Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]([O:6][C:7]([N:9]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:18][CH2:17][CH:16]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:15]2=[O:38])[CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C(O[K])(C)(C)C.C([O:58][C:59]([C:61]1[N:62]2[CH:65]([S:66][CH2:67][C:68]=1[CH:69]=O)[CH:64]([NH:71][C:72](=[O:101])[C:73]([C:95]1[N:99]=[C:98]([NH2:100])[S:97][N:96]=1)=[N:74][O:75][C:76]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[C:63]2=[O:102])=[O:60])(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1.C1COCC1>[NH2:100][C:98]1[S:97][N:96]=[C:95](/[C:73](=[N:74]/[O:75][C:76]([C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)([C:83]2[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)/[C:72]([NH:71][C@@H:64]2[C:63](=[O:102])[N:62]3[C@@H:65]2[S:66][CH2:67][C:68](/[CH:69]=[C:16]2/[C:15](=[O:38])[N:14]([C@@H:11]4[CH2:12][CH2:13][N:9]([C:7]([O:6][C:2]([CH3:3])([CH3:4])[CH3:5])=[O:8])[CH2:10]4)[CH2:18][CH2:17]/2)=[C:61]3[C:59]([OH:60])=[O:58])=[O:101])[N:99]=1
Reactant: Nc1nc(C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(C=O)CSC23)ns1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC([P+](c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)C1
Agent: CC(C)(C)O[K]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2CC/C(=C\C3=C(C(=O)O)N4C(=O)[C@@H](NC(=O)/C(=N\OC(c5ccccc5)(c5ccccc5)c5ccccc5)c5nsc(N)n5)[C@H]4SC3)C2=O)C1
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
4.2 (small scale): To a solution of 2.45 g of (1′-tert.-butoxycarbonyl-2-oxo-[1,3′]-bipyrrolidinyl-3-(R,S)-yl)-triphenyl-phosphonium bromide (preparation according EP 1 067 131 A1) in 6 ml of dichloromethane and 15 ml of toluene was added at −78° C. a solution of 432 mg of t-C4H9OK in 6 ml of THF over 10 min and stirring was continued at −78° C. for 10 min. The solution was treated at −78° C. with a solution of 3.50 g 7-[2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid benzhydryl ester in 6 ml of THF over 15 min and stirring was continued at −78° C. for 6 h and at −50° C. for 1 h after which time HPLC showed almost completion of the reaction. The reaction was quenched with a solution of 0.95 g of citric acid in 9 ml of water followed by addition of 12 ml of ethyl acetate, the organic layer was washed with NaHCO3 and brine, dried over MgSO4, filtered and the filtrate was evaporated. The residue was chromatographed on silica with ethyl acetate/hexane 10:1 to give 1.82 g of the title compound as a foam. IR (Nujol): 3450 m (NH2, NH), 1779 s, 1724 s, 1678 s, 1653 s (C═O). 1H-NMR (d6-DMSO): 9.93 (d, J=8.8, 1H, NH); 8.13 (s, br., 2H, NH2); 7.6-7.3 (m, 26H, H—ar., HC—C(3)); 6.96 (s, 1H, CH(Ph)2); 6.15 (dd, J=8.8 and 4.8, 1H, H—C(7)); 5.33 (d, J=4.8, 1H, H—C(6)); 4.59 (m, 1H, CH—N)); 3.91, 3.85 (d each, J=18 each, 2H, CH2—S(5)); 3,5-3,3 and 2.9 and 2.7 and 2.0 (m each, 6H and 1H and 1H and 2H, 5×CH2); 1.41 (s, 9H, (CH3)3C). MS (CI): 1044/100 (M+H+).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][N:5]2[C:6](=[O:15])[C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:4]2[CH:3]=1.[C:18]1([C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[C:18]1([C:24]2[N:25]=[CH:26][N:27]([C:2]3[CH:17]=[CH:16][N:5]4[C:6](=[O:15])[C:7]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=5[N:9]=[C:4]4[CH:3]=3)[CH:28]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1c2c(nc3cc(Br)ccn13)CCCCC2
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(nc3cc(-n4cnc(-c5ccccc5)c4)ccn13)CCCCC2
Yield: 38 %

Procedure:
A solution of 3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one (50 mg, 0.17 mmol), 4-phenyl-1H-imidazole (37.4 mg, 0.26 mmol), CuI (8 mg, 0.04 mmol) and Cs2CO3 in DMF was stirred at 80° C. under nitrogen. The completion of the reaction was monitored by TLC. After the suspension was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL), the combined organic phases were concentrated to crude product and 23 mg desired product was obtained by column chromatography purification. MS (ESI): 357 (MH+); MS (ESI): 357 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.15-9.13 (d, J=7.83 Hz, 1H), 8.16 (s, 1H), 7.87-7.85 (d, J=7.38 Hz, 2H), 7.72 (s, 1H), 7.57-7.56 (d, J=2.19 Hz, 1H), 7.48-7.44 (t, J=7.35 Hz, 2H), 7.38-7.35 (d, J=7.08 Hz, 1H), 7.26 (m, 1H), 3.00-2.97 (m, 4H), 1.93-1.91 (m, 2H), 1.79-1.77 (m, 2H), 1.71-1.69 (m, 2H).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2.C(OCC)C.C(OCC)(=O)C.C1(C)C(C)=CC=CC=1.[H+].[B-](F)(F)(F)[F:37]>>[F:37][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: Nc1cccc2ncccc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Fc1cccc2ncccc12
Reaction time: 1 h
Yield: 55 %

Procedure:
Add sodium nitrite in portions to a suspension of 5-aminoquinoline (50 g, 347 mmol) in 48% HBF4 (200 mL) at 0° C. Stir for 1 hour and then pour into 1:1 diethyl ether/ethyl acetate (500 mL). Filter the resulting suspension and dry the solid. Add this solid (82.5 g, 338 mmol) in portions to refluxing xylene (1 L), stir for 2 hours, and then cool. Decant the xylene and dissolve the residue in 1N hydrochloric acid (600 mL). Neutralize with sodium carbonate, extract with ethyl acetate (10×500 mL), dry the extracts over sodium sulfate, filter and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 10-20% diethyl ether in hexanes. Combine fractions containing product and concentrate them under reduced pressure to provide the desired compound (28.1 g, 55%). MS (EL, m/z) C9H6FN (M+1) 148.0
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][CH3:3].[H-].[Na+].[CH:10](OCC)=[O:11].O>O1CCCC1>[CH3:3][CH:2]([CH:10]=[O:11])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC=O
Reactant: CCOC(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)C=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 23.5 %

Procedure:
Into a 500-mL 3-neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl propionate (11.3 mL, 97.9 mmol) in tetrahydrofuran (160 mL). The solution was cooled to 0° C., then sodium hydride (4.1 g, 103 mmol, 60% dispersion in mineral oil) was added in portions. The mixture was stirred at 0° C. for 10 min, then ethyl formate (7.92 mL, 98.5 mmol) was added and the resulting mixture was stirred overnight at room temperature. The reaction was carefully quenched water (100 mL) by drop-wise addition and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure (50 mm Hg) and the fraction between 70-80° C. was collected to obtain the title compound as a colorless liquid (3.0 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[N+:21]([C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22].N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][S:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=3)(=[O:31])=[O:32])[CH:17]=1)=[CH:5]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol), was mixed with 3-nitrobenzenesulfonyl chloride (0.466 g, 2.0 mmol) and pyridine (9 mL) was added, and the reaction mixture was heated briefly to 50° C. and then allowed to stand overnight at room temperature. Water (15 mL) was added and the mixture allowed to stand 1.5 hours at room temperature. The mixture was partitioned between water (200 mL) and ethyl acetate (200 mL), and the organic layer was washed with 1N HCl (100 mL), water (100 mL), and brine (100 mL), dried (magnesium sulfate), filtered, and concentrated to a yellow solid. The solid was triturated with hexanes/ethyl acetate, 1/1, dried in vacuo, taken up in tetrahydrofuran, concentrated to dryness, triturated with hexanes/ethyl acetate, 4/1, v/v and was collected by filtration (0.488 g), mp 228-230° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.Cl.Cl.[N:16]1([C:22]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[C:1]1([S:7]([N:19]2[CH2:20][CH2:21][N:16]([C:22]([O:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:17][CH2:18]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Oc1cccnc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(Oc1cccnc1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to a dichloromethane (5 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[CH3:20]>>[OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][N:7]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[CH3:20])[C@H:6]1[CH3:10])([CH3:4])[CH3:3]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: Cc1cc(C#N)ccc1F
Product: Cc1cc(C#N)ccc1N1CC[C@H](C(C)(C)O)[C@@H]1C

Procedure:
Using compound 1 and 4-fluoro-3-methylbenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 1 (reaction temperature 90° C., reaction time 3 hr).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[ClH:26].[N:27]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: ClCCCCCCBr
Reactant: C1CCNC1
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCCC3)cc12

Procedure:
The compound was prepared by the method of Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane, and pyrrolidine: mp 179°-181 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2.[Cl:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1>C1COCC1.CCOCC>[ClH:12].[NH:17]1[CH2:16][CH2:15][N:14]=[C:13]1[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[N:6]=[CH:5]2
Reactant: ClC1=NCCN1
Reactant: Cn1ncc2cc(N)ccc21
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cl
Product: Cn1ncc2cc(NC3=NCCN3)ccc21
Reaction time: 48 h

Procedure:
5-amino-1-methyl-indazole is dissolved in absolute THF and treated with a solution of an equimolar quantity of 2-chloro-imidazoline in ether. The mixture is stirred for 48 hours in a darkened, sealed flask at room temperature. The precipitated reaction product is separated and recrystallized from ethanol. The purified, white, crystallized hydrochloride has a melting point from 240° to 241° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH:5]=[C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=O)[O:7]1.O.[NH2:22][NH2:23]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:7])[NH:23][N:22]=1
Reactant: NN
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1N
Solvent: O
Product: COc1ccc(Cc2n[nH]c(=O)c3ccccc23)cc1N
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A stirred mixture of the above 3-(3-amino-4-methoxybenzylidene)-3H-isobenzofuran-1-one (1.336 g, 0.005 mol), industrial methylated spirit (20 ml) and hydrazine monohydrate (0.25 g, 0.005 mol) was heated under reflux for 1.5 hours then cooled to ambient temperature. The resulting solid was collected by filtration, washed with water (5 ml), and dried in vacuo to give 4-(3-amino-4-methoxybenzyl)-2H-phthalazin-1-one (1.15 g) as a beige solid, m.pt. 211.5–214.5° C.; 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.75 (s, 3H) (—OCH3), 4.15 (s, 2H) (ArCH2—), 4.75 (s, 2H) (—NH2) 6.5–6.6 (m, 2H) (2×ArH), 6.7–6.75 (m, 1H) (ArH) 7.8–8.0 (m, 3H)(3×ArH), 8.3 (d, 1H) (ArH), 12.65 (s, 1H) (CONH); m/z (M+H)+. 282, 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH2:9]2)=[CH:4][C:3]=1[O:16][CH3:17].C([O-])([O-])=O.[K+].[K+].[Br:24][CH2:25][CH2:26][CH2:27]Br>C(#N)C>[Br:24][CH2:25][CH2:26][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:14]=[O:15])[CH:9]=[CH:10][CH:11]=[CH:12][CH2:13]2)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1cc(C2(C=O)C=CC=CC2)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C2(C=O)C=CC=CC2)ccc1OCCCBr
Yield: 13.2 %

Procedure:
A mixture of 1-(4-hydroxy-3-methoxyphenyl)phenyl-methanone (14 g, 61.4 mmol), K2CO3 (13 g, 92.1 mmol), and 1,3-dibromopropane (28 g, 86 mmol) in acetonitrile (400 ml) was heated at reflux for 4 hours. The reaction was followed by thin layer chromatography. At the end of the reaction, the inorganics were filtered off and the solvent was removed on a rotary evaporator. The residue was purified on a flash chromatographic column (SiO2, 140 g, eluted with 4:1 hexane:dichloromethane, 1.2 l) to give a partially solidified material: 15.44 g (72%). Recrystallization twice from ethanol gave 2.84 g of 1-[4-(3-bromopropoxy)-3-methoxyphenyl]phenylmethanone as white crystals, m.p.=88°-89° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:26]1([N:17]2[C:16]3[CH:32]=[C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][C:6]([OH:33])=[O:5])[CH:13]=[CH:14][C:15]=3[N:19]=[C:18]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)COCCOc1ccc2nc(-c3ccccc3)n(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
50 mg of 2-[2-[(1,2-diphenyl-1H-benzimidazol-6-yl)oxy]ethoxy]acetic acid-tert-butyl ester was dissolved in 0.5 ml of trifluoroacetic acid and stirred for 48 hours. Then, it was diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was chromatographed on silica gel.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:48][CH2:47][C@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1.C(OCC)(=O)C>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:48][CH2:47][C@H:46]([NH:49][C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.7 %

Procedure:
12 ml of trifluoroacetic acid and 0.38 ml of trifluoromethanesulfonic acid were added to a suspension of 1.47 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 2.3 ml of anisole, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed with hexane to remove the anisole, and then diethyl ether was added. The mixture was then cooled to -78° C., and the solidified product was broken up and separated by decantation. Several repetitions of this procedure yielded a powder and oily materials, which were dissolved in 100 ml of ethyl acetate to give a solution. The resulting solution was washed with an aqueous solution of sodium hydrogencarbonate, and the aqueous washings were extracted with 30 ml of ethyl acetate. The washings were combined with the ethyl acetate solution, and the combined organic phase was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1.26 g of the title compound, as a powder.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][C:13]([CH3:15])=O.[OH2:16]>>[CH:1]1([CH:13]([CH3:15])[CH:12]=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)=O
Product: CC(C=O)C1CCCCC1

Procedure:
100.0 g of a compound (Ia) was hydrogenated in a solution of 2 g of p-toluene sulfonic acid, 200 ml of acetone, and 500 ml of water at 60° C. for 24 hours. The hydrogenated product was distilled to obtain 66.5 g of 2-cyclohexylpropanal (purity: 98.5%, boiling point: 65° C./5 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[ClH:15].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[CH:8]=1
Reactant: COc1ccc(NC(N)=S)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2nc(N)sc2c1
Product: Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
182 Parts of 4-methoxyphenyl-thiourea are suspended in 900 parts of toluene; 310 parts of thionyl chloride are added over a period of 1 hour at 20° to 30° C. The temperature of the mixture is then uniformly raised to 110° C. within 2 hours while stirring, stirring is continued for 2 hours under reflux, 20 parts of kieselguhr are added and the toluene is distilled off by blowing in steam. The solution of 6-methoxy-2-aminobenzthiazole hydrochloride obtained is clarified by adding 5 parts of charcoal, filtered and the clear filtrate is added to 175 parts of 25% aqueous ammonia solution.
Reaction SMILES: [NH2:1][CH:2]([CH3:28])[CH2:3][N:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[O:7][CH2:6][CH:5]1[CH2:12][NH:13][C:14]1[CH:15]=[C:16]([Cl:27])[CH:17]=[C:18]2[C:26]=1[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1.[CH3:29][C:30]1[C:35]([C:36](O)=[O:37])=[C:34]([CH3:39])[N:33]=[CH:32][N:31]=1.C([O-])(=[O:42])C.[NH4+]>>[Cl:27][C:16]1[CH:17]=[C:18]2[C:26](=[C:14]([NH:13][C:12]([CH:5]3[CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH2:9][N:4]3[CH2:3][CH:2]([NH:1][C:36]([C:35]3[C:34]([CH3:39])=[N:33][CH:32]=[N:31][C:30]=3[CH3:29])=[O:37])[CH3:28])=[O:42])[CH:15]=1)[NH:25][C:24]1[CH:23]=[N:22][CH:21]=[CH:20][C:19]2=1
Reactant: CC(N)CN1CC(C)(C)OCC1CNc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CC(=O)[O-]
Agent: [NH4+]
Product: Cc1ncnc(C)c1C(=O)NC(C)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 51 %

Procedure:
The desired compound was prepared using [4-(2-Amino-propyl)-6,6-dimethyl-morpholin-3-ylmethyl]-(6-chloro-9H-beta-carbolin-8-yl)-amine and 4,6-dimethylpyrimidine-5-carboxylic acid following Method E in 51% yield. 1H-NMR (300 MHz, DMSO): δ 11.27 (1H, s), 10.02 (1H, s), 9.0 (1H, s), 8.86 (1H, s), 8.5 (1H, d), 8.3 (1H, d), 8.22 (2H, m), 7.88 (1H, s), 4.1 (1H, m), 3.9 (2H, m), 2.99 (2H, m), 2.36 (6H, s), 2.1 (2H, m), 1.3 (3H, s), 1.24 (6H, m). Retention time (LC, method: ammonium acetate standard): 1.50 min. MS (M+H+): 551
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[C:19]#N.C(O)=[O:22]>[Ni]>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[CH:4][C:3]=1[CH:19]=[O:22]
Reactant: O=CO
Reactant: N#Cc1cnn(-c2ccc(OC(F)(F)F)cc2Cl)c1N
Agent: [Ni]
Product: Nc1c(C=O)cnn1-c1ccc(OC(F)(F)F)cc1Cl
Yield: 62 %

Procedure:
12 g (0.042 mol) of 5-amino-4-cyano-1-(2-chloro-4-trifluoromethoxy-phenyl)-pyrazole are boiled under reflux with 5 g of Raney nickel in 50 ml of 75% strength aqueous formic acid for 1 hour; the still warm solution is filtered under suction, the residue is rinsed with water, the filtrate is extracted several times with ether, and the combined ether phases are washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated down in vacuo. 8.0 g (62% of theory) of 5-amino-1-(2-chloro-4-trifluoromethoxy-phenyl)-4-formyl-pyrazole are obtained in the form of an oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][Br:28]>CC#N>[Br-:28].[OH:10][C:9]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])([CH2:2][CH2:3]1)[CH2:8][CH2:7]2
Reactant: OC(c1ccccc1)(c1ccccc1)C12CCN(CC1)CC2
Reactant: COCCCBr
Solvent: CC#N
Product: COCCC[N+]12CCC(C(O)(c3ccccc3)c3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 86.1 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.0632 g, 0.215 mmol) and 3-bromopropyl methyl ether (0.0461 g, 0.301 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0826 g, 86.0%). EI-MS m/z 366(M+) Rt (1.55 min).