Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[Cl:31][C:32]1[C:37]([N+:38]([O-:40])=[O:39])=[C:36](Cl)[N:35]=[CH:34][N:33]=1>CC#N>[Cl:31][C:32]1[N:33]=[CH:34][N:35]=[C:36]([O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:4][CH:3]=2)[C:37]=1[N+:38]([O-:40])=[O:39]
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ncnc(Cl)c2[N+](=O)[O-])c2ccccc12
Yield: 34.2 %

Procedure:
To a stirred solution of tert-butyl (4-hydroxynaphthalen-1-yl)carbamate (20.0 g, 73.0 mmol) in MeCN (200 mL) under N2 was added DBU (13 mL, 87 mmol) and after 1 hr at RT the resulting mixture was treated dropwise with a solution of 4,6-dichloro-5-nitropyrimidine (15.5 g, 80.0 mmol) in MeCN (150 mL). After 2.5 hr at RT the mixture was evaporated in vacuo and the residue was triturated with DCM (150 mL) and isohexane (200 mL). The insoluble residue was separated and set aside and the triturant was evaporated in vacuo. The residue so obtained was partitioned between DCM (200 mL) and sat aq NaHCO3 (200 mL) and the organic layer was separated and evaporated in vacuo. The residue was triturated with EtOAc to give an off white solid (batch 1). The EtOAc triturant was concentrated in vacuo to ˜20 mL and the precipitate which formed was isolated by filtration and washed with EtOAc to afford a second batch of same material, also as an off white solid. The first and second batches of product were combined to afford tert-butyl (4-((6-chloro-5-nitropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (10.4 g, 34%); Rt 2.69 min (Method 2); m/z 439/441 (M+Na)+ (ES+).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:25])(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:27]([O:29][NH:30][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)[CH2:6][C:5]1=[O:25])[CH3:2])[CH3:28]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCONC(C)=C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O

Procedure:
0.4 Gram of 2-acetyl-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione and 0.1 g of ethoxyamine hydrochloride were dissolved in 10 ml of methanol and 0.15 g of potassium carbonate was added to the resulting solution which was then refluxed for 3 hours. The reaction solution was poured into water and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.3 g of 2-(1-ethoxyaminoethylidene)-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)CC>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:17][CH2:16][N:15]([CH2:14][C:11]3([CH3:10])[O:12][C:2]4=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]4[CH2:13]3)[CH2:20][CH2:19]2)=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Product: CC1(CN2CCN(c3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Yield: 30.2 %

Procedure:
To a solution of 2-chloro-4-nitro-1H-imidazole (1.59 g, 10.8 mmol) and 1-(2-methyloxiran-2-ylmethyl)-4-(4-trifluoromethylphenyl)piperazine (3.23 g, 10.8 mmol) in 1-propanol (20 ml), sodium hydrogencarbonate (1.95 g, 23.8 mmol) was added followed by stirring under reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was added water, and the solution was extracted with methylene chloride. The organic phase was dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-isopropyl ether to afford 2-[4-(4-trifluoromethylphenyl)piperazin-1-yl]methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole (1.34 g, yield 29%) as a a light yellow powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2cc(S(=O)(=O)Oc3c(C)cc(-c4c5ccccc5c(Br)c5sc(C)c(C)c45)cc3C)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 18 h
Yield: 73.3 %

Procedure:
At ambient temperature, to a stirred solution containing 4-[4-(9-bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.402 g, 0.602 mmol) and pyridine (0.292 mL, 3.61 mmol) in CH2Cl2 (6.02 mL) was added a solution of p-anisoyl chloride (0.208 g, 1.20 mmol) in CH2Cl2 (1.20 mL). After 18 h, the reaction was quenched with H2O (30 mL) and extracted with ether. The combined ethereal extracts were washed with sat. aq. NaHCO3 (3×), with sat. aq. CuSO4 (3×), with brine (3×), dried (MgSO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 15% acetone/hexane to give 0.354 g (73%) of the title compound. 1H NMR (DMSO-d6) δ 1.33 (s, 9 H), 1.54 (s, 3 H), 2.16 (s, 6 H), 2.34 (s, 3 H), 3.90 (s, 3 H), 7.13-7.19 (m, 4 H), 7.46-7.48 (m, 2 H), 7.60-7.70 (m, 1 H), 8.08-8.13 (m, 4 H), 8.20 (d, 2 H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[NH:14][CH:13]=[C:12]2[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>ClCCCl>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:23])=[N:14][CH:13]=[C:12]2[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cc(F)c2cc(SCc3ccccc3)ccc12
Solvent: ClCCCl
Product: Fc1cnc(Cl)c2ccc(SCc3ccccc3)cc12
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A vial was charged with 6-(benzylthio)-4-fluoroisoquinolin-1(2H)-one (0.083 g, 0.291 mmol) and DCE (1.454 ml). POCl3 (0.136 ml, 1.454 mmol) was added and the reaction was stirred overnight at 90° C. The reaction was quenched into ice water and extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford crude 6-(benzylthio)-1-chloro-4-fluoroisoquinoline as a light yellow solid. The material was carried forward without further purification. (ESI) 304.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[O:8][CH:7]([C:17]([F:20])([F:19])[F:18])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2.[CH3:26]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOCCOC>[CH2:13]([NH:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:7]([C:17]([F:20])([F:19])[F:18])[O:8]2)=[CH:3][C:2]=1[CH3:26])[CH:14]([CH3:16])[CH3:15]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(NCC(C)C)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C1=Cc2cc(C)c(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 115 °C
Yield: 25 %

Procedure:
A mixture of ethyl 6-chloro-7-(isobutylamino)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 608b, Step 1 (2.10 g, 5.57 mmole), trimethylboroxine (1.58 mL, 12.66 mmole), [(tBu3P)PdBr]2 (0.04 g), and Cs2CO3 (3.17 g, 9.74 mmole) in anhydrous diglyme (10.0 mL) was heated to 115° C. under a dry N2 atmosphere for 18 hrs. The contents were poured into water (40 ml) and extracted with EtOAc (2×40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil which was subject to flash chromatography (silica gel) and eluted with 0-15% EtOAc/hexanes to give yellow oil (0.5 g, 25%). No further purification was performed. GCMS m/z 357.0 (M+). LCMS m/z 358.0 (M+H).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][C:17]4[N:18]=[CH:19][C:20]([C:23](Cl)=[O:24])=[N:21][CH:22]=4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:26][NH2:27]>ClCCl>[CH3:26][NH:27][C:23]([C:20]1[CH:19]=[N:18][C:17]([O:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[CH:22][N:21]=1)=[O:24]
Reactant: CN
Reactant: O=C(Cl)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Solvent: ClCCl
Product: CNC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 123, step 1 (1.59 mmol) in dry dichloromethane (10 ml) was treated with methylamine (5 ml, 10 mmol, 2M solution in THF) and stirred at room temperature for 18 hours. The mixture was reduced in vacuo and the resulting crude material was applied to a SCX ion exchange cartridge (Varian bond-elute, 10 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The basic fractions were then reduced and the crude product purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (0.2:1.8:98 and then 0.4:3.6:96) to afford the title compound (E125). 1H NMR (CDCl3) δ 8.91 (1H, d, 1.3 Hz), 8.26 (1H, d, 1.3 Hz), 7.61 (1H, br quartet, 4.8 Hz), 7.15 (1H, m), 6.92 (2H, m), 3.03 (3H, d, 5.1 Hz), 2.93 (4H, m), 2.79 (1H, m), 2.47 (4H, m), 2.08 (2H, m), 1.91 (2H, m), 1.70-1.62 (2H, m).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[CH:5]=1.O.[NH2:13][NH2:14]>>[CH3:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([NH:13][NH2:14])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccnc(C)c1
Solvent: O
Product: Cc1cc(C(=O)NN)ccn1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
2-Methyl-isonicotinic acid methyl ester (316.5 mg, 2.093 mmol) was dissolved in MEOH (7 mL) under Argon and hydrazine monohydrate 98% (1 mL, 20.93 mmol) was added. The reaction was allowed to stir under Argon at room temperature for eighteen hours. The reaction was concentrated to give the title compound (271.9 mg, 86%) as a white solid. 1H NMR CDCl3 δ (ppm): 8.59 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 3.09 (br. s, 3H), 2.60 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.[CH2:9]([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])[CH3:10].[NH4+].[Cl-]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[NH:14][C:3]2[C:2]([Cl:1])=[CH:6][S:5][C:4]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: O=Cc1cc(Cl)cs1
Reactant: CCOC(=O)CN=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2scc(Cl)c2[nH]1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
4-chloro-thiophene-2-carbaldehyde (Iriarte, J.; Martinez, E.; Muchowski, J. M., J. Heterocycl. Chem., 13: 393-4 (1976)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.2 M of ester) such that reaction temperature maintained at 0° C.; reaction mixture allowed to warm to 10° C., stirred for 1.5 h, poured into cold saturated aqueous NH4Cl; after ether extractions, combined acrylate organic phases washed with water until aqueous phase was neutral; acrylate not purified).
Reaction SMILES: [Br-:1].[CH2:2]([N+:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CC(C)=O>[Br-:1].[CH2:2]([N+:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][O:17][C:26](=[O:28])[CH3:27])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC[N+](C)(C)CCO
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCC[N+](C)(C)CCOC(C)=O
Temperature: 60 °C

Procedure:
In a reaction vessel was placed 13.14 grams of dodecyl dimethyl 2-hydroxyethyl ammonium bromide, 21.22 grams of acetone solvent and 4.72 grams of sodium carbonate. While stirring under nitrogen, 3.27 grams of acetyl chloride was added dropwise. Gas evolution occurred. The mixture was then refluxed (approx. 60° C.) for 6 hours. The solvent was removed under vacuum. The residue was extracted with isopropanol to dissolve the quat and the solution was filtered hot to removed sodium chloride and sodium carbonate. The filtrate was evaporated under vacuum leaving as the product dodecyl dimethyl acetyloxyethyl ammonium bromide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16].C(N(CC)CC)C>O1CCCC1>[C:15]([NH:18][C:19]1[NH:20][CH:21]=[C:22]([C:27]2[CH:28]=[N:29][C:30]([NH:33][C:13]([NH:12][C:3]3[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=3[F:1])=[O:14])=[CH:31][CH:32]=2)[C:23]=1[C:24]([NH2:26])=[O:25])(=[O:17])[CH3:16]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: CC(=O)Nc1[nH]cc(-c2ccc(N)nc2)c1C(N)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1[nH]cc(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)nc2)c1C(N)=O
Reaction time: 18 h
Yield: 6.6 %

Procedure:
0.068 cm3 (0.466 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate is added at a temperature in the region of 23° C. and under an argon atmosphere to 0.11 g (0.424 mmol) of 2-acetylamino-4-(6-aminopyridin-3-yl)-1H-pyrrole-3-carboxamide in solution in 20 cm3 of tetrahydrofuran. After stirring for 1 hour at a temperature in the region of 20° C., 0.059 cm3 (0.424 mmol) of triethylamine is added to the medium. The reaction mixture is then stirred for 18 hours at this temperature and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography [eluent: dichloromethane/methanol (95/5 by volume) and pure ethyl acetate gradient]. After concentrating the fractions under reduced pressure, 0.013 g of 2-acetylamino-4-{6-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]pyridin-3-yl}-1H-pyrrole-3-carboxamide is obtained in the form of a white solid. ES+: m/z=466 (MH+).
Reaction SMILES: [K].[S:2]([CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)([OH:5])(=[O:4])=[O:3].[N-:13]=[N+:14]=[N-:15].[Na+].O>CC(C)=O>[S:2]([CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)([OH:5])(=[O:4])=[O:3]
Reactant: CSC(=S)NCCS(=O)(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [K]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)(O)CCn1nnnc1S

Procedure:
A mixture of 21.5 g. (0.087 mol.) of methyl 2-sulfoethyldithiocarbamate potassium salt (0.5 hydrate) and 7.16 g. (0.11 mol.) of sodium azide in 200 ml. of water was refluxed for two hours. The solution was cooled to 25° and extracted with ethyl acetate. The aqueous phase was treated with Amberlite IR-120H resin, washed with ether and evaporated to give an oil. The oil was dissolved in acetone, the solution was filtered and the filtrate was evaporated to dryness to give 1-(2-sulfoethyl)-tetrazole-5-thiol. The thiol was dissolved in isopropanol, cyclohexylamine was added until pH 8-9 and acetonitrile was added to give 1-(2-sulfoethyl)tetrazole-5-thiol as the di-cyclohexylamine salt.
Reaction SMILES: [CH2:1]([C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.Br[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:32][O:31][C:29](=[O:30])[CH2:28][CH2:27][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[CH2:13][O:12][C:11]1[CH:19]=[CH:20][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Cc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: COC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCN1CCC[C@H]1COc1ccc(Cc2ccccc2)cc1
Temperature: 60 °C
Yield: 14 %

Procedure:
(S)-2-(4-Benzyl-phenoxymethyl)-pyrrolidine (200 mg, 0.658 mmol) was taken into DMF (2 mL), and methyl 3-bromopropionate (121 mg, 0.724 mmol) was added, followed by potassium carbonate (182 mg, 1.317 mmol). The mixture was heated to 60° C. and left to react overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The compound was then purified by flash chromatography (eluted with 1% methanol in dichloromethane with a 30:1 silica ratio) to obtain the title product (32.6 mg, 0.092 mmol, 14% yield); LCMS; m/z 353.47, found 354.3 (M+1); 1H NMR (400 MHz, CDCL3) δ 3.92 (s, 1H), 1.59 (s, 2H), 1.76-1.78 (m, 1H), 1.93-2.00 (m, 1H), 2.28-2.30 (m, 1H), 2.52-2.55 (m, 2H), 2.67-2.74 (m, 1H), 2.84-2.91 (m, 1H), 3.11-3.15 (m, 1H), 3.20-3.27 (m, 1H), 3.66 (s, 3H), 3.73-3.77 (m, 1H), 3.91-3.92 (m, 2H), 6.81-6.84 (m, 2H), 7.07-7.09 (m, 2H), 7.16-7.29 (m, 5H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22]CC)=[O:21])=[CH:5][N:4]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.O>CS(C)=O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cnc(SC)nc1NCc1ccc(OC)c(Cl)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Temperature: 25 °C

Procedure:
2-Methylthio-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (prepared in Example 67-(1)) 2.00 g is suspended in dimethyl sulfoxide 10 ml, and the suspension is treated with a 10% aqueous sodium hydroxide solution 10 ml. The reaction mixture is still in suspension even 6 hours later. After addition of dimethyl sulfoxide 5 ml the mixture is stirred at room temperature over night. The resulting clear reaction solution is acidified with citric acid. The excess water (about 50 ml) is added thereto and resulting precipitate is filtered, washed with isopropylalcohol and then isopropyl ether, and concentrated in vacuo to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine as a pale yellow impalpable powder, 1.864 g.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.[CH:18]1[C:23]([C:24]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][C:33]([OH:35])=[CH:34][C:27]=3[O:26][CH:25]=2)=[CH:22][CH:21]=[C:20]([OH:36])[CH:19]=1.[OH-].[K+].CO>CC(C)=O>[OH:36][C:20]1[CH:21]=[CH:22][C:23]([C:24]2[C:29](=[O:30])[C:28]3[C:27](=[CH:34][C:33]([O:35][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][N:7]([C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[CH2:6][CH2:5]4)=[CH:32][CH:31]=3)[O:26][CH:25]=2)=[CH:18][CH:19]=1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: COc1ccc(N2CCN(CCCl)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COc1ccc(N2CCN(CCOc3ccc4c(=O)c(-c5ccc(O)cc5)coc4c3)CC2)cc1

Procedure:
To a solution of 1-[4-(2-chloroethyl)piperazinyl]-4-methoxybenzene (0.929 mmol) and 4,7-dihydroxyisoflavone (0,929 mmol) in acetone (10 ml)was added 11% potassium hydroxide (0.5 ml), and the mixture stirred at reflux temperature for 48 hours. Sufficient methanol was added to precipitate unreacted starting material, which was filtered off, and solvent was removed from the filtrate under reduced pressure. The residue was purified by biotage column chromatography, eluting with 5% methanol/methylene chloride, to provide pure 3-(4-hydroxyphenyl)-7-{2-[4-(4-methoxyphenyl)piperazinyl]ethoxy}chromen-4-one.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18](Br)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41]#[CH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:23](=[O:24])[CH:22]=[C:21]3[C:16]([CH:17]=[C:18]([C:42]#[C:41][CH2:40][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:19]=[CH:20]3)=[CH:15]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(Br)ccc3cc2=O)cc1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ccc3cc2=O)cc1
Temperature: 65 °C

Procedure:
A solution of 4-(7-bromo-3-oxo-2H-isoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (1.50 g, 3.62 mmol) in dimethylformamide (10 mL) is degassed with nitrogen, then treated with triethyl-amine (2.07 mL, 14.8 mmol), CuI (0.050 g, 0.26 mmol), Pd(Ph3P)4 (0.173 g, 0.15 mmol), and 3-phenyl-1-propyne (1.13 mL, 9.05 mmol). The reaction mixture is heated in an oil bath at 65° C. for 5 hours, cooled to room temperature, the DMF is evaporated, and the residue is dissolved in ethyl acetate. The solution is washed with 1N HCl, brine, dried over MgSO4 and evaporated onto silica gel. Purification on a 3.5×18 cm silica gel column eluted with hexane/ethyl acetate 4:1, followed by drying, will afford the desired product.