Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:28]([CH3:30])[CH3:29])[C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21](OS(C)(=O)=O)[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][CH:21]1[CH2:20][N:19]([C:16]2[S:17][CH:18]=[C:14]([C:12](=[O:13])[N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2])[CH:28]([CH3:30])[CH3:29])[N:15]=2)[CH2:22]1)(=[O:34])[CH3:32]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 1-(4-{N-[2-(t-butyldimethylsilyloxy)ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (649 mg, 1.35 mmol) (obtained as described in Reference Example 59(4)) in dimethylformamide (19 ml) was added potassium thioacetate (930 mg, 8.14 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (3:1) ethyl acetate as the eluant to afford 3-acetylthio-1-(4-{N-[2-(t-butyldimethylsilyloxy)-ethyl]-N-isopropyl-carbamoyl}-1,3-thiazol-2-yl)azetidine (618 mg, yield 100%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>O1CCOCC1.O>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: NCc1ccncc1
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(NCc2ccncc2)nc(N2CCOCC2)n1
Yield: 25.5 %

Procedure:
A stirred mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (0.183 g, 0.5 mmol) and 4-aminomethylpyridine (0.135 g, 1.25 mmol) in 10 mL dioxane was heated under gentle reflux for 5 min, before being cooled and diluted with water. The mixture was extracted with CH2Cl2 and the organic layer was dried with Na2SO4. Chromatography on alumina, eluting with CH2Cl2/EtOAc (9:1), followed by chromatography on silica, eluting with CH2Cl2/EtOAc (3:2) gave 56 mg (26% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(4-pyridinylmethyl)-1,3,5-triazin-2-amine: mp 188-190° C.; 1H NMR (CDCl3) (rotamers) δ8.60 (br s, 2H), 8.42 and 8.13 (2d, J=7.4 and 8.0 Hz, 1H), 7.88 (m, 1H), 7.64 (t, JHF=53.6 Hz, 1H), 7.44-7.25 (m, 4H), 5.78 and 5.71 (2 m, exchangeable with D2O, 1H), 4.74 and 4.70 (2 d, J=6.0 and 6.0 Hz, 2H), 3.92-3.69 (m, 8H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH-:4].[Na+].C(OC1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]4[O:33][CH2:34][O:35][C:29]=4[CH:28]=3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:36])[CH:21]=3)[N:16]=2)[C:11](=C=O)[CH2:10]1)C>O>[C:1]([CH:2]1[CH2:14][CH2:13][N:12]([C:15]2[N:24]=[C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]4[O:33][CH2:34][O:35][C:29]=4[CH:28]=3)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:36])[CH:21]=3)[N:16]=2)[CH2:11][CH2:10]1)([OH:4])=[O:3]
Reactant: [OH-]
Reactant: CCO
Reactant: CCOC1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)C(=C=O)C1
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(Cl)ccc3n2)CC1

Procedure:
10 ml of ethanol, 5 ml of water and 820 mg of sodium hydroxide were added to 1 g of 2-(4-ethoxy-carbonylpiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was refluxed for 20 minutes, concentrated under a reduced pressure and neutralized with 1N hydrochloric acid. The crystals thus precipitated were recovered by filtration to give 920 mg of the title compound.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][CH:46]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=2)[CH2:34][S:35][CH2:36][CH2:37][C:38](O)=[O:39])=[O:30])[CH:11]=1)=[O:9].C(N(C(C)C)CC)(C)C.[O:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][NH2:66])[CH2:60][CH2:59]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:58]1[CH2:63][CH2:62][N:61]([CH2:64][CH2:65][NH:66][C:38](=[O:39])[CH2:37][CH2:36][S:35][CH2:34][C:33]2[CH:32]=[C:31]([CH:43]=[CH:42][CH:41]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:44]=[CH:45][CH:46]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:4]=2)=[O:9])=[O:30])[CH2:60][CH2:59]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
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
Product: O=C(CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1)NCCN1CCOCC1
Reaction time: 24 h
Yield: 38.8 %

Procedure:
A solution of 25 mg of 3-(3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzylthio)propanoic acid 1.1, 19 mg of diisopropylethylamine, and 6 mg of 2-morpholinoethylamine in 1 mL of DMF was treated with 15 mg of HATU and stirred for 24 h. The product was isolated by reverse phase HPLC eluting with 0.05% TFA in a water/acetonitrile gradient to give 11.3 mg of product. MS (ES, m/z): 789 [M+H]+
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27](=[O:30])[CH2:28]Br)#[N:23]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:28]=1[C:27]([C:26]1[CH:25]=[C:24]([CH:33]=[CH:32][CH:31]=1)[C:22]#[N:23])=[O:30]
Reactant: CC(C)N1CCN(c2ccc(N=C=S)cc2)CC1
Reactant: N#Cc1cccc(C(=O)CBr)c1
Reactant: N#CN
Product: CC(C)N1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(C#N)c4)s3)cc2)CC1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothio-cyanatophenyl)-4-isopropypiperazine (of Example 3) and 3-cyanophenacyl bromide (Maybridge Chemical Co. Ltd.) following the procedure used in Example 24. Mass spectrum (ES) MH+=447.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=2[Cl:26])[CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:26][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:7]1[CH:8]=[CH:9][C:10]([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:6]=1)=[O:27]
Reactant: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 381 mg (0.93 mmol) N-[3-(2-amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 mL CH2Cl2 at 0° C. was added 0.389 mL Et3N and 0.072 mL (0.93 mmol) methanesulfonylchloride. After 5 min, the reaction was stirred at RT for 30 min. The reaction was diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum, yielding the titled compound as a white foamy solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1([CH2:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:57]3[CH2:56][CH2:55][N:54]([CH2:53][CH2:52][CH2:51][N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)[CH2:59][CH2:58]3)=[O:22])[N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: C1CCN(CCCN2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CCCN4CCCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (100 mg, 0.28 mmol), EDCI (75 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) DIPEA (0.06 mL, 0.33 mmol), 1-(3-pyrrolidin-1-yl-propyl)-piperazine (66 mg, 0.33 mmol) and DCM (10 mL).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH3:42][C:43]1[CH:48]=[CH:47][C:46]([C@@H:49]([NH2:51])[CH3:50])=[CH:45][CH:44]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:51][C@H:49]([C:46]2[CH:47]=[CH:48][C:43]([CH3:42])=[CH:44][CH:45]=2)[CH3:50])=[O:40])=[CH:18][CH:17]=1
Reactant: Cc1ccc([C@H](C)N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 102.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(4-methylphenyl)ethylamine (31 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (52 mg, yield 48%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1)=[O:5].Cl.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.[CH3:25][N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C(N(CC)CC)C>[CH3:25][N:26]1[CH2:31][CH2:30][C:29]2[N:23]([CH2:2][CH2:3][C:4]([N:6]3[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]3)=[O:5])[C:20]3[CH:19]=[CH:18][C:17]([CH3:16])=[CH:22][C:21]=3[C:28]=2[CH2:27]1
Reactant: O=C(O)C1CCN(C(=O)CCBr)CC1
Reactant: Cc1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(C(=O)O)CC2)CCN(C)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(3-bromopropanoyl)piperidine-4-carboxylic acid, 4-methylphenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:21])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (14.1 g, 48.06 mmol) in tetrahydrofuran/water (300 mL, 3:1) was treated with lithium hydroxide (4.35 g, 103.67 mmol). The reaction was stirred at 25° C. for 21 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (75 mL) and extracted with ether (3×75 mL). The aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×75 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (11.97 g, 93.6%) as a yellow solid: mp 119-125° C.; EI-HRMS m/e calcd for C14H17NO4 (M+) 263.1157, found 263.1162.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[C:27]([CH3:29])[C:6]([C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH2:16][CH2:15]2)[CH3:13])=[O:8])=[C:5]([CH3:30])[N:4]=1)#[N:2].Cl.[NH2:32][OH:33]>CCO.C(Cl)Cl.O.C([O-])(O)=O.[Na+]>[OH:33][NH:32][C:1]([C:3]1[CH:28]=[C:27]([CH3:29])[C:6]([C:7]([NH:9][CH2:10][CH2:11][C@H:12]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH2:21][C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH2:16][CH2:15]2)[CH3:13])=[O:8])=[C:5]([CH3:30])[N:4]=1)=[NH:2]
Reactant: Cc1cc(C#N)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C(=N)NO)nc(C)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Yield: 77 %

Procedure:
To a solution of 6-cyano-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (208 mg, 0.49 mmol) in EtOH (3 ml) was added hydroxylamine HCl (190 mg, 2.73 mmol) and NaHCO3 (239 mg, 2.84 mmol) and the reaction heated to reflux overnight. The mixture was diluted with CH2Cl2 (25 ml) and water (10 ml) and saturated aqueous NaHCO3 (20 ml). The aqueous layer was extracted with CH2Cl2 (2×5 ml) and the combined organic extracts were dried (Na2SO4) and concentrated to afford 6-(N-hydroxycarbamimidoyl)-2,4-dimethyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (173 mg) as a beige foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:13]([C:11]#[N:12])[C:14]([NH:16][NH2:17])=[O:15]
Reactant: N#CCC(=O)NN
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)NN
Yield: 50.2 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.55 g (5.5 mmol) cyanoacethydrazide in 40 ml ethanol was added 2 drops piperidine. After 2½ hours of reflux, the reaction mixture was cooled, filtered and washed with cold ethanol to give 0.55 g (50% yield) of product, an orange solid, m.p. 220° C. (decomposition).
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[ClH:12].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H]([N:43]5[CH:48]=[C:47]([C:49]([NH2:51])=O)[CH2:46][CH:45]=[CH:44]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[ClH:12].[ClH:12].[NH2:5][CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:43][NH:51][CH:49]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: 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: Cl
Product: NCCCc1cn[nH]c1
Temperature: 4 °C

Procedure:
This phthalimide intermediate (8.0 gram, 0.03 mole) was refluxed in 100 ml. of 6 normal hydrochloric acid overnight. The clear solution was cooled to 4° C., phthalic acid removed by filtration, and the filtrate evaporated to dryness to give a product which, after recrystallization from a mixture of ethanol and ethyl ether, amounted to 4.4 grams of a white solid identified as 4-(3-aminopropyl)-pyrazole dihydrochloride, melting point 189°-190° C. This pyrazole compound could be coupled to the activated dextran by reaction of the terminal amino group, but the resulting affinity resin, in which the coupling arm had a length of only 6 Angstrom units, had poor binding capacity for the binary complex of alcohol dehydrogenase and NAD.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[C:5]([C:15]([OH:17])=[O:16])=[CH:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:25]([N:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][CH2:34]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:32]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:33][CH2:34][O:16][C:15]([C:5]1[C:6](=[O:14])[C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:13][CH2:34][CH2:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:8]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:17])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(O)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)OCCN(Cc2ccccc2)Cc2ccccc2)c(=O)c2cc(OCCN(Cc3ccccc3)Cc3ccccc3)ccc21
Temperature: 65 °C
Reaction time: 72 h
Yield: 120.1 %

Procedure:
1-Ethyl-6-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (GB 1433774) (1.4 g, 6 mmol) was dissolved in dry DMF (80 mL). To this was added potassium carbonate (5 g, 36 mmol) and dibenzyl-(2-chloroethyl)amine hydrochloride (4.37 g, 14.8 mmol). The mixture was heated at 65° C. with stirring for 72 h, then allowed to cool overnight. The mixture was evaporated to a small volume, diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried and evaporated under reduced pressure to give a dark viscous oil (4.9 g). This residue was purified by chromatography on silica gel (100 g), eluting with 0.2-3.8% methanol in dichloromethane, to give the title compound as a brown solid (2.46 g, 60%); ESMS m/z 680 [M+H]+ (100%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][C:10]2([CH2:37][C:38]([OH:40])=O)[CH2:12][N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]5[CH2:36][C@:26]6([C:34]7[C:29](=[N:30][CH:31]=[CH:32][CH:33]=7)[NH:28][C:27]6=[O:35])[CH2:25][C:20]=5[CH:21]=4)[N:16]=3)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1.[NH:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]=[C:2]1[CH2:11][C:10]2([CH2:37][C:38](=[O:40])[N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH2:12][N:13]([CH2:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][C:19]5[CH2:36][C@:26]6([C:34]7[C:29](=[N:30][CH:31]=[CH:32][CH:33]=7)[NH:28][C:27]6=[O:35])[CH2:25][C:20]=5[CH:21]=4)[N:16]=3)[C:8]3[C:9]2=[C:4]([CH:5]=[CH:6][CH:7]=3)[NH:3]1
Reactant: C1CCNC1
Reactant: O=C(O)CC12CC(=O)Nc3cccc(c31)N(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)C2
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C1CC2(CC(=O)N3CCCC3)CN(Cc3ccc4cc5c(cc4n3)C[C@]3(C5)C(=O)Nc4ncccc43)c3cccc(c32)N1

Procedure:
A mixture of [4-oxo-1-{[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2-yl]methyl}-1,2,4,5-tetrahydropyrrolo[4,3,2-de]quinolin-2a(3H)-yl]acetic acid, diastereomer A (50 mg, 0.094 mmol, described in Example 2), pyrrolidine (20 mg, 0.282 mmol), EDC (22 mg, 0.113 mmol), HOBT (17 mg, 0.113 mmol), and N,N-diisopropylethylamine (0.082 mL, 0.470 mmol) was stirred in DMF (0.5 mL) at ambient temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (10 mL). The organic layer was removed and the aqueous layer was extracted further with CH2Cl2 (2×10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=585 (M+1). HRMS: m/z=585.2620; calculated m/z=585.2609 for C35H33N6O3.
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[CH:11]=[C:10]2[CH2:12][CH:13]=[CH:14][CH:15]=[C:9]2[O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)=[O:4].[OH:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH2:12]1[C:10]2=[CH:11][N:5]([C:3](=[O:4])[CH2:2][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[C:6]3[CH:19]=[CH:18][CH:17]=[CH:16][C:7]=3[O:8][C:9]2=[CH:15][CH:14]=[CH:13]1
Reactant: O=C(CBr)N1C=C2CC=CC=C2Oc2ccccc21
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(OCC(=O)N2C=C3CC=CC=C3Oc3ccccc32)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 32.4 %

Procedure:
Title compound 455 (0.890 g, 2.81 mmol) and the methyl 4-hydroxybenzoate (0.512 g, 3.37 mmol) were dissolved in acetonitile (10.0 mL) and the cesium carbonate (1.83 g, 5.62 mmol) was added. The reaction mixture was stirred at 100° C. in a sealed tube for 4 hours. The mixture was cooled down to room temperature and diluted with ethyl acetate. The organic layer was washed with water (2 times) and brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (30-40% ethyl acetate in hexanes) to afford title compound 456 (355 mg, 32%) as white foam. MS (m/z): 390.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1cccc2c1C(=O)C(O)=CC2=O
Reactant: O=[N+]([O-])O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1C(=O)C(O)=C([N+](=O)[O-])C2=O
Yield: 43 %

Procedure:
A solution of 3-hydroxy-5methyl-1,4-naphthoquinone (1.9g) in chloroform (200ml) was nitrated with fuming nitric acid according to example 1(a). A yield of 1.01g (43%) of material of m.p. 148°-149° C (d) was obtained. (Found; C, 56,69; H, 3.16; N, 5.73; C11H7NO5 requires; C, 56.66; H, 3.03; N, 6.01%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[N:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].[OH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[CH:19][NH:20]2>>[NH2:13][C:12]1[O:15][CH:16]2[C:17]3[C:21](=[CH:22][CH:23]=[C:24]2[CH:8]([C:6]2[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=2)[C:11]=1[C:10]#[N:14])[N:20]=[CH:19][CH:18]=3
Reactant: N#CCC#N
Reactant: Oc1cccc2[nH]ccc12
Reactant: Cc1cncc(C=O)n1
Product: Cc1cncc(C2C3=CC=C4N=CC=C4C3OC(N)=C2C#N)n1
Yield: 22 %

Procedure:
The title compound was prepared from 6-methyl-pyrazine-2-carbaldehyde, malononitrile and 4-hydroxyindole by a procedure similar to Example 57 in 22% yield. 1-NMR (DMSO-d6): 11.30 (brs, 1H), 8.44 (dd, J=15.6, 1.10 Hz, 2H), 7.36 (dd, J=3.03, 0.83 Hz, 1H), 7.09 (d, J=8.51 Hz, 1H), 7.00 (s, 2H), 6.69 (d, J=8.24 Hz, 1H), 6.45 (m, J=3.03, 1.10, 0.83 Hz, 1H), 4.97 (s, 1H), 2.44 (s, 3H).