Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:27]([CH:28]([CH2:32]C)[CH2:29][CH2:30][CH3:31])[C:8]2[N:9]=[C:10]([N:13]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Cl.CCCCCCC.CCOC(C)=O>C1COCC1>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:27]([CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[C:8]2[N:9]=[C:10]([NH2:13])[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CCCC(CC)n1c(C(=O)N(C)C)cc2cnc(N=C(c3ccccc3)c3ccccc3)nc21
Agent: Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cnc(N)nc2n1C1CCCC1
Reaction time: 0.33 h
Yield: 76.9 %

Procedure:
To a solution of 2-(benzhydrylidene-amino)-7-(1-ethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (3.5 g, 8.0 mmol) in 26.7 mL THF was added aqueous 2M HCl (1.32 mL) and the mixture was stirred for 20 min. To this was added 60 mL heptane:EtOAc (4:1 v/v) and 60 mL aqueous 0.5N HCl and the layers were separated. The acidic aqueous layer was basified to pH 10 with aqueous 25% NaOH solution and extracted again with EtOAc. The organic extract was then washed with brine, dried (Na2SO4), concentrated and purified via SiO2 column chromatography (0-20% MeOH in EtOAc) to give 2-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a white solid (1.68 g, 6.15 mmol, 77% yield). MS m/z 274.4 (M+H)+.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][S:20]([OH:23])(=[O:22])=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.S(Cl)(Cl)=O.C([N:31](CC)[CH:32]([CH3:34])[CH3:33])(C)C.C1(N)CC1>ClCCl.CN(C)C=O.O>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][S:20]([NH:31][CH:32]3[CH2:34][CH2:33]3)(=[O:22])=[O:23])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: CCN(C(C)C)C(C)C
Reactant: O=S(=O)(O)C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: NC1CC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1)NC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methanesulfonic acid (17.8 mg, 0.0530 mmol) in dichloromethane (1.5 mL) and N,N-dimethylformamide (1.8 mL) was stirred with thionyl chloride (0.00770 mL, 0.106 mmol) at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane (1.0 mL) and mixed with N,N-diisopropylethylamine (0.0923 mL, 0.530 mmol) and cyclopropylamine (0.0148 mL, 0.212 mmol) under cooling with ice and then stirred at room temperature for 1 day. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl hexane/acetate=4/1→1/1→1/3 (v/v)) to give the title compound as a brown solid (1.50 mg, yield 7.5%).
Reaction SMILES: C([O:3][C:4](=[O:29])/[C:5](=[N:25]\[O:26][CH2:27][CH3:28])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH2:27]([O:26]/[N:25]=[C:5](/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)\[C:4]([OH:29])=[O:3])[CH3:28]
Reactant: CCO/N=C(\C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C
Yield: 50.8 %

Procedure:
As in Example 306, a solution of (E)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0.131 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 45 minutes. After the usual work up, the isolated product was crystallized from ethyl acetate-hexane to afford 0.062 g of (E)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 17°-108° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: CCCCCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid (4.75 g) and 4-nitrophenol (2,5 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.1 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, 4.85 g of (E,E)-5-(4-methoxyphenyl)-2,4-tridecadienoic acid 4-nitrophenyl ester was obtained as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(C(C)=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
28.87 g (187.5 mM) of 2-nitro-4-hydroxyaniline in 600 ml of methyl ethyl ketone (MEK) are treated with 77.6 g of potassium carbonate and 22.3 ml (187.5 mM) of benzyl bromide. The reaction mixture is heated at reflux for3 h and is then evaporated to dryness. The evaporation residue is triturated in hexane, is filtered and dried under vacuum. There are thus isolated 40 g (88.9%) of the expected derivative, of melting point 106° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9](Cl)=[O:10]>ClCCl>[Cl:7][CH2:8][C:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:10]
Reactant: O=C(Cl)CCl
Reactant: C1CCNCC1
Solvent: ClCCl
Product: O=C(CCl)N1CCCCC1
Temperature: 0 °C

Procedure:
To a solution of piperidine (0.084 mL, 0.86 mmol, d=0.862) stirring in dichloromethane (4 mL) at 0° C., was added chloro acetylchloride (0.034 mL, 0.43 mmol, d=1.419). After stirring at 0° C. for a hour, the reaction mixture was diluted with dichloromethane (25 mL), washed with dilute citric acid, water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to obtain 2-chloro-1-(piperidin-1-yl)ethanone.
Reaction SMILES: [C:1]([N:4]([CH2:71][C:72](=[O:95])[NH:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][CH2:86][NH:87]C(=O)OC(C)(C)C)[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[NH:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:70])[CH2:41][CH2:42][CH:43]([NH:47][C:48](=[O:69])[C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C:57]2[N:58]=[C:59]3[C:64](=[N:65][CH:66]=2)[N:63]=[C:62]([NH2:67])[NH:61][C:60]3=[O:68])=[CH:51][CH:50]=1)[C:44]([OH:46])=[O:45])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([N:4]([CH2:71][C:72](=[O:95])[NH:73][CH2:74][CH2:75][CH2:76][O:77][CH2:78][CH2:79][O:80][CH2:81][CH2:82][O:83][CH2:84][CH2:85][CH2:86][NH2:87])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:22](=[O:23])[C:21](=[O:24])[C:20]=1[NH:25][CH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][NH:39][C:40](=[O:70])[CH2:41][CH2:42][CH:43]([NH:47][C:48](=[O:69])[C:49]1[CH:54]=[CH:53][C:52]([NH:55][CH2:56][C:57]2[N:58]=[C:59]3[C:64](=[N:65][CH:66]=2)[N:63]=[C:62]([NH2:67])[NH:61][C:60]3=[O:68])=[CH:51][CH:50]=1)[C:44]([OH:46])=[O:45])(=[O:3])[CH3:2]
Reactant: CC(=O)N(CCCOCCOCCOCCCNc1c(NCCCOCCOCCOCCCNC(=O)CCC(NC(=O)c2ccc(NCc3cnc4nc(N)[nH]c(=O)c4n3)cc2)C(=O)O)c(=O)c1=O)CC(=O)NCCCOCCOCCOCCCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CCCOCCOCCOCCCNc1c(NCCCOCCOCCOCCCNC(=O)CCC(NC(=O)c2ccc(NCc3cnc4nc(N)[nH]c(=O)c4n3)cc2)C(=O)O)c(=O)c1=O)CC(=O)NCCCOCCOCCOCCCN

Procedure:
0.2 g of 1-({2-[(14-acetyl-34,34-dimethyl-16,32-dioxo-4,7,10,21,24,27,33-heptaoxa-14,17,31-triazapentatriacont-1-yl)amino]-3,4-dioxo-1-cyclobuten-1-yl}amino)-18-[(4-{[(2-amino-4-oxo-3,4-dihydro-6-pteridinyl)methyl]amino}benzoyl)amino]-15-oxo-4,7,10-trioxa-14-azanonadecan-19-oic acid is dissolved in 2 ml of trifluoroacetic acid at ambient temperature.
Reaction SMILES: S=C1[N:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18](=[O:20])[CH3:19])=[C:13]([O:21][CH3:22])[CH:12]=2)=[O:8])[CH2:5][CH2:4]S1.C(N)[C:24]1[CH:29]=[CH:28]C=[CH:26][CH:25]=1>C1COCC1.C(OCC)C>[C:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:7](=[O:8])[NH:6][CH2:5][C:4]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[CH:12][C:13]=1[O:21][CH3:22])(=[O:20])[CH3:19]
Reactant: COc1cc(COC(=O)N2CCSC2=S)ccc1OC(C)=O
Reactant: NCc1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(COC(=O)NCc2ccccc2)ccc1OC(C)=O
Reaction time: 8 h
Yield: 7 %

Procedure:
Compound VII (339 mg, 0.993 mmol) was dissolved in anhydrous THF (5 mL). To the stirred, yellow solution was added at room temperature a solution of benzylamine (160 mg, 163 pt, 1.5×0.993 mmol) in anhydrous THF (5 mL), After being stirred overnight, the reaction solution was diluted with diethyl ether and extracted with 1N HCl, water and saturated NaCl. The organic phase was dried over anhydrous MgSO4, filtered and concentrated. Purification by column chromatography on silica gel eluting with hexanes/ethyl acetate (7:3-1:1, v/v) afforded 23 mg (7%) of 8 as a clear oil: Rf=0.30 (hexanes/ethyl acetate, 1:1, v/v); 1HNMR (CDCl3) δ 7.34-7.25 (m, 5H), 6.99 (d, 3J=8.0 Hz, 1H), 6.96 (s, 1H), 6.92 (d, 3J=8.1 Hz, 1H), 5.09 (s, 2H), 5.04 (bs, 1H, NH), 4.38 (d, 3J=6 Hz, 2H), 3.81 (s, 3H) and 2.29 (s, 3H). While the synthesis proceeded in excellent yield, product isolation was compromised by decomposition during work-up.
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].[Cl:8][C:9]1[N:18]=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:8][C:9]1[N:18]=[C:17]([C:3]2[S:2][CH:6]=[CH:5][N:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: [Zn+]c1nccs1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1nc(-c2nccs2)c2ccccc2n1
Temperature: 110 °C

Procedure:
To a 0.5 M solution of 2-thiazolyl zinc bromide in THF (12.1 mL, 6.03 mmol, 1.2 equiv; commercially available from Aldrich) under Ar was added 2,4-dichloro-quinazoline (1.0 g, 5.02 mmol, 1.0 equiv) and tetrakis(triphenylphosphine) palladium(0) (232.2 mg, 0.20 mmol, 0.04 equiv) and the reaction mixture heated by microwave irradiation to 110° C. After 30 min additional 2-thiazolyl zinc bromide in THF (12.1 mL, 6.03 mmol, 1.2 equiv) was added and the reaction mixture heated to 110° C. for another 30 min. The crude reaction mixture was concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.36 g (29%) of the title compound. MS (ISP): 248.3 [M+H]+.
Reaction SMILES: [CH2:1]([S:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].O[N:33]1[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.C(N(CC)CC)C>[N:33]1([O:28][C:27](=[O:29])[C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH2:7][CH2:6][CH:5]([S:4][CH2:1][CH2:2][CH3:3])[CH2:10][CH2:9]5)=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:31][CH:30]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=[N:34]1
Reactant: On1nnc2ccccc21
Reactant: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCSC1CCN(c2ccc(N3CCN(c4ccc(C(=O)On5nnc6ccccc65)cc4)CC3)cc2)CC1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
To a solution of 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid (0.98 g), 1-hydroxybenzotriazole (0.39 g) in dichloromethane (20 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.85 g), and the mixture was stirred for 15 minutes. To the solution was added triethylamine (0.31 ml), and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into a mixture of 0.1N-hydrochloric acid (25 ml) and dichloromethane (60 ml). The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the resulting precipitates were washed with water and IPE (50 ml), collected by filtration and dried under reduced pressure to give 4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl)piperazin-4-yl]benzoic acid benzotriazol-1-yl ester (1.04 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:29])[CH3:28].[C:32]([O:35][CH2:36][C:37](Cl)=[O:38])(=[O:34])[CH3:33].C(#N)C>C(OCC)(=O)C>[C:32]([O:35][CH2:36][C:37]([NH:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[CH:9]=2)[O:4][C:3]=1[C:26](=[O:31])[C:27]([OH:30])([CH3:28])[CH3:29])=[O:38])(=[O:34])[CH3:33]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CC(C)(O)C(=O)c1oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc2c1N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)Nc1c(C(=O)C(C)(C)O)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
The product of Step B (0.120 g; 0.253 mmol) and acetoxyacetyl chloride (0.11 mL; 1.01 mmol) were added to 2 mL of acetonitrile and stirred at room temperature. After 50 minutes the reaction mixture was diluted with ethyl acetate and washed two times with aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate then concentrated. The residue was triturated in 10 mL of methanol. The solid product was collected and rinsed two times with methanol then dried in vacuo. HPLC/MS 576.8 (M+2); Rt=4.32 min.
Reaction SMILES: [C:1]([CH:4]([O:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9](=O)[CH:8]=1)[CH3:5])([OH:3])=[O:2].[NH:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27](=[O:30])(=[O:29])[NH2:28])=[CH:23][N:22]=1)[NH2:20]>Cl.C(O)(=O)C>[S:27]([C:24]1[CH:25]=[CH:26][C:21]([N:19]=[N:20][C:9]2[CH:8]=[C:7]([O:6][CH:4]([C:1]([OH:3])=[O:2])[CH3:5])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]=2[OH:17])=[N:22][CH:23]=1)(=[O:29])(=[O:30])[NH2:28]
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Reactant: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Agent: Cl
Solvent: CC(=O)O
Product: CC(Oc1cc(N=Nc2ccc(S(N)(=O)=O)cn2)c(O)c2ccccc12)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(1-Carboxyethoxy)-1,2-naphthoquinone (0.26 g, 1.06×10-3 mole) and 2-hydrazino-5-sulfamoylpyridine (0.2 g, 1.06×10-3 mole) were added to acetic acid (5 ml), along with 2 to 3 drops of concentrated hydrochloric acid. After stirring for 3 hours, at room temperature, the mixture was filtered to remove traces of solid. The filtrate was poured into distilled water (30 ml) and filtered again. The precipitate was washed with water and air dried; yield 0.26 g (59 percent).
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][CH:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.S([O-])([O-])(=O)=O.[Mg+2].[C:17]([NH2:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:9]([O:8][C:6]([CH:4]1[CH2:5][CH:3]1[CH2:1][NH:36][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C1CC1C=O
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: CO
Product: CCOC(=O)C1CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 72 h

Procedure:
To a mixture of ethyl 2-formylcyclopropane-1-carboxylate (1.00 g; 7.03 mmol) and magnesium sulfate (0.85 g; 7.03 mmol) in 50 ml methanol is added tritylamine (1.82 g; 7.03 mmol). To this is then added sodium cyanoborohydride (0.88 g; 14.06 mmol) and stirred for 48 hrs. To this is then further added 0.20 g of ethyl 2-formylcyclopropane-1-carboxylate and stirring continued for another 72 hrs. The reaction mixture is filtered, concentrated in vacuo and flash chromatographed using hexane:ethylacetate; 9:1 to obtain ethyl-2-triphenylmethylaminomethyl-cyclopropane-1-carboxylate as a colorless oil which is used directly in the next step.
Reaction SMILES: [CH3:1][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]([CH3:1])=[CH:6][S:5][C:4]=2[CH:7]=1)=[O:17])[CH3:10]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: Cc1csc(C=O)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2scc(C)c2[nH]1

Procedure:
4-Methyl-thiophene-2-carbaldehyde (Detty, M. R.; Hays, D. S., Heterocycles, 40: 925-37 (1995)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.1 M of ester); reaction poured into cold saturated aqueous NH4Cl; after ether extractions, acrylate organic phase washed with water until aqueous phase was neutral; acrylate not purified).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])=[CH:21][C:20]=1[CH3:46])(=[O:18])=[O:17])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>C(Cl)Cl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[NH2:8][CH2:9][C@H:10]([NH:15][S:16]([C:19]1[C:24]([CH3:25])=[CH:23][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](=[O:45])[NH:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[O:36])=[CH:21][C:20]=1[CH3:46])(=[O:17])=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CN)NS(=O)(=O)c1c(C)cc(OCCCC(=O)NCCNC(=O)OCc2ccccc2)cc1C

Procedure:
Compound 22 was dissolved in CH2Cl2:Trifluoroacetic acid and stirred at room temperature for 30 min under nitrogen, after which it was concentrated, evaporated 6×CH2Cl2, and dried under high vacuum to afford 23 (pale yellow oil, 3.14 g). This was used as is in Step 17.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11](=O)[C:10]2[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:16]([I:18])[O:17][C:9]1=2)C1C=CC=CC=1.C(Cl)(Cl)[Cl:26].C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:26][C:11]1[CH:12]=[CH:13][N:8]=[C:9]2[O:17][C:16]([I:18])=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:10]=12
Reactant: O=c1ccn(Cc2ccccc2)c2oc(I)c(-c3ccccc3)c12
Reactant: ClC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Clc1ccnc2oc(I)c(-c3ccccc3)c12

Procedure:
A 100-ml round bottomed flask equipped with a reflux condenser fitted with a nitrogen inlet adapter was charged with 7-benzyl-2-iodo-3-phenylfuro[2,3-b]pyridin-4(7H)-one 4f (3.08 g, 3.46 mmol) and chloroform (35 mL). Oxalyl chloride (1.76 g, 1.21 mL, 13.84 mmol) and N,N-dimethylformamide (0.20 mL) were added, and the reaction was heated at reflux for 18 h. The reaction mixture was concentrated, and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black oil. Purification via column chromatography on silica gel (gradient elution with 0-25% ethyl acetate-hexane) afforded 4-chloro-2-iodo-3-phenylfuro[2,3-b]pyridine 6d as a brown oil. MS (MH+) 356.0; Calculated 355 for C13H7ClINO.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:19]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)C.[IH:35]>C(OCC)C>[IH:35].[F:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:19]2[C:18]3[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=3[N:16]=[C:15]2[N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: I
Solvent: CCOCC
Solvent: CCO
Product: Fc1ccc(Cn2c(N3CCCNCC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.12 g, 2.64 mmol) and ethanol (15 mL). Add aqueous hydriodic acid (5 mL, 57%). Heat to reflux. After 1 hour, cool to ambient temperature and dilute with diethyl ether (250 mL) and stir to give a solid. Collect the solid by filtration, rinse with diethyl ether, and dry to give the title compound: Rf =0.16 (silica gel, 10% methanol/dichloromethane/0.01% concentrated aqueous ammonia.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>CC#N>[CH:25]1([NH:30][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCC1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NC3CCCC3)n2)cc1
Yield: 41.6 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.50 g, 1.31 mmol) in MeCN (10 ml) was added cyclopentylamine (0.34 g) and the resultant solution heated under reflux for 18 h. The cooled reaction mixture was concentrated in vacuo and the residue partitioned between 2N HCl and ethyl acetate. The organic phase was separated, washed with 2N HCl then water and concentrated in vacuo to a yellow oil. This oil was purified by SPE chromatography with cyclohexane:ethyl acetate (3:1) as eluant. Concentration in vacuo of the combined fractions containing pure product gave crystals which were isolated by filtration to give the title compound as a white crystalline solid (0.21 g, 53%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[CH3:19][S:20]([O:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1cccc(OCc2ccccc2)c1
Product: CS(=O)(=O)OCCCc1cccc(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 85, 3-(3-benzyloxyphenyl)propanol was allowed to react with methanesulfonyl chloride to give 3-(3-benzyloxyphenyl)propyl methanesulfonate. The yield was quantative. Oily substance.