Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25](I)=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4].O1C=C[CH:37]=[C:36]1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)CCCC)=C.[F-].[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:5]1([CH2:31][CH2:32][CH2:33][CH3:34])[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([OH:16])=[C:7]([C:17]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([CH:36]=[CH2:37])=[CH:26][C:20]=3[S:19](=[O:29])(=[O:28])[N:18]=2)[C:6]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)c2cc(F)ccc21
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3cc(F)ccc3C(CCCC)(CCCC)C1=O)N2
Temperature: 50 °C
Yield: 523.6 %

Procedure:
A solution of the compound of Example 20B (120 mg, 0.20 mmol), tri-(2-furyl)phosphine (5 mg, 0.020 mmol), tris-(dibenzylideneacetone)palladium (0) (9 mg, 0.010 mmol) in tetrahydrofuran (2 mL) was stirred at ambient temperature for 10 min, during which time the solution changed from a deep maroon color to pale green. The solution was treated with vinyltributylstannane (118 □L, 0.403 mmol) followed by warming at 50° C. for 1.5 h. The solution was cooled, diluted with ethyl acetate and stirred for 1 h with 1 M KF solution. The mixture was filtered through Celite® and the layers separated. The organic layer was washed with saturated NaCl solution and dried over Na2SO4. Concentration in vacuo afforded an oil which was purified by flash chromatography eluting with ethyl acetate in hexane. These procedures afforded the title compound (52 mg, 52%) as a white solid. 1H NMR (300 MHz, CDCl3): δ 0.59 (m, 2 H) 0.73 (m, 6 H) 0.89 (m, 2 H) 1.15 (m, 4 H) 1.88 (m, 2 H) 2.31 (m, 2 H) 5.41 (d, J=11.03 Hz, 1 H) 5.85 (d, J=17.65 Hz, 1 H) 6.74 (dd, J=17.47, 10.85 Hz, 1 H) 7.30 (m, 2 H) 7.43 (m, 2 H) 7.68 (m, 1 H) 7.94 (m, 2 H) 16.80 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=2)[NH2:19])[CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:19][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([F:23])[CH:25]=3)(=[O:32])=[O:31])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(N)c2)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1
Yield: 100 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]aniline (1.0 g, 3.0 mmol) and 3-fluorobenzenesulfonyl chloride (0.60 mL, 4.5 mmol) the title compound of Step A was obtained (1.46 g, 2.99 mmol, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.48-7.65 (m, 4H), 7.37 (t, J=7.7 Hz, 1H), 7.20-7.28 (m, 3H), 6.97 (d, J=5.1 Hz, 1H), 3.30-3.37 (m, 1H), 1.38 (d, J=7.0 Hz, 6H). MS (ESI): 489.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[N:31](S(C2C=CC(C)=CC=2)(=O)=O)[C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]1[NH:31][C:18]2=[N:19][CH:20]=[CH:21][C:22]([CH2:23][NH:24][CH2:25][C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[C:17]2[CH:16]=1
Reactant: COc1cc2c(-c3cc4c(CNCc5cccs5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4c(CNCc5cccs5)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 69.1 %

Procedure:
[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine is prepared as described in Example 179a starting with 0.11 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.85 cm3 of 5N potassium hydroxide. 0.056 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]thiophen-2-ylmethylamine is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([CH:16]=1)[OH:15])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:18][C:19]1([CH3:34])[CH:24]2[CH2:25][CH:20]1[CH:21]=[CH:22][C:23]2(OC(=O)C)[O:26]C(=O)C>>[CH3:9][C:2]([C:10]1[CH:11]=[C:12]([OH:17])[C:13]([CH:21]2[CH:20]3[CH2:25][CH:24]([C:19]3([CH3:34])[CH3:18])[C:23](=[O:26])[CH2:22]2)=[C:14]([OH:15])[CH:16]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)(C)c1cc(O)cc(O)c1
Reactant: CC(=O)OC1(OC(C)=O)C=CC2CC1C2(C)C
Product: CCCCCCC(C)(C)c1cc(O)c(C2CC(=O)C3CC2C3(C)C)c(O)c1

Procedure:
Following the same procedure, 1.18 g. of 5-(1,1-dimethylheptyl)resorcinol and 1.19 g. of (+)-6,6-dimethyl-2,2-diacetoxy-3-norpinene were reacted to afford (+)-4-[4-(1,1-dimethylheptyl)-2,6-dihydroxyphenyl]-6,6-dimethyl-2-norpinanone having the identical physical properties as that obtained as described in Example 3.
Reaction SMILES: C(OC(N1CCN(C(Cl)=O)[C@H](CC)C1)=O)(C)(C)C.FC1C=CC=C(F)C=1CO.[F:29][C:30]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:31]=1[CH2:32][O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][C@H:37]1[CH2:49][CH3:50])=[O:35]>>[F:55][C:51]1[CH:52]=[CH:53][CH:54]=[C:30]([F:29])[C:31]=1[CH2:32][O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][C@H:37]1[CH2:49][CH3:50])=[O:35]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)cccc1F
Agent: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)Cl
Agent: OCc1c(F)cccc1F
Product: CC[C@@H]1CNCCN1C(=O)OCc1c(F)cccc1F

Procedure:
This compound was prepared from (R)-4-chlorocarbonyl-3-ethyl-piperazine-1-carboxylic acid tert-butyl ester and 2,6-difluorobenzylalcohol via (R)-2-ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(2,6-difluoro-benzyl) ester according to the procedures described in Example 177 to give the product as a yellowish oil (69 mg); MS (ISP): 285.2 (M+H)+.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH2:19]SC)[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Ni].C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([CH3:19])[CH:13]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CSCc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N
Agent: [Ni]
Solvent: CCO
Product: Cc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N

Procedure:
23.2 g. (0.0764 mole) of 4-(1-adamantyloxy)-2-(methylthiomethyl)-aniline was stirred for 2 hours with approximately 96 g. of Raney nickel in 600 ml. of absolute ethanol. The catalyst was filtered and the solvent was evaporated. Purification by chromatography on silica gel followed by recrystallization from CH2Cl2 -Skellysolve B afforded the desired product, a tan solid, m.p. 143.4°-145.1° C. The NMR spectrum was in accord with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][CH:10]1[C:14]2([CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:9][CH:10]2[C:14]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13][N:12]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC(N)C2(CCCC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(Nc2ccnc(Cl)n2)C2(CCCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (600 mg, 4.03 mmol) and tert-butyl 4-amino-2-azaspiro[4.4]nonane-2-carboxylate (1.07 g, 4.43 mmol) in EtOH (20 mL) was added Et3N (815.6 mg, 8.06 mmol). After addition, the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=10/1 to 1/1) to give the product as a white solid (528 mg, 37.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CN.[N:14]1C=CC=C[CH:15]=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:14][CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccncc1
Agent: CN
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 16 h

Procedure:
4-bromo-N-methylbenzenesulfonamide was prepared by stirring a solution of 4-bromobenzenesulfonyl chloride (400 mg, 1.57 mmol), methylamine (0.78 mL, 2M solution in THF) and pyridine (1 mL) in dichloromethane (5 mL) was at rt for 16 h. The mixture was then diluted with dichloromethane and washed with H2O and then brine. The organic phase was collected, dried (MgSO4) and concentrated in vacuo to give 4-bromo-N-methylbenzenesulfonamide. 1H NMR (d6-DMSO) δ 10.12 (s, 1H0, 9.04 (s, 1H), 8.45 (d, 2H), 8.38 (s, 1H), 8.00 (d, 2H), 7.96 (s, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 3.87 (s, 3H), 2.47 (s, 3H); LC-MS method B, (ES+) 385.0, RT=7.45 min.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)[N:3]=1.Cl.[CH:30]([NH2:32])=[NH:31].C(N(CC)CC)C>CN(C=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH2:21][N:14]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:20]2[C:12]([C:4]2[N:3]=[C:2]3[NH:32][CH:30]=[N:31][C:8](=[O:10])[C:7]3=[CH:6][N:5]=2)=[N:13]1
Reactant: COC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Reactant: N=CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1nc[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc12
Reaction time: 8 h

Procedure:
150 mg (0.38 mmol) of methyl 4-chloro-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carboxylate (example 106A) and 78.5 mg (0.75 mmol) of formamidine hydrochloride were initially charged in 1.5 ml of DMF. Subsequently, 260 μl (1.89 mmol) of triethylamine were added and conversion was effected at 80° C. overnight. After cooling, the precipitated solid was filtered off and the mother liquor was then purified by means of preparative HPLC [column: Reprosil C18, 10 μm, 250*40 mm; eluent: acetonitrile/0.05% formic acid; gradient: 10% acetonitrile→>90% acetonitrile]. Thus, 65 mg (46% of theory) of the target compound were obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].CC(C)=O.[C:24](Cl)(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>O.[OH-].[Na+]>[C:24]([NH:1][C@H:2]([C:8]([NH:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
A suspension of 20 g (0.0724 mols) of α-glutamylglutamic acid in 70 ml of water was dissolved in a 27-% sodium hydroxide aqueous solution until the pH reached 11, and 35 ml of acetone were added thereto. To the solution were added dropwise 15.8 g (0.0724 mols) of lauroyl chloride over a period of 1 hour. When adding lauroyl chloride, the temperature was maintained at 10° C., and 27-% sodium hydroxide was added dropwise simultaneously to keep the pH constant. After the addition of lauroyl chloride, the reaction solution was warmed at 30° C., and allowed to stand for 30 minutes. Subsequently, the pH was adjusted to 1 with the addition of conc. hydrochloric acid. The solid precipitate was separated by filtration, and dried to obtain 30.6 g of N-(N'-lauroyl-α-glutamyl)glutamic acid in a yield of 92%. This solid was analyzed by infrared spectrophotometry. A peak diagnostic of an amide group was observed at 1,650 cm-1 and a peak diagnostic of a carboxyl group was observed at 1,730 cm-1, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1.[SH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:10]=2)[NH:5][C:4](=[O:18])[CH:3]=1
Reactant: Sc1ccccn1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCBr)cc12
Product: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccccn3)cc12

Procedure:
Prepared analogous to Example 122 from 4-methyl-6-(4-bromo-butoxy)-carbostyril (m.p. 217°-219° C.) and 2-mercapto-pyridine.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([NH:18][C:19]([C:21]4[CH:25]=[CH:24][S:23][CH:22]=4)=[O:20])=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=1[N:44]=[C:45]=[O:46]>O1CCCC1>[S:23]1[CH:24]=[CH:25][C:21]([C:19]([NH:18][C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([NH:2][C:45]([NH:44][C:35]5[CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=[CH:39][C:34]=5[F:33])=[O:46])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][N:14]=2)=[O:20])=[CH:22]1
Reactant: Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3c2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 24 °C
Reaction time: 3.5 h

Procedure:
A solution of 1.72 g of 6-(4-aminophenyl)-3-[(thiophen-3-yl)carbonylamino]-1H-indazole hydrochloride and 0.65 mL of triethylamine in 70 mL of tetrahydrofuran is admixed slowly under an argon atmosphere with 0.67 mL of 2-fluoro-5-trifluoromethylphenyl isocyanate. The reaction mixture is stirred at 24° C. for 3.5 hours and then concentrated under reduced pressure. The residue is purified by flash chromatography on a silica column (60; 35-70 μM), eluting with a dichloromethane/methanol (97/3 by volume) mixture, to give 0.4 g of 1-(4-{3-[(thiophen-3-yl)carbonylamino]-1H-indazol-6-yl}phenyl)-3-(2-fluoro-5-trifluoromethylphenyl)urea, whose characteristics are as follows:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:4]=[CH:3]1.[CH:37](OCC)=[O:38]>>[CH:37]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]2[CH:17]=[N:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:6]3)=[N:20][CH:19]=2)[CH2:28][CH2:27]1)=[O:38]
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCNCC5)cn4)c3)n2)c1
Reactant: CCOC=O
Product: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCN(C=O)CC5)cn4)c3)n2)c1

Procedure:
239 mg (0.5 mmol) of 3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile are suspended in 10 ml of ethyl formate and refluxed for 8 h. The reaction mixture is evaporated and purified by means of column chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].Br.[NH2:38][CH:39]1[CH2:44][CH2:43][O:42][C:40]1=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:38][CH:39]1[CH2:44][CH2:43][O:42][C:40]1=[O:41])=[O:24]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NC1CCOC1=O
Agent: Br
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NC2CCOC2=O)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 2-amino-4-butyrolactone hydrobromide.
Reaction SMILES: CCCCCCCC/C=C\CCCCC[CH2:16][CH2:17][C:18]([O:20]CC(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:19].[C:31]([NH2:35])(=[O:34])[CH:32]=[CH2:33].C(O)(=O)C=C.[OH-].[Na+:42].N(C(C)(C)C#N)=NC(C)(C)C#N>CC(C)=O.O>[C:31]([NH2:35])(=[O:34])[CH:32]=[CH2:33].[C:18]([O-:20])(=[O:19])[CH:17]=[CH2:16].[Na+:42]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Agent: C=CC(=O)O
Agent: C=CC(N)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CC(C)=O
Solvent: O
Product: C=CC(=O)[O-]
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
The following components are mixed in a vessel provided with a stirrer, thermometer and nitrogen inlet and outlet: 347 parts of a mixture of 84% of saturated aliphatic hydrocarbons and 16% of naphthenic hydrocarbons (boiling point of the mixture 192°-254° C.), 53.3 parts of sorbitan monooleate and 20 parts of oxyethylated nonylphenol (degree of oxyethylation from 8 to 12). A solution of 133.6 parts of acrylamide and 59 parts of acrylic acid in 389.4 parts of water, the pH of the solution having been brought to 8.0 with 18 parts of sodium hydroxide, is then added and the aqueous solution is emulsified in the hydrocarbon oil. Nitrogen is then passed over the mixture for 30 minutes, after which the mixture is heated to 60° C. in the course of 15 minutes. At this temperature, a solution of 0.212 part of 2,2'-azo-bis-isobutyronitrile dissolved in a small amount of acetone is added. When the mixture has been heated at 60° C. for 3 hours, the polymerization is complete. A coagulate-free, sedimentation-stable water-in-oil dispersion of a copolymer of 35% of acrylamide and 65% of sodium acrylate is obtained, which is used as a thickener, having co-binder properties, in paper coating compositions. The K value of the polymer is 247.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]([F:28])([F:27])[C:22](OCC)=[O:23]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:10]([OH:12])=[O:11])[NH:9][C:22](=[O:23])[C:21]([F:28])([F:27])[F:20])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(C(=O)O)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(O)C(NC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
A mixture of 2-(p-chlorophenyl)glycine (37.1 g, 0.2 mol) in methanol is treated with triethylamine (20.2 g, 0.2 mol), stirred for 10 minutes, treated dropwise with ethyl trifluoroacetate (35.5 g, 0.25 mol), stirred for 4 days, diluted with methanol and treated with Dowex 50×8-100 ion exchange resin. The reaction mixture is stirred for 10 minutes and filtered. The filter cake is washed with methanol. The filtrates are combined and concentrated in vacuo to afford a yellow solid which is recrystallized from 1,2-dichloroethane to give the title compound as white crystals, 26.4 g (46.8% yield), mp 170-172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(N(CC)C(C)C)(C)C.Br[CH2:37][CH:38]1[CH2:40][CH2:39]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[CH:38]1([CH2:37][NH:26][C:5]2[CH:6]=[CH:7][C:8]([C:9]3[O:10][C:11]([C:14]4[C:15]([C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:16][O:17][C:18]=4[CH3:19])=[N:12][N:13]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:40][CH2:39]1
Reactant: BrCC1CC1
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc(NCC2CC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a suspension of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in THF was added N,N-diisopropyl ethyl amine (128 μL, 0.75 mmol) and bromomethyl-cyclopropane (61 μL, 0.63 mmol) and the reaction mixture was stirred for 24 h at ambient temperature. After addition of potassium bis(trimethylsilyl)amide (0.91 M in THF, 0.82 mL, 0.75 mmol) was added stirring was continued for 15 min and further bromomethyl-cyclopropane (78 μL, 0.80 mmol) was added. After stirring for 18 h at ambient temperature further bromomethyl-cyclopropane (0.12 mL, 1.2 mmol) was added and stirring continued for 24 h at this temperature. The reaction mixture was extracted with aqueous sodium carbonate (saturated, 20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers dried over sodium sulfate. Concentration and then purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=40:40:20 to 0:80:20) afforded the title compound (34 mg, 15%) as a light brown solid. MS: m/e=403.4 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[NH2:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]([NH2:32])[C:24]([NH:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:17][N:16]=1.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:28]([N:27]1[C:24]2[CH:25]=[CH:26][C:21]([C:18]3[CH:17]=[N:16][C:15]([NH2:14])=[N:20][CH:19]=3)=[CH:22][C:23]=2[N:32]=[C:8]1[C:7]1[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=1[C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: O=Cc1ccccc1-c1nccs1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)n1c(-c2ccccc2-c2nccs2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 15.6 %

Procedure:
A solution of 2-thiazol-2-yl-benzaldehyde (100 mg, 0.53 mmol) and 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (120 mg, 0.45 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours and then at 80° C. for 60 hours. After this time the reaction is cooled to room temperature and pour into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (30 mg, 16%). LCMS (ESMS): m/z 427.20 (M++1)
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12>CN(C=O)C>[N:49]1[O:53][N:52]=[C:51]2[CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=[CH:57][C:50]=12
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3nonc3c2)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(Nc1cccc(-c2ccc3nonc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 19.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-benzo[1,2,5]oxadiazol-5-yl-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.005 g of product in 18% yield: LCMS (ESI) m/z 400 (MH+).