Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NN.C(O)C.[C:6]([O:10][C:11]([N:13]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][N:47]1C(=O)C2=CC=CC=C2C1=O)[CH2:14][CH2:15][N:16]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]1C(=O)C2=CC=CC=C2C1=O)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[NH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]
Reactant: CC(C)(C)OC(=O)N(CCCCCCN1C(=O)c2ccccc2C1=O)CCN(CCCCCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCCCCCN)CCN(CCCCCCN)C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84 %

Procedure:
A solution of anhydrous hydrazine (1 ml) was added to a stirred mixture of anhydrous ethanol (30 ml) and methylene chloride (20 ml) containing N,N′-bis(t-butyloxycarbonyl)-N,N′-bis(6-phthalimidohexyl)-1,2-diaminoethane (2.8 g; example 9). The reaction was continued overnight and the precipitated phthalazinedione by-product was removed by filtration. The filtrate on concentration at reduced pressure gave the title compound (1.5 g) as an oil.
Reaction SMILES: C[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O-:5])=[O:4].S(=O)(=O)(O)O.[C:17]([O-])(O)=O.[Na+]>CO>[C:6]1([CH2:2][C:3]([O:5][CH3:17])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC(C(=O)[O-])c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccccc1
Reaction time: 2 h
Yield: 95 %

Procedure:
To a stirred solution of 2-methyl-2-phenylacetate (10 g, 1 eq) in dry MeOH was added sulfuric acid (1.0 mL) dropwise and heated to reflux. Stirring was then continued for 2 hours. The reaction mixture was then cooled and poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil (10.5 g, 95%) that was not further purified.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=O)[CH3:11].[CH3:13][Mg]Cl.Cl.O>C1COCC1.[Pd]>[CH:10]([C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[OH:1])([CH3:11])[CH3:13]
Reactant: C[Mg]Cl
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled solution of 1-(2-Hydroxy-5-methoxy-phenyl)-ethanone (10.0 g) in 80 mL of THF was gradually added 46.4 g of 3M solution of MeMgCl in THF at a rate such that the reaction mixture temperature did not exceed 25 degrees C. Following addition of the MeMgCl solution, the reaction mixture was stirred at ambient temperature for 18 hours. To the stirred solution was then added 10% palladium on carbon (1.02 g, 50% water wet) suspended in 4 mL of THF. The reaction mixture was placed under a hydrogen atmosphere at 5 psig and cooling was applied to maintain a temperature of approximately 25° C. To the cooled mixture was gradually added concentrated HCl (20 mL) while maintaining the reaction temperature at 25° C. The resultant mixture was stirred at ambient temperature for 18 hours, then treated with 45 mL water and filtered through a bed of Celite to remove suspended catalyst. The filter cake was rinsed with EtOAc and the combined filtrate was separated. The organic phase was washed with water, then concentrated under reduced pressure to give 10.4 g of 2-isopropyl-4-methoxy-phenol, MS (M+H)=167. This product was dissolved in 2-butanone (20.4 g) and the crude solution was employed directly in the next step.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[C:15]2[CH2:14][S:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5].C(N(CC)CC)C.[C:23]([O:27][C:28](N=[N+]=[N-])=[O:29])([CH3:26])([CH3:25])[CH3:24]>O.O1CCOCC1>[C:23]([O:27][C:28]([C:3]([NH2:2])([C:7]1[C:15]2[CH2:14][S:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Reactant: NC(C(=O)O)c1cccc2c1CSC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N)(C(=O)O)c1cccc2c1CSC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
α-Amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid hydrochloride (0.01 m) is dissolved in a mixture of equal parts of water and dioxane. Triethylamine (0.01 m) and tert-butoxycarbonylazide (0.01 m) are added to the mixture which is stirred for 18 hours at room temperature. The dioxane is evaporated from the mixture, ethyl acetate is added and the pH of the aqueous phase is adjusted to about 2.5 with the addition of 1 N hydrochloric acid. The phases are separated and the aqueous phase is extracted a second time with additional ethyl acetate. The ethyl acetate is separated from the aqueous phase. These extracts are combined and dried over magnesium sulfate. Evaporation of the ethyl acetate gives α-(tert-butoxycarbonyl)amino(1,3-dihydrobenzo[c]thien-4-yl)acetic acid.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:41])([CH3:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 78.2 %

Procedure:
4.2 g of 4-(diphenylmethoxy)-1-piperidinepropaneamine and 1.76 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 192-200° C. for 3.5 hours. After cooling, an aqueous sodium bicarbonate solution was added thereto and extracted with ethyl acetate. The extract was washed with a brine solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with ethyl acetate:methanol:triethyl amine (100:5:1). The desired fraction was collected and dissolved in 16 mL of ethyl acetate, and a solution prepared by dissolving 867 mg of fumaric acid in 16 mL of methanol was added thereto, followed by concentration. To the residue was added acetone and the crystals formed were collected by filtration, washed with acetone and dried to provide 2.30 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:21]1([CH2:27][C:28](=O)[C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:27]([C:28]1[C:29](=[O:30])[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccnc1Nc1cccc(-c2cccnc2)c1
Reactant: O=C(O)C(=O)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=c1c(Cc2ccccc2)nc2cccnc2n1-c1cccc(-c2cccnc2)c1
Yield: 56.9 %

Procedure:
A mixture of 3-amino-2-[3-(3-pyridyl)phenylamino]pyridine (150 mg) and 3-phenylpyruvic acid (113 mg) in ethanol (4 ml) was stirred under reflux for 2 hours. The mixture was cooled and then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was crystallized from ethanol to give 2-benzyl-4-[3-(3-pyridyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (127 mg).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[NH2:8][C@H:9]([C:14]([O:16][CH:17]1[C:23]2[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=2[N:21]([C:29](=[O:48])[C:30]2[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:45])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH3:44])=[CH:32][C:31]=2[O:46][CH3:47])[CH2:20][CH2:19][CH2:18]1)=[O:15])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(NC(=O)c2ccccc2C)ccc1C(=O)N1CCCC(OC(=O)[C@@H](N)CCSC)c2cc(Cl)ccc21

Procedure:
A uniform solution of 1.27 g of 5-(N-tert-butoxycarbonyl-L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo-azepine, 2.5 ml of trifluoroacetic acid and 0.6 ml of anisole was stirred at room temperature for 2 hours. The most part of trifluoroacetic acid was removed by distillation under reduced pressure. To the residue was added a 0.2N aqueous sodium hydroxide solution to make the residue alkaline. The mixture was subjected to extraction with dichloromethane. The dichloromethane layer was water-washed, then dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (elutant: ethyl acetate) to obtain 0.34 g of an isomer A and 0.35 g of an isomer B both of 5-(L-methionyloxy)-7-chloro-1-[2-methoxy-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Br[C:13]1[C:25]2[NH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:22]1([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])[C:23]2[NH:24][C:25]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Brc1cccc2c1[nH]c1ccccc12
Reactant: COC(=O)c1ccccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1Nc1cccc2c1[nH]c1ccccc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
35.51 g (234.9 mmol) of methyl anthranilate are dissolved in 500 ml of toluene and degassed well. 52 g (213 mmol) of 1-bromocarbazole, 2.1 g (10.7 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, 1.19 g (5.34 mmol) of Pd(OAc)2 and 76.5 g (234.9 mmol) of Cs2CO3 are added, and the mixture is then degassed and stirred at 100° C. under a protective-gas atmosphere for 24 h. The solids are subsequently filtered off via Celite, and the organic phase is washed with water, dried over MgSO4 and evaporated. The crude product is washed by stirring with hot heptane, giving 57.4 g (108 mmol), 86% of theory, purity according to HPLC 86%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:16][C:15]3[C:10](=[C:11]([Cl:19])[C:12]([Cl:18])=[C:13]([OH:17])[CH:14]=3)[C:9]2=[O:20])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+].Cl>CN(C)C=O.CCCCCC.O>[O:20]=[C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:17][CH2:29][C:30]([OH:32])=[O:31])=[C:12]([Cl:18])[C:11]=2[Cl:19])[CH2:16][C:8]1([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CC1(c2ccc(F)cc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: CC1(c2ccc(F)cc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 80 °C

Procedure:
A stirred mixture of 2-(4-fluorophenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (1.04 g., 0.0032 mole), potassium carbonate (0.885 g., 0.0064 mole) and ethyl bromoacetate (1.07 g., 0.0064 mole) in dimethylformamide (30 ml.) is warmed at 55°-60° C. for 3 hours, then treated with water (30 ml.)-10N sodium hydroxide solution (1 ml., 0.01 mole) and heated at 80° C. for one hour. The reaction mixture is added slowly to water (500 ml.) -12N hydrochloric acid (10 ml.) to precipitate 450 mg. of [1-oxo-2-(4-fluorophenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid which melts at 150°-156° C. after crystallization form ethyl acetate:hexane, 1:3.
Reaction SMILES: Cl.Cl.[CH:3]1(NC(C2C3C=C(C4C([Cl:24])=CN=C(NCCC5CCN(CC)CC5)N=4)SC=3C=CC=2)=O)C[CH2:4]1.[CH:36]1([NH:39][C:40]([C:42]2[C:50]3[CH:49]=[C:48]([C:51]4[C:56]([Cl:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH2:61][CH:62]5[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]5)[N:52]=4)[S:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:38][CH2:37]1.ICC>>[ClH:24].[ClH:57].[CH:36]1([NH:39][C:40]([C:42]2[C:50]3[CH:49]=[C:48]([C:51]4[C:56]([Cl:57])=[CH:55][N:54]=[C:53]([NH:58][CH2:59][CH2:60][CH2:61][CH:62]5[CH2:63][CH2:64][N:65]([CH2:3][CH3:4])[CH2:66][CH2:67]5)[N:52]=4)[S:47][C:46]=3[CH:45]=[CH:44][CH:43]=2)=[O:41])[CH2:37][CH2:38]1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCC4CCNCC4)ncc3Cl)cc12
Reactant: CCN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Solvent: CCI
Product: CCN1CCC(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-ethylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide di-hydrochloride, the title compound may be prepared as the di-hydrochloride acid salt from 2-[5-chloro-2-(3-piperidin-4-yl-propylamino)-pyrimidin-4-yl]-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and iodoethane. ES+(m/z) 498 (35Cl) and 500 (37Cl) [M(free base)+H].
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@H:9]([CH3:20])[O:8][C@@H:6]1[S:7][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]/[CH:29]=[CH:30]\[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:3])[CH3:2]
Reactant: CCCCCCCC/C=C\CCCCCCCCI
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](S)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCCS[C@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 48 h

Procedure:
A solution of 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranose (2.0 g, 6.5 mmol) and oleyl iodide (2.5 g, 6.6 mmol) in dichloromethane (40 ml) containing triethylamine (1 ml) is kept under nitrogen for 2 days at room temperature. The solution is worked up in the normal manner and the resulting syrup is column chromatographed on silica gel with 2-10% ethyl acetate in chloroform as eluents. Oleyl 2,3,4-tri-O-acetyl-1-thio-β-L-fucopyranoside is isolated as a syrup (1.2 g, 32%), [α]D +26° (c, 2.19, chloroform).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21](=[O:26])[C:22]([O:24][CH3:25])=[O:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:25][O:24][C:22](=[O:23])[C:21]([NH:20][C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:26]
Reactant: COC(=O)C(=O)Nc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(=O)Nc1cnc(N2CCNCC2)nc1

Procedure:
A solution of tert-Butyl-4-(5-{[methoxy(oxo)acetyl]amino}pyrimidin-2-yl)piperazine 1-carboxylate (Intermediate 53; 4.14 g, 11.33 mmol) in a 4M solution of HCl in dioxane (40 mL) was stirred for 16 h. The precipitate was collected by filtration and washed with ether to give N-(5-{[methoxy(oxo)acetyl]amino}pyrimidin-2-yl)piperazine hydrochloride as a solid. Pyridine (9.16 mL, 113.30 mmol), followed by acetyl chloride (0.97 mL, 13.60 mmol) were added to an ice-cooled suspension of this solid (3.4 g) in DCM (100 mL) and the mixture was allowed to warm to ambient temperature and stirred for 1 h. Water (100 mL) was added and the mixture was extracted with DCM (3×100 mL). The organic extracts were combined, dried and concentrated by evaporation. The residue was triturated with isohexane to give the title compound (2.45 g, 70%) as a solid; 1H NMR δ: 10.79 (1H, s), 8.65 (2H, s), 3.84 (3H, s), 3.75-3.65 (4H, m), 3.52-3.45 (4H, m), 2.04 (3H, s); MS m/e MH+: 308.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][C:7]([C:10]([NH:12][NH2:13])=[NH:11])=[CH:6][C:5]=12.[CH:14]([CH:16]=O)=O>C(O)C>[N:13]1[CH:16]=[CH:14][N:11]=[C:10]([C:7]2[CH:8]=[CH:9][N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=2)[N:12]=1
Reactant: O=CC=O
Reactant: N=C(NN)c1ccn2ccnc2c1
Solvent: CCO
Product: c1cnc(-c2ccn3ccnc3c2)nn1
Reaction time: 1 h
Yield: 80 %

Procedure:
To half the material from step d (ca. 2.3 mmol) was added glyoxal (40% in water, 1 ml) and ethanol (15 ml) and the mixture heated to 100 deg C. After 1 hour the reaction was allowed to cool and was concentrated in vacuo. Water and dichloromethane was added and the mixture filtered under suction. The organic liquors were discarded and the aqueous layer was basified with 2N sodium hydroxide solution. To this was added dichloromethane and the mixture was again filtered under suction. The dichloromethane layer was separated and concentrated to furnish 289 mg of a yellow solid (80% clean). MS: [M+H]+198
Reaction SMILES: [C:1]1([C:7]2[N:8]([N:18]=[C:19]([CH3:23])[C:20](=O)[CH3:21])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[C:29]1([C:35]2[N:36]([NH2:46])[C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]([N:18]=[C:19]([C:20](=[N:46][N:36]3[C:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:38][CH:39]=[C:35]3[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:21])[CH3:23])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=Nn1c(-c2ccccc2)ccc1-c1ccccc1)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 18.6 %

Procedure:
A suspension of 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (2.45 g, 8.1 mmol) in toluene (28 mL) was treated with DMF (14 mL), 2,5-diphenyl-pyrrol-1-ylamine (1.99 g, 8.5 mmol) and p-toluene sulfonic acid (73 mg). The resulting suspension was fitted with a Dean Stark trap and heated to reflux in an oil bath for 21 h, then cooled to rt and allowed to stand under Ar for 4 days. The desired compound did not crystallize, therefore the solution was concentrated in vacuo. Approximately half of the residue was purified by flash chromatography (SiO2, 5-100% EtOAc/heptane) to afford some pure desired 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (780 mg) and some desired contaminated with starting 2,5-diphenyl-pyrrol-1-ylamine. The remaining crude residue was flash chromatographed (SiO2, 33-50% CH2Cl2/heptane) in an attempt to remove excess amino pyrrole. No separation was achieved, therefore all of the fractions were combined, together with the impure material from the first column and concentrated in vacuo. This mixture was suspended in toluene (15 mL) and treated with DMF (5 mL), 2,3-butanedione (0.81 mL, 9.24 mmol) and p-toluene sulfonic acid (7 mg). The resulting suspension was heated to 70° C. in an oil bath, and stirred under Ar for 3 h, then cooled to rt and concentrated in vacuo. The resulting solid was washed with water, heptane and toluene (to remove 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one and 2,3-butanedione) and dried in vacuo to afford 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane (1.42 g) as a yellow solid. Overall, 2.2 g (52% based on 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one) of 2,3-bis(2,5-Diphenyl-pyrrol-1-ylimino)-butane was isolated as a yellow solid: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.71 (s, 6H), 6.44 (s, 4H), 7.22-7.36 (m, 20H).
Reaction SMILES: [BrH:1].C(O)(=O)C.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=O)[CH2:15][S:16][C:17]#[N:18].O>C(O)(=O)C>[Br:1][C:17]1[S:16][CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[N:18]=1
Reactant: N#CSCC(=O)c1ccc(F)cc1F
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2csc(Br)n2)c(F)c1
Temperature: 130 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A 25% hydrogen bromide/acetic acid (25 ml) solution was added to a solution of 2-(2,4-difluorophenyl)-2-oxoethyl thiocyanate (3.39 g, 15.9 mmol) in acetic acid (25 ml), and the mixture was stirred at 130° C. for 2 hours and stirred at room temperature for 1 hour. Water was poured to the reaction mixture, and crystals were collected by filtration and washed with water to give 3.23 g (73.6%) of the desired product as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[O:4][CH2:3]1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH:34]=O)=[N:26]1>CO.N1CCCCC1>[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](/[CH:34]=[C:3]2\[O:4][C:5]3[C:10]([CH2:11][N:12]4[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]4)=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]\2=[O:1])=[N:26]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2n[nH]c4ccccc24)C3=O)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
A solution of tert-butyl 4-[(3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.0359 g, 0.108 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0166 g, 0.113 mmol) and piperidine (5 drops), and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0332 g, 67%).