NH2:14].[C:16](O)(=O)C.C(N)=N.CCOC(C)=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:14])=[C:6]([Cl:13])[C:7]2[N:11]([CH3:16])[CH:12]=[N:10][C:8]=2[CH:9]=1)=[O:15]
Reactant: CNc1c(N)cc(C(=O)OC)c(N)c1Cl
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ncn(C)c2c(Cl)c1N
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 1 g (4.35 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester in 153 ml of EtOH, is added 700 mg (6.53 mmol) of formamidine acetate. The mixture is stirred at a temperature of 80° C. for 24 hours. EtOAc is added and the organic phase is washed once with H2O and once with brine. Then the organic layer is dried on Na2SO4, filtrated and concentrated. After purification by flash chromatography on silica gel 0.68 g (2.84 mmol, 65%) of a dark violet solid were obtained. LC/MS: 240/242 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]2=[O:29])=[C:11]([OH:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]2[C:15]3([CH2:31][O:30][C:11]=2[CH:10]=1)[C:23]1[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=1)[N:17]([CH2:24][CH2:25][CH:26]([CH3:27])[CH3:28])[C:16]3=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: CC(C)CCN1C(=O)C(c2ccc(OCc3ccccc3)cc2O)c2ccccc21
Product: CC(C)CCN1C(=O)C2(COc3cc(OCc4ccccc4)ccc32)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(3-methylbutyl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 6-(benzyloxy)-1′-(3-methylbutyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (67%): 1H NMR (300 MHz, CDCl3) 7.41-7.28 (m, 7H), 7.14-7.12 (m, 1H), 7.04-6.99 (m, 1H), 6.90-6.87 (m, 1H), 6.59-6.55 (m, 1H), 6.44-6.30 (m, 1H), 5.00 (s, 2H), 4.79 (ABq, 2H), 3.87-3.64 (m, 2H), 1.71-1.56 (m, 3H), 0.98 (d, J=6.0 Hz, 6H); MS (ES+) m/z 414.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:17][C:13]3[S:14][CH:15]=[CH:16][C:12]=3[C:11]2=O)=O)=[CH:4][CH:3]=1.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:10]3[CH2:17][C:13]4[S:14][CH:15]=[CH:16][C:12]=4[C:11]=3[NH:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Br)nc1)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc(-c2n[nH]c3c2Cc2sccc2-3)cn1
Temperature: 25 °C
Yield: 65 %

Procedure:
5-(6-Bromo-pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.29 g, 4 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.4 mL) and ethanol (20 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(6-Bromo-pyridin-3-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.83 g, 2.6 mmol) as white solid in 65% yield.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)CC(OCC)=O.[O-:31][CH2:32][CH3:33].[Na+]>C(O)C>[O:31]=[C:32]1[O:1][C@H:2]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:33]1
Reactant: CC[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate was treated with 1.1 equivalents of diethyl malonate and 1.05 equivalents of sodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25° C. for 5 hrs. The reaction mixture was quenched with acetic acid till the pH of the mixture was about 6. The reaction mixture was extracted with ethyl acetate (4 L) and the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L), dried over NaSO4, filtered, concentrated and chased with 2 L of methyl tert-butyl ether to dryness. The oil was dissolved in 950 mL of methyl tert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to −5° C. The solid was isolated by filtration to provide tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate. A mixture of the tert-butyl (1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g, 1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05 equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. was treated with a solution of sodium ethoxide (77.5 g sodium ethoxide in 0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reaction mixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate (215.6 g, 5.138 mol, 5 equivalents) was added all at once and the temperature rose to 10° C. The mixture was stirred at 10° C. for 2 hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirred at 60° C. for 17 hours. The reaction mixture was treated with distilled water (4 L) over 20 minutes while maintaining the internal temperature >55° C. The slurry was cooled slowly to 14° C. over 2.5 hours, filtered, washed with 1:1 ethanol:water (total volume=2 L), heptanes (2 L) and dried at 55° C. vacuum oven under N2 for 40 hours to give the title compound (451.9 g, 91% yield). 1H NMR (CDCl3): δ 8.65(m, 1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H), 4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H), 1.74(m, 1H), 1.36 (s, 9H).