Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]2[O:25][C:26]([CH2:29]Cl)=[N:27][N:28]=2)[CH:23]=1>>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2[O:25][C:26]([CH2:29][N:4]3[C:5]4[C:10](=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH:2]([F:1])[F:16])=[N:27][N:28]=2)[CH:21]=[N:20][CH:19]=1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3cncc(Br)c3)o2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: MS (ES) m/z 455 and 457 (M+1 Br isotopes).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]([NH2:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])=[O:5])C.S(O)(C1C=CC(C)=CC=1)(=O)=O.O.C1CCN2[C:33](=[N:34]CCC2)[CH2:32][CH2:31]1.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH2:15]([O:14][C:12]([C:9]1[C:10]([CH3:11])=[C:6]2[C:4](=[O:5])[C:32]([C:33]#[N:34])=[CH:31][NH:17][N:7]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1cn(N)c(C(=O)OCC)c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2[nH]cc(C#N)c(=O)c2c1C
Temperature: 25 °C
Yield: 40 %

Procedure:
To a solution of 1-amino-3-methyl-1H-pyrrole-2,4-dicarboxylic acid diethyl ester (1.08 g, 4.50 mmol) in toluene (15 mL) were added 1,1-diethoxypropionitrile (2.02 mL, 1.93 g, 13.5 mmol) and TsOH-H2O (171 mg, 0.90 mmol). The reaction mixture was heated at reflux for 12 h and then cooled to 25° C. DBU (0.18 mL, 0.822 g, 5.40 mmol) was added and the resulting dark brown mixture was heated at 80° C. for 1 h and then coded to room temperature. The reaction mixture was poured onto dichloromethane (50 mL) and NH4Cl (sat. aq., 50 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×30 mL) and the combined organic extracts were washed with water (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-30% methanol/dichloromethane) to provided 441 mg (40%) of compound 1C as a brown solid. HPLC: 100% at 3.383 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 246.09 [M+H]+. D Preparation of 4-Chloro-3-cyano-5-methylpyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (1D)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[S:11][C:12]([CH3:17])=[CH:13][C:14]=2[C:15]#[N:16])=[C:4]([N+:18]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)[Cl:24].Cl>C(O)C>[ClH:24].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:18]=[C:15]([NH2:16])[C:14]3[CH:13]=[C:12]([CH3:17])[S:11][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1cc(C#N)c(Nc2cc(F)c(F)cc2[N+](=O)[O-])s1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Temperature: 86.5 °C
Yield: 99.7 %

Procedure:
Add 2-(4,5-difluoro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (94.0 g, 318 mmol) and tin (II) chloride dihydrate (225 g, 997 mmol) to ethanol (1400 mL) and aqueous 6N HCl (1400 mL) with stirring under nitrogen. Heat at gentle reflux (86-87° C.) for 0.3 hours, and then allow cooling to ambient temperature. Filter, rinse with water (3×250 mL) and dry at 50-60° C. to give 95.7 g (100%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (bs, 1H), 9.84 (bs, 1H), 9.33 (bs, 1H), 8.93 (bs, 1H), 7.00 (m, 2H), 6.85 (s, 1H), 2.28 (s, 3H). HRMS (ES) exact mass M+H calcd for C12H9F2N3S (freebase) 266.0563; found 266.0555.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.[N+](C1C=CC([O:33][S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35])=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1O
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
After dissolving 6-methoxy-4-(4-nitrophenoxy)quinolin-7-ol (1.0 g) in dimethylformamide (10 ml), there were added trifluoromethanesulfonic acid 4-nitrophenyl ester (640 mg) and potassium carbonate (1.3 g), and the mixture was stirred at room temperature for 5 hours. Water was added, extraction was performed with ethyl acetate, the organic layer was washed with water and saturated saline in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (1.0 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[O:13][C:12]([CH3:17])(C)OC1=O)=[O:8])=[N+:2]=[N-:3].OCC[C:22]#[N:23].C(=O)=O>ClCl>[C:22]([CH2:17][CH2:12][O:13][C:14](=[O:15])[CH2:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])#[N:23]
Reactant: N#CCCO
Reactant: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Agent: ClCl
Agent: O=C=O
Product: N#CCCOC(=O)CC(=O)CCCN=[N+]=[N-]

Procedure:
5-(4-Azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (5.25 g, 72.0 mmol) at 80° C. until no more CO2 was released. The reaction mixture was diluted with CH2 Cl2 (100 ml), washed with water (100 ml) and brine (100 ml). After drying and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3 :MeOH=95:5), 4-azidobutanoylacetic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.86 g, 53.2%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([O:19][CH2:21][C:22](=[O:23])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: O=C(C[C@@H]1CCCN1C(=O)OCc1ccccc1)OCC(=O)c1ccccc1
Yield: 48.3 %

Procedure:
The title compound (0.700 g) was prepared from (S)-2-carboxymethyl-pyrrolidine-1-carboxylic acid benzyl ester (1.00 g, Aoyama et al, Chem. Pharm. Bull., 3249, 29,11,1981) and 2-bromoacetophenone (0.760 g) according to the method of description 36.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+].[C:17](#N)C.IC>C[Si](C)(C)N[Si](C)(C)C>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:17])[C:4](=[O:9])[CH:3]=1
Reactant: Nc1cc(=O)[nH]c(=O)[nH]1
Reactant: CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CI
Product: Cn1c(=O)cc(N)[nH]c1=O
Reaction time: 6 h
Yield: 42.6 %

Procedure:
To a solution of the 6-aminopyrimidine-2,4(1H,3H)-dione (15 g, 118 mmol) in 1,1,1,3,3,3-hexamethyldisilazane (50 mL) was added ammonium sulfate (0.671 g, 5 mmol), then the resulting mixture was heated to reflux with stirring for 6 h. The mixture was concentrated to give a light-yellow solid. This solid was combined with acetonitrile (50 mL) and iodomethane (15 mL, 250 mmol) was added. The resulting mixture was stirred at 40° C. for 16 h. Then the mixture was concentrated, neutralized with saturated sodium bicarbonate to pH=7, filtered, and the filter cake was washed with brine and ethanol, dried under vacuum to give 6-amino-3-methylpyrimidine-2,4 (1H,3H)-dione (7.1 g, 42.6% yield) as yellow solid. LCMS MH+ 142.
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1.[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][N:23]([CH2:31][C:28]3([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]3)[CH2:22][CH2:21]2)[C:5]([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[O:9][N:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2cc(C(=O)N(C3CCNCC3)C3CC3)no2)cc1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Product: N#Cc1ccc(-c2cc(C(=O)N(C3CC3)C3CCN(CC4(C(F)(F)F)CC4)CC3)no2)cc1

Procedure:
The title compound is prepared from 5-(4-cyano-phenyl)-isoxazole-3-carboxylic acid cyclopropyl-piperidin-4-yl-amide and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 3. LC (method 4): tR=1.34 min; Mass spectrum (ESI+): m/z=459 [M+H]+.
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[N:9]=1)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCCCCC>C(OCC)(=O)C>[C:22]1([NH:21][C:4]2[N:5]=[CH:6][C:7]3[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:8]=3[N:9]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)c1ncc2ccc(=O)n(-c3ccccc3)c2n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=c1ccc2cnc(Nc3ccccc3)nc2n1-c1ccccc1
Temperature: 175 °C
Yield: 39 %

Procedure:
A mixture of 2-methanesulfinyl-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one (197 mg, 0.69 mmol) and 1 mL of aniline was heated at 175° C. for 10 minutes then cooled to room temperature. Hexane and ethyl acetate were added, and the solid was collected by filtration and purified by flash chromatography eluting with ethyl acetate. The fractions containing product were concentrated, and the residue was recrystallized first from hexane and ethyl acetate then from chloroform and ethyl acetate to provide 85 mg (39%) of 2-phenylamino-8-phenyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 300-302° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:20]=[O:21])[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:22]([CH3:24])[CH3:23])=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH2:25]([O:19][C:13]1[C:12]([CH:20]=[O:21])=[C:11]2[C:16]([C:17](=[O:18])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:9]([CH:22]([CH3:24])[CH3:23])[O:10]2)=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)c1oc2c(C=O)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1oc2c(C=O)c(OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 3-(4-chlorophenyl)-7-hydroxy-2-isopropyl-4-oxo-4H-chromene-8-carbaldehyde (7.95 g, 23.2 mmol) and benzyl bromide (7.93 g, 46.4 mmol) in N,N-dimethylformamide (200 ml) is added K2CO3 (9.61 g, 69.5 mmol), and the reaction mixture is stirred at room temperature for 96 h. The mixture is poured into ice/water, extracted with CH2Cl2, dried (MgSO4) and concentrated in vacuo. The resulting solid residue is stirred with hexane/ethyl acetate for 1 h, the solvent is decanted, and the solid is stirred with hexane/diethyl ether for 16 h. The title compound is collected by filtration and washed with hexane to afford a pale brown solid.
Reaction SMILES: [O:1]=[CH:2][C@H:3]1[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@@H:4]1[OH:5].[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:15]1([CH2:14][O:5][C@H:4]2[C@H:6]([O:7][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@@H:8]([CH2:10][O:11][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:9][C@@H:3]2[CH:2]=[O:1])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
According to Flowchart C, 2,5-anhydro-D-mannose 24, is protected as the dimethyl acetal 25 which is reacted with sodium hydride in dimethylformamide, followed by benzyl bromide giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose, dimethyl acetal 26. Compound 26 is treated with tetrafluoroboric acid in acetonitrile giving 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 27 which is reacted with diphenyl triphenylphosphoranylidenemethylphosphonate in toluene at reflux, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-4,5,7-tris-O-(phenylmethyl)-D-manno-hept-1-enitol 28. Compound 28 is hydrogenated over palladium on carbon in methanol and acetic acid, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol 29, which is reacted with diphenyl chlorophosphate in pyridine, giving 3,6-anhydro-1,2-dideoxy-1-(diphenoxyphosphinyl)-D-manno-heptitol, 7-(diphenyl phosphate) 30, which is then hydrogenated with platinum oxide, giving the product 3,6-anhydro-1,2-dideoxy-1-phosphono-D-manno-heptitol, 7-(dihydrogen phosphate) 31. ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:56]2[CH:61]=[CH:60][C:59]([O:62][CH3:63])=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:10][CH2:11][CH2:12][CH2:13][N:14]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[N:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=3[Cl:49])=[CH:34][CH:33]=2)[CH2:15][CH2:16][CH2:17][C:18](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:19])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:71]1[C:75]2=[C:76]3[C:80](=[CH:81][CH:82]=[C:74]2[NH:73][CH:72]=1)[NH:79][CH:78]([C:83]([O:85][CH3:86])=[O:84])[CH2:77]3>CN(C=O)C>[CH3:63][O:62][C:59]1[CH:60]=[CH:61][C:56]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:10][CH2:11][CH2:12][CH2:13][N:14]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[N:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][C:41]=3[Cl:49])=[CH:34][CH:33]=2)[CH2:15][CH2:16][CH2:17][C:18]([N:73]2[C:74]3[C:75](=[C:76]4[C:80](=[CH:81][CH:82]=3)[NH:79][CH:78]([C:83]([O:85][CH3:86])=[O:84])[CH2:77]4)[CH:71]=[CH:72]2)=[O:19])=[CH:57][CH:58]=1
Reactant: COC(=O)C1Cc2c(ccc3[nH]ccc23)N1
Reactant: COc1ccc(C(OCCCN(CCCC(=O)Oc2c(F)c(F)c(F)c(F)c2F)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2c(ccc3c2ccn3C(=O)CCCN(CCCOC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccc(N=Nc3ccc([N+](=O)[O-])cc3Cl)cc2)N1
Reaction time: 0.25 h

Procedure:
To a solution of 22 (3.0 g, 3.37 mmol) in 15 mL anhydrous DMF is added triethylamine (0.75 mL) followed by methyl pyrrolo[4,5-e]indoline-7-carboxylate (Boger, D. L., Coleman, R. S., Invergo, B. J. (1987) J. Org. Chem. 52, 1521.) (0.8 g, 3.7 mmol). The resultant solution is stored at room temperature for 20 h. The reaction is analyzed by HPLC to confirm its completeness. DMF is removed on a rotary evaporator equipped with an oil pump. The residue, dark syrup is suspended in 50% ethylacetate/hexanes (˜25 mL). The mixture is sonicated to initiate the crystallization. The crystals are stirred for 15 min, collected by filtration on a sintered glass funnel, washed with methanol (2×30 mL) and dried under vacuum. The yield of the desired product is 2.7 g (87%) as a deep-purple solid. 1H NMR (DMSO-d6) δ: 11.93 (d, J=1.7 Hz, indole NH, 1H), 8.43 (d, J=2.5 Hz, aromatic proton, 1H), 8.3-8.2 (m, aromatic protons, 2H), 7.85-7.75 (m, aromatic protons, 3H), 7.45-7.18 (m, aromatic protons, 10 H), 7.05 (d, J=1.8 Hz, aromatic proton, 1H), 6.97 (d, J=9 Hz, aromatic protons, 2H), 6.87 (d, J=9 Hz, aromatic protons, 4H), 4.12 (t, J=8 Hz, aliphatic protons, 2H), 3.87 (s, ester CH3, 3H), 3.71 (s, CH3, 6H), 3.60 (br t, aliphatic protons, 2H), 3.45 (br t, aliphatic protons, 2H), 3.29 (br t, aliphatic protons, 2H), 3.08 (t, J=5 Hz, aliphatic protons, 2H), 2.5 (br t, obscured by DMSO signal, aliphatic protons, 2H), 1.88 (br m, aliphatic protons, 4H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39](=[N:41]O)[NH2:40])[CH2:35][CH2:34]2)[CH2:32][CH2:31]1>>[CH:30]1([N:33]2[CH2:38][CH2:37][CH:36]([C:39]3[N:41]=[C:27]([CH:13]4[CH2:14][CH:15]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)[CH2:16][N:11]([C:9]([N:6]5[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]5)=[O:10])[CH2:12]4)[O:28][N:40]=3)[CH2:35][CH2:34]2)[CH2:31][CH2:32]1
Reactant: NC(=NO)C1CCN(C2CC2)CC1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(C4CCN(C5CC5)CC4)no3)C2)CC1

Procedure:
155 mg (0.363 mmol) of the compound from Example 100A and 100 mg (0.545 mmol) of the compound from Example 75A were reacted according to the General Method 2. Yield: 76 mg (38% of theory)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:26]2[CH:33]=[N:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[C:27]=2[CH:28]=[O:29])=[CH:3]1.[BH4-].[Na+]>CO>[OH:29][CH2:28][C:27]1[C:26]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH:22]5[CH2:25][O:24][CH2:23]5)[CH2:20][CH2:21]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][N:32]=[CH:31][C:30]=1[N:34]1[CH2:46][CH2:45][N:37]2[C:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=3[CH:44]=[C:36]2[C:35]1=[O:47]
Reactant: Cn1cc(-c2cncc(N3CCn4c(cc5c4CCCC5)C3=O)c2C=O)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2cncc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
A mixture of 101m (135 mg, 0.21 mmol) and NaBH4 (20 mg, 0.5 mmol) in MeOH (5 mL) was stirred at 0° C. for 0.5 h. The mixture was quenched with water and the residue was extracted with EtOAc (5 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 101 (55 mg, 40%). LCMS: [M+H]+ 637. 1H NMR (500 MHz, DMSO) δ 8.58 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 7.86 (d, J=3.0, 1H), 7.38-7.37 (m, 2H), 7.25-7.23 (m, 1H), 6.54 (s, 1H), 5.16 (t, J=3.0, 1H), 4.56-4.40 (m, 6H), 4.19-4.12 (m, 3H), 3.95 (t, J=3.0, 1H), 3.60 (s, 3H), 3.43-3.41 (m, 1H), 3.06 (s, 4H), 2.57-2.61 (m, 2H), 2.45-2.48 (m, 6H), 1.78-1.80 (m, 2H), 1.69-1.70 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Product: O=S(=O)(/C=C/c1ccc(F)cc1)Cc1ccc(Cl)cc1
Yield: 72 %

Procedure:
A solution of 4-chlorobenzyl sulfonylacetic acid (0.01 mol) and 4-fluorobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 72% yield.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].[C:25](O)(=[O:27])[CH3:26]>>[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][N:11]2[C:25](=[O:27])[CH3:26])=[O:9])[CH2:6][CH2:5]1)#[N:3]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was coupled with acetic acid in analogy to experiment A1 to give (2S,4R)-1-acetyl-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a colorless solid. MS: 496.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5](O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:13](OC=C)(=O)[CH3:14]>>[CH3:1][O:2][C:3]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13]1)=[O:4]
Reactant: COC(=O)N(O)c1ccccc1
Reactant: C=COC(C)=O
Product: COC(=O)n1ccc2ccccc21

Procedure:
A solution of 12.0 g of N-methoxycarbonyl-N-hydroxyaniline in 120 ml of vinyl acetate is stirred with 200 mg of Li2PdCl4 for 7 hours at 60° C.; it is then washed with brine, dried over magnesium sulfate and concentrated by evaporation. Chromatography through silica gel (toluene/ethyl acetate 4:1) yields 7.3 g of N-methoxycarbonylindole as colourless oil; IR spectrum (CHCl3): 1730 (CO): NMR spectrum (60 MHz, CDCl3): 1.47 (t, J=7, CH3); 4.47 (q, J=7, CH2); 6.53 (d, J=3.5, CH); 7.1-7.7 (m, 4H); 8.13 (m, 1H) ppm. 1.4 g of an O-acetylated educt in the form of yellow oil are obtained as a second fraction of chromatography.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:16][CH3:17])=[C:5]([C:13](Cl)=[O:14])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])[CH2:27][NH:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:22]=[CH:23][C:24]=1[Cl:25]>C(N(CC)CC)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH3:40])[CH2:27][N:28]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[C:4]=2[CH2:16][CH3:17])=[O:14])[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: CCc1c(C#N)cc2ccccc2c1C(=O)Cl
Reactant: CCCC=CCCC(CNCCC(=O)O)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: CCCC=CCCC(CN(CCC(=O)O)C(=O)c1c(CC)c(C#N)cc2ccccc12)c1ccc(Cl)c(Cl)c1
Yield: 56.7 %

Procedure:
3-Cyano-2-ethyl-1-naphthoyl chloride (0.49 g) was combined with N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-amine (0.57 g) and triethyl amine under standard acylation conditions to afford N-[2-(3,4-dichlorophenyl)-4-pentenylbutyl]-N-[(carboxymethyl)methyl]-3-cyano-2-ethyl-1-naphthamide (0.51 g) as a solid after purification by chromatography (5:4:1 Hexane:DCM:EtOAc); MS: m/z 509 (M+); 1H NMR (CDCl3) δ 8.29 (s), 8.26 (s), 7.83 (d), 7.98-7.30 (m), 7.01 (d), 6.80 (s), 6.53 (d), 5.30-5.11 (m), 4.85-4.52 (m), 4.35-4.03 (m), 4.22 (s), 3.84 (s), 3.80 (s), 3.45 (dd), 3.32 (dd), 3.20-2.91 (m), 1.37 (t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([Br:26])=[CH:11][C:10]=1[C:23](=[O:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
51.2 g of 1-(2,4-Bis-benzyloxy-phenyl)-ethanone (0.154 mol, 1 eq) were dissolved in 250 ml DMF. 27.42 g N-bromosuccinimide (0.154 mol, 1 eq) in 100 ml DMF were added dropwise. The mixture was stirred at room temperature over night. The reaction mixture was poured onto 700 ml of water and the precipitate filtered off. The filter cake was rinsed with water and the colourless solid was recrystallised from 370 ml acetonitrile.