Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]3[N:10](C(OC(C)(C)C)=O)[CH:11]=[C:12]([C:13]4[C:14]([CH3:28])=[N:15][N:16]([CH2:19][C:20]5[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[CH:37]=2)[CH2:3][CH2:2]1>Cl.O1CCOCC1>[CH:1]1([C:4]2[N:9]=[C:8]3[NH:10][CH:11]=[C:12]([C:13]4[C:14]([CH3:28])=[N:15][N:16]([CH2:19][C:20]5[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=5)[C:17]=4[CH3:18])[C:7]3=[CH:6][C:5]=2[C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[C:38]([NH:44][S:45]([CH3:48])(=[O:46])=[O:47])[CH:37]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)cn(C(=O)OC(C)(C)C)c3nc2C2CC2)cc1NS(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c[nH]c3nc2C2CC2)cc1NS(C)(=O)=O
Yield: 8.4 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 6-cyclopropyl-3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-methoxy-3-(methylsulfonamido)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (70 mg, 0.103 mmol) was deprotected in HCl in 1,4-dioxane (2 ml). This afforded 5 mg (9.1% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.24 (s, 1H), 7.66 (s, 1H), 7.59-7.58 (m, 1H), 7.38-7.34 (dd, 1H), 7.22-7.19 (m, 1H), 6.93-6.90 (m, 1H), 6.82-6.76 (m, 1H), 5.45-5.39 (t, 2H), 3.96 (s, 3H), 2.94 (s, 3H), 2.5-2.4 (m, 1H), 2.25 (s, 3H), 1.4-1.0 (m, 4H). MS: m/z=538.1 (M+1), HPLC: 81% method B.
Reaction SMILES: Cl[CH:2]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[O:6][C:7]=1[CH2:8][O:9][CH3:10].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH:19]1([CH:2]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:3]2[CH:4]=[C:5]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:6][C:7]=2[CH2:8][O:9][CH3:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COCc1oc(-c2ccc(OC)nc2)cc1C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.4 %

Procedure:
A mixture of 5-{4-[chloro(cyclohexyl)methyl]-5-(methoxymethyl)furan-2-yl}-2-methoxypyridine (0.4 g), ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.3 g), sodium carbonate (0.2 g) and sodium iodide (0.2 g) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 70% ethyl acetate/hexane). To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.45 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (104 mg, 16%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[N:20](CC=C)[C:19]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:33][CH3:34])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O.C(N(CC)CC)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[C:21](=[O:22])[NH:20][C:19]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:18]2)(=[O:16])=[O:15])=[C:10]([O:33][CH3:34])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)nn(S(=O)(=O)c2ccc(C(=O)NC(C)(C)C)cc2OC)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC(C)(C)C)ccc1S(=O)(=O)n1nc(-c2ccc(Cl)cc2)[nH]c1=O

Procedure:
An amount of 194 mg (0.384 mmol) of N-tert-butyl-4-{[3-(4-chlorophenyl)-5-oxo-4-prop-2-en-1-yl-4,5-dihydro-1H-1,2,4-triazol-1-yl]sulphonyl}-3-methoxybenzenecarboxamide from Example 1 was dissolved under argon in 2 ml of degassed dioxane and admixed with 18 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium(0), 29 μl (0.77 mmol) of formic acid and 134 μl (0.96 mmol) of triethylamine. The mixture was stirred under reflux for 2 h. The dioxane was concentrated on a rotary evaporator and the residue in the flask was taken up in methanol. It was filtered over kieselguhr, the solid product was washed with methanol and the solvent was removed on a rotary evaporator. Ethyl acetate was added to the residue in the flask. Washing with water was carried out twice. The organic phase was dried over sodium sulphate and freed from the solvent on a rotary evaporator. Purification of the residue by flash chromatography on silica gel (solvent gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate 100%) gave 152 mg (85% of theory) of the target compound.
Reaction SMILES: [CH:1]([C:3]1([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]1)=O.Cl.[F:11][C:12]1([F:18])[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:11][C:12]1([F:18])[CH2:16][CH2:15][C@@H:14]([NH:17][CH2:1][C:3]2([C:6]([O:8][CH3:9])=[O:7])[CH2:5][CH2:4]2)[CH2:13]1
Reactant: N[C@@H]1CCC(F)(F)C1
Reactant: COC(=O)C1(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1(CN[C@@H]2CCC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
Methyl 1-formylcyclopropanecarboxylate (45% w/w, 3.205 g, 11.26 mmol) and (R)-3,3-difluorocyclopentanamine hydrochloride (1.774 g, 11.26 mmol) were dissolved in dichloromethane (20 mL) at 0° C. under nitrogen. To this solution was added sodium acetate (0.923 g, 11.26 mmol) followed by sodium triacetoxyborohydride (3.46 g, 16.32 mmol). The reaction mixture was allowed to warm up to room temperature overnight. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate and stirred at room temperature for a further 10 minutes. The aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated under vacuo. The residue was purified on silica gel by flash column chromatography to give the required compound (2.631 g, quantitative yield).
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:27])([F:26])[O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:17]=[N:16][C:15]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=3)=[N:14]2)=[CH:9][CH:8]=1>CCO.O>[N:2](=[CH:22]/[C:21]1[CH:24]=[CH:25][C:18]([C:15]2[N:16]=[CH:17][N:13]([C:10]3[CH:11]=[CH:12][C:7]([O:6][C:5]([F:27])([F:26])[F:4])=[CH:8][CH:9]=3)[N:14]=2)=[CH:19][CH:20]=1)\[NH2:3]
Reactant: NN
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: O
Solvent: CCO
Product: N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C

Procedure:
To a 250 mL round-bottomed flask containing hydrazine hydrate (64% aq solution; 7.27 mL, 15.0 mmol) in EtOH (100 mL) at 80° C. was added 4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzaldehyde (5.00 g, 1.50 mmol) portionwise over 5 min. The solution was stirred at reflux for an additional 3 h before being diluted with H2O (300 mL) and cooled to 0° C. The precipitated product was collected by vacuum filtration as a white solid (4.89 g, 93%) mp 222-226° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.22 (d, J=8.2 Hz, 2H), 7.84-7.79 (m, 2H), 7.66 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.2 Hz, 2H), 7.29 (s, 1H), 5.63 (br s, 2H); ESIMS m/z 348 (M+H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@:9]([OH:31])([C@H:16]([S:18][C@@H:19]1[CH2:24][O:23][C@@H](C2C=CC=CC=2)[O:21][CH2:20]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1>C1(C)C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@:9]([OH:31])([C@H:16]([S:18][CH:19]([CH2:20][OH:21])[CH2:24][OH:23])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](S[C@H]1CO[C@H](c2ccccc2)OC1)[C@](O)(Cn1cncn1)c1ccccc1F
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccccc1F
Temperature: 50 °C
Yield: 53.8 %

Procedure:
110 ml (110 mmol) of 1 N hydrochloric acid were added to a solution of 13 g (30.3 mmol) of (2R,3R)-2-(2-fluorophenyl)-3-[(trans-2-phenyl-1,3-dioxan-5-yl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol [prepared as described in Step 5(i) above] in 80 ml of toluene. The resulting mixture was heated at 50° C. for 2.5 hours. At the end of this time, the water layer was separated and the oily layer was extracted twice with dilute hydrochloric acid and then with an aqueous sodium chloride solution. The aqueous layers were combined and sodium hydrogen carbonate was carefully added thereto in small portions until bubbles of carbon dioxide were no longer detected. The resulting mixture was extracted with ethyl acetate and the extract was then concentrated under reduced pressure to afford a solid residue. This residue was collected by filtration and then washed with a small amount of ethyl acetate to afford 5.57 g (yield 55%) of the title compound as a pale brown solid.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([CH:7]([CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:8]#[N:9])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2-].[Na+].Cl[CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39]>O>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([C:7]([CH2:35][CH2:36][N:37]([CH:41]([CH3:43])[CH3:42])[CH:38]([CH3:40])[CH3:39])([CH2:10][CH2:11][N:12]([CH:13]([CH3:14])[CH3:15])[CH:16]([CH3:18])[CH3:17])[C:8]#[N:9])=[CH:3][CH:2]=1
Reactant: CC(C)N(CCCl)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccc(-c2ccccc2)cc1)C(C)C
Temperature: 100 °C

Procedure:
To a solution of 16 parts of α-(4-biphenylyl)-α-[2-(diisopropylamino)ethyl]acetonitrile in 150 parts by volume of toluene is added 2.7 parts of sodium amide and the solution is heated over a period of 15 minutes at about 100° C. Then 13 parts of 2-chloro-N,N-diisopropylethylamine in 40 parts by volume of toluene is added slowly over a period of 20 minutes. This mixture is heated at 100°-105° C. for about 90 minutes and then cooled to room temperature when 150 parts by volume of water is added. The organic layer is separated, dried over calcium sulfate, filtered and the solvent evaporated to afford α-(4-biphenylyl)-α,α-bis[2-(diisopropylamino)ethyl]acetonitrile, as a low melting solid. This compound is identical with the compound of Example 2, Method A.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][CH2:44][CH3:45])(=[O:41])=[O:40])=[CH:35][CH:34]=3)[S:13][C:12]=2[CH:46]=1)(=O)=O)[CH2:2][CH2:3][CH3:4].CCOCC.[ClH:52]>C(OCC)(=O)C>[ClH:52].[CH2:1]([S:5][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]4)=[CH:20][CH:19]=3)=[O:17])=[C:14]([C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH2:42][CH2:43][CH2:44][CH3:45])(=[O:41])=[O:40])=[CH:37][CH:38]=3)[S:13][C:12]=2[CH:46]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)c1ccc(-c2sc3cc(S(=O)(=O)CCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCSc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)CCCC)cc3)sc2c1

Procedure:
5.4g of [6-(n-Butylsulfonoyl)-2-[4-(n-butylsulfonoyl)phenyl]benzo[b]thien-3-yl][4-[2-(1piperidinyl)ethoxy]-phenyl]methanone was dissolved in ethyl acetate (EtOAc) and a solution of ether, saturated with HCl, was added until no more precipitate was formed. The liquid was decanted off and the solid was triturated with ether. The title compound was crystallized from hot EtOAc to afford 3.74 g, as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.[Zn]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:9]#[N:10])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(Cl)nc1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cl)cn1
Temperature: 25 °C
Yield: 46 %

Procedure:
Add 2,5-dichloropyridine (6.0 g, 40.5 mmol), zinc cyanide (2.9 g, 24.7 mmol), zinc dust (16 mg, 1.8 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (20 mg, 0.98 mmol) to a flask containing DMF (40 mL). Heat the mixture to reflux for 5 h, then cool to ambient temperature. Dilute the mixture with EtOAc (300 mL) and wash with 10% aqueous NaCl (3×75 mL). Collect the organic layer, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (2.6 g, 46%).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:12][C@@H:11]1[CH2:13][C:14]([OH:16])=[O:15])C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH2:9][C@H:10]1[CH2:12][C@@H:11]1[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)C[C@H]1C[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)C[C@H]1C[C@@H]1CO
Yield: 103.7 %

Procedure:
A mixture of 2-((1R,2S)-2-((benzyloxy)methyl)cyclopropyl)acetic acid (884 mg, 4.01 mmol) in MeOH (20 mL) was stirred in the presence of 10% palladium-carbon (310 mg, 50%, wet) at room temperature for 3 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added toluene (about 20 mL), and the mixture was concentrated to give 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (542 mg, 4.16 mmol, quant.) as a colorless oil.
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[CH:24]1([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([O:42]CC)=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][N:28]2[C:32](=[O:33])[N:31]([C:34]3[S:35][C:36]([C:40]([OH:42])=[O:41])=[C:37]([CH3:39])[N:38]=3)[CH:30]=[N:29]2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1sc(-n2cnn(CC3CC3)c2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(-n2cnn(CC3CC3)c2=O)sc1C(=O)O
Yield: 92 %

Procedure:
Following the procedure as described in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(cyclopropylmethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 92% yield: 1H NMR (300 MHz, DMSO-d6) δ 13.39 (br s, 1H), 8.72 (s, 1H), 3.63 (d, J=7.1 Hz, 2H), 2.57 (s, 3H), 1.19-1.04 (m, 1H), 0.53-0.42 (m, 2H), 0.36-0.27 (m, 2H); MS (ES−) m/z 279.0 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[CH:8][C:7]=2[CH:22]=1)#[N:2].O[N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:24]1([O:18][C:17]([C:16]2[CH:20]=[CH:21][C:13]([CH2:12][CH2:11][C:9]3[O:10][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:22][C:7]=4[CH:8]=3)=[CH:14][CH:15]=2)=[O:19])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[N:25]1
Reactant: N#Cc1ccc2oc(CCc3ccc(C(=O)O)cc3)cc2c1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#Cc1ccc2oc(CCc3ccc(C(=O)On4nnc5ccccc54)cc3)cc2c1
Reaction time: 3 h
Yield: 78.5 %

Procedure:
At room temperature, 1 g of 4-[2-(5-cyano-2-benzofuranyl)ethyl]benzoic acid and 578 mg of 1-hydroxybenzotriazole were dissolved in 100 ml of dichloromethane, followed by the addition of 780 mg of 1,3-dicyclohexylcarbodiimide and by subsequent stirring at the same temperature for 3 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a chloroform/ethanol mixture as an elution solvent, and the thus purified product was crystallized from a benzene/n-hexane mixture. In this way, 1.1 g of 2-[2-[4-[[(1-benzotriazolyl)oxy]-carbonyl]phenyl]ethyl]-5-benzofurancarbonitrile was obtained in a powdery form.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:16]([O-])=O)=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:19].C(O)C.[H][H]>[Pd].C1COCC1>[NH2:16][C:11]1[CH:10]=[C:9]2[C:14](=[C:13]([F:15])[CH:12]=1)[N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:20])[C:6](=[O:19])[CH2:7][CH2:8]2
Reactant: [H][H]
Reactant: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCN1C(=O)CCc2cc(N)cc(F)c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (500 mg, 1.77 mmol) was weighed into a round bottom flask equipped with a stirbar. Ethanol (10 mL) and THF (2 mL) were added, followed by Pd, 10 wt. % on activated carbon. The flask was fitted with a balloon of hydrogen, evacuated of air and backfilled with hydrogen. The black suspension was stirred for 3 h at room temperature. The solid palladium was then filtered off through a plug of celite and the celite pad washed with methanol. The filtrate was concentrated, then chromatographed on silica gel using 0-10% (2M NH3 in MeOH) in ethyl acetate to give the product. Yield: 325 mg, 72%. EI-MS: 251 (M+, 3), 58 (100).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)O1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[N:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=1>CCCCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:37][C:34]1[N:35]=[CH:36][C:31]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3([C:21]#[N:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:13][CH:14]=2)=[N:32][CH:33]=1
Reactant: CC1(C)OB(c2ccc(C3(C#N)CCOCC3)cc2)OC1(C)C
Reactant: Nc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: N#CC1(c2ccc(-c3cnc(N)cn3)cc2)CCOCC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
A solution of 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (1.53 g, 4.86 mmol), Pd(PPh3)4 (271 mg, 0.24 mmol), 2.0 M aq. Na2CO3 (4.9 mL) and the 5-bromopyrazin-2-amine (846 mg, 4.86 mmol) were combined in n-BuOH (20 mL). The slurry was degassed for 10 min under a bubbling stream of anhydrous nitrogen, then heated at 90° C. for 2 h. The resulting mixture was filtered, concentrated and purified by flash chromatography on silica (1-5% MeOH/DCM eluent) to provide 4-(4-(5-aminopyrazin-2-yl)phenyl)tetrahydro-2H-pyran-4-carbonitrile (1.08 g, 79% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]1(=[N:25][N:26]([CH3:28])[CH3:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:29][O:30][C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39](Cl)=[O:40])[CH2:35][CH2:34]1)=[O:32].C(O)(=O)C>O1CCCC1>[CH3:29][O:30][C:31]([C@H:33]1[CH2:38][CH2:37][C@H:36]([C:39]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:19]2=[N:25][N:26]([CH3:28])[CH3:27])=[O:40])[CH2:35][CH2:34]1)=[O:32]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: CN(C)N=C1CCCCC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)C2CCCCC2=NN(C)C)CC1
Reaction time: 1.5 h

Procedure:
To a solution of N,N-diisopropylamine (1.59 ml, 11.2 mmol) in dry tetrahydrofuran (10 ml) was added 1.6 M n-butyl lithium in n-hexane (7.00 ml, 11.2 mmol) at 0-5° C. Addition of N′-cyclohexylidene-N,N-dimethyl-hydrazine (1.50 g, 10.7 mmol) after 15 minutes was followed by stirring for 90 minutes. The resulting solution was cannulated dropwise to a solution of trans-4-chlorocarbonyl-cyclohexanecarboxylic acid methyl ester (2.19 g, 10.7 mmol) in dry tetrahydrofuran (50 ml) at −65° C. The reaction mixture was stirred for 20 h at −78° C. The cooling bath was removed and the reaction mixture was quenched by addition of acetic acid (0.65 ml, 11 mmol) at −5° C. The mixture was partitioned between ethyl acetate (150 ml) and saturated ammonium chloride solution (100 ml). The layers were separated. The aqueous layer was extracted with one 100-ml portion of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/ethyl acetate as eluent gave the title compound (0.98 g, 30%) as light yellow oil with a purity of 60%. MS m/e: 309 ([M+H]+)
Reaction SMILES: [C:1]([C@@:8]([NH2:15])([CH2:12][O:13][CH3:14])[C:9]([OH:11])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][C:26]1=[O:31])[NH:20][CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[C:1]([C@@:8]([NH2:15])([CH2:12][O:13][CH3:14])[C:9]([N:20]([CH3:21])[C:19]1[CH:22]=[CH:23][C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][C:26]2=[O:31])=[C:17]([CH3:16])[CH:18]=1)=[O:11])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC[C@@](N)(C(=O)O)C(=O)OC(C)(C)C
Reactant: CNc1ccc(N2CCOCC2=O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COC[C@](N)(C(=O)OC(C)(C)C)C(=O)N(C)c1ccc(N2CCOCC2=O)c(C)c1

Procedure:
Prepared analogously to Example 1d from (2R)-2-Boc-amino-3-methoxy-propionic acid and 3,N-dimethyl-4-(3-oxo-morpholin-4-yl)-aniline with TBTU and TEA in DMF.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[S:23][C:22]([S:24]([NH:27][NH2:28])(=[O:26])=[O:25])=[CH:21][CH:20]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:28][NH:27][S:24]([C:22]1[S:23][C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)=[CH:20][CH:21]=1)(=[O:25])=[O:26]
Reactant: NNS(=O)(=O)c1ccc(-c2ccccn2)s1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNS(=O)(=O)c1ccc(-c2ccccn2)s1
Temperature: 100 °C
Yield: 23 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 5-(2-pyridinyl)-2-thiophenesulfonohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 23 mg of the title compound (23%) as a yellow solid in 94.8% purity by HPLC (Rt: 3.68, 5.13, gradient of 8 min, MaxPlot detection between 230 and 400 nm).