Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:23]C)=[C:5]([O:25][CH3:26])[C:4]=1[O:27][CH3:28].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(=O)(O)[O-].[Na+].O>[CH3:28][O:27][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][CH2:13][C:7]=2[C:6](=[O:23])[C:5]=1[O:25][CH3:26]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1cccnc1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3cccnc3)CC2)C1=O
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a mixture of 3-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]pyridine (470 mg), pyridine-2,6-dicarboxylic acid (607 g), THF (10 ml), and water (5 ml) was added an water (5 ml) solution of CAN (2.65 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (310 mg).
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:18])[CH2:12][N:13]1[N:17]=[N:16][CH:15]=[N:14]1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.ClC1C=CC=CC=1[C@@H](O)CN1N=NC=N1>C(OCC)(=O)C.C(OCCCC)(=O)C.CC(O)C.OCC(CO)O>[Cl:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:18])[CH2:12][N:13]1[N:17]=[N:16][CH:15]=[N:14]1
Reactant: O=C(Cn1ncnn1)c1ccccc1Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O[C@@H](Cn1ncnn1)c1ccccc1Cl
Agent: [Cl-]
Solvent: CC(C)O
Solvent: OCC(O)CO
Solvent: CCCCOC(C)=O
Product: OC(Cn1ncnn1)c1ccccc1Cl
Temperature: 25 °C
Yield: 99.6 %

Procedure:
50 ml of the enzyme solution 2 containing the oxidoreductase SEQ NO: 2 were added to a mixture of 250 ml of a buffer (100 mM TEA, pH 8, 1 mM MgCl2, 10% glycerol), 50 g (225 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (2N ketone), 4 mg NAD, 300 ml of 2-propanol and 150 mL of butyl acetate. The reaction mixture was stirred at room temperature. After 48 hours more than 98% of 2N ketone was reduced to corresponding (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol) with >99% ee values. To this resulting mixture, 500 mL of ethyl acetate was added. After being separated, the organic layer thus formed was washed with 10% brine (3×500 mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 50.4 g (224 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (R-2N alcohol, optical purity 99.9%) as an oily residue. To this resulting crude product, 450 mL of tetrahydrofuran was added. After cooling to −15° C., 38 g (267 mmol) of chlorosulfonyl isocyanate was slowly added and stirred at −10° C. for 2 h. The slow addition of water induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 300 mL of the solvent was removed. The concentrate was diluted with 600 mL of ethyl acetate and washed with 10% brine (3×500 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (90 mL) to which heptane (180 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 51.8 g (194 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (optical purity 99.9%).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH:9]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]([O:6]CC)=[O:5].[OH-].[K+].CCCCCC.CC(O)C>C(O)C.O>[ClH:1].[NH2:2][CH:3]([CH:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[S:16][C:17]2[C:22]1=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(N)C1c2ccccc2Sc2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: NC(C(=O)O)C1c2ccccc2Sc2ccccc21
Yield: 18.5 %

Procedure:
Ethyl α-amino-9H-thioxanthene-9-acetate hydrochloride (3.5 g, 10 mmol) is dissolved in 30 mL of absolute ethanol and 33 mL of 1.25 M ethanolic potassium hydroxide solution (4 equivalents) is added. The reaction mixture is stirred at room temperature for 22 hours when TLC (SiO2, hexane:2-propanol/3:1) shows no starting material. Ethanol is stripped under vacuum and the residue taken up in 75 mL of water and extracted with diethyl ether. The aqueous solution is acidified with 1N hydrochloric acid to pH 7 and a precipitate is collected by filtration, washed with water, dried at 45° C./2 mm Hg over phosphorous pentoxide (P2O5). This gives 1.65 g of the title compound; mp 244°-246° C. The mother liquor is concentrated, cooled at +3° C. to furnish the second crop (0.57 g) of the title compound as a hydrochloride free base mixture. The above solids are combined in 50 mL of water and treated with 1N hydrochloric acid to pH 1. The mixture is stripped to dryness under vacuum and the residue dried at 50° C./2 mm Hg to give the title compound; mp 269°-273° C. (dec).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromo-4-methylpyridine
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])CCC.Cl>CN(C=O)C.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:20]1[S:21][CH:22]=[CH:23][C:24]=1[P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1ccsc1I
Agent: Cl[Cu]
Agent: Cl
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1ccsc1-c1sccc1P(=O)(OCC)OCC
Temperature: 80 °C
Reaction time: 10 h
Yield: 71 %

Procedure:
At room temperature, 0.6790 g (1.96 mmols) of the 3-(diethoxyphosphoryl)-2-iodothiophene obtained in Example 12(1) and 0.9982 g (1.96 mmols) of the 2-(tributylstannyl)-3-(diethoxyphosphoryl)thiophene obtained in Example 12(2) were dissolved in DMF, to which 0.2326 g (2.35 mmols) of commercially available copper(I) chloride was added at room temperature. Thereafter, the reaction mixture was heated to 80° C. and stirred for 10 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a 10% hydrochloric acid aqueous solution, followed by extraction of the resulting product with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a silica gel column (gradiated from ethyl acetate:hexane=1:1 with acetone) to obtain the specified substance in the form of white crystals at a yield of 0.6101 g (yield: 71%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:9][O:10][C:11](=[O:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][C:15]=1[CH3:22].Cl[CH2:25][C:26]1[CH:31]=[N:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:28][N:27]=1>CS(C)=O.CCOCC>[CH3:9][O:10][C:11](=[O:23])[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[CH2:25][C:26]2[CH:31]=[N:30][C:29]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][N:27]=2)=[CH:16][C:15]=1[CH3:22]
Reactant: CNc1ccc(OCC(=O)OC)c(C)c1
Reactant: FC(F)(F)c1ccc(-c2cnc(CCl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)COc1ccc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)cn2)cc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 235.7 %

Procedure:
A suspension of 53 mg (0.39 mmol) potasium carbonate and 52 mg (0.35 mmol) sodium iodide and 73 mg (0.35 mmol) (2-methyl-4-methylamino-phenoxy)-acetic acid methyl-ester (example 5F) in 2 ml of DMSO was treated with 32 mg (0.12 mmol) of 2-chloromethyl-5-(4-trifluoromethyl-phenyl)-pyrazine (example 33E]). After 1.5 h at RT, the second portion of 32 mg (0.12 mmol) of 2-chloromethyl-5-(4-trifluoromethyl-phenyl)-pyrazine was added. The third part was added after 2 h. The reaction mixture was stirred for total 19 h at RT. It was then taken up in ether and washed with aqueous 10% KHSO4-solution and water. The organic phase was washed with NaCl (10%), dried (Na2SO4) and evaporated. Purification by flash chromatography (SiO2, heptane/AcOEt=9/1) gave 126 mg of pure (2-methyl-4-{methyl-[5-(4-trifluoromethyl-phenyl)-pyrazin-2-ylmethyl]-amino}-phenoxy)-acetic acid methyl ester.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.C(NC(N)=[S:26])(=O)C.C(OCC)(=O)C>C(O)C>[SH:26][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)NC(N)=S
Reactant: CC(=O)Nc1nc(CCc2ccc(CCBr)cc2)cs1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(CCS)cc2)cs1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a suspension of N-(4-{2-[4-(2-bromoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (353.3 mg, 1.000 mmol) in ethanol (4 ml) was added 1-acetyl-2-thiourea (177.4 mg, 1.501 mmol), and the mixture was heated under reflux for 7 hr. 1-Acetyl-2-thiourea (176.6 mg, 1.495 mmol) was added, and the mixture was heated under reflux for 17 hr. The mixture was cooled to room temperature, ethyl acetate (10 ml) was added, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and purified twice by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM-2035 21 g, ethyl acetate:hexane=2:3→1:1) to give N-(4-{2-[4-(2-sulfanylethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (210.4 mg, 0.687 mmol, 68.7%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].[N:22]1([C:27]2[CH:28]=[C:29]([C:33]3[O:38]C(C)(C)[O:36][C:35](=O)[CH:34]=3)[CH:30]=[CH:31][CH:32]=2)[CH:26]=[CH:25][N:24]=[CH:23]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:35](=[O:36])[CH2:34][C:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)[CH:28]=1)=[O:38])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Yield: 99.9 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (142 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (170 mg, 0.63 mmol) according to the general procedure K. Obtained as a light yellow foam (248 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]1[C@H:20]2[C@H:15]([CH2:16][CH2:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)[NH:14][CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:14]2[C@@H:15]3[C@@H:20]([C:19]4[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=4[CH2:17][CH2:16]3)[CH2:11][CH2:12][CH2:13]2)=[O:8])=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Nc1ccc(C(=O)N2CCC[C@@H]3c4ccccc4CC[C@@H]32)cc1
Yield: 66 %

Procedure:
The title compound is prepared from 4-amino-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 66% of theory; LC (method 4): tR=1.81 min; Mass spectrum (ESI+): m/z=307 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:21]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22]1>ClCCl.CO>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:30]3[CH2:31][CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:29]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Reactant: C1CNCC(CCN2CCCC2)C1
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)N2CCCC(CCN3CCCC3)C2)c2cc(Cl)ccc21
Yield: 42 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 3-[2-(1-pyrrolidinyl)ethyl]piperidine in a yield of 42% of theory. Colourless crystals, m.p. 136°-139° C., Rf 0.25 (Merck DC ready made TLC plates, silica gel 60 F254 ; eluant: dichloromethane/methanol/conc. ammonia 90/10/1, v/v/v).
Reaction SMILES: [CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=O)[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21]>C(O)C.N1C=CC=CC=1>[CH2:1]([N:8]1[C@H:17]2[C@@H:12]([CH2:13][CH2:14][C:15](=[N:20][OH:21])[CH2:16]2)[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C1CC[C@H]2CCCN(Cc3ccccc3)[C@@H]2C1
Yield: 88 %

Procedure:
To (±)-1-benzyl-trans-decahydro-7-quinolinone (D.11) (1.17 g), dissolved in ethanol (20 ml) and pyridine (0.8 ml), was added hydroxylamine hydrochloride (0.4 g), and the mixture was heated under reflux for 1 hr. On cooling, the ethanol was removed under reduced pressure and the residue was treated with dilute potassium carbonate solution. The product was extracted with chloroform and dried (K2CO3). Removal of the solvent afforded crude (±)-1-benzyl-trans-decahydro-7-quinolinone oxime (D.12) (1.1. g, ca 88%).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+](=[CH2:31])=[N-].CCOCC>CO>[CH3:31][NH:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[C:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[C:13]2[CH3:28])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: C=[N+]=[N-]
Reactant: COC(=O)CC1=C(C)C(=Cc2ccc(S(N)(=O)=O)cc2)c2ccc(OC)cc21
Solvent: CCOCC
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C=C2C(C)=C(CC(=O)OC)c3cc(OC)ccc32)cc1
Yield: 29 %

Procedure:
A solution of 4a (100 mg) in methanol (20 ml) was treated with excess diazomethane ether solution to give two products. They are separated via preparative tlc using 1500 μm silica gel plates developed 3 times with 5% ethyl acetate in chloroform to give Z methyl 1-(4-(N-methylaminosulfonyl)phenyl)methylene-5-methoxy-2-methyl-1H-3-indenylacetate (6a) (30 mg, 29% yield): m.p. 167°-169° C.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([S:15](Cl)(=[O:17])=[O:16])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[OH-].[NH4+:20]>>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([S:15](=[O:17])(=[O:16])[NH2:20])[C:8]([Cl:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(=O)N1CCc2ccc(Cl)c(S(=O)(=O)Cl)c2C1
Agent: [OH-]
Product: CC(=O)N1CCc2ccc(Cl)c(S(N)(=O)=O)c2C1

Procedure:
2-Acetyl-8-amino-7-chloro-1,2,3,4-tetrahydroisoquinoline (0.04 mole) in concentrated hydrochloric acid (8.4 ml.) is cooled to 3° C. and treated with sodium nitrite (0.044 mole) dissolved in water (6 ml.). After stirring for 30 minutes, the reaction is tested for nitrous acid with starch/iodide paper. If the test for nitrous acid is negative, more sodium nitrite is added in small portions with stirring over a period of time until the test is positive. When a positive reaction is obtained, magnesium chloride (0.032 mole) is added and the resulting mixture is added to a mixture of acetic acid (40 ml.) saturated with sulfur dioxide and cuprous chloride dihydrate (0.0129 mole) maintained at 30° C and stirred. After about 30 minutes, the mixture is diluted with water (60 ml.) and extracted with ether. The extract is then washed with dilute aqueous sodium bicarbonate/sodium carbonate solution at pH 8-9, then with water, and dried over sodium sulfate. The ether is evaporated to yield 2-acetyl-8-chlorosulfonyl- 7-chloro-1,2,3,4-tetrahydroisoquinoline. 2-Acetyl-8-chlorosulfonyl-7-chloro-1,2,3,4-tetrahydroisoquinoline (0.022 mole) is treated with concentrated ammonium hydroxide (30 ml.) with cooling. The resulting solid is filtered off and washed with water to give 2-acetyl-7-chloro-8-sulfamyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.CN.C[CH2:26][N:27](C(C)C)C(C)C>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:27][CH3:26])[C:5]2[C:10]([I:11])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(Cl)nc(Cl)nc32)cc1
Agent: CN
Solvent: CCCCO
Product: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
To a mixture of 2,4-dichloro-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (0.6 g, 1.28 mmol) in nBuOH (2 mL) was added methylamine (2M THF, 0.77 mL, 1.54 mmol) and DIPEA (0.274 mL, 1.54 mmol). After stirring at ambient temperature for 1 h, the resulting precipitate was collected by filtration to give 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.275 g).
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH:4]=[C:5]([CH3:9])[C:6]([OH:8])=[O:7].[H][H]>[Pt]=O.CO>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:3]=1[CH2:4][CH:5]([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CC(=Cc1ccc(F)cc1F)C(=O)O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CC(Cc1ccc(F)cc1F)C(=O)O
Reaction time: 0.5 h

Procedure:
In 800 ml. of methanol, 60 g. (0.3 mole) of 2,4-difluoro-α-methylcinnamic acid with 1.5 g. of platinum oxide catalyst is shaken under an initial pressure of 42 lbs. of hydrogen until one equivalent of hydrogen is absorbed. The reaction time is 30 minutes. The catalyst is removed by filtration and washed with methanol. The methanol, when evaporated off, leaves near colorless 2,4-difluoro-α-methyldihydrocinnamic acid as an oil which is used in the next step without further purification.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([C:24](O)=[O:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:24]([C:22]1[O:23][C:19]([C:16]3[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=3)=[CH:20][CH:21]=1)=[O:25])[CH2:4]2
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
Prepared by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and 5-(4-chlorophenyl)furoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 331, 333 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12]#[N:13].Br[CH:15](Br)[CH3:16].[OH-].[Na+].Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1([C:12]#[N:13])[CH2:16][CH2:15]1
Reactant: Cc1cc([N+](=O)[O-])ccc1CC#N
Reactant: CC(Br)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Product: Cc1cc([N+](=O)[O-])ccc1C1(C#N)CC1
Temperature: 70 °C

Procedure:
A mixture of (2-methyl-4-nitrophenyl)acetonitrile (100 mg), benzyltriethylammonium chloride (129 mg), dibromoethane (73.4 μL) and 50% sodium hydroxide solution was heated at 70° C. for 1 hour. After quenching the reaction by the addition of concentrated hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=2:1) of the residue gave 1-(2-Methyl-4-nitrophenyl)cyclopropane-1-carbonitrile (92.1 mg).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Na].[CH3:25][NH:26][NH2:27]>C(O)(=O)C>[O:22]=[C:13]1[C:14]2[C:15](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:17])[N:12]1[CH2:11][CH2:10][C:9]1[N:26]([CH3:25])[N:27]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1
Reactant: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CNN
Agent: [Na]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(CCN2C(=O)c3ccccc3C2=O)n(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A modification of the method described in Part A of Example 11 was followed. A mixture of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt (prepared as described in Part A of Example 23, 100 g, 295 mmol) in glacial acetic acid (0.3 L) was cooled to 9° C. before the addition of methylhydrazine (16.0 mL,300 mmol). During the addition, the reaction temperature did not exceed 16° C. Solids were rinsed from the inside of the flask walls into the mixture with acetic acid (50 mL) and the mixture was allowed to warm to ambient temperature and stir overnight. Water was added to the mixture and additional solid precipitated. The solid was isolated by filtration, dried, and recrystallized from ethanol. The solid was isolated and dried to yield 75.2 g of ethyl 5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carboxylate.