Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:26][C:27]1[CH:28]=[C:29]([S:36](Cl)(=[O:38])=[O:37])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([S:36]([N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=2)[C:9]2[S:13][N:12]=[CH:11][N:10]=2)(=[O:37])=[O:38])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1F
Reactant: COc1ccc(CNc2ncns2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A 250-mL round bottom flask was charged with N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (INTERMEDIATE H, 2.032 g, 9.18 mmol) and THF (30 mL). The flask was cooled to −78° C. and lithium bis(trimethylsilyl)amide (1M in THF) (10.02 mL, 10.02 mmol) was added dropwise, rapidly. The flask was placed in an ice/water bath for 10 minutes, and then returned to −78° C., at which time a solution of 3-fluoro-4-nitrobenzenesulfonyl chloride (Matrix Scientific, Columbia, S.C., 2.000 g, 8.35 mmol) in THF (5 mL with a 1 mL wash) was added dropwise. After 15 minutes, the reaction was complete, and was quenched with aqueous saturated ammonium chloride solution. The mixture was warmed to RT and extracted with EtOAc. The organics were combined and dried over sodium sulfate, filtered and concentrated. The solids were taken up in methanol, and after triturating, were filtered and washed with methanol to yield 3-fluoro-N-(4-methoxybenzyl)-4-nitro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide. (INTERMEDIATE I) (2.76 g, 6.50 mmol) as a light yellow solid. m/z (ESI) 446.7 (M+Na)+.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)=O.[Na].[CH2:13]([NH:16][OH:17])[CH2:14][CH3:15]>>[CH2:13]([N+:16]([O-:17])=[CH:1][C:3]1[O:7][C:6]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:5][CH:4]=1)[CH2:14][CH3:15]
Reactant: CCCNO
Reactant: O=Cc1ccc(S(=O)(=O)O)o1
Agent: [Na]
Product: CCC[N+]([O-])=Cc1ccc(S(=O)(=O)O)o1
Yield: 41 %

Procedure:
Following the procedure of Example 1 above and using 5-formylfuran-2-sulfonic acid, sodium salt hydrate and N-propylhydroxylamine, the title compound was prepared in 41% yield as the sodium salt, m.p. 230-233° C. (dec.).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]([CH:14]1[CH2:19][C:18]([CH2:21][CH:22]=[CH2:23])(O)[CH2:17][CH2:16][N:15]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13].[NH4+].[Cl-]>C(Cl)Cl>[CH3:10][O:11][C:12]([CH:14]1[CH2:19][C:18]([F:7])([CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16][N:15]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:13]
Reactant: C=CCC1(O)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a stirred solution of DAST (0.55 g, 3.4 mmol) in DCM (5 mL) at −78° C., 4-hydroxyproline 12b (P=Boc, m=1, R9=n-butyl) (520 mg, 1.7 mmol) in dry DCM (5 mL) was added slowly. The mixture was stirred at −78° C. for 1 h and then at −10° C. for an additional 1 h. DCM (50 mL) was added, followed by aq. NH4Cl (10%, 30 mL). The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The residue obtained was purified by column chromatography using 5% EtOAc in hexanes to obtain 4-fluoro-4-butylproline methyl ester 12c (P=Boc, m=1, R9=n-butyl) (270 mg, 52%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 4.41 (m, 2), 3.83 (m, 1), 3.71 (s, 3), 3.45 (dd, J=12.3, 32.7, 2), 2.48 (m, 1), 1.73 (m, 2), 1.40 (m, 12), 0.89 (m, 3); MS (ESPOS): 326 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10](/[CH:12]=[CH:13]/[C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:39][N:40]([CH:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:41](=[O:56])[CH:42]([NH:54][CH3:55])[CH2:43][C:44]1[CH:53]=[CH:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH:45]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10](/[CH:12]=[CH:13]/[C:14](=[O:16])[N:54]([CH3:55])[C@@H:42]([C:41](=[O:56])[N:40]([CH3:39])[C@@H:57]([C:65](=[O:68])[NH:66][CH3:67])[CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:43][C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH2:11]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)C(Cc1ccccc1)N(C)C(=O)C(Cc1ccc2ccccc2c1)NC
Reactant: CC(C)(C)OC(=O)N1CC(/C=C/C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.5 %

Procedure:
3-((E)-2-Carboxyvinyl)azetidine-1-carboxylic acid tert-butyl ester (0.28 g; 1.24 mmol) was dissolved in methylene chloride (3 mL). 1-Hydroxy-7-azabenzotriazole (0.17 g; 1.24 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.26 g; 1.36 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. N-Methyl-2-methylamino-N-(1-(methyl-carbamoyl)-2-phenylethyl)-3-(2-naphthyl)propionamide (0.50 g; 1.24 mmol) (prepared as in example 1) was dissolved in methylene chloride (3 mL) and added to the reaction mixture. Ethyldiisopropylamine (0.21 mL; 1.24 mmol) was added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (20 mL) was added and the reaction mixture was washed with water (10 mL), an aqueous solution of sodium hydrogen sulfate (10 mL; 10%), an aqueous solution of sodium hydrogen carbonate (10 mL; sat.) and water (10 mL). The organic phase was dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (2,5×20 cm) using 2.5%(7% ammonia in ethanol) in methylene chloride as eluent to afford 0.49 g of 3-((E)-2-(methyl((1R)-1-(methyl((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)vinyl)azetidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1.[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([OH:42])=[N:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:25]([N:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:34]([O:42][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=2)=[N:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: CCOc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture of 4-(4-chloromethyl-2-ethoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (2.33 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl 1-benzyl-3-[(3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (3.02 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:8]=2[CH:9]=1)=O.[C:16]([NH2:19])(=[S:18])[CH3:17]>C(O)C>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([C:3]3[N:19]=[C:16]([CH3:17])[S:18][CH:2]=3)=[CH:9][C:8]=2[CH:10]=1
Reactant: CC(N)=S
Reactant: COc1ccc2oc(C(=O)CBr)cc2c1
Solvent: CCO
Product: COc1ccc2oc(-c3csc(C)n3)cc2c1

Procedure:
A solution of 2-bromo-1-(5-methoxy-benzofuran-2-yl)-ethanone (0.6 g, 2.2 mmol) and thioacetamide (0.4 g, 5.1 mmol) in ethanol (15 mL) were refluxed for 1 hour. The reaction mixture was concentrated in vacuo and subjected to flash chromatography on silica gel (14% ethyl acetate:hexanes) to afford the title compound as a solid, (0.47 g; m.p. 136°-137° C.).
Reaction SMILES: O.[C@@H:2]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([NH2:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>CO>[CH3:22][N:23]([CH:25]=[N:15][C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:19]=2[N:18]=[CH:17][N:16]=1)[C@@H:2]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1)[CH3:24]
Reactant: Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: O
Product: CN(C)C=Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 50 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
To a stirred solution of 2′-deoxyadenosine monohydrate 54 (1.00 g; 3.71 mmol) in methanol (43 mL), N,N-dimethylformamide dimethyl acetal (2.48 mL; 18.6 mmol) was added. The reaction was stirred at 50° C. for 16 h. After evaporation, CH2Cl2-hexane (1:1) was added. The white solid formed was then filtered, collected and washed by hexane to afford 55 as white solid (1.13 g; 99% yield): 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H, CHN(CH3)2), 8.44 (s, 1H, 2-H), 8.43 (s, 1H, 8-H), 6.48 (dd, J=6.2, 7.8 Hz, 1H, 1′-H), 4.59 (m, 1H, 3′-H), 4.07 (m, 1H, 4′-H), 3.86 (dd, J=3.1, 12.2 Hz, 1H, one of 5′-H), 3.76 (dd, J=3.5, 12.2 Hz, 1H, one of 5′-H), 3.25 (s, 3H, one of NCH3), 3.24 (s, 3H, one of NCH3), 2.80-2.88 (ddd, J=5.9, 7.8, 13.5 Hz, 1H, one of 2′-H), 2.40-2.47 (ddd, J=2.8, 6.1, 13.4 Hz, 1H, one of 2′-H); 13C NMR (100 MHz, CD3OD) δ 161.0, 159.9, 152.8, 151.1, 142.8, 127.0, 89.7, 86.9, 72.9, 63.5, 41.5 (N(CHO 2) 35.3; HRMS (FAB+) calcd for C33H19O3N6 (M+H+): 307.1519. found: 307.1511.
Reaction SMILES: C([O:3][CH2:4][CH3:5])C.Cl[C:7](Cl)(Cl)[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=N.FC(F)(F)S(O)(=O)=O>C(OCC)(=O)C>[C:12]1([CH2:11][O:10][C:8]23[CH2:14][CH:13]([CH2:12][CH2:17][CH2:16]2)[CH2:5][C:4](=[O:3])[CH2:7]3)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCOCC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(OCc3ccccc3)(C1)C2
Temperature: 25 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
A diethyl ether solution of 260 mg of 2,2,2-trichloro-1-(phenylmethoxy)ethanimine synthesized in the production example 30 was added to 4 ml of a diethyl ether solution of the compound obtained in the production example 29 to prepare the homogeneous solution, and the flask was immersed in an ice water bath. The solution in the flask was mixed with 10 μl of trifluoromethanesulfonic acid, gradually heated up to room temperature, and simultaneously stirred for 17 hours. After the reaction was finished, the reaction solution was diluted with ethyl acetate and extracted. The obtained organic layers were integrated, sequentially washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, and then dried over Na2SO4. The solvent was distilled away under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (120 mg, 70%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:16].[Li]CCCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([F:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 23 c], 1-bromo-2-fluoro-4-(phenylmethoxy)-benzene was treated with n-BuLi and N,N-dimethylformamide in dry tetrahydrofuran to yield 4-benzyloxy-2-fluoro-benzaldehyde as off-white crystals.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:15]([NH2:17])=[O:16])[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[H][H].[C:22]([OH:25])(=[O:24])[CH3:23]>[Pd]>[C:22]([OH:25])(=[O:24])[CH3:23].[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: NC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
Palladium on activated carbon (moistened with about 50% water, 0.3 g/mmol) was added to a solution of 500 mg (1.88 mmol) of 5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide (Example 50A) in 60 ml of acetic acid, and the mixture was hydrogenated in a 60 bar hydrogen atmosphere at 85° C. overnight. The catalyst was then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates were concentrated under reduced pressure. This gave 0.61 g (98% of theory) of the target compound, which was reacted without any further purification steps.
Reaction SMILES: [OH-].[K+].[CH:3]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8](=[CH:18][C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH:27]([F:29])[F:28]>C(O)(C)C>[F:28][CH:27]([F:29])[O:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH:18]=[C:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][C:13]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]1=2
Reactant: Oc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: FC(F)Oc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 20 %

Procedure:
Add pellets of KOH (376 mg, 6.7 mmol) to a solution of 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenol (200 mg, 0.67 mmol) in isopropanol (10 mL). Bubble chlorodifluoromethane (Freon 22) slowly into the reaction mixture for 2 h. Concentrate the reaction mixture, and take the residue up in 1N HCl. Extract into ethyl acetate, dry organics (MgSO4), filter, and concentrate to a milky tan oil containing the title compound. Purify via silica gel chromatography (1:20 ethyl acetate:hexanes) to afford 108 mg (20%) of a white solid, mp 91.3° C. 1H NMR (CDCl3) δ 2.66-3.56 (br m, 4H), 6.12 (t, 1H, J=80 Hz), 6.55-7.43 (m, 13H); MS (EI) 348. HPLC shows 97% purity.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C@@H:6]2[CH2:9][OH:10].C(N(CC)CC)C.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:10][CH2:9][C@H:6]2[CH2:5][CH2:4][C@H:3]3[CH2:8][C@@H:7]2[C:2]3([CH3:11])[CH3:1])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)[C@H]2CC[C@H](CO)[C@@H]1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H]3C[C@@H]2C3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (7.0 mL, 44.2 mmol) and triethylamine (13.5 mL, 97.0 mmol) in dichloromethane (60 mL) was cooled to 0° C. A solution of 4-methylbenzene-1-sulfonyl chloride (10.9 g, 57.4 mmol) in dichloromethane (20 mL) was added drop wise at 0° C. The reaction was stirred at room temperature for 16 hours. The mixture was washed with saturated aqueous NaHCO3 and the aqueous layer was extracted twice with dichloromethane. The organic extracts were dried over sodium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.C1COCC1>CO>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NCc2cccnc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(S(=O)(=O)NCc2cccnc2)c1

Procedure:
Hydrogenation of a stirred solution of 3-nitro-N-pyridin-3-ylmethyl-benzenesulfonamide [CAS-No. 436095-43-1; commercially available] (1.42 g, 4.84 mmol) in methanol (90 ml) and THF (50 ml) on palladium/carbon (10%, 0.14 g) for 2 h at room temperature yielded after removal of the catalyst by filtration, evaporation and crystallization from ethyl acetate/hexane the title compound (1.15 g, 90%) as a light yellow solid. MS (ISP) 264.1 [(M+H)+]; mp 129° C.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][S:8][CH2:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:22]>ClCCCl>[Cl:22][C:4]1[C:5]2[CH2:9][S:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2c1CSC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2c1CSC2
Yield: 81.5 %

Procedure:
To a solution of the 5,7-dihydrothieno[3,4-d]pyrimidin-4-ol (0.50 g, 3.2 mmol) in DCE (50 mL) was added DIEA (0.42 g, 3.2 mmol) and POCl3 (1.5 g, 9.8 mmol). The mix was refluxed overnight. After cooling, the solvent was removed and the residue was subject to silica gel chromatography, eluting with hexane/ethyl acetate (4:1) to give 4-chloro-5,7-dihydrothieno[3,4-d]pyrimidine (0.45 g, 80%). 1H NMR (CDCl3, 400 MHz) δ 8.84 (s, 1H), 4.37 (s, 2H), 4.27 (s, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:37][CH2:36][C:11]2[N:12]([CH3:35])[C:13]3[CH:14]=[C:15]([N:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]5[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=5)=[CH:21][C:20]4=[O:34])[CH:16]=[CH:17][C:18]=3[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:38]>CO.CCOCC>[ClH:33].[ClH:38].[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:22]2[CH:23]=[CH:24][N:19]([C:15]3[CH:16]=[CH:17][C:18]4[C:10]5[CH2:9][NH:8][CH2:37][CH2:36][C:11]=5[N:12]([CH3:35])[C:13]=4[CH:14]=3)[C:20](=[O:34])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 71 %

Procedure:
tert-Butyl-7-(4-(4-chlorobenzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (143 mg, 0.275 mmol) was dissolved in MeOH (1 mL) and 2 N HCl in Et2O (5 mL) was added. The reaction was allowed to proceed for 3 h. The resulting precipitate was collected by filtration and washed with Et2O to provide the title compound (95 mg, 71%) as a yellow solid: mp 305-310° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.54 (br s, 2H), 7.57 (m, 2H), 7.51 (s, 5H), 6.99 (d, J=7.8 Hz, 1H), 6.12 (dd, J=7.8, 2.7 Hz, 1H), 5.99 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.33 (br s, 2H), 3.68 (s, 3H), 3.52-3.48 (m, 2H), 3.12-3.08 (m, 2H); ESI MS m/z 420 [M+H]+; HPLC (Method B) 97% (AUC), tR=13.99 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].[CH2:14]([C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[CH:18][CH:17]=1)[CH3:15]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([Cl:13])=[CH:10][C:11]=1[NH:22][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:14][CH3:15])[N:21]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: CCc1cccc(N)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(CC)n1
Temperature: 140 °C
Yield: 35.5 %

Procedure:
4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (500 mg, 2.26 mmol) and 6-ethylpyridin-2-amine 415 mg, 3.39 mmol) were dissolved in acetonitrile (7 mL), then heated at 140° C. for 3 d. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 50% ethyl acetate in hexanes) gave 6-chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (246 mg, 35%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.68 (br. s., 1H) 9.30 (s, 1H) 7.61 (t, J=7.8 Hz, 1H) 6.91 (d, J=7.3 Hz, 1H) 6.77 (d, J=7.8 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.86 (q, J=7.6 Hz, 2H) 1.52 (t, J=7.1 Hz, 3H) 1.38 (t, J=7.5 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H].
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27](O)[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19].C(Cl)Cl>>[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27]([Cl:3])[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19]
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1Br
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Yield: 75.8 %

Procedure:
Cyanuric chloride (0.11 g, 0.59 mmol) was dissolved in N,N-dimethylformamide (3 mL, 40 mmol). After stirring for a few minutes, a solution of 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile (150 mg, 0.49 mmol) in methylene chloride (3 mL, 50 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane. The organic layer was washed with sat. NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography, eluting a gradient of 0-30% EtOAc/Hexane to give 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (0.12 gm, 75%) as a semisolid, LCMS calculated for C11H10BrCl2NO m/z=323.9, 320.9; found: (poor ionization).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][O:6][C:7](=[O:17])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9]O.[Na]>O>[CH3:5][O:6][C:7](=[O:17])[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:9][N:3]([CH3:4])[CH3:2]
Reactant: COC(=O)C(=CO)c1ccccc1
Reactant: CNC
Agent: Cl
Agent: [Na]
Solvent: O
Product: COC(=O)C(=CN(C)C)c1ccccc1
Reaction time: 2 h
Yield: 72.2 %

Procedure:
97 weight-parts of dimethylamine hydrochloride are dissolved in 250 weight-parts of water, and 200 weight-parts of sodium 3-hydroxy-2-phenyl acrylic acid methyl ester are added. The mixture is stirred for 2 hours, and the organic phase is separated and distilled. 148 weight-parts of 3-dimethylamino-2-phenyl acrylic acid methyl ester are obtained, corresponding to a yield of 72.2% of the theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in DCM (5 mL) is added pyridine (0.066 mL, 0.815 mmol, 1.2 eq.). The resulting solution is cooled to 0° C. followed by the addition of acetoxy acetyl chloride (0.073 mL, 0.679 mmol, 1 eq.). After stirring at 0° C. for 15 min., the reaction is warmed to 25° C. and stirred for 12 h. The reaction is diluted with DCM and sequentially washed with 1 N HCl (aq) and saturated aqueous NaHCO3. The resulting organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:6 hexanes/EtOAc) to give Acetic acid (1-oxo-indan-5-ylcarbamoyl)-methyl ester as an off-white solid (136 mg, 81% yield). [MS: (ES+) 248.1 (M+1)+].