Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[N+:24]([O-])=O)[CH3:2].[H][H]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:27])[NH:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:9]=[C:8]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:7]=1[NH2:24])[CH3:2]
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)Nc1cc(C(F)(F)F)nc(NCc2ccccc2)c1N
Yield: 99.3 %

Procedure:
(2-benzylamino-3-nitro-6-trifluormethyl-pyridin-4-yl)-carbamic acid ethyl ester (95 mg, 0.25 mmol) was dissolved in 10 mL of ethanol and Raney Nickel (20 mg, 20% MW) was added then the reaction mixture was stirred at room temperature in a bomb under 50 PSI of hydrogen for 2 h. The mixture was filtered through arbocel and the filtrate was concentrated in vacuo to give 88 mg of the title compound as a pale green gum.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1.CS(O[CH2:34][CH2:35][CH:36]1[CH2:38][C:37]1([F:40])[F:39])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:39][C:37]1([F:40])[CH2:38][CH:36]1[CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:15]=[C:14]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[N:13]=[CH:12][C:11]=3[N:28]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Reactant: C[C@@H](COc1cc2oc(-c3ccc(O)cc3)nc2cn1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc2oc(-c3ccc(OCCC4CC4(F)F)cc3)nc2cn1)NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
A mixture of tert-butyl ((2S)-1-((2-(4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)carbamate (300 mg), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (312 mg), potassium carbonate (215 mg) and DMF (5 mL) was stirred overnight at 70° C. The reaction mixture was allowed to cool to room temperature, and 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (935 mg) and potassium carbonate (645 mg) were added thereto. The obtained mixture was stirred overnight at 70° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (239 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]3[N:17]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][N:20]=3)[CH:10]=2)[N:3]=1.[Cl:40][C:41]1[NH:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=1.C([O-])([O-])=O.[K+].[K+]>C(C#N)(C)=O>[Cl:40][C:41]1[N:45]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][C:16]4[N:17]([C:21]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:18]=[CH:19][N:20]=4)[CH:10]=3)[N:3]=2)[C:44]2[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=2[N:42]=1
Reactant: Clc1ncnc(Nc2cccc(Cc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)n1
Reactant: Clc1nc2ccccc2[nH]1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1nc2ccccc2n1-c1ncnc(Nc2cccc(Cc3nccn3C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)n1
Temperature: 70 °C

Procedure:
(4-Chloro-[1,3,5]triazin-2-yl)-[3-(1-trityl-1H-imidazol-2-ylmethyl)phenyl]amine (331 mg, 0.6256 mmol) is combined with 2-chlorobenzimidazole (114.6 mg, 0.7508 mmol) and K2CO3 (190 mg, 1.376 mmol) in AcCN (5 ml) and heated at 65-75° C. for 2 to 20 h. The reaction mix is cooled to RT. The product precipitates out of AcCN, and is filtered off. The crude solid is treated with water, filtered and dried, giving [4-(2-chloro-benzoimidazol-1-yl)-[1,3,5]triazin-2-yl]-[3-(1-trityl-1H-imidazol-2-ylmethyl)phenyl]amine.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:35])([CH3:34])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36](O)=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH:10]1([N:13]2[C:17]([C:18]3[CH:19]=[C:20]([CH:24]4[CH2:33][C:32]([CH3:34])([CH3:35])[C:31]5[C:26](=[CH:27][CH:28]=[C:29]([C:36]([NH:9][S:6]([CH:3]6[CH2:5][CH2:4]6)(=[O:8])=[O:7])=[O:37])[CH:30]=5)[NH:25]4)[CH:21]=[CH:22][CH:23]=3)=[N:16][N:15]=[N:14]2)[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)C1CC1
Reactant: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(-c3nnnn3C3CC3)c2)Nc2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a suspension of 60% sodium hydride (535 mg, 13.7 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (1.65 g, 13.8 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A41. A solution of 2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (544.6 mg, 1.4 mmol) and 1,1′-carbonyldiimidazole (442 mg, 2.76 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B41. Solution B41 was added to Solution A41 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(1-cyclopropyl-1H-tetrazol-5-yl)-phenyl]-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (206.6 mg, 30%) as a white solid: MS (ESI) M+1=493.2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]CCC)=[N+:2]=[N-:3].[CH2:22](C1C=CC(C(Cl)=O)=CC=1)[CH2:23]CCCC.N(CCN)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Agent: [N-]=[N+]=NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Yield: 84 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, 4-hexylbenzoyl chloride (0.293 g, 1.30 mmol) was reacted with 2-azidoethanamine (0.112 g, 1.30 mmol) and triethylamine (0.264 g, 2.61 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)-4-hexylbenzamide (0.299 g, 84%). 1H NMR (300 MHz, CDCl3) δ 7.75 (d, 2H), δ 7.43 (t, 1H), δ 7.17 (d, 2H), δ 3.55 (q, 2H), δ 3.46 (t, 2H), δ 2.59 (t, 2H), δ 1.58 (m, 2H), δ 1.29 (m, 4H), δ 0.87 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.6, 147.3, 131.7, 130.3, 128.8, 127.5, 50.9, 39.7, 35.9, 31.6, 31.1, 22.7, 14.2 ppm; HRMS (ESI) calcd for C15H22N4O (M+) 274.1794. Found 274.1789.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH2:15]O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[Cl:4][CH2:15]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: F/C=C(/CCl)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Combine oxalyl chloride (2.71 g, 21.4 mmol) and toluene (20 mL). Cool to 0° C. Add N,N-dimethylformamide (1.62 g, 22.2 mmol) as a solution in toluene (2 mL). Warm to ambient temperature. After 10 minutes, cool to 0° C. Add (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (4.0 g, 20.2 mmol). Warm to ambient temperature. After 18 hours, pour the reaction mixture into a saturated sodium chloride solution (100 mL). Extract the aqueous layer 3 times with toluene. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.52 (m, 2H), 2.75 (m, 2H), 3.91 (d, J=6 Hz, 2H), 6.65 (d, J=82.5 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Cl:12])[O:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][C:2]2[N:6]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][C:11]=3[Cl:12])[O:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Nc1noc(-c2sccc2Cl)n1
Solvent: Cc1ccccc1
Product: Clc1ccc(C=Nc2noc(-c3sccc3Cl)n2)cc1

Procedure:
Compounds of this invention with a linker between middle ring and Ar2 may be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of 3-chloro-thiophene-2-carbonyl chloride with cyanamide produces N-cyano-3-chloro-thiophene-2-carboxylic acid amide, followed by treating with hydroxyamine to give 3-amino-5-(3-chloro-2-thienyl)-1,2,4-oxadiazole. The amine was refluxed with 4-chlorobenzaldehyde in toluene to produce (4-chloro-benzylidene)-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19]O)=[CH:7]2.O=S(Cl)[Cl:23]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH2:19][Cl:23])=[CH:7]2
Reactant: O=S(Cl)Cl
Reactant: OCc1cc2cccc(Cl)c2nc1Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: ClCc1cc2cccc(Cl)c2nc1Oc1ccccc1

Procedure:
Prepared according to Procedure C using (8-chloro-2-phenoxyquinolin-3-yl)-methanol (1.0 eq) and SOCl2 (5 eq) in CHCl3 (0.25M) at rt. 8-chloro-3-(chloromethyl)-2-phenoxyquinoline was obtained after purification as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].Cl[S:27]([C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:27]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])(=[O:29])=[O:28])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COC(=O)c1ccccc1S(=O)(=O)N1CCC(N2N=C(c3ccc(OC)c(OC)c3)C(C)(C)C2=O)CC1

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and methyl 2-(chlorosulfonyl)benzoate as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[O:104]=[C:105]1[CH:109]=[CH:108][C:107](=[O:110])[N:106]1[CH2:111][CH2:112][CH2:113][CH2:114][CH2:115][C:116]([NH:118][NH:119][CH3:120])=[O:117]>CN(C=O)C>[O:110]=[C:107]1[CH:108]=[CH:109][C:105](=[O:104])[N:106]1[CH2:111][CH2:112][CH2:113][CH2:114][CH2:115][C:116]([NH:118][N:119]([C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:63])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:59]([CH3:62])[CH2:60][CH3:61])[C@H:24]([O:57][CH3:58])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:55][CH3:56])[C@@H:34]([CH3:54])[C:35]([NH:37][C@@H:38]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:39]([N:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)=[O:40])=[O:36])=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH3:120])=[O:117]
Reactant: CNNC(=O)CCCCCN1C(=O)C=CC1=O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)N(C)NC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.9 mg (8 μmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide were dissolved in 2540 μl of DMF and then admixed with 3.6 mg (9 μmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 3 μl of N,N-diisopropylethylamine and with 4.1 mg (12 μmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N′-methylhexanehydrazide trifluoroacetate. The mixture was stirred at RT overnight. Subsequently, the solvent was removed under reduced pressure and the remaining residue was purified by means of preparative HPLC. Thus, 3.9 mg (45% of theory) of the title compound were obtained as a colourless foam.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:34](NN)(=O)CC>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH2:32][CH3:34])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=O)NN
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 152 and using propionohydrazide instead of acetohydrazide. m/z (ES+) 454 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.75-7.43 (m, 3H), 7.40-7.17 (m, 3H), 5.18-4.81 (m, 1H), 4.30-3.91 (m, 1H), 3.84-3.55 (m, 1H), 3.21-2.99 (m, 1H), 2.92-2.69 (m, 4H), 2.40 and 2.32 (2 singlets, amide rotamers, ArCH3, 3H), 2.25-1.84 (m, 7H), 1.83-1.42 (m, 3H), 1.32 (t, 3H).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])C.[NH2-].[Li+].[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13]C#C)[CH3:11].BrCC>CCCCCC>[CH3:8][O:9][C:10]([CH3:16])([O:12][CH2:13][C:5]#[C:3][CH2:2][CH3:1])[CH3:11]
Reactant: C=CC(=C)C
Reactant: C#CCOC(C)(C)OC
Agent: [Li+]
Agent: [NH2-]
Solvent: CCCCCC
Solvent: CCBr
Product: CCC#CCOC(C)(C)OC
Reaction time: 1 h
Yield: 105.6 %

Procedure:
259 mg (37 mmol) of granulated lithium were added within 5 minutes to 47.7 g (1.9 mol) of liquid ammonia at −40° C. The mixture was stirred until no more lithium floated (after approximately 10 minutes). A dark blue solution of lithium in liquid ammonia was obtained. 4.0 ml (40 mmol) of isoprene were added portion wise within 10 minutes. The end of the formation of lithium amide could be recognized by the discoloration of the reaction mixture. 2.9 g (20 mmol) of 3-(1-methoxy-1-methyl-ethoxy)-propyne (88.9% GC) were added with a dropping funnel to the reaction mixture at −40° C. within 20 minutes. The reaction mixture was held at −40° C. for about 1 hour. 8.9 g (80 mmol) of bromoethane were added with a dropping funnel to the reaction mixture within 10 minutes. The reaction mixture was subsequently stirred for 1 hour. 20 ml of n-hexane were added to the reaction mixture and the liquid ammonia was evaporated under normal pressure within 5 hours. 20 ml of water were added to the reaction mixture at 22° C., and the mixture was stirred until all salt was dissolved. The organic layer was separated and dried over 2 g of anhydrous magnesium sulfate. The solution was concentrated under reduced pressure (40° C., 40 mbar) and the crude product was analyzed by GC. 3.3 g of crude 1-(1-methoxy-1-methyl-ethoxy)-pent-2-yne were obtained with a purity of 75.6% (yield 80.0% based on 3-(1-methoxy-1-methyl-ethoxy)-propyne).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:16]I>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:16])[C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: CC1(C)C(=O)Nc2cc(Br)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(C)(C)c2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.2 %

Procedure:
In a 25-mL, round-bottomed, single-necked flask was placed 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one (500 mg, 2.07 mmol) in DMF (5 mL). The mixture was cooled to 0° C. followed by an addition of NaH (60%, 99.55 mg, 2.49 mmol). The reaction mixture was stirred at 0° C. for 20 min. To this was added MeI (0.39 ml, 6.22 mmol) at 0° C. Then, it was slowly warmed to room temperature and stirred for 3 h. The reaction mixture was quenched with sat. NH4Cl (5 mL) and the organic layers were extracted with EtOAc (3×5 mL). The combined organic layers were washed with water (2×5 mL) and brine (1×5 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% Hexane to 100% EtOAc) to give 455 mg (86%) of 6-bromo-1,3,3-trimethyl-1H-pyrrolo[3,2-b]pyridin-2(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:4][CH:3]=1.[C:14](Cl)(=[O:20])[CH2:15][CH2:16][C:17](Cl)=[O:18]>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:14](=[O:20])[CH2:15][CH2:16][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH3:11])=[O:7])=[CH:12][CH:13]=2)=[O:18])=[CH:13][CH:12]=1)=[O:7])[CH2:10][CH3:11]
Reactant: CCCOC(=O)c1ccc(O)cc1
Reactant: O=C(Cl)CCC(=O)Cl
Product: CCCOC(=O)c1ccc(OC(=O)CCC(=O)Oc2ccc(C(=O)OCCC)cc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 7.8 g of propyl p-hydroxybenzoate and 18 g of succinic acid dichloride to yield di(p-propyloxycarbonylphenyl)succinate, m.p 122°-123.5° C., as white crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[O:14][CH2:15][C:10]=3[C:9]([C:20](=[O:24])[CH2:21][C:22]#[N:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.Cl>CN(C)C=O>[C:22]([CH:21]([C:20]([C:9]1[C:10]2[CH2:15][O:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:11]=2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:24])[C:32]([NH:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])#[N:23]
Reactant: O=C=Nc1ccccc1
Reactant: N#CCC(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1COc1ccccc1-2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.1 g) is reacted with phenyl isocyanate (0.8 g) in the presence of triethylamine (0.75 g) in dimethylformamide (20 ml) under stirring at 25°-30° C. for 90 minutes. The reaction mixture is diluted with ice water, acidified to pH 2 with HCl and the precipitate is filtered and washed with water. Crystallization from dichloromethane/methanol gives 2.5 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 280°-282° C., NMR (CDCl3) δppm: 5.54 (s) (2H, --CH2O--), 6.7-7.7 (m) (14H, phenyl protons), 8.94 (s) (1H, CONH--), 16.4 (bs) (1H, enol).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH3:46])[CH:41]=[C:40]([O:47][CH:48]([CH3:50])[CH3:49])[C:39]=2[F:51])[C:27]2[CH:36]=[CH:35][C:30]([C:31]([NH2:34])=[N:32][OH:33])=[CH:29][CH:28]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:52][C:53](OC(C)=O)=[O:54].CO>CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:26]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH3:46])[CH:41]=[C:40]([O:47][CH:48]([CH3:50])[CH3:49])[C:39]=2[F:51])[C:27]2[CH:36]=[CH:35][C:30]([C:31]([NH2:34])=[N:32][O:33][C:53](=[O:54])[CH3:52])=[CH:29][CH:28]=2)[N:5]([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1cc(CN(c2ccc(C(N)=NO)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(CN(c2ccc(C(N)=NOC(C)=O)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of Intermediate 66.1 in 20 mL EtOAc, was added 0.5 mL Ac2O. The reaction mixture was stirred at rt for 1 h, then was treated with 1 mL MeOH and evaporated to afford Intermediate 66.2, which was used in the following step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:14](N)(=O)[C:15]1C=CC=C[CH:16]=1.C(Cl)(=O)C>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:14]([CH2:15][CH3:16])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccccc1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Solvent: CC(=O)Cl
Product: CCc1nc(O)c2ccc(OC)c(C)c2n1
Yield: 100 %

Procedure:
The general procedure described above was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and acetic acid chloride as acid chloride [B], which gave the title compound (2.2 g, 100%).