Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH2:12])[S:8][C:5]2=[N:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][NH:12][S:20]([CH3:19])(=[O:22])=[O:21])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1nc2cc(Br)cnc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1nc2cc(Br)cnc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a cooled (ice-water) solution of (6-bromothiazolo[5,4-b]pyridin-2-yl)methanamine (800 mg, 3.28 mmol) and pyridine (800 mg, 9.85 mmol) in CH2Cl2 (10 mL) is slowly added methanesulfonyl chloride (380 mg, 3.28) and stirred at room temperature for 3 hours. Reaction mixture is washed with water (2×10 mL) dried over Na2SO4 and concentrated. Obtained crude product purified on silica gel column using 0 to 5% methanol/CH2Cl2 to give the title compound (800 mg): m/z (Cl) M+2 324.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([OH:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH2:12](Br)[CH3:13]>CS(C)=O.O>[CH2:12]([O:11][C:5]1[C:6]([OH:10])=[C:7]([C:2]([F:1])=[CH:3][CH:4]=1)[CH:8]=[O:9])[CH3:13]
Reactant: O=Cc1c(F)ccc(O)c1O
Reactant: CCBr
Solvent: CS(C)=O
Solvent: O
Product: CCOc1ccc(F)c(C=O)c1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.1 %

Procedure:
To a solution of 6-fluoro-2,3-dihydroxy-benzaldehyde (1.00 g, 6.40 mmol) in dry DMSO (10 mL) was added NaOBut (1.23 g, 12.81 mmol) and ethyl bromide (0.77 g, 7.04 mmol) under N2 and stirred at RT for 18 h. The resultant mixture was diluted with water, acidified to pH ˜6 with 2N.HCl and extracted with EtOAc (4×25 mL). Combined organic layers were washed with water and brine and dried over MgSO4. Filtration and removal of the solvent under reduced pressure provided 1.05 g (5.70 mmol, 89%) of the title compound as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.24 (s, 1H), 7.04 (dd, J=8.8, 5.3 Hz, 1H), 6.61-6.50 (m, 1H), 4.09 (q, J=7.0 Hz, 3H), 1.46 (t, J=7.0 Hz, 3H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −132.19-−132.15 (m, 1F).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([O:34]C(=O)C)[CH2:29][O:30]C(=O)C)=[O:25])[C:5]([I:23])=[C:6]([C:21]=1[I:22])[C:7]([NH:9][CH2:10][CH:11]([O:17]C(=O)C)[CH2:12][O:13]C(=O)C)=[O:8].[C:39](Cl)(=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61].C(OCC)(=O)C>ClCCl>[OH:17][CH:11]([CH2:12][OH:13])[CH2:10][NH:9][C:7](=[O:8])[C:6]1[C:21]([I:22])=[C:2]([NH:1][C:39](=[O:62])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]#[C:49][C:50]#[C:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:3]([I:38])=[C:4]([C:24]([NH:26][CH2:27][CH:28]([OH:34])[CH2:29][OH:30])=[O:25])[C:5]=1[I:23]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Cl
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino,N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide (2.19 g, 2.5 mmol) and 10,12-tricosadiynoyl chloride (1.82 g, 5 mmol) were dissolved in 20 ml dichloromethane. The solution was stirred for 3 days at ambient temperature under a nitrogen atmosphere. TLC (ethyl acetate) indicated that the reaction was complete. The reaction mixture was evaporated and dissolved in a mixture of methanol (30 ml) and 1M sodium hydroxide solution (15 ml). After 1 hour TLC (methanol/chloroform) indicated that the reaction was complete. The solution was neutralized with concentrated hydrochloric acid. The residue was dissolved in chloroform and filtered. The solvent was removed and the reaction mixture was purified through silica gel with methanol/chloroform (1:3) to give the title compound. 1H NMR (300 MHz, DMSO): δ 0.8 (CH3, t), 1.2-1.7 (17×CH2, m), 2.2-2.3 (2×CH2, t) , 3.1-3.2 (2×CH2NH, m) , 3.3-3.5 (2×CH2OH, m), 3.6-3.8 (2×CHOH), 4.4-4.7 (4×OH, m), 8.4-8.5 (2×CONH, m), 9.8 (2×ArNHCO, s).
Reaction SMILES: C([O:8][P:9]([CH2:19][C:20]1([C:25]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]CC3C=CC=CC=3)=[O:41])[C:29]2=[O:50])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)([O:11]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[P:9]([CH2:19][C:20]1([C:25]([NH:27][C@H:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:50])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]1)([OH:10])([OH:11])=[O:8]
Reactant: [H][H]
Reactant: O=C(CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(OCc3ccccc3)OCc3ccccc3)CCCC2)CCc2ccccc21)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CP(=O)(O)O)CCCC2)CCc2ccccc21
Yield: 77.5 %

Procedure:
1.9 g of benzyl (3S)-3-(1-dibenzylphosphonomethylcyclopentane-1-carbonylamino)-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation see Example 1G) were dissolved in 100 ml of ethanol. 1.2 g of a 5% strength palladium catalyst on active carbon were added to the solution and it was hydrogenated for 3 hours at a hydrogen pressure of 5.5 bar. For workup, the catalyst was filtered out, the filtrate was evaporated in vacuo and the residue was dried. 0.9 g of the title compound was obtained as a foamy product, IR: 3400, 1720, 1630 cm-1 (KBr); [α]D20 =-140.8° (c=0.5 in methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([CH2:18]Cl)=[O:17]>CC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][C:16](=[O:17])[CH2:18][N:11]3[CH2:10][CH2:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(C)=O
Product: O=C(CN1CCN(c2ccc(F)cc2)CC1)CN1CCN(c2ccc(F)cc2)CC1

Procedure:
To a solution of 1-(4-fluorophenyl)piperazine (12 g) in acetone (40 ml) kept at reflux temperature a solution of 1,3-dichloroacetone (1.3 g) in acetone (10 ml) was added dropwise. The mixture was refluxed for another 2 hours. Acetone was evaporated in vacuo. The remaining viscous oil was subjected to column chromatography on silica gel (eluted with ethyl acetate/ethanol/triethylamine 80:20:4). The title compound 13a crystallized from diethyl ether. Yield 0.6 g. Mp 106°-107° C. 1H NMR (CDCl3) δ2.70 (t,8H), 3.15 (t,8H), 3.45 (s, 4H), 6.85-7.00 (m,8H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=2)[C:6]([O:8]CC)=[O:7].[OH-].[K+]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=2)[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)c(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1-c1cc2cc(Cl)c(Cl)cc2[nH]1
Yield: 96.3 %

Procedure:
Ethyl 3-methoxy-4-(5,6-dichloro-1H-indol-2-yl)-benzoate (1 g, 2.7 mmol) was added to a solution of KOH (0.4 g, 7 mmol) in EtOH (50 ml) and the mixture was refluxed for 4 h. The solvent was concentrated and the residue was dissolved in water. The aqueous solution was acidified with HCl then extracted with AcOEt. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo yielding 0.89 g (2.6 mmol, yield 99%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([OH:14])=O)[CH3:11])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[N:16]1.S(Cl)([Cl:27])=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([C:12]([Cl:27])=[O:14])[CH3:11])=[CH:4][C:3]=1[N:15]1[C:23](=[O:24])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C:17]2=[N:16]1
Reactant: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(Oc1cc(-n2nc3n(c2=O)CCCC3)c(Cl)cc1Cl)C(=O)Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3.7 Parts of 2-[2,4-dichloro-5-(1-carboxy-ethoxy)phenyl]-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-A]pyridin-3(2H)-one, 15 parts of chloroform and 1.2 parts of thionyl chloride were combined and refluxed for 3 hours. The reaction was stirred for an additional 12 hours at room temperature. Solvent and excess thionyl chloride were removed from the product by evaporation on a rotary evaporator at reduced pressure. 4.0 Parts of crude product were obtained and used in the next step without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[C:25]([CH3:26])=[CH:24][C:23]([N+:27]([O-])=O)=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[NH2:27][C:23]1[CH:24]=[C:25]([CH3:26])[C:16]([C:10]2[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=2[OH:8])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1ccc(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(N)cc(C)c1-c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 64 %

Procedure:
Methyl 2-(2-benzyloxy-4-fluorophenyl)-3-methyl-5-nitrobenzoate (Reference Compound No. 1-4-(4), 10.7 g, 27.0 mmol) was dissolved in a mixture of methanol (50 mL) and tetrahydrofuran (50 mL), then 10% palladium on charcoal (1.00 g) was added thereto, and then the reaction mixture was stirred under hydrogen atmosphere (3 kgf/cm2) at room temperature for 3 days. After the mixture was filtered, the solvent was removed under reduced pressure. Ethyl acetate was added to the obtained residue, and then filtered to give the titled reference compound (4.79 g) as a pale gray solid. (Yield 64%)
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[S:19][C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[CH:5]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=1>>[F:28][C:26]1[CH:27]=[C:22]([CH:23]=[C:24]([F:29])[CH:25]=1)[CH2:21][N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[C:6]3[CH:5]=[C:4]([Cl:3])[S:19][C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:18][CH2:17]1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: Cl
Product: Fc1cc(F)cc(CN2CCC(Nc3ncnc4sc(Cl)cc34)CC2)c1

Procedure:
The title compound was prepared (0.80 g, 51%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine dihydrochloride (1.38 g, 4.05 mmol) and 1-(bromomethyl)-3,5-difluorobenzene (0.84 g, 4.05 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 6.99 (s, 1H), 6.89 (d, 2H), 6.70 (t, 1H), 4.89 (d, 1H), 4.19 (m, 1H), 3.50 (s, 2H), 2.86 (d, 2H), 2.24 (t, 2H), 2.01 (d, 2H), 1.59 (m, 2H); MS (ESI) m/z: Calculated for C18H18ClF2N4S, 395.09; Observed: 395.0 (M++1).
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7]Br)[C:3]([NH2:5])=[O:4].[H-].[Na+].[F:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:2]3[CH2:6][CH2:7][NH:5][C:3]3=[O:4])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: NC(=O)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Product: O=C1NCCC1Oc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Typical Procedure 2 was followed. Reaction of 2,4-dibromo-butyramide with NaH and 4-(4-fluoro-phenoxy)-phenol provided the title compound. MS ESI+: m/z=288 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[N:11]([C:13](Cl)=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:21]([N:24]([CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:35][CH2:36][NH2:37])[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]>>[Cl:1][C:2]1[C:12]2[N:11]([C:13]([NH:37][CH2:36][CH2:35][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]3[CH2:28][N:24]([CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27])=[O:14])[C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[C:8](=[O:20])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2cccc(Cl)c2N(C(=O)Cl)c2ccccc21
Reactant: CCCN(CCC)CC1CCCCN1CCN
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccc(Cl)c21
Yield: 2.6 %

Procedure:
Prepared analogously to Example 1 from 6-chloro-5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(dipropylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 2.6% of theory. Colourless crystals, m.p. 71°-78° C., presumably a mixture of 2 diastereomers.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([NH:15][C@H:16]([C:34](OC)=[O:35])[CH2:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:38][OH:39]>O1CCCC1.CO>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C:13]([NH:15][CH:16]([CH2:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:34]([NH:38][OH:39])=[O:35])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)NC(=O)CNC(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NC(CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.2 %

Procedure:
To a solution of the title compound of Example 16b (440 mg, 0.81 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added NH2OH (50% aqueous solution, 0.74 mL, 12 mmol). After stirring for 20 hours at room temperature, the solution was concentrated. Purification by flash chromatography (5:95 MeOH/CHCl3) yielded the title compound as a white solid (80 mg, 18%): Anal. Calcd. for C25H25N3O7S2.0.25 H2O: C, 54.78; H, 4.69; N, 7.67; S, 11.70. Found: C, 54.78; H, 4.72; N, 7.46; S, 11.53.
Reaction SMILES: [CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[SH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)=[CH2:36]>C(O)(=O)C>[CH2:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[S:21][CH2:36][CH2:35][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccncc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Cc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCCc2ccncc2)c1Cc1ccccc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 4-benzyl-3-mercapto-5-sulfamylbenzoic acid (3.25 g), sodium hydrogen carbonate (2.0 g), sodium dithionite (2.0 g), 4-vinylpyridine (1.5 ml) and saturated sodium hydrogen carbonate (33 ml) is stirred at 70° C. for 4 hours. After cooling, the mixture is acidified with 4 N acetic acid. The separated material is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzyl-3-(4-pyridylethylthio)-5-sulfamylbenzoic acid is obtained as a hemihydrate with a melting point of 180° -182° C..
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Yield: 57 %

Procedure:
The product from Example 7b (1.0 g, 4.30 mmol) was reacted with 12 mL of POCl3 for 4 h following the procedure from Example 7d giving the title compound as a brownish-pink solid (619 mg, 57%).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[NH:8][C:9]=1[C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])([CH3:4])[CH3:3].CC(C)([O-])C.[K+].[C:27]([O:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[CH:47]=[CH:46][C:43]([CH2:44][N:8]2[C:9]([C:10]([O:12][CH2:13][CH2:14][CH3:15])=[O:11])=[C:5]([C:2]([OH:1])([CH3:4])[CH3:3])[N:6]=[C:7]2[CH2:16][O:17][CH2:18][CH2:19][CH3:20])=[CH:42][CH:41]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCOCc1nc(C(C)(C)O)c(C(=O)OCCC)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 75.6 %

Procedure:
Following a procedure similar to that described in Example 82(a), but using 0.20 g of propyl 4-(1-hydroxy-1-methylethyl)-2-propoxymethylimidazole-5-carboxylate [prepared as described in Preparation 45(iii)], 82 mg of potassium t-butoxide and 290 mg of 4-[2-(t-butoxycarbonyl)phenyl]benzyl bromide and then purifying the product by column chromatography through silica gel using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, 293 mg of the title compound were obtained as a syrup.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][CH2:15]1.CN(C)[CH:25]=[O:26]>CCCCCC.O>[CH:25]([C:19]1[C:18]2[O:14][CH2:15][CH2:16][C:17]=2[CH:22]=[CH:21][CH:20]=1)=[O:26]
Reactant: c1ccc2c(c1)CCO2
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: O=Cc1cccc2c1OCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
108 ml of an n-butyllithium solution (2.1M) in hexane and 26.7 g (230 mmol) of tetramethylethylenediamine (TMEDA) are introduced into a 1 liter round-bottomed flask. The mixture is stirred at room temperature for 15 minutes and 23 g (190 mmol) of 2,3-dihydrobenzofuran are added. The mixture is stirred for 4 hours at 35° C., cooled to -78° C. and 13.9 g (190 mmol) of dimethylformamide are added. The temperature is allowed to return to 20° C., 500 ml of water are added and extraction is carried out with ethyl acetate (3×200 ml). The organic phases are combined, dried and concentrated under vacuum. The residue is purified by silica flash chromatography (elution: 5% ethyl acetate in petroleum ether). 9.85 g (Yield: 35%) of 7-formyl-2,3-dihydrobenzofuran are obtained--M.p.: 55° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=[N:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Yield: 63.7 %

Procedure:
A solution of methyl 4-bromo-5-chloro-2-thiophenecarboxylate (5 g, 19.57 mmol)[prepared in Preparation 2], 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.28 g, 20.55 mmol)[prepared in Preparation 1], potassium carbonate (10.82 g, 78 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.500 g, 0.978 mmol) in 1,4-dioxane (82 ml) and water (16.31 ml) was stirred at 80° C. in a sealed tube for 2 h. The reaction mixture was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 25% EtOAc in hexanes) yielding methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (3.2 g, 12.47 mmol, 63.7% yield) as a white solid: LCMS m/e ES 257, 259 (M, M+2)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]([NH2:13])([CH3:12])([CH3:11])[CH3:10]>CS(C)=O.O>[Br:8][C:4]1[N:3]=[C:2]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC(C)(C)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Nc1cccc(Br)n1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A stirred solution of 2,6-dibromopyridine (4.0 g, 16.5 mmol) and tert-butylamine (1.8 ml, 17.2 mmol) in dimethylsulfoxide (10 ml) was heated at 100° C. in a sealed tube for 20 h. After cooling to ambient temperature the reaction was diluted with water and extracted into dichloromethane. Combined organic extracts were washed with water and saturated brine then dried over magnesium sulfate, filtered and evaporated in vacuo to give a solid. Purification by chromatography on silica gel eluting with 20% diethyl ether in isohexane gave 6-bromo-N-(tert-butyl)pyridin-2-ylamine (0.4 g) as a solid: δH (360 MHz, CDCl3) 1.40 (9H, s), 6.34 (1H, d, J 8), 6.66 (1H, d, J 8), 7.18 (1H, dd, J 8 and 8); m/z (ES+) 229/231 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]1([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)[CH2:28][CH2:27]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:29]([CH:26]2[CH2:27][CH2:28]2)[CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39][CH3:40])[CH:32]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CNC2CC2)cc1OC
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: COc1ccc(CN(C(=O)CN(c2ccc(C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)cc1OC

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with cyclopropyl-(3,4-dimethoxy-benzyl)-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5](=[O:8])[NH:6][CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(O)(=O)C>[Br:10][C:7]1[NH:6][C:5](=[O:8])[C:4]([OH:9])=[CH:3][C:2]=1[Cl:1]
Reactant: O=c1[nH]cc(Cl)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: O=c1[nH]c(Br)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 5.2 %

Procedure:
To 5-chloro-3-hydroxypyridin-2(1H)-one (500 mg) was added acetic acid (20 ml), and N-bromosuccinimide (734 mg) was added at room temperature. The reaction mixture was stirred at room temperature for 5 hr. The obtained solid was collected by filtration and washed with ethyl acetate. The obtained residue was purified by reversed-phase column chromatography (methanol-0.1% aqueous formic acid solution) and solidified by dimethylformamide to give 6-bromo-5-chloro-3-hydroxypyridin-2(1H)-one (40 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:6][C@H:5]2[CH3:16].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C@H:5]2[CH3:16]
Reactant: C[C@@H]1Nc2ccccc2-c2ccc(F)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3[C@@H]2C)cc1
Yield: 39.3 %

Procedure:
The title compound was prepared according to the procedure of Example 19, starting from the (S)-8-Fluoro-6-methyl-5,6-dihydrophenanthridine of Example 20 (38.4 g) and 4-methoxyphenylsulfonyl chloride (37.2 g). The crude product (65.6 g) was purified by filtration over a flash silica gel plug (1 Kg) eluting with 20-25% hexane-ethyl acetate to provide 54.1 (78.4% yield) of product. The material (54.1 g) was recrystallized twice from hot 30% toluene in ethanol. The solution was seeded hot and allowed to cool to room temperature. After about 3 hours the crystalline solid was collected, rinsed with 30% toluene in ethanol (1×15 mL) and with hexane (2×15 mL), and dried to provide 27.1 g (39.3% yield based on (S)-8-fluoro-6-methyl-5,6-dihydrophenanthridine) of title compound. The compound was analyzed by chiral stationary phase HPLC (Chiralpak AD-25×0.46 cm column) on a HP1100 using 90:10 hexane-isopropanol as the mobile phase with a 1 mL/min flow rate. The analysis showed the material to be a 98.7:1.3 mixture of enantiomers,