Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[N:16](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:17]=[N:18][C:14]=3[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(/C=C/COCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)C=CC=CC=1>C(O)(=O)C.O>[C:1]1(/[CH:7]=[CH:8]/[CH2:9][O:10][CH2:11][CH:12]2[CH2:39][CH2:38][C:15]3[NH:16][CH:17]=[N:18][C:14]=3[CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1ccccc1)\COCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: C(=C/c1ccccc1)\COCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: CC(=O)O
Solvent: O
Product: C(=C/c1ccccc1)\COCC1CCc2[nH]cnc2C1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of (E)-5-(3-phenylallyloxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and (E)-5-(3-phenylallyloxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (501 mg, 0.98 mmol) was dissolved in a mixture of acetic acid (5.0 ml) and water (0.6 ml). The reaction mixture was stirred for 2 hours at 90° C. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 179 mg of the title compound.
Reaction SMILES: OO.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:20]=[N:19][CH:18]3[C:11]42[CH:21]([OH:22])[CH:17]3[CH:16]2[CH:13]([NH:14][NH:15]2)[CH2:12]4)=[CH:6][CH:5]=1.CO.[OH-].[Na+]>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[N:20]=[N:19][CH:18]3[C:11]42[CH:21]([OH:22])[CH:17]3[CH:16]2[CH:13]([N:14]=[N:15]2)[CH2:12]4)=[CH:6][CH:5]=1
Reactant: OC1C2C3NNC3CC13C2N=NN3c1ccc(Br)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC1C2C3N=NC3CC13C2N=NN3c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 5 h

Procedure:
35 parts of 30 percent strength aqueous H2O2 were added dropwise, in the course of 1 hour, to 50 parts of 8-(4-bromophenyl)-12-hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]dodec-9ene (Compound No. 69) in 400 parts of methanol and 5 parts of 25 percent strength by weight aqueous NaOH, at 65° C., while stirring, and stirring was continued for 5 hours at 65° C. The mixture was cooled to 20° C., after which 1,500 parts of water were added, and the product was filtered off under suction, washed with 300 parts of water and dried at 30° C. under 1 mbar. 44 parts (88 mole %) of 8-(4-bromophenyl)-12hydroxy-3,4,8,9,10-pentazatetracyclo[5,4,1,02,5,07,11 ]-dodeca-3,9-diene of melting point 187° C. (decomposition) were obtained (Compound No. 3).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.[OH-].[Na+]>Cl>[NH2:10][C:4]1[CH:3]=[C:2]([Br:1])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(Br)cc1N

Procedure:
To a suspension of 4-bromo-2-nitro-benzonitrile (2.60 g, 0.0115 mol) in 12N HCl at 0° C., add SnCl2-2H2O portionwise. As the reaction is stirred vigorously, a white precipitate will form. After 1 h add ice to the reaction vessel followed by 10N NaOH until the solution is basic. Extract the aqueous mixture with ether (2×) and EtOAc (1×) and wash the combined organic layers with brine. Dry the solution (Na2SO4) and remove the solvents under reduced pressure to give 2-amino-4-bromo-benzonitrile as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[I:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:10][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[I:9]
Reactant: Cc1cccc(Cl)c1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(CBr)c1I
Temperature: 70 °C
Yield: 71.4 %

Procedure:
A mixture of 1-chloro-2-iodo-3-methylbenzene (7.5 g, 30 mmol) in 60 mL CCl4 stirred at 70° C. was treated with 1-bromopyrrolidine-2,5-dione (7.9 g, 45 mmol) and dibenzoyl peroxide (0.72 g, 3.0 mmol) slowly. The mixture was refluxed under a sunlight lamp for 15 hours. The mixture was cooled to room temperature, filtered through a plug of Celite, and rinsed with 10% EtOAc/hexane. The filtrate was concentrated and purified by column chromatography (0-10% EtOAc/hexane) to give 7.1 g pink oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Sc1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: c1ccncc1
Product: O=C(CSc1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
To 300 mL of pyridine was added a-bromoacetophenone (150 g, 750 mmol) and thiophenol (83 g, 750 mmol). The mixture was heated at reflux for six hours. The pyridine was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed exhaustively with 1 N sodium hydroxide, then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated to yield a brown oil. The product was crystallized from ethanol at 0° C. to yield 116 g of the title compound.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:34]=[CH:33][C:32]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][C:24]=2[CH:23]=1.C([Li])CCC.Cl[Si:41]([CH3:44])([CH3:43])[CH3:42].C1(C)C=CC=CC=1>C1COCC1>[CH3:42][Si:41]([CH3:44])([CH3:43])[N:25]1[C:24]2[CH:23]=[C:22]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:2]3[CH:3]=[CH:4][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[N:12]([Si:41]([CH3:44])([CH3:43])[CH3:42])[C:13]=4[CH:1]=3)[CH:34]=[CH:33][C:32]=2[C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2
Reactant: C[Si](C)(C)Cl
Reactant: c1ccc2c(c1)[nH]c1cc(OCCCCCCOc3ccc4c(c3)[nH]c3ccccc34)ccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)n1c2ccccc2c2ccc(OCCCCCCOc3ccc4c5ccccc5n([Si](C)(C)C)c4c3)cc21
Yield: 84 %

Procedure:
To a solution of 1,6-bis(carbazol-2-yloxy)hexane (30 g) in dry THF (200 ml) was added butyllithium (56 ml; 1.6M in hexane). Once the butyllithium addition was completed, the solution was heated to reflux for 1.5 hours and then allowed to cool. Chlorotrimethylsilane (12 ml) was added dropwise to the cooled mixture and then heated to reflux for 4 hours. Toluene (150 ml) was added to the cool mixture which was then filtered to remove LiC1. The filtrate was collected and the solvent removed under vacuum leaving a crude gray compound. The crude product was further purified by vacuum distillation to give a white compound (E.1) in an 84% yield.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][C:44]([CH3:82])([CH2:59][NH:60][C:61]([C:63]1[NH:64][C:65]2[C:70]([CH:71]=1)=[CH:69][CH:68]=[CH:67][C:66]=2[N:72]([CH3:81])[S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74])=O)[CH2:45][N:46]1[CH2:51][CH2:50][N:49](C(OC(C)(C)C)=O)[CH2:48][CH2:47]1)C1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:81][N:72]([C:66]1[CH:67]=[CH:68][CH:69]=[C:70]2[C:65]=1[NH:64][C:63]([C:61]1[S:43][C:44]([CH3:82])([CH2:45][N:46]3[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]3)[CH2:59][N:60]=1)=[CH:71]2)[S:73]([C:76]1[S:77][CH:78]=[CH:79][CH:80]=1)(=[O:75])=[O:74]
Reactant: CN(c1cccc2cc(C(=O)NCC(C)(CN3CCN(C(=O)OC(C)(C)C)CC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CN(c1cccc2cc(C3=NCC(C)(CN4CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.1 %

Procedure:
To a solution of triphenylphosphine oxide (3.09 g) in acetonitrile (20 ml) was slowly added trifluoromethanesulfonic anhydride (0.93 ml) at 0° C., and the mixture was stirred for 10 min. tert-Butyl 4-{2-(benzylthio)-2-methyl-3-[({7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}carbonyl)amino]propyl}piperazine-1-carboxylate (1.55 g) was added, and the reaction mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried (MgSO4). 4N Hydrogen chloride-ethyl acetate solution was added to the ethyl acetate layer, and the precipitated solid was collected by filtration, and washed with ethyl acetate. The obtained solid was suspended in saturated aqueous sodium hydrogencarbonate, and the mixture was stirred for 30 min. The solid was collected by filtration, washed with water and ethyl acetate, and dried to give the title compound (0.49 g, yield 45%) as colorless crystals. melting point 178-180° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]([C:33]2[C:34](=[O:49])[N:35]([CH3:48])[C:36](=[O:47])[C:37]=2[C:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)=[CH:25]1)(=O)C.[OH-].[NH4+]>CO>[CH3:48][N:35]1[C:36](=[O:47])[C:37]([C:38]2[C:46]3[C:41](=[N:42][CH:43]=[CH:44][CH:45]=3)[NH:40][CH:39]=2)=[C:33]([C:26]2[C:27]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[N:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])[CH:25]=2)[C:34]1=[O:49]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4c[nH]c5ncccc45)C(=O)N(C)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)C(c2c[nH]c3ncccc23)=C(c2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of the compound of Example 14b (0.054 mmol), dissolved in 14 ml of methanol, there is added 28% aqueous ammonium hydroxide solution (10 ml). The reaction mixture is stirred for 26 hours at ambient temperature. After evaporating off the solvents, the residue is purified by chromatography on silica gel (ethyl acetate/methanol: 9/1), allowing the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])(=[O:11])=[O:10].FC(F)(F)C(O)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([CH2:12][NH:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCS(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
For two hours, a solution of 430 mg (1.17 mmol) of tert.-butyl 3-[(2,3-dichlorobenzenesulphonyl)methylamino]propionate and 2.0 ml of trifluoroacetic acid in 30 ml of tetrahydrofuran was stirred at room temperature and then evaporated to dryness. About 30 ml of water were added to the residue and the mixture was extracted three times with in each case 20 ml of ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The product obtained in this manner was reacted further without additional purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])[CH:7]=1.C([N:25](C(C)C)CC)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH2:25])=[O:13])[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(N)=O
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoic acid (1.78 g, 5.1 mol, 1 equiv) in DMF (6 mL) at room temperature were added diisopropylethylamine (DIPEA) (1.95 mL, 11.2 mmol, 2.2 equiv) and fluoro-N,N,N′-tetramethylformamidinium hexafluorophosphate (TFFH) (1.48 g, 5.6 mmol, 1.1 equiv). The homogeneous solution was allowed to stir for 1.5 hr, during which time the color changed to green. Ammonia gas was bubbled into the solution and the color changed to yellow and a precipitate was formed. The heterogeneous slurry was allowed to stir for 5 hr and then diluted with H2O and ethyl acetate. The phases were separated and the organic portion was washed with brine, dried over MgSO4, filtered and concentrated to give 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzamide in quantitative yield. The crude product was used without further purification. LCMS ES+ 352 (M+1), 354 (M+3).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#N.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[CH:17]=[CH:16][C:1]([C:3]2[CH:8]=[CH:7][C:6]([O:9][C@H:23]([CH2:18][C@@H:19]([O:24][C:21]3[CH:22]=[CH:23][C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:10]#[N:11])=[CH:17][CH:16]=4)=[CH:19][CH:20]=3)[CH3:20])[CH3:22])=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)#[N:11]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: N#Cc1ccc(O)cc1
Product: C[C@@H](C[C@H](C)Oc1ccc(-c2ccc(C#N)cc2)cc1)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
The procedure of Example 11 was repeated except that the 4-cyanophenol was replaced with 0.60 g of 4-(4'-cyanophenyl)phenol. The crude product thus obtained was then recrystallized from ethyl alcohol. Thus 0.49 g of optically active (S,S)-2,4-bis[4'-(4"-cyanophenyl)phenoxy]pentane was obtained (m.p.: 139.5° C.).
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[BrH:13].O>C1(C)C=CC=CC=1>[Br:13][C:3]1[CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:6][CH:2]=1
Reactant: O=C(C#CCO)c1ccccc1
Reactant: Br
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1coc(-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 50 %

Procedure:
To a solution of 4-hydroxy-1-phenylbut-2-yn-1-one (3.2 g, crude) in toluene (60 mL) was added HBr (40%, 15 mL). The resulting solution was stirred for 40 min at 50° C. and then the reaction mixture was poured into water (300 mL), extracted with Et2O (4×100 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (petroleum ether) to afford 4-bromo-2-phenylfuran as a yellow solid (1.3 g, 50%).
Reaction SMILES: ClC1C=CC=CC=1[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][CH2:12]2)=[CH:8][C:7]=1[NH:15][CH:16]=[CH:17][N+:18]([O-:20])=[O:19])=O.C1CCN2C(=NCCC2)CC1>C1C=CC=CC=1>[N+:18]([C:17]1[CH:16]=[N:15][C:7]2[C:6]([CH:4]=1)=[CH:14][C:13]1[CH2:12][CH2:11][CH2:10][C:9]=1[CH:8]=2)([O-:20])=[O:19]
Reactant: O=C(c1ccccc1Cl)c1cc2c(cc1NC=C[N+](=O)[O-])CCC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cnc2cc3c(cc2c1)CCC3
Temperature: 90 °C

Procedure:
6-(2-Chlorobenzoyl)-5-(2-nitroethenylamino)indan (4.8 g) was added in small portions to a solution of DBU (4.8 g) in benzene (50 ml) with heating at 90° C. The mixture was refluxed for 30 minutes and, then, washed with 2N HCl and water and dried (MgSO4). The solvent was then distilled off to give crystals of 4-2-chlorophenyl)-7,8-dihydro-3-nitro-6H -cyclopenta[g]quinoline. The crystals were collected by filtration and washed with methanol (4.50 g, 99.1%). Recrystallization from ethanol gave light brown prisms, mp. 175°-176° C.
Reaction SMILES: [CH3:1][N:2]([CH2:22][C:23]1[N:24]([CH3:32])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3](/[CH:5]=[CH:6]/[C:7]1[CH:21]=[N:20][C:10]2[NH:11][C:12](=[O:19])[N:13]([CH2:15][C:16](O)=[O:17])[CH2:14][C:9]=2[CH:8]=1)=[O:4].[ClH:33].C[N:35]1[CH2:41][C:40]2C=C(/C=C/C(O)=O)C=N[C:39]=2[NH:38][C:37](=O)[CH2:36]1.CN1CCNCC1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:33].[CH3:1][N:2]([CH2:22][C:23]1[N:24]([CH3:32])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:3](=[O:4])/[CH:5]=[CH:6]/[C:7]1[CH:21]=[N:20][C:10]2[NH:11][C:12](=[O:19])[N:13]([CH2:15][C:16]([N:35]3[CH2:36][CH2:37][N:38]([CH3:39])[CH2:40][CH2:41]3)=[O:17])[CH2:14][C:9]=2[CH:8]=1
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CC(=O)O)C(=O)N2
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CCNCC1
Agent: Cl
Product: CN1CCN(C(=O)CN2Cc3cc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cnc3NC2=O)CC1
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting (E)-(6-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting 1-methylpiperazine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (173 mg, 43%) was prepared as a off-white solid: 1H NMR (300 MHz, DMSO-d6) □ 10.78 (br s, 1H), 10.07-10.03 (m, 1H), 8.41-8.37 (m, 1H), 7.98-7.90 (m, 1H), 7.57-7.39 (m, 3H), 7.25-6.99 (m, 3H), 6.42-6.17 (m, 1H), 5.04-4.85 (m, 2H), 4.46-4.03 (m, 5H), 3.72-3.68 (m, 3H), 3.44-3.41 (m, 3H), 3.11-2.91 (m, 7H), 2.78 (s, 3H); MS (ESI) m/e 516 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:13].CN(C)[CH:18]=[O:19].[OH-].[Na+]>ClC1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:5]1[NH:6][C:7]([Cl:13])=[C:8]([CH:18]=[O:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([C:5]1[NH:6][C:7](=[O:10])[CH2:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN(C)C=O
Agent: CCCCC1=NCC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C=O)c(Cl)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-n-Butyl-2-imidazolin-5-one (9.81 g, 70 mmol) was added to a solution of phosphoroxychloride (26.83 g, 175 mmol) in chlorobenzene (50 ml) at room temperature. The orange suspension was heated to 100° C. within 5 minutes, and then N,N-dimethylformamide (12.79 g, 175 mmol) was added within 3 minutes. The black mixture was kept for 2 hours at 100° C., cooled to 40° C. and poured on water (84 ml). After addition of ethyl acetate (42 ml), the mixture was stirred for 15 minutes at 26° to 28° C. and then adjusted to pH 7 by addition of 30 percent sodium hydroxide solution (67 ml). The phases were separated, and the aqueous phase was extracted twice with 70 ml of ethyl acetate each. The combined organic phases were dried (MgSO4), filtered and concentrated by evaporation on a Rotavapor. The title compound was obtained in a yield of 8.31 g (64 percent) relative to the 2-n-butyl-2-imidazolin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1C(OC(C)(C)C)=O)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][NH:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1

Procedure:
In analogy to the procedure described in example 253a, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 208 c) was treated with trifluoroacetic acid in dichloromethane to give the title compound as yellow oil. MS (ESI): m/z=356.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[NH:9][C:10]3[C:15]([C:16]=2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>>[C:1]1([C:7]2[C:8](=[S:33])[NH:9][C:10]3[C:15]([C:16]=2[C:17]([O:19][CH:20]([CH3:22])[CH3:21])=[O:18])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OC(=O)c1c(-c2ccccc2)c(=O)[nH]c2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)OC(=O)c1c(-c2ccccc2)c(=S)[nH]c2ccccc12

Procedure:
307 mg (1 mmol) of isopropyl 3-phenylquinolin-2(1H)-one-4-carboxylate (Example 7) are reacted with Lawesson's reagent according to the process described in Example 5 and purified by chromatography on silica gel as indicated above (mobile phase: n-heptane/ethyl acetate=411).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[C:6](=[O:12])[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CN1CCOc2cc(N)ccc2C1=O
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)OCCN(C)C3=O)ncc1Cl
Yield: 40.8 %

Procedure:
Following the procedure of 512f, 8-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.04 g, 0.0002 mol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl benzamide (0.062 g, 0.0002 mol) were reacted giving 2[5-chloro-2-(4-methyl-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide (0.037 g, 41%) as a white solid. MP: 288-9° C.; 1H-NMR (DMSO-d6) δ 11.62 (s, 1H), 9.74 (s, 1H), 8.78 (d, 1H), 8.70-2 (d, 1H), 8.29 9s, 1H), 7.75-7 (d, 1H), 7.53-8 (m, 3H), 7.35-8 (d, 1H), 7.17-9 (t, 1H), 4.32-4 (m, 2H), 3.06 (s, 3H), 2.80-1 (d, 3H); LC/MS (ESI+): 453 (M+H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[N:9]([CH2:10][CH2:11][CH2:12][CH:13]=[N+:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH2:15]2)[C:8](=[O:26])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[O:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[Cl:2][C:3]1[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)=[CH:16][CH2:15]2)[C:8](=[O:26])[C:7]2[CH:27]=[CH:28][CH:29]=[CH:30][C:6]=2[O:5][CH:4]=1
Reactant: O=C1c2ccccc2OC=C(Cl)N1CCCC=[N+]1C=CC(c2ncccn2)=CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2OC=C(Cl)N1CCCCN1CC=C(c2ncccn2)CC1

Procedure:
560 mg of the compound of Example 24 was dissolved in 15 ml of ethanol, 98 mg (2 equivalents) of sodium borohydride was added under ice cooling, then the resultant mixture was agitated at room temperature for 10 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=5)[CH:20]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5cccc(C(F)(F)F)c5)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.