Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[N:18]=[CH:17][NH:16][C:15]=2[C:14](=[O:20])[NH:13][C:12]1=[S:21].C(N(CC)CC)C.[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31][CH:30]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][NH:8][CH2:9][CH2:10][N:11]2[C:19]3[N:18]=[CH:17][NH:16][C:15]=3[C:14](=[O:20])[NH:13][C:12]2=[S:21])=[CH:31][CH:30]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: NCCn1c(=S)[nH]c(=O)c2[nH]cnc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=S)n(CCNCc2ccnc3ccccc23)c2nc[nH]c12
Yield: 29.3 %

Procedure:
3-(2-Aminoethyl)-2-thioxo-1,2,3,7-tetrahydro-6H-purin-6-one trifluoroacetate (98 mg, 0.3 mmol, obtained from Example 26(b)) and triethylamine (0.043 mL, 0.31 mmol) was stirred in dry methanol for 15 min. 4-Quinoline carboxaldehyde (47 mg, 0.3 mmol) and acetic acid (3 drops) were added and the mixture was stirred o.n. Sodium cyanoborohydride (28 mg, 0.45 mmol) was added and the mixture was stirred for 5 h. The mixture was then concentrated and purified by preparative HPLC, giving 31 mg (29% yield) of the title compound
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:33]([OH:37])[CH2:34][C:35]#[CH:36]>N1CCCCC1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.[Cu]I>[OH:37][CH2:33][CH2:34][C:35]#[C:36][C:2]1[S:10][C:9]2[C:8]([NH:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)=[CH:16][CH:15]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: O=C(Nc1ccc(CCNc2ncnc3cc(Br)sc23)cc1)c1cccc(C(F)(F)F)c1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Solvent: C1CCNCC1
Solvent: N#Cc1ccccc1
Product: O=C(Nc1ccc(CCNc2ncnc3cc(C#CCCO)sc23)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a nitrogen purged solution of compound 20.2 (0.79 mmol), 3-butyn-1-ol (2.5 equivalents), Pd(PhCN)2Cl2 (0.2 equivalent) in piperidine was added CuI (0.5 equivalent) followed by stirring at room temperature for 3 hours. The reaction mixture was then subjected to an aqueous work-up and purified by flash column chromatography on silica gel to provide N-(4-{2-[6-(4-hydroxy-but-1-ynyl)-thieno[3,2-d]pyrimidin-4-ylamino]-ethyl}-phenyl)-3-trifluoromethyl-benzamide (compound 23.1).
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH2:21][CH2:22][CH3:23]>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:25]=[C:20]([CH2:21][CH2:22][CH3:23])[N:24]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Reactant: CCCC(=N)N
Agent: Cl
Product: CCCc1ncc(C(=O)O)c(-c2ccccc2)n1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and butyramidine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-propyl-pyrimidine-5-carboxylic acid.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([CH:29]1[CH2:32][CH:31]([CH:33]=O)[CH2:30]1)[CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:33][CH:31]1[CH2:32][CH:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:30]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)CC1CC(C=O)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)CC1CC(C=C(Br)Br)C1
Reaction time: 0.33 h

Procedure:
To a solution of carbon tetrabromide (168 g) in methylene chloride (252 mL) was added dropwise a solution of triphenylphosphine (266 g) in methylene chloride (350 mL) at ice temperature. The mixture was stirred at ice temperature for 20 min. To the mixture was then added dropwise a solution of 3-isobutylcyclobutanecarbaldehyde in methylene chloride at ice temperature. The mixture was stirred at ice temperature for 20 min. After an addition of aqueous 10 w/v % sodium carbonate (1 L) dropwise to the mixture, the mixture was extracted with methylene chloride (200 mL×2). The combined organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. To the resultant residue were added hexane/chloroform=1/1 (750 mL), silica gel (750 mL) and hexane (900 mL). The mixture was filtered and the filtrate was concentrated in vacuo. To the resultant residue was added hexane (500 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: hexane) to give the title compound (76.21 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][O:18][CH2:19][C:20]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:10]=2)=[CH:5][CH:4]=1)#[N:2].CO>ClCCl.FC(F)(F)C(O)=O>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][C:11]=1[CH2:17][O:18][CH2:19][C:20]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: COc1ccc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc(-c2ccc(C#N)cc2)cc1COCC1(c2ccccc2)CCNCC1
Reaction time: 0.75 h

Procedure:
tert-Butyl 4-(((4′-cyano-4-methoxybiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (47 mg, 0.092 mmol) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (1 mL). The reaction was stirred for 45 min and concentrated. The residue was dissolved in methanol and loaded onto an strong cation exchange cartridge. The cartridge was flushed with plenty of methanol which was discarded. The product was then eluted using 2 M ammonia in methanol. The solvent was evaporated to give 34 mg (90%) as a colorless oil. Retention time: 2.20 min. (Phenomenex C18 3.0×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=3 min., Flow rate=4 mL/min.) Mass spec.: 413.39 (MH)+. Accurate mass spec.: m/z 413.2245 [MH]+, Δ=3.9 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[CH3:30][N:31]1[CH2:37][C:35](=[O:36])[NH:34][C:32]1=[O:33]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:34]1[C:35](=[O:36])[CH2:37][N:31]([CH3:30])[C:32]1=[O:33]
Reactant: CN1CC(=O)NC1=O
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)CN(C)C2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol) and methylhydantoin (16 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (petroleum ether/ethyl acetate 1:1) to provide the title compound, which was impure. The product was further purified by preparative TLC (petroleum ether/ethyl acetate 1:1) to furnish the pure title compound as yellow oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH3:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1>C(Cl)Cl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([N:15]([CH3:16])[C:12]3[CH:13]=[CH:14][C:9]([CH2:8][N:6]4[CH2:5][CH2:4][N:3]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C@@H:2]([CH3:1])[CH2:7]4)=[CH:10][CH:11]=3)(=[O:46])=[O:45])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(Cc2ccc(N(C)S(=O)(=O)c3ccc(-c4ccc(F)cc4)cc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 30.9 %

Procedure:
D3 (100 mg, 0.31 mmol) and triethylamine (65 ul, 0.47 mmol) were combined in dry DCM (3 mL) under argon. 4′-Fluoro-4-biphenylsulfonyl chloride (93 mg, 0.34 mmol) was added dropwise in a solution of dry DCM (3 mL). The reaction mixture was stirred at room temperature under argon for 19 h and diluted with DCM (20 mL) and washed with water then the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by chromatography eluting with 0-100% Et2O/petroleum ether to afford the title compound (53 mg), δH (CDCl3), 400 MHz: 1.23 (3H, d), 1.46 (9H, s), 2.01 (1H, m), 2.14, 1H, dd), 2.57 (1H, m), 2.74 (1H, m), 3.10 (1H, m), 3.21 (3H, s), 3.39-3.51 (2H, AB), 3.81 (1H, d), 4.19 (1H, br.s), 7.08 (2H, d), 7.17 (2H, t), 7.28 (2H, m), 7.57 (2H, dd), 7.61 (4H, s). MS (ES+): MH+ 554.3
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([C@@H:15]1[CH2:18][CH2:17][C@H:16]1[CH2:19][OH:20])=[O:14].C(N(CC)CC)C>ClCCl.O>[CH3:11][O:12][C:13]([C@@H:15]1[CH2:18][CH2:17][C@H:16]1[CH:19]=[O:20])=[O:14]
Reactant: COC(=O)[C@@H]1CC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1CC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
At −78° C., oxalyl Chloride (9.2 mL, 106.5 mmol) was solved in dichloromethane (250 mL) and (15.5 mL, 218 mmol) of dimethylsulfoxide in 20 mL of dichloromethane was added. After 15 minutes of stirring at −78° C., Trans-2-Hydroxymethyl-cyclobutanecarboxylic acid methyl ester (14 g, 95.17 mmol) was added in 78 mL of dichloromethane and 10 minutes later triethylamine (67 mL, 479 mmol) was added and the mixture was stirred for 2 h at −78° C. 150 mL of dichloromethane added and 200 mL of water were added and the aqueous phase was extracted with 200 mL of dichlormethane and the combined organic phases were purified with column chromatography on silica using n-heptane/AcOEt (4+1) to yield 11.1 g, (78 mmol, 82% yield) of the title compound as a colourless liquid. MS (m/e): 165.2 (M+Na+)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)nc1C(F)(F)F

Procedure:
Protocol T was followed using 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3); 8.15 (s, 1H), 6.98-7.04 (m, 2H), 6.86-6.92 (m, 2H), 5.1 (s, 2H), 4.28-4.38 (q, 2H), 3.78-3.84 (m, 2H), 3.62-3.74 (m, 2H), 3.04-3.2 (m, 4H), 1.3-1.4 (t, 3H). 13C NMR (400 MHz, CDCl3): 163.4, 160.5, 159.2, 156.2, 147, 137.2, 119, 118.8, 116, 115.8, 61, 54, 50.8, 50.0, 45.0, 42.2, 14.2.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1OC)[C:6]([OH:8])=[O:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.[F:49][C:50]1[CH:67]=[CH:66][C:53]2[N:54]([CH2:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[C:55]([SH:57])=[N:56][C:52]=2[CH:51]=1>C1COCC1>[C:62]([O:61][C:59](=[O:60])[CH2:58][N:54]1[C:53]2[CH:66]=[CH:67][C:50]([F:49])=[CH:51][C:52]=2[N:56]=[C:55]1[S:57][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=[O:7])[CH:4]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2cc(F)ccc21
Reactant: COc1ccc(C(=O)O)cc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(SCc2cccc(C(=O)O)c2)nc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 181.4 %

Procedure:
To a solution of 3-hydroxymethyl-4-methoxy-benzoic acid (Starting material H-00e, 910 mg, 5 mmol) in dry THF (50 ml) cooled to 0° C. under inert atmosphere are added successively triphenylphosphine (1782 mg, 6 mmol, 1.2 eq.) and di-tert-butyl-azodicarboxylate (1381 mg, 6 mmol, 1.2 eq). The initially deep yellow colour disappears after 10 min. Then tert-butyl (5-fluoro-2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-III, 1270 mg, 0.9 mmol, 0.9 eq.) is added. The reaction mixture is allowed to warm up to rt and stirred at this temperature for 1 h. Evaporation of the solvent in vacuo and purification by flash-chromatography on silica gel (AcOEt/heptane/AcOH, 10:90:1), provides the title compound (680 mg) in 30% as beige solid:
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6][CH3:7])[CH2:3][CH3:4].[CH2:8]([O:15][NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([O:15][N:16]([CH:2]([CH2:3][CH3:4])[CH2:5][CH2:6][CH3:7])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCCC(Br)CC
Reactant: O=C(NOCc1ccccc1)Nc1ccccc1
Product: CCCC(CC)N(OCc1ccccc1)C(=O)Nc1ccccc1
Yield: 34.5 %

Procedure:
Using the general method of Compound 42 Part B, 3-bromohexane (4.59 mL, 32.6 mmole) was reacted with 1-benzyloxy-3-phenylurea (7.3 g, 30.2 mmole) to provide 3.4 g of 1-benzyloxy-1-(1-ethylbutyl)-3-phenylurea.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=O.CO.[OH-].[Na+]>C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2].CCOCC.O>[Cl:8][C:6]1[CH:7]=[C:2]([NH:1][CH2:17][C:16]2[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:15]=2[CH3:14])[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: Cc1nc2c(N)cc(Cl)cn2c1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1CNc1cc(Cl)cn2c(C)c(C)nc12
Yield: 36.3 %

Procedure:
A mixture of 8-amino-6-chloro-2,3-dimethylimidazo[1,2-a]pyridine (0.894 g, 4.57 mmol), 2,6-dimethylbenzaldehyde (0.77 g, 5.7 mmol), ZnCl2 (1.08 g, 7.92 mmol), NaB(CN)H3 (0.36 g, 5.7 mmol) and MeOH (35 ml) was refluxed for 3.5 h. More 2,6-dimethylbenzaldehyde (0.25 g in 4 ml MeOH), ZnCl2 (0.55 g) and NaB(CN)H3 (0.35 g) were added. The reaction mixture was refluxed for additional 4 h. Subsequent workup by addition of 1 M NaOH (150 ml), and water (50 ml), followed by extraction of the mixture with CH2Cl2, drying, and evaporation of solvent gave a solid residue. The crude product dissolved in ethyl acetate and ether was added. Filtration and evaporation of solvent gave a residue which was recrystallized from ethyl acetate to give 0.52 g product.
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[C:12](=O)[CH:11]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22](OCC)=[O:23])[CH2:10]3)[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C([O-])(=O)C.[NH4+:37]>C(O)(=O)C>[C:4]1(=[O:27])[N:5]([CH2:6][C:7]2[CH:15]=[CH:14][C:13]3[C:12]4[NH:37][C:22](=[O:23])[C:18]5[N:17]([CH:21]=[CH:20][N:19]=5)[C:11]=4[CH2:10][C:9]=3[CH:8]=2)[C:1](=[O:32])[C:2]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:3]12
Reactant: [NH4+]
Reactant: CCOC(=O)c1nccn1C1Cc2cc(CN3C(=O)c4ccccc4C3=O)ccc2C1=O
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Temperature: 20 °C
Yield: 66.1 %

Procedure:
8-Phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one can be obtained in the following way: a mixture of 17 g of ethyl 1-(5-phthalimidomethyl-1oxoindan-2yl)imidazole-2-carboxylate and 153 g of ammonium acetate in 355 ml of glacial acetic acid is heated at reflux for 16 hours. The reaction mixture is cooled to a temperature in the region of 20° C. The precipitate is filtered on sintered glass, rinsed with distilled water to neutral pH and then washed with acetone. After drying under vacuum (1 mbar) at 80° C., 10 g of 8-phthalimidomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one are obtained in the form of a brown solid (1H NMR spectrum in d6-DMSO, T=300 K, δ in ppm: 4.00 (2H, s, CH2), 4.83 (2H, s, NCH2), 7.47 (1H, d, J=7 Hz, arom. CH), 7.55 (2H, d, J=7 Hz, arom. CH), 7.80 (1H, d,J=7 Hz, arom. CH), between 7.85 and 8.00 (4H, m, phthal. H), 12.30 (1H, broad s, NH)).
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]([OH:11])[CH3:10].[Br:12][C:13]1[CH:14]=[C:15]([NH2:20])[CH:16]=[CH:17][C:18]=1[CH3:19].O>C1(C)C=CC=CC=1>[Br:12][C:13]1[CH:14]=[C:15]([NH:20][CH2:10][CH2:9][OH:11])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1ccc(N)cc1Br
Reactant: CC(O)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(NCCO)cc1Br
Temperature: 100 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
Triethylamine (0.28 mL, 2.00 mmol) and bromoethanol (0.14 mL, 1.98 mmol) were added to a solution of 3-bromo-4-methyl-phenylamine (240 mg, 1.29 mmol) in toluene (2 ml). The mixture was stirred at 100° C. overnight and H2O was then added, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/AcOEt) to give 2-(3-bromo-4-methyl-phenylamino)-ethanol (185 mg, 62%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:6](Cl)=[O:7])#[N:2].[CH3:13][C:14]1[C:19]2[NH:20][C:21](=[O:23])[O:22][C:18]=2[CH:17]=[CH:16][CH:15]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[F:12][C:10]1[CH:11]=[C:3]([CH:4]=[C:5]([C:6]([C:16]2[CH:15]=[C:14]([CH3:13])[C:19]3[NH:20][C:21](=[O:23])[O:22][C:18]=3[CH:17]=2)=[O:7])[CH:9]=1)[C:1]#[N:2]
Reactant: N#Cc1cc(F)cc(C(=O)Cl)c1
Reactant: Cc1cccc2oc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(F)cc(C#N)c2)cc2oc(=O)[nH]c12
Temperature: 0 °C

Procedure:
1.84 g (10.0 mmol) 3-cyano-5-fluoro-benzoic acid chloride, 1.49 g (10.0 mmol) 4-methyl-3H-benzoxazol-2-one and 5.33 g (40.0 mmol) aluminium trichloride were heated to 125° C. for 1.5 h with stirring. Then the mixture was mixed with ice water. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[OH:19])([CH3:8])([CH3:7])[CH3:6].[CH:20]12[O:25][CH:21]1[CH2:22][CH2:23][CH2:24]2>C(O)C>[CH3:6][C:5]([C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:10]=1[O:19][C@@H:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[OH:25])([CH3:8])[CH3:7]
Reactant: C1CC2OC2C1
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1ccc(O[C@@H]2CCC[C@H]2O)c(C(C)(C)C)c1
Reaction time: 0.08 h

Procedure:
To a solution of sodium ethoxide in ethanol (prepared by dissolving 230 mg of sodium in 25 ml of ethanol) was added 2.06 g (10.0 mmoles) of 2,4-di-t-butylphenol. The mixture was stirred for 5 minutes, and then 841 mg (10.0 mmoles) of cyclopentene oxide was added. After refluxing overnight, the mixture was cooled and evaporated, the residue partitioned between diethyl ether and dilute aqueous hydrochloric acid, the aqueous layer further extracted with ether, the combined organic extracts washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using 10% ethyl acetate-hexane as eluent gave the title compound, 1.25 g, as a white crystalline solid, m.p. 111.5°-112° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1.O.CN([CH:25]=[O:26])C>>[Cl:6][C:7]1[C:12]([CH:25]=[O:26])=[N:11][CH:10]=[C:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][O:19][CH3:20])[N:8]=1
Reactant: COCC1CCCN1c1cncc(Cl)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COCC1CCCN1c1cnc(C=O)c(Cl)n1
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Phosphoryl chloride (1.2 mL) was added dropwise to DMF (10 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-chloro-6-[2-(methoxymethyl)pyrrolidin-1-yl]pyrazine (1.45 g) in DMF (3 mL), and the mixture was stirred at 50° C. for 16 hr. Water was added to the reaction mixture, and the mixture was stirred for 2 hr, and extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient: 5→50% ethyl acetate/hexane) to give the title compound (1.04 g, 64%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([Br:19])[C:6]2[O:10][C:9]([Br:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:18]=1.[CH3:20][N:21](C)C=O.[C-]#N.[Na+]>O>[C:20]([CH2:2][C:3]1[CH:4]=[C:5]([Br:19])[C:6]2[O:10][C:9]([Br:11])=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]=2[CH:18]=1)#[N:21]
Reactant: CN(C)C=O
Reactant: BrCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1cc(Br)c2oc(Br)c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
A solution of 17.8 g. (0.040 mole) of 5-bromomethyl-2,7-dibromo-3-phenylbenzofuran in 150 ml. of N,N-dimethylformamide, 2.0 g. (0.04 mole) of sodium cyanide and 15 ml. of water is heated on a steam bath for 1.5 hours. The mixture is poured into one liter of water and stirred for about 16 hours. The mixture is extracted with 500 ml. of ethyl acetate, the extracts washed with water, then dried. Evaporation followed by trituration with hexane-ethyl acetate gives 5-cyanomethyl-2,7-dibromo-3-phenylbenzofuran as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([SH:25])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:26](I)[CH2:27][CH3:28]>N>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[N:14]=[CH:15][CH:16]([C:18]2[C:23]([CH3:24])=[CH:22][N:21]=[C:20]([S:25][CH2:26][CH2:27][CH3:28])[N:19]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Reactant: CCCI
Agent: N
Product: CCCSc1ncc(C)c(C2C=NC(C(=O)N[C@H](CO)c3ccccc3)=C2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-mercapto-5-methyl-pyrimidin-4-yl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (7.7 mmol, 2.74 mmol) in aqueous ammonia (15%) was added at room temperature n-propyliodide (11.6 mmol, 1.1 mL). The solution was stirred overnight at room temperature. The resulting solid was collected by filtration and used directly for the next step. 1H NMR consistent with the structure.