Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OS(OC)(=O)=O.C(=O)(O)[O-].[K+].[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36][S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:33]2=[O:58])=[C:29](\[OH:31])/[CH3:30])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[C:13]1([CH:19]([O:26][C:27](=[O:59])/[C:28](/[N:32]2[CH:35]([S:36][S:37]([C:40]3[CH:41]=[CH:42][C:43]([CH3:46])=[CH:44][CH:45]=3)(=[O:38])=[O:39])[CH:34]([NH:47][C:48](=[O:57])[CH2:49][O:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[C:33]2=[O:58])=[C:29](/[O:31][CH3:1])\[CH3:30])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CO/C(C)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(avi) 3.78 g (30 mmols) of dimethylsulphate and 30 ml of 20 percent strength aqueous potassium bicarbonate solution are added to a suspension of 6.72 g (10 mmols) of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) and 0.36 g (1 mmol) of tetera-n-butylammonium iodide in 100 ml of toluene and the mixture is stirred vigorously for 4 hours at room temperature. During the first 15 minutes, the solid dissolves. The mixture is diluted with toluene and washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulphate, and concentrating it, crystallisation from ethyl acetate/diethyl ether gives 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid diphenylmethyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:24]=[CH:23][N:22]=3)[CH:14]=2)=[O:11])=[CH:6][CH:5]=1)([O-])=O.[CH3:33][N:34]1[CH2:38][CH2:37][C:36](=O)[CH2:35]1>CCO>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH:1][CH:36]3[CH2:37][CH2:38][N:34]([CH3:33])[CH2:35]3)=[CH:5][CH:6]=2)=[O:11])=[CH:14][C:15]=1[NH:20][C:21]1[N:26]=[C:25]([C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:24]=[CH:23][N:22]=1
Reactant: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CN1CCC(=O)C1
Solvent: CCO
Product: Cc1ccc(NC(=O)c2ccc(NC3CCN(C)C3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above nitro compound was hydrogenated under hydrogen atomosphere in EtOH for 1 hour and filtered through Celite. To the solution was added NaBHCN (1.3 eq) and 1-methyl-3-pyrrolidinone (1 eq), the reaction was stirred at RT overnight and evaporated in vacuo and further purified by flash chromatography on silica gel afforded title compound. Mass: (M+1), 480.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:7]([C:8]([O:10]C)=[O:9])[C:6]=1[C:15]([O:17]C)=[O:16])[CH:2]=[CH2:3].[OH-].[Na+].Cl>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:15]([OH:17])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc(C(=O)OC)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOc1cccc(C(=O)O)c1C(=O)O

Procedure:
A mixture of 68.5 g of dimethyl 3-allyloxy-phthalate and 154 ml of a 5 N aqueous solution of sodium hydroxide is heated to the reflux temperature for 3 hours, whilst stirring, and then cooled to a temperature of +10°. 129 ml of 6 N hydrochloric acid are added in portions to the clear reaction solution and during the addition the temperature is not allowed to rise above 20°. After standing for several hours at 0°, the crystalline precipitate is filtered off and washed with a little ice water. After drying at 50°/0.1 mm Hg to constant weight, 3-allyloxy-phthalic acid is obtained; melting point 166°-167°.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[CH3:6][S:7]([O:5][CH:2]([C:3]#[CH:4])[CH3:1])(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: C#CC(C)O
Solvent: ClCCl
Solvent: O
Product: C#CC(C)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
But-3-yn-2-ol (25 ml, 317 mmol) was dissolved in DCM (6 vol) under nitrogen atmosphere. TEA (66 ml, 475.5 mmol) was added and the mixture was cooled to 5° C. Methanesulfonyl chloride (29 ml, 380.4 mmol) was added drop-wise. The reaction was then allowed to warm up to RT and the stirring was continued overnight. The reaction mixture was then poured into water, and extracted with DCM (twice). The collected organic phases were washed with a saturated solution of NaHCO3, dried over Na2SO4 filtered and concentrated under vacuum to give the title compound as a thick oil (34 g).
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[CH2:17][C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39].CS(C)=[O:42]>CCCCCC.C(COC)OC>[CH3:1][CH2:2][C@H:3]1[O:8][C@:7]2([O:13][C@@H:12]3[CH2:14][CH:15]=[C:16]([CH3:38])[C@H:17]([OH:42])[C@@H:18]([CH3:37])[CH:19]=[CH:20][CH:21]=[C:22]4[CH2:23][O:24][C@@H:25]5[C@H:30]([OH:31])[C:29]([CH3:32])=[CH:28][C@@H:27]([C:33]([O:35][C@@H:10]([CH2:11]3)[CH2:9]2)=[O:34])[C@:26]45[OH:36])[CH2:6][CH2:5][C@@H:4]1[CH3:39]
Reactant: CS(C)=O
Reactant: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)C[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(/C)[C@H](O)[C@@H](C)/C=C\C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Agent: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](C/C=C(\C)C[C@@H](C)/C=C/C=C3\CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Solvent: CCCCCC
Solvent: COCCOC
Product: CC[C@H]1O[C@]2(CC[C@@H]1C)C[C@@H]1C[C@@H](CC=C(C)[C@H](O)[C@@H](C)C=CC=C3CO[C@@H]4[C@H](O)C(C)=C[C@@H](C(=O)O1)[C@]34O)O2
Reaction time: 72 h

Procedure:
0.25 g of milbemycin A4 and 5 ml of DMSO are added to a 1-day-old culture of S. violascens in 200 ml of medium 3 and the whole is shaken at 250 rpm. at 28° C. After 3 days, a further 50 ml of medium 3 is added. The course of the reaction is monitored by HPLC (column Kontron LiSi 60, 25 cm/0.5 cm, eluant hexane/dimethoxyethane 3:1, 1 ml/min., UV detector 220 nm). After shaking for 7 days and a 91% conversion rate, 92% 13β-hydroxymilbemycin A4 and 8% 14,15-epoxymilbemycin A4 are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17]O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].N1C=CC=CC=1.S(Cl)([Cl:27])=O.O>O1CCCC1>[Cl:27][CH2:17][C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=1
Reactant: COCCOc1ccc(CO)cc1OCCOC
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COCCOc1ccc(CCl)cc1OCCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.82 g, 3.2 mmol) and pyridine (0.41 mL 5.1 mmol) in tetrahydrofuran (20 mL) at 0° C. was added thionyl chloride (0.26 mL, 3.5 mmol) and the reaction mixture warmed to room temperature and stirred for one hour. Then it was poured into water (40 mL) and extracted with ethyl acetate (3×40 mL). The combined extract was washed with water and brine (40 mL each), dried over sodium sulfate, filtered and concentrated to give 4-(chloromethyl)-1,2-bis{[2-(methyloxy)ethyl]oxy}benzene (0.65 g, 2.4 mmol, 75% yield) 1H NMR (400 MHz, CDCl3): 6.95-6.84 (m, 3H), 4.53 (s, 2H), 4.17-4.13 (m, 4H), 3.78-3.74 (m, 4H), 3.44 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].C(O)(=O)C.[N+:13]([O-])([OH:15])=[O:14].C(OC(=O)C)(=O)C>O>[N+:13]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1

Procedure:
After 20 g of 4-nitroimidazole was put in a flask, 36.4 mL of acetic acid was added thereto and while the temperature of the reaction solution was kept below 20° C., 14.6 mL of 97 mass % nitric acid was added dropwise thereto. After the dropwise addition of nitric acid was completed, 36.4 mL of acetic anhydride was added dropwise thereto and after the temperature of the reaction solution elevated to 25° C., the resultant mixture was allowed to react for 3 hours. After the reaction ended, the reaction solution was added into 100 g of iced water. Extraction with 100 mL of p-xylene was performed four times and this organic layer was washed twice with 100 mL of a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and 30 g of magnesium sulfate was added thereto for dehydration to obtain 1,4-dinitroimidazole as a p-xylene solution. Subsequently, the solvent was evaporated with an evaporator to about two third amount, and the solution was heated to 125° C. and allowed to react for 24 hours so as to perform conversion to 2,4-dinitroimidazole. After the reaction ended, the deposited solid was filtered to obtain 24.1 g of 2,4-dinitroimidazole as a solid wetted with p-xylene (wetted with 15 mass % of p-xylene, yield 74.9%). This was identified to be 2,4-dinitroimidazole by
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6](S(O)(=O)=O)[CH:7]=1.O[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:17]=1S(O)(=O)=O.ClC1C=CC([N+]([O-])=O)=CC=1.[OH-].[Na+]>[C].[Pd]>[CH:6]1[C:5]([NH2:12])=[CH:4][CH:3]=[C:2]([O:1][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(S(=O)(=O)O)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1S(=O)(=O)O
Agent: [Pd]
Agent: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: Nc1ccc(Oc2ccc(N)cc2)cc1

Procedure:
A 5-hydroxy-2-nitrobenzenesulfonic acid derivative (e.g. sodium 5-hydroxy-2-nitrobenzenesulfonate) or a 2-hydroxy-5-nitrobenzenesulfonic acid derivative (e.g. sodium 2-hydroxy-5-nitrobenzenesulfonate) is reacted with 4-chloronitrobenzene in the presence of an alkali (e.g. sodium hydroxide), followed by hydrogenation using palladium-carbon, to give the corresponding 4,4′-diaminodiphenyl ether derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[S:1]1[C:10]2[CH2:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[CH2:6][N:5]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CNc1ccsc1C2
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3sccc32)cn1

Procedure:
As described for Example 1, 5, 10-dihydro-4H-thieno[3,2-c][2]benzazepine in dichloromethane in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a solid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][C:38]=1[C:46]([O:48][CH3:49])=[O:47].[C:50]([OH:53])(=[S:52])[CH3:51]>C1COCC1>[C:50]([S:52][CH2:35][CH2:36][C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[NH:39][C:38]=1[C:46]([O:48][CH3:49])=[O:47])(=[O:53])[CH3:51]
Reactant: CC(O)=S
Reactant: COC(=O)c1[nH]c2ccccc2c1CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of triphenylphosphine (1.196 g, 4.56 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (0.9 mL; 4.56 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 minutes. A solution of methyl 3-(2-hydroxyethyl)-1H-indole-2-carboxylate (1.000 g of the above material) and thioacetic acid (0.34 mL, 4.76 mmol) in THF (5 mL) was dropwise added to the mixture at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The solvent was removed under a reduced pressure and the residue was purified by column chromatography (5 to 10% EtOAc in hexanes) to afford methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.864 g, 63% for the three steps) as a white solid: 1H NMR (DMSO-d6) 2.35 (s, 3H), 3.10–3.16 (m, 2H), 3.28–3.35 (m, 2H), 3.92 (s, 3H), 7.13 (t, J=7.3 Hz, 1H), 7.31 (t, J=7.5 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:17])C.[Li+].[BH4-].Cl>C1COCC1>[CH3:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)Cc1oc(-c2ccccc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)oc1CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
Ethyl(4-methyl-2-phenyl-1,3-oxazol-5-yl)acetate (0.922 g, 3.76 mmol) in THF (6 mL) at rt, was added LiBH4 2M/THF (9.41 mL, 4.70 mmol). The reaction was stirred overnight at rt, then treated with 2 N HCl until pH 7. The solvent THF was removed under reduced pressure, EtOAc was added, and phases separated. The combined organic extracts were dried over MgSO4 and solvent concentrated in vacuo. The crude material was purified by Biotage using a gradient of 10 to 100% EtOAc/Hexane as solvent mixture. This gave 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethanol (0.193 g, 25% yield) as colorless oil. ES-MS m/z 204.2 (MH)+); HPLC RT (min.) 2.02; 1H NMR (Acetone-d6) δ 7.98-7.95 (m, 2H), 7.52-7.42 (m, 3H), 3.95 (s br, 1H), 3.82 (t, 2H)m, 2.90 (t, 2H), 2.13 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[CH:21]=[CH2:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[C:3]=1[CH:21]=[CH2:22]
Reactant: BrCc1ccccc1
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 80 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid (prepared by the methods described in U.S. Pat. No. 7,786,044 B2; 0.150 g, 0.463 mmol), (bromomethyl)benzene (0.103 g, 0.602 mmol), and lithium carbonate (Li2CO3; 0.044 g, 0.602 mmol) were combined in DMF (1.5 mL) and heated at 60° C. overnight. The cooled reaction mixture was concentrated and then partitioned between EtOAc and water. The organic phase was dried, concentrated and purified by column chromatography (eluting with an EtOAc/hexanes gradient) to yield benzyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylate as a white solid (0.154 g, 80%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J=8.5, 7.5 Hz, 1H), 7.49-7.42 (m, 2H), 7.42-7.32 (m, 3H), 7.21 (dd, J=8.6, 1.7 Hz, 1H), 6.70 (dd, J=17.8, 11.6 Hz, 1H), 5.60 (dd, J=7.7, 1.0 Hz, 1H), 5.57 (s, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.00 (d, J=0.8 Hz, 3H); ESIMS m/z 414 ([M+H]+).
Reaction SMILES: [Ca].[S:2]([C:6]1[C:7]2[NH:11][C:10]([CH:12]=[C:13]3[N:29]=[C:16]([CH:17]=[C:18]4[NH:28][C:21](=[CH:22][C:23]5[CH:24]=[CH:25][C:26]=1[N:27]=5)[CH:20]=[CH:19]4)[C:15]1[N:30]=[CH:31][CH:32]=[CH:33][C:14]3=1)=[C:9]([S:34]([OH:37])(=[O:36])=[O:35])[C:8]=2[S:38]([OH:41])(=[O:40])=[O:39])([OH:5])(=[O:4])=[O:3].S(C1C2[NH:51]C(C=C3N=C(C=C4NC(=CC5C=CC=1N=5)C=C4)C1N=CC=CC3=1)=C(S(O)(=O)=O)C=2S(O)(=O)=O)(O)(=O)=O.C1C([N:88]=NC2C(=O)N(C3C=CC(S([O-])(=O)=O)=CC=3)N=C2C([O-])=O)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+].[Na+].C1C(C(N)=O)=CN(C2OC(COP(OP(OCC3OC(N4C5N=CN=C(N)C=5N=C4)C(OP([O-])([O-])=O)C3O)([O-])=O)([O-])=O)C(O)C2O)C=C1.[Na+].[Na+].[Na+].[Na+]>>[NH4+:11].[NH4+:51].[NH4+:88].[S:2]([C:6]1[C:7]2[NH:11][C:10]([CH:12]=[C:13]3[N:29]=[C:16]([CH:17]=[C:18]4[NH:28][C:21](=[CH:22][C:23]5[CH:24]=[CH:25][C:26]=1[N:27]=5)[CH:20]=[CH:19]4)[C:15]1[N:30]=[CH:31][CH:32]=[CH:33][C:14]3=1)=[C:9]([S:34]([OH:37])(=[O:35])=[O:36])[C:8]=2[S:38]([OH:41])(=[O:40])=[O:39])([OH:5])(=[O:4])=[O:3]
Reactant: O=C([O-])C1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1N=Nc1ccc(S(=O)(=O)[O-])cc1
Agent: NC(=O)C1=CN(C2OC(COP(=O)([O-])OP(=O)([O-])OCC3OC(n4cnc5c(N)ncnc54)C(OP(=O)([O-])[O-])C3O)C(O)C2O)C=CC1
Agent: O=S(=O)(O)c1c(S(=O)(=O)O)c2[nH]c1cc1nc(cc3ccc(cc4nc(c2S(=O)(=O)O)C=C4)[nH]3)-c2ncccc2-1
Agent: [Ca]
Product: [NH4+]

Procedure:
tri sulfo pyrido porphine calcium, tri ammonium salt; tri sulfo pyrido porphine, tri sodium salt; meso-disulfopyrryl-meso-disulfo phenyl porphine, tetra sodium salt; meso-disulfo-pyrryl-meso-disulfo phenyl porphine zinc, tetra sodium salt; meso-disulfopyrryl-meso-disulfo phenyl porphine, tetra sodium salt, 1,2,3,4,5,6,7,8-octamethyl-meso-disulfopyrryl-meso-disulfo pheyl porphine, tetra ammonium salt; 1,2,3,4,5,6,7,8-octa n-propyl -meso-disulfopyrryl-meso-disulfo phenyl porphine zinc, tetra sodium salt; disulfobenzo-meso-tetrasulfophenyl porphine, hexa sodium salt; disulfobenzo-meso-tetra(sulfo-4-pyridyl) porphine zinc, hexa sodium salt.
Reaction SMILES: [CH:1]1([C:4](=[O:41])[CH2:5][O:6][C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:23][CH:22]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.CO>[CH:1]1([CH:4]([OH:41])[CH2:5][O:6][C@H:7]2[CH2:8][CH2:9][C@H:10]([N:13]3[C:18](=[O:19])[C:17]([CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:27]5[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=5)=[CH:25][CH:26]=4)=[C:16]([CH2:35][CH2:36][CH3:37])[N:15]4[N:38]=[CH:39][N:40]=[C:14]34)[CH2:11][CH2:12]2)[CH2:2][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)C3CC3)CC2)c2ncnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(O)C3CC3)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-({4-[trans-4-(2-Cyclopropyl-2-oxoethoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.23 g) was dissolved in tetrahydrofuran (2 mL) and methanol (4 mL), sodium tetrahydroborate (0.027 g) was added at 0° C., and the mixture was stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 72%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]([CH3:32])([CH3:31])[CH2:13][C:14]1[N:15]([CH2:28][CH2:29][CH3:30])[N:16]=[C:17]2[C:26]=1[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:19]=[C:18]2[NH2:27].C(N(CC)CC)C>ClCCl>[NH2:27][C:18]1[C:17]2=[N:16][N:15]([CH2:28][CH2:29][CH3:30])[C:14]([CH2:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)([CH3:32])[CH3:31])=[C:26]2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
Nicotinoyl chloride hydrochloride (1.62 g, 9.08 mmol) was added to a stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 1.08 g, 3.63 mmol) and triethylamine (2.8 mL, 20 mmol) in dichloromethane (32.4 mL). After 2 h, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL). Concentrated hydrochloric acid (4 mL) was added and the solution was heated at reflux for 30 minutes, then was allowed to cool to ambient temperature. To the solution was added 2 M aqueous sodium carbonate until the pH was basic, then water was added. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to yield a brown oil that was purified by IFC (silica gel, elution with CMA in chloroform). The appropriate fractions were combined and concentrated to produce a yellow foam that was crystallized from ethyl acetate/hexanes. The solid was isolated by filtration and dried to yield 418 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]nicotinamide as a pale yellow solid, mp 203-205° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Br:25][C:26]1[CH:27]=[C:28]([NH:33][CH3:34])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[CH3:44][O:45][C:46]([CH:48]1[CH2:50][CH:49]1[C:51](O)=O)=[O:47]>CN(C=O)C.O>[Br:25][C:26]1[CH:31]=[CH:30][C:29]2[N:32]=[C:51]([CH:49]3[CH2:50][CH:48]3[C:46]([O:45][CH3:44])=[O:47])[N:33]([CH3:34])[C:28]=2[CH:27]=1
Reactant: CNc1cc(Br)ccc1N
Reactant: COC(=O)C1CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CC1c1nc2ccc(Br)cc2n1C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (554 mg) was added to a solution of 4-bromo-N2-methylbenzene-1,2-diamine (279 mg), diisopropylethylamine (0.727 mL) and (1RS,2SR)-2-(methoxycarbonyl)cyclopropanecarboxylic acid (200 mg) in DMF (5 mL) at room temperature. The mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was dissolved in acetic acid (5 mL), and the mixture was stirred at 80° C. for 1 hr. After concentration of the reaction mixture, saturated sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (80 mg) as a pale brown solid.