Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.[C:8]1([S:14][CH2:15][CH2:16][CH2:17]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:17][CH2:16][CH2:15][S:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1S
Reactant: BrCCCSc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSc1ccccc1
Yield: 65.4 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (1.2 g) is dissolved in acetone (50 ml). To the solution are added 3-bromopropyl phenyl sulfide (2.5 g) and potassium carbonate (1.5 g) and the mixture is refluxed for 4 hours. Acetone is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Kieselgel 60). The column is eluted with benzenechloroform (3:2) to obtain 1-methyl-5-(3-phenylthiopropyl)thio-1,2,3,4-tetrazole (1.8 g) as colorless liquid, nD18 =1.6008.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6]([CH2:36][C:37]([O:39]C)=O)=[CH:7][N:8]2[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][C:18]3[CH2:35][C@:25]4([C:33]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:27][C:26]4=O)[CH2:24][C:19]=3[CH:20]=2)[N:15]=1)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O.CCO>[O:39]=[C:37]1[CH2:36][C:6]2=[CH:7][N:8]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][C:18]5[CH2:35][C@:25]6([C:33]7[C:28](=[N:29][CH:30]=[CH:31][CH:32]=7)[N:27]=[CH:26]6)[CH2:24][C:19]=5[CH:20]=4)[N:15]=3)[C:9]3[C:5]2=[C:4]([CH:12]=[CH:11][CH:10]=3)[NH:1]1
Reactant: COC(=O)Cc1cn(Cc2ccc3cc4c(cc3n2)C[C@]2(C4)C(=O)Nc3ncccc32)c2cccc([N+](=O)[O-])c12
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1Cc2cn(Cc3ccc4cc5c(cc4n3)C[C@@]3(C=Nc4ncccc43)C5)c3cccc(c23)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl (4-nitro-1-{[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl]methyl}-1H-indol-3-yl)acetate from Step A (22 mg, 0.041 mmol) in H2O (0.5 mL) and EtOH (0.5 mL) was added sodium hydrosulfite (ca. 85%; 108 mg, 0.53 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then at 50° C. for 90 min. The reaction mixture was allowed to cool, more sodium hydrosulfite (ca. 85%; 55 mg, 0.27 mmol) was added, and the resulting mixture was heated to 70° C. for 4 h. 3 N hydrochloric acid (0.55 mL, 1.65 mmol) was added and the solution was heated to 70° C. for 18 h. EtOH (1 mL) was added and heating was continued at 100° C. for 24 h, then the cooled mixture was concentrated in vacuo. The residue was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=472 (M+1). HRMS: m/z=472.1764; calculated m/z=472.1768 for C29H22N5O2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].ClC1C=C2C(C(CC(O)=O)=[C:30]([C:34]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:35])N2)=CC=1>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:30]=1[C:34]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=1)=[O:35]
Reactant: Cc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2CC(=O)O)nc1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Product: COC(=O)Cc1c(C(=O)c2ccc(C)cn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-5-methylpyridine (Preparation is described in step 1 of Example 32).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([BH3-])#N.[Na+].O.[OH-].[Na+]>C(O)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of methyl 1H-indole-5-carboxylate 19a (2 g, 11.4 mmol) in glacial acetic acid (15 mL) at 0° C. was slowly added sodium cyanoborohydride (1.08 g, 17.2 mmol). The mixture was allowed to warm up and stirred at room temperature for 2 h. Water was added to the resulting mixture at 0° C., and the solution was adjusted to pH˜12 with 1N aqueous NaOH. The mixture was extracted with CH2Cl2 and the organic layer was washed with brine and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (silica gel, 15% EtOAc/heptane) to give compound 24a (1.79 g). MS m/z (M+H+) 178.1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:15].[N+:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CCc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc2C1
Reaction time: 24 h
Yield: 51.9 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 9.53 g) was added dropwise to THF solution (15 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (1.5 g), 4-nitrobenzylalcohol (3.35 g), and triphenylphosphine (5.74 g) at room temperature, which was stirred for 24 hours. The reaction mixture was concentrated, and the residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=8:1), and recrystallized (ethyl acetate-hexane) to give the titled compound (1.29 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:17])(C(OC)=O)[CH:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1.[I-].[Li+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C@@H:9]([OH:17])[C@@H:8]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH2:7][C:6]=2[CH:26]=1
Reactant: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1ccc([C@H]2Cc3cc(Cl)ccc3NC(=O)[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro-3-hydroxy-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (16.4 g, 43.7 mmole) and lithium iodide (23.7 g, 174.6 mmole) in 290 ml of pyridine containing 1% water was refluxed under argon until complete conversion to product by TLC (ca. 1.5 hours). The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and extracted with 1N hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride. The solution was dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to afford 6.8 g of pure cis product.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>>[C:4]1([CH:3]=[CH:2][CH:1]=[CH:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: ClCC=Cc1ccccc1
Product: COC(=O)CC=CC=Cc1ccccc1
Yield: 65 %

Procedure:
The procedure described in Example 28 is repeated, except that 8.35 g (0.05 mol) of cinnamyl chloride and 5.4 g (0.0625 mol) of methyl acrylate are used. After a reaction time of 50 hours at 120° C., 6.10 g (0.0325 mol) of methyl 5-phenyl-2.4-pentadienecarboxylate are obtained, corresponding to a yield of 65% of theory; melting point 71° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][N:4]=1.[C:9]1(=[O:19])[NH:13][C:12](=[O:14])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.[K]>CN(C)C=O>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:13]2[C:9](=[O:19])[C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:14])=[N:4][CH:5]=1
Reactant: ClCc1ccncn1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccncn1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 4-(chloromethyl)pyrimidine (4.10 g, 31.9 mmol, prepared according to R. W. Carling et al., J. Med. Chem., (2004), Vol. 47, pp. 1807-1822) and potassium phthalimide (5.91 g, 31.89 mmol) in N,N-dimethylformamide (60 mL) was heated to 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature, and concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL), washed with water (50 mL) and brine (50 ml). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 40-50% ethyl acetate in hexanes to afford 2-(pyrimidin-4-ylmethyl)isoindoline-1,3-dione in 40% yield (3.0 g): 1HNMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.70 (br s, 1H), 7.93-7.86 (m, 2H), 7.79-7.75 (m, 2H), 7.30 (d, J=6.0 Hz, 1H), 4.99 (s, 2H): MS (ES+) m/z 240.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[NH:14][C:13]2=[O:26])=[C:4]([F:27])[CH:3]=1.[C:28](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:25])([F:24])[C:20]([F:23])([F:21])[F:22])[N:14]=[C:13]2[O:26][CH3:28])=[C:4]([F:27])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione with sodium bicarbonate and dimethyl sulphate in acetone there is obtained 1-(4-chloro-2-fluoro-5-isopropoxyphenyl)-2-methoxy -4-pentafluoroethyl-6(1H)-pyrimidinone, m.p. 79°-81° C.;
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][NH:27][C:28]=1[Sn](CCCC)(CCCC)CCCC>>[Cl:1][C:2]1[C:21]([C:28]2[NH:27][N:26]=[CH:25][C:24]=2[F:23])=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1[nH]ncc1F
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2[nH]ncc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 13.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 25.2) and 4-fluoro-5-(tributylstannyl)-1H-pyrazole to afford an off-white powder. HPLC (Condition 4) tR=5.69 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=415 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10](F)[CH:9]=1)([F:7])[F:6].O>CO>[CH3:1][O:2][C:10]1[CH:9]=[C:8]([C:5]([F:7])([F:6])[F:4])[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccc1C=O

Procedure:
A solution of sodium methoxide (25% wt in methanol, 50 ml) was added to a solution of (4-(1,1,1-trifluoromethyl)-2-fluoro-benzaldehyde (5.0 g) in methanol (50 ml) and the mixture heated under reflux for 2 h. Water (200 ml) was added and the mixture extracted with ethyl acetate. The organics were dried and evaporated under reduced pressure to give a residue that was purified by chromatography on silica eluting with isohexane/diethylether 3:1, yield 3.18 g.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([OH:12])[CH2:4][CH2:3]1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([OH:12])[CH2:4][CH:3]1[CH:13]=[O:14]
Reactant: COC(Cl)Cl
Reactant: OC1CCC(O)c2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=CC1CC(O)c2ccccc2C1O
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-tetralin (1.640 g, 0.010 mol) in dichloromethane (50 ml) was added titanium tetrachloride (5.69 g, 0.03 mol). Then 1,1-dichlorodimethyl ether (1.73 g, 0.015 mol) was added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally 5% hydrochloric acid (10 ml) was added under ice-cooling. The organic phase was separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue was crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure title compound in about 60% yield (1.080 g), m.p. 145° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.O1CCOCC1>CCOC(C)=O>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:22]([CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: NCC1CCOCC1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1

Procedure:
5-Nitro-isochromen-1-one (1.0 g, 0.0052 mol) and C-(tetrahydro-pyran-4-yl)-methylamine (0.72 g, 0.0063 mol) were stirred in 1,4-dioxane (3 mL, 0.04 mol) at 120° C. for 18 hours. The mixture was diluted with EtOAc (200 mL), washed with 1 N HCl (30 mL×2), brine (30 mL) and dried over Na2SO4. After the filtration the solvent was removed and the residue was purified via flash chromatography (40 g of silica gel, 40% EtOAc/Hexanes) to give a yellow oil. MS m/z (M+H) 289.1.
Reaction SMILES: [F:1][C:2]1[N:3]=[C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)[S:5][C:6]=1[N:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O>ClCCl>[C:11]([O:10][C:8](=[O:9])[NH:7][C:6]1[S:5][C:4]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([F:28])[CH:27]=2)=[N:3][C:2]=1[F:1])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1sc(-c2cncc(F)c2)nc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1sc(-c2cncc(F)c2)nc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
To a solution of di(tert-butyl) 4-fluoro-2-(5-fluoropyridin-3-yl)-1,3-thiazol-5-ylimidodicarbonate (320 mg, 0.77 mmol) in DCM (7 mL) was added trifluoroacetic acid (TFA) (0.7 mL). The solution was stirred at room temperature for 10 minutes, before quenched slowly with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (DCM). The combined organic layer was dried over Na2SO4, filtered and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to give product as a pale yellow solid (166 mg, 68%): mp 188-191° C.; 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.46 (d, J=2.7 Hz, 1H), 7.85 (ddd, J=9.1, 2.6, 1.7 Hz, 1H), 6.92 (br s, 1H), 1.55 (s, 9H); ESIMS m/z 312 (M-1).
Reaction SMILES: [CH2:1]([S:8]([C:11]1[N:15]=[CH:14][NH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].Cl>N1C=CC=CC=1>[CH2:1]([S:8]([C:11]1[N:15]=[CH:14][N:13]([C:19](=[O:20])[N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(Cc1ccccc1)c1nc[nH]n1
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)Cc2ccccc2)n1
Reaction time: 8 h

Procedure:
To a solution of 3-benzylsulfonyl-1,2,4-triazole, 4.8 g (0.022 m) in 25 ml dry pyridine, 3.3 g (0.024 m) diethylcarbamoyl chloride is added dropwise. Let it stir overnight and pour into ~100 ml cold dilute hydrochloric acid. The product is extracted with ethyl acetate. Dry the organic layer and evaporate to give the desired product. Recrystallize from toluene-hexane to give white crystals, 5.8 g (81%) m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:25]([C:42]([O-])=[O:43])[CH2:26][C:27](=[O:41])[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:27]2([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=3)=[O:29])[CH2:26][CH:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:42](=[O:43])[O:41]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Reactant: O=C(CC(Cc1ccccc1)C(=O)[O-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CON(C2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CC(Cc3ccccc3)C(=O)O2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
In 6 ml of dichloromethane were dissolved 286 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 540 mg of the Compound (73) obtained in Example 73. To the solution was added 325 mg of DCC dissolved in 2 ml of dichloromethane. The mixture was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate, and the crystals which separated out were filtered off. The filtrate was washed with water and dried (Na2SO4), followed by evaporating off the solvent. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 553 mg of the subject Compound (75) as a pale yellow oily product.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>O1CCCC1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:19]2[S:18][CH:17]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Brc1ccc(Br)c2nsnc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: C1CCOC1
Product: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1

Procedure:
An analogous process is described by Kim et al. in “Journal of Material Chemistry” (2008), Vol. 18, pages 5223-5229, in which 4,7-di-2-thienyl-2,1,3-benzothia-diazole (DTB) can be prepared by reacting 4,7-dibromo -2,1,3-benzothiadiazole and tri-n-butyl(thien-2-yl)stannane, in the presence of tetrahydrofuran, at 66° C., for 3 hours. Bis(triphenylphosphine)palladium-(II)chloride [PdCl2(PPh3)2] is used as catalyst. Also in this case, at the end of the reaction, the solvent is removed by evaporation at reduced pressure and the residue obtained is purified by elution on a silica gel chromatographic column using a mixture of methylene chloride/hexane (1/1 vol/vol) as eluent, obtaining 4,7-di-2-thienyl-2,1,3-benzothiadiazole (DTB) with a yield equal to 88%.
Reaction SMILES: [CH:1]([C:4]1[C:13]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:23])[CH:5]=1)([CH3:3])[CH3:2].O.[OH-].[Li+].CO>O>[CH:1]([C:4]1[C:13]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:23])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCc1nnc(-c2cc(C(=O)OC)c(C)cc2C(C)C)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCc1nnc(-c2cc(C(=O)O)c(C)cc2C(C)C)[nH]1
Reaction time: 3 h

Procedure:
To crude methyl 4-isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoate (compound 198.5, 0.12 mmol, 1.0 equiv) from the previous step in a 4-mL vial was added lithium hydroxide monohydrate (10.1 mg, 0.24 mmol, 2.0 equiv), methanol (0.9 mL) and water (0.3 mL). The resulting mixture was stiffed at room temperature for 3 hours followed by 50° C. for 3 hours and 40° C. for 17 hours. The solvents were removed in vacuo and the residue was diluted with water (7 mL) plus saturated NaHCO3 (1 mL) and the aqueous was washed with diethyl ether (2 mL). The organic was back extracted with a mix of water (2 mL) plus saturated NaHCO3 (0.5 mL). The combined aqueous was acidified to pH=3 with 1 M H3PO4 and extracted with dichlormethane (3×5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo to obtain the title compound as a white waxy solid (31.5 mg, 88% over 2 steps). m/z (ES+) 304 (M+H)+.
Reaction SMILES: [C:1]1([P:7]([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1C(O)=C[CH:17]=[C:16]([CH3:21])[CH:15]=1.C(O)C>>[C:1]1([P:7]([O:11][C:12]2[CH:14]=[CH:15][C:16]([CH3:21])=[CH:17][CH:13]=2)[O:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: CCOP(OCC)c1ccccc1
Solvent: CCO
Product: CCOP(Oc1ccc(C)cc1)c1ccccc1
Temperature: 130 °C
Yield: 90 %

Procedure:
18.8 g (0.6 mol) of diethyl phenylphosphonite and 64.9 g (0.6 mol) of p-cresol were mixed and heated at 300 to 500 mbar to 130° C. Ethanol distilled off via a small column. The temperature was increased to 165° C. stepwise, and the vacuum was simultaneously increased to 100 mbar. In total, 21 g (0.458 mol) of ethanol distilled off. The reaction mixture was then distilled. After a first fraction which contained the unreacted starting materials, 107 g were obtained having a boiling point of 118° to 120° C. at 0.1 mbar. At a 76% conversion rate, the yield was approximately 90% of theory.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].[N+:10]([CH:13]=[C:14](SC)[S:15]([CH3:17])=O)([O-:12])=[O:11]>CO>[N+:10]([CH:13]=[C:14]([S:15][CH3:17])[NH:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])([O-:12])=[O:11]
Reactant: CCOC(CN)OCC
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Solvent: CO
Product: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Yield: 49 %

Procedure:
A solution of aminoacetaldehyde diethylacetal (11g, 0.08 mol) and 1-nitro-2-methylthio-2-methylsulphinyl-ethylene (15g, 0.08 mol) in methanol (200 ml) was stirred for 21/2 hours at room temperature. The solvent was removed in vacuo leaving a yellow oily residue which after trituration with propan-2-ol gave 1-nitro-2-methylthio-2-(2,2-diethoxy-ethylamino)ethylene (9.8, 49%) m.p. 72-74°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]2[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2.[CH2:19]([O:26][C:27]1[C:32]([CH2:33]Cl)=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCOCC1>[CH2:19]([O:26][C:27]1[C:32]([CH2:33][N:9]2[CH2:8][CH2:7][C:6]3[C:11](=[C:2]([Cl:1])[C:3]([C:13]4[N:17]([CH3:18])[N:16]=[CH:15][CH:14]=4)=[CH:4][CH:5]=3)[C:10]2=[O:12])=[C:31]([CH3:35])[CH:30]=[C:29]([CH3:36])[N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Reactant: Cn1nccc1-c1ccc2c(c1Cl)C(=O)NCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCc3ccc(-c4ccnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Yield: 68.4 %

Procedure:
A solution of 8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66b, 48.0, 0.180 mmol), 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 71.7 mg, 0.274 mmol), and KHMDS (182 mg, 0.915 mmol) in 1,4-dioxane (5 mL) was heated at 80° C. overnight. To the reaction mixture was added H2O (10 mL), the solution was extracted with EtOAc (10 mL), the organic layer concentrated under vacuum, and the residue purified by prep chromatography to give 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (66c, 60 mg, 67%) as a colorless oil.