Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12](=O)[CH2:13][CH3:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:16]1(=[O:23])[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1.C([O-])(=O)C.[NH4+:28]>C(O)C>[CH2:13]([C:12]1[NH:28][C:18]2[CH2:19][CH2:20][CH2:21][C:16](=[O:23])[C:17]=2[CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:11]=1)[CH3:14]
Reactant: CCC(=O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=C1CCCC(=O)C1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCC1=CC(c2cccc([N+](=O)[O-])c2)C2=C(CCCC2=O)N1
Yield: 36.7 %

Procedure:
A mixture of 1-(3-nitrophenyl)-1-penten-3-one (2.42 g), 1,3-cyclohexanedione (1.36 g), ammonium acetate (2.00 g) and ethanol (70 mL) was heated at reflux for 7.5 hours. Removal of solvent, chromatography (ethyl acetate/hexane, 2:1 and methylene chloride/acetonitrile, 9:1), trituration with hot diethyl ether and recrystallization from ethyl acetate provided the title compound (1.29 g) as a yellow solid; mp 182°-184° C.; NMR: 1.03 (t,3, J=7.4, CH3), 1.70-1.95 (m,2, CH2), 2.07 (q,2, J=7.5, CH2), 2.17 (m,2, CH2), 2.48 (m,2, CH2), 4.59 (d,1, J=4.8, CH), 4.66 (dd, 1, J=4.8, 0.9, CH), 7.53 (m,1, Ar), 7.64 (m,1, Ar), 7.98 (m,2, Ar), 8.55 (s,1, NH). MS: m/z= 298(M). Analysis for C17H18N2O3 : Calculated: C., 68.44; H, 6.08; N, 9.39; Found: C, 68.43; H, 6.09; N, 9.39.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:6][CH:7]=1.[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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.CN(C=O)C>[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1C
Reactant: O=C(Nc1cncc(Br)c1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1cccc(-c2cncc(NC(=O)c3ccccc3)c2)c1C
Temperature: 85 °C
Reaction time: 12 h

Procedure:
At 50° C., 3.93 g (13.9 mmol) of N-(5-bromopyridin-3-yl)benzamide, 2.50 g (16.7 mmol) of (2,3-dimethylphenyl)boronic acid and 3.84 g (27.8 mmol) of potassium carbonate were dissolved in 50 ml of 1,2-dimethoxyethane, 17 ml of water and 100 ml of DMF. The mixture was flushed with argon, 81 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the mixture was stirred at 85° C. for 12 h. The reaction mixture was concentrated slightly on a rotary evaporator, diluted with water and extracted with dichloromethane. The organic phase was concentrated under reduced pressure and the residue was triturated with methyl tert-butyl ether, the solid was filtered off and the filtrate was purified by column chromatography on silica gel (cyclohexane/ethyl acetate 2:1→1:1). The separated solid and the appropriate fraction from the chromatography were combined. Yield: 4.2 g (96% of theory)
Reaction SMILES: [C:1]([C:4]1[C:19]([OH:20])=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#N)=[C:6]([CH2:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2].[OH-:23].[K+].C(O)C.Cl.[OH2:29]>>[C:1]([C:4]1[C:19]([OH:20])=[CH:18][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]([OH:29])=[O:23])=[C:6]([CH2:21][CH3:22])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C#N)c1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: CCc1cc(C(C)=O)c(O)cc1OCc1cccc(C(=O)O)c1

Procedure:
A mixture of 1.5 g of 3-[(4-acetyl-5-hydroxy-2-ethyphenoxy)methyl]benzonitrile, 1.14 g of potassium hydroxide, 75 ml of ethanol and 75 ml of water was heated at reflux overnight. The mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was extracted with 1N sodium hydroxide. The base layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo providing 1.06 g of the desired title product, m.p.=161°-164° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:13])[C:3]=1[NH:14][N:15]=[C:16](Cl)[C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:22]([N:24]([CH2:27][CH3:28])[C:25]#[N:26])[CH3:23].O1CCCC1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Cl:13])[C:3]=1[N:14]1[C:25]([N:24]([CH2:27][CH3:28])[CH2:22][CH3:23])=[N:26][C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:15]1
Reactant: CC(C)(C)C(Cl)=NNc1c(Cl)cc(OC(F)(F)F)cc1Cl
Reactant: CCN(C#N)CC
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCN(CC)c1nc(C(C)(C)C)nn1-c1c(Cl)cc(OC(F)(F)F)cc1Cl
Yield: 87 %

Procedure:
7.3 g (0.02 mol) of 2,2-dimethylpropionyl chloride 2,6-dichloro-4-trifluoromethoxyphenylhydrazone and 2.0 g (0.02 mol) of N,N-diethylcyanamide were added to 100 ml of tetrahydrofuran, and 2.2 g (0.02 mol) of triethylamine was dropwise added under reflux and stirring. After completion of the dropwise addition, the mixture was stirred at the same temperature for 0.5 hour. After cooling, the reaction solution was poured into water, and the precipitate was extracted with chloroform. The chloroform layer was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.4 g (yield: 87.1%) of the desired compound as a pale yellow liquid. Refractive index nD20 : 1.4940.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([OH:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:17]N(C=O)C>>[N:12]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1]([O:3][CH3:17])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: CN(C)C=O
Reactant: C1CCNC1
Product: COC(=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6.20 mL (44.5 mmol) of TEA and 4.70 g (21.8 mmol) of 4-carboxybenzyl bromide in 50 mL of DMF was treated with 2.10 mL (25.2 mmol) of pyrrolidine at 50° C. for 3 h. The reaction mixture was cooled, evaporated in vacuo, and the residue was taken up in 50 mL of MeOH. The solution was treated with a rapid stream of HCl (g) for 15 min, the reaction vessel was sealed and the reaction stirred at ambient temperature for 16 h. Evaporation of the solvent afforded 2.56 g of an oil which was purified by radial chromatography (SiO2; 80:18:2 hexanes-THF-TEA) to afford 2.30 g (10.5 mmol; 48%) of the title compound as an oil.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:22])[S:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)=[O:5])C.[NH2:23][CH2:24][C:25]([O-:27])=[O:26].[Na+]>COCCO>[CH2:18]([O:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([OH:16])=[C:6]([C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5])[C:7](=[O:22])[S:8]2)=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NCC(=O)[O-]
Reactant: CCCCOc1ccc2c(O)c(C(=O)OCC)c(=O)sc2c1
Agent: [Na+]
Solvent: COCCO
Product: CCCCOc1ccc2c(O)c(C(=O)NCC(=O)O)c(=O)sc2c1
Yield: 78.7 %

Procedure:
A mixture of 7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid ethyl ester (140 mg, 0.434 mmol) and sodium glycinate (420 mg, 4.34 mmol) in 2-methoxyethanol (10 mL) was refluxed overnight (16 h). Reaction mixture was concentrated, and crude residue was dissolved in water, acidified to pH 3 using 1 N HCl to precipitate the product. The precipitate was collected by filtration and dried to provide [(7-butoxy-4-hydroxy-2-oxo-2H-thiochromene-3-carbonyl)-amino]-acetic acid (120 mg, 80%). MS ESI(−) m/e: 350.21 (M−1).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([S:22]C#N)[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.P([O-])(O)(O)=O.[K+].SCC(C(CS)O)O>>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([SH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:11])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: N#CSc1ccc2nc(NC(=O)CCCN3CCOCC3)sc2c1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: O=C(CCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Yield: 8.4 %

Procedure:
The 4-morpholin-4-yl-N-(6-sulphanyl-1,3-benzothiazol-2-yl)butanamide was prepared according to the method described in Example 1 b, but using 906 mg of 4-morpholin-4-yl-N-(6-thiocyanato-1,3-benzothiazol-2-yl]butanamide, 14 mg of potassium dihydrogen phosphate and 1.12 g of DL-dithiothreitol. 71 mg of 4-morpholin-4-yl-N-(6-sulphanyl-1,3-benzothiazol-2-yl)butanamide are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [C:1]([CH2:8][CH2:9][CH2:10][NH:11][NH2:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1F)[C:24]#[N:25]>CN(C=O)C>[C:1]([CH2:8][CH2:9][CH2:10][N:11]([NH2:12])[C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:20])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)CCCNN
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCCN(N)c1ccc(C#N)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.49 g (20 mmol) 3-Boc-amino-propylamine in 5 ml DMF are combined with 2.75 ml (25 mmol) NMM. After the addition of 3.11 g (20 mmol) 3-chloro-4-fluoro-benzonitrile the mixture is stirred for 3.5 hours at ambient temperature under a nitrogen atmosphere, heated to 105° C. for 20 minutes and extracted with ethyl acetate. The combined organic phases are washed with water and sat. sodium chloride solution, dried over magnesium sulphate and evaporated down i. vac. The residue is further reacted without any more purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[C:10](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:11].C([Sn](CCCC)(CCCC)C=C)CCC.[Na].C(NN)=O>C1(C)C=CC=CC=1.CO>[CH:10]([C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)=[CH2:11]
Reactant: N#Cc1ccc(Br)cn1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: NNC=O
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: C=Cc1ccc(C#N)nc1

Procedure:
A 5-vinylpicolinonitrile intermediate (1-2) was prepared by adding 5-bromopicolinonitrile (1-1), tetrakis(triphenylphosphine) (Pd(PPH3)4), and 2,6-di-t-butyl-4-methylphenol (BHT) in toluene, adding tributyl(vinyl)stannane thereto, and reacting the resulting mixture at 80° C. for 24 hours. The intermediate (1-2) was added to a methanol solution, in which sodium metal was dissolved, and reacted at 70° C. for 3 hours and then cooled. Formohydrazide (1-3) was added to the reaction solution and reacted at 70° C. for 15 minutes. Then, the temperature was lowered to 25° C. and the reaction solution was reacted for 24 hours until yellow crystals were formed. Upon completion of the reaction, the yellow crystals were collected by filtration, and 2-(4H-1,2,4-triazol-3-yl)-5-vinylpyridine (1-4) was purified by column chromatography using chloroform and methanol as solvents.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.[O:48](C(OC(C)(C)C)=O)[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:52]([O:51][C:49]([N:4]([CH2:5][C@:6]12[CH2:44][CH2:43][C@@H:42]([C:45]([CH3:47])=[CH2:46])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:41])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:26])([CH3:27])[C:15]([C:28]2[CH:40]=[CH:39][C:31]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1)[CH2:3][CH2:2][OH:1])=[O:48])([CH3:55])([CH3:54])[CH3:53]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCO)C(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 0 °C
Reaction time: 6 h

Procedure:
tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-hydroxyethylamino)methyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (600 mg, 0.932 mmol) was dissolved in CH2Cl2 (10 mL), BOC2O (0.260 mL, 1.118 mmol) was added followed by Hunig's Base (0.163 mL, 0.932 mmol) to form a colorless solution that was stirred at 0° C. for 6 hrs. LCMS indicated formation of desired product (M+23=767). The solvent was removed in vacuo and the resultant white solid was used as is in the next step.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH:36]1[CH2:37][CH:34]([NH:33][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:7]=4[N:20]=3)=[C:23]([O:31][CH3:32])[CH:24]=2)[CH2:35]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)(C)OC(=O)N1CC(N)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: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CNC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl 3-aminoazetidine-1-carboxylate (41.3 mg, 0.24 mmol), HATU (125 mg, 0.33 mmol), and DIEA (80 μL, 0.44 mmol). The reaction mixture was stirred for 1 h. It was then poured into 100 mL of rapidly stirring water. A peach solid forms and was filtered, washed with water and dried. This solid was treated with TFA in DCM (3 mL 1:1) for 30 minutes. The solvent was then removed, and the product purified by reverse phase HPLC, free based and lyophilized to yield a white solid (37.4 mg, 34% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.79 (m, 6 H) 1.93 (br. s., 2 H) 3.52-3.66 (m, 4 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.56-4.84 (m, 2 H) 7.45-7.58 (m, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 8.28 (d, J=8.34 Hz, 1 H) 8.75 (d, J=7.07 Hz, 1 H). [M+H] calc'd for C24H29F2N7O3, 502; found 502.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:19]3)[NH:9][C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1>O=P(Cl)(Cl)Cl>[Cl:1][CH:2]1[NH:7][CH:6]=[CH:5][N:4]2[C:10]([CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:9][C:8]([C:16]3[CH:17]=[C:18]4[C:23]([N:22]=[CH:21][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[N:19]4)=[CH:24][CH:25]=3)=[C:3]12
Reactant: O=C(NC(c1ccc2ncc(-c3ccccc3)nc2c1)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: ClC1NC=Cn2c(C3CCC3)nc(-c3ccc4ncc(-c5ccccc5)nc4c3)c21
Temperature: 25 °C

Procedure:
N-[(3-chloropyrazin-2-yl)(3-phenylquinoxalin-6-yl)methyl]-cyclobutanecarboxamide (56 mg, 0.13 mmol) was heated in POCl3 (5 mL) under Ar at 70° C. for 26 h. Later the reaction was cooled to rt, evaporated under reduced pressure and then high vacuum. A solution of NH3 in i-PrOH (2 M, 10 mL was added to the crude material cooled in an ice-H2O bath under Ar. The mixture was stirred, sonicated and filtered. The solids and the reaction flask were washed with i-PrOH multiple times. The filtrate was concentrated under reduced pressure. The light yellow residue was partitioned between DCM (60 mL) and H2O (20 mL). The aq. layer was extracted with DCM (2×). Combined organic phase was washed with brine and dried (Na2SO4) to afford the title compound as a light yellow solid; 1H NMR (400 MHz, CD3CN) δ 9.40 (s, 1H), 8.36 (s, 1H), 8.32-8.25 (m, 2H), 8.13-8.11 (m, 2H), 7.77 (d, J=4.8 Hz, 1H), 7.63-7.51 (m, 3H), 7.32 (d, J=4.8 Hz, 1H), 3.97 (qund, J=1.2 Hz, 8.4 Hz, 1H), 2.60-2.45 (m, 4H), 2.05-1.95 (m, 2H). MS (ES+): m/z 412.0 (40) [MH+]; HPLC: tR=4.10 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]2O)[C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[OH2:24].[NH2:25][NH2:26]>O>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:24])[C:2]1[NH:25][N:26]=[C:11]([NH2:12])[C:10]2=1
Reactant: O
Reactant: NN
Reactant: N#Cc1c(Cl)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Product: Nc1n[nH]c2c1c1cc(Cl)c(Cl)cc1n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2,5,6-Trichloro-3-cyano-1-(β-D-ribofuranosyl)indole (4.4, 102 mg, 0.27 mmol) was dissolved in hydrazine hydrate (2 mL), and the resulting solution was stirred at room temperature for 30 min. The suspension thus obtained was diluted with water (8 mL), cooled to 0° C., and the suspension filtered and the solids rinsed with water. The solids were recrystallized from MeOH/H2O to yield 91 mg (90%) of 4.37 as a white crystalline solid: mp 198-201° C.; Rf 0.3 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 8.68 (s, 1H, D2O exch.), 7.76 (s, 1H), 7.27 (s, 1H), 5.81 (d, 1H), 5.78 (b, 1H, D2O exch.), 5.31-5.28 (m, 2H, D2O exch.), 4.84 (s, 2H, D2O exch.), 4.27 (q, 1H), 4.07 (s, 1H), 4.00 (s, 1H), 3.68 (q, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 155.50, 131.99, 129.00, 123.60, 121.60, 116.91, 115.45, 111.96, 88.32, 85.95, 71.06, 69.95, 63.28, 60.78. HRMS (EI) m/z calcd. for C14H14Cl2N4O4 372.0392. found 372.0397. Anal calcd for C14H14Cl2N4O4.¼H2O: C, 44.52; H, 3.87; N, 14.83. Found: C, 44.63; H, 4.10; N, 14.72.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[N:4][CH:5]=[CH:6][N:7]=1.[NH2:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15]([OH:17])=[O:16].C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[NH:7][CH:6]=[CH:5][N:4]=[C:3]1[C:8]([NH:12][C@@H:13]([CH2:14][C:15]([OH:17])=[O:16])[C:18]([OH:20])=[O:19])=[O:10]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: COC(=O)c1nccnc1O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(O)C[C@H](NC(=O)c1ncc[nH]c1=O)C(=O)O
Temperature: 50 °C
Reaction time: 6 h
Yield: 17.4 %

Procedure:
In 4 mL of dimethyl sulfoxide is dissolved 0.4 g of methyl 3-hydroxy-2-pyrazinecarboxlate. Then, 0.27 g of L-aspartic acid and 0.85 mL of triethylamine are successively added to the solution, which is then stirred at 50° C. for 6 hours. The deposited crystals are filtered off, and the filtrate is concentrated under reduced pressure. Then, 2 mL of water and 0.2 mL of methanol are added to the resulting residue. The precipitate formed is collected by filtration to obtain 0.09 g of (2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl)-carbonyl]amino}-butanedioic acid.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=2)[C:24]([CH:32]2[CH2:34][CH2:33]2)=[N:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:29]=2)[C:24]([CH:32]2[CH2:33][CH2:34]2)=[N:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Oc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCOc1ccc2c(C3CC3)nn(Cc3ccccc3)c2c1)OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Benzyl 2-bromoethylcarbamate (1.0563 g) which can be prepared according to the method described in Reference example 40, etc. was dissolved in dehydrated DMF (5 mL), added with 1-benzyl-3-cyclopropylindazol-6-ol (533.4 mg) which can be prepared according to the method described in Reference example 3, etc. and potassium carbonate (879.1 mg), and stirred overnight at 50° C. under nitrogen atmosphere. After cooling to room temperature, the reaction solution was added to water and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over sodium sulfate. After the solvent was evaporated under reduced pressure, the resulting reside was purified by column chromatography (“COLUMN-B”; n-hexane:ethyl acetate=81:19→60:40) to obtain the title compound as a crude product (508.2 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH:7]=[CH:8]3)[C:5]=2[C:4]=1[OH:15].CCOC(C)=O.C(Cl)(Cl)Cl>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH2:7][CH2:8]3)[C:5]=2[C:4]=1[OH:15]
Reactant: COc1cc(O)c2c(c1O)C1C=CC2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(O)c2c(c1O)C1CCC2C1

Procedure:
A solution of 1,4-dihydro-6-methoxy-1,4-methanonaphthalene-5,8-diol (48, 1.30 g, 6.36 mmol) in MeOH (100 mL) was hydrogenated (Parr hydrogenator, 20 psi) over Pd (10% on C, 100 mg, Aldrich) for 15 min. TLC analysis (10% EtOAc, 90% CHCl3) indicated total consumption of the organic starting material to give a higher Rf product. The catalyst was removed by filtration through celite during which time the filtrate turned light green. Color change was attributed to trace air oxidation of the desired product to the corresponding quinone. After MeOH removal, the residue was filtered through silica gel with CHCl3 elution. Solvent removal yielded 52 as a brown gummy solid, which was found suitable for the next reaction without further purification (1.28 g, 98%, purity >95% by TLC and 1H NMR analyses); 1H NMR (CDCl3) δ1.20 (m, 2H), 1.49 (d, J=8.7 Hz, 1H), 1.70 (m, 1H), 1.88 (m, 2H), 3.42 (s, 1H), 3.62 (s, 1H), 3.80 (s, 3H), 4.37 (s, 1H), 5.17 (s, 1H), 6.19 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.B(F)(F)F.[CH3:29][CH2:30]OCC>C1(C)C=CC=CC=1>[CH:11]([CH:5]1[C:4]2[C:3](=[CH:2][CH:9]=[CH:8][CH:7]=2)[CH:30]=[CH:29]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Agent: NCc1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: C1=CC(C(c2ccccc2)c2ccccc2)c2ccccc21
Yield: 95 %

Procedure:
To a solution of 3,4-difluorobenzylamine (9.8 g, 69 mmol) and benzophenone (13.0 g, 71.0 mmol) in toluene (200 mL) was added a catalytic amount of BF3.OEt2 and the resulting solution was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo, yielding an oil (21 g, >95%), which was characterized by NMR analysis and subjected to the following reaction without any further purification.