Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15](Br)[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.[C:19](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:20].C(C([Sn])=C(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:16]=[C:15]([CH:19]=[CH2:20])[CH:14]=[C:6]([C:7]([N:9]([CH3:13])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1
Reactant: CCCN(C)C(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: CCCCC([Sn])=C(CCCC)CCCC
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(C(=O)N(C)CCC)c1
Yield: 70 %

Procedure:
Dissolve 5-bromo-N-methyl-N-propyl-isophthalamic acid methyl ester (2.7 g, 8.6 mmol) in toluene (16 mL) and place the solution under nitrogen. Add in sequence 2,6-di-tert-butyl-4-methylphenol (a few crystals), tetrakis(triphenylphosphine)palladium (0) (185 mg, 0.16 mmol), and tributylvinyl tin (3 g, 9.5 mmol) and reflux for 4 h. Filter through a filtering agent and concentrate. Add diethyl ether (70 mL) and 20% aqueous potassium fluoride (70 mL) and stir vigorously. Collect the diethyl ether layer and extract with diethyl ether two additional times. Concentrate and purify (silica gel chromatography, eluting with 0:100 to 50:50 ethyl acetate:hexanes) to give the title compound (1.58 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[CH3:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20][NH2:21])=[O:19].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[C:3]([C:9]([NH:21][NH:20][C:18]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[CH3:12])=[O:19])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Cc1ccsc1C(=O)NN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)NNC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
To a suspension of 3-amino-6-bromo-pyrazine-2-carboxylic acid (13.26 g, 60.82 mmol) and 3-methylthiophene-2-carbohydrazide (10 g, 60.82 mmol) in DMF (95.00 mL) cooled in an ice bath was added Et3N (7.385 g, 10.17 mL, 72.98 mmol) followed by TBTU (23.43 g, 72.98 mmol) portionwise after complete addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (50 mL) and water (50 mL). The layers were separated and the organic extracts washed with water (1×50 mL) and brine (1×50 mL), dried over MgSO4 and concentrated to leave a brown solid (7.85 g, 36% yield) which was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[NH2:39][OH:40].ClCCl.C(O)C>C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:39][OH:40])=[CH:23][CH:24]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: NO
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: Cn1c(CNc2ccc(C(=N)NO)cc2)nc2cc(C(=O)N(CCC(=O)NS(C)(=O)=O)c3ccccn3)ccc21
Yield: 27 %

Procedure:
Prepared analogously to Example 96 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-[2-(methanesulphonylaminocarbonyl)-ethyl]-amide and hydroxylamine. Yield: 27% of theory, C26H28N8O5S (564.6) Rf value: 0.75 (silica gel; dichloromethane/ethanol=7:3+1% glacial acetic acid) ##EQU137##
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][O:16][C:17]3[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: ClCc1cccnc1-c1ccc(Cl)cc1
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccc(Cl)cc2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(4-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 148.2 mg (20%) of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.69 (m, 1H), 8.16 (m, 2H), 7.64 (m, 2H), 7.50 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H); MS (ESI) m/z 355 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:19][S@@](C(C)(C)C)=O)([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[NH2:19][C@@:9]([C:4]1[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH2:10][F:11])[CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:15])[F:17]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cc(Br)cnc1F
Temperature: 25 °C

Procedure:
(R)-N-((2S,4S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (3.68 g, 8.12 mmol) was dissolved in 36 mL methylene chloride and 18 mL MeOH. The solution was stirred at room temperature. Hydrogen chloride, 4M in 1,4-dioxane (20.30 ml, 81 mmol) was added and the reaction mixture was stirred for 1.5 h. The reaction was concentrated, then EtOAc and water was added, followed by addition of saturated sodium bicarbonate solution for neutralization. The layers were separated and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude material of (2S,4S)-4-amino-4-(5-bromo-2-fluoropyridin-3-yl)-1,1,1,5-tetrafluoropentan-2-ol that was used without further purification.
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18](O)=O)[CH2:14][CH2:13]1)=[O:11].CN(C=O)C>C(Cl)Cl>[C:18]([C@H:15]1[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH3:8])=[O:11])[CH2:13][CH2:14]1)#[N:5]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](C#N)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Chlorosulfonyl isocyanate (1.0 mL, 0.012 mol) was added to a solution of trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (2.00 g, 0.0107 mol) in DCM cooled to 0° C. The resulting solution was heated at reflux for 15 minutes and then cooled 0° C. and treated dropwise with DMF. The mixture was stirred at room temperature overnight then poured onto ice water and the organic phase separated and washed with a saturated solution of sodium bicarbonate. The solvent was removed in vacuo and the crude material was taken up in ethyl acetate, washed with 1N aq. NaOH (10 mL) and the ethyl acetate removed in vacuo. The resulting crude product was used in subsequent steps without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.70 (4 H, m), 2.01-2.18 (4 H, m), 2.24-2.54 (2 H, m) and 3.68 (3 H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: C=COCCON
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCl (40 mg, 0.21 mmol) al room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.CS(Cl)(=O)=O.[H-].[Na+].O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:23][CH:22]=1>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[N:30]1([CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:12][CH2:11][C:9]3[N:10]=[C:6]([N:1]4[CH:2]=[CH:3][CH:4]=[CH:5]4)[S:7][CH:8]=3)=[CH:22][CH:23]=2)[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: OCc1csc(-n2cccc2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccn(-c2nc(COc3ccc(CCCn4ccnc4)cc3)cs2)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a mixture of 2-(1-pyrrolyl)-4-thiazolylmethanol (0.45 g), triethylamine (0.42 ml) and ethyl acetate (20 ml) was added dripwise methanesulfonyl chloride (0.23 ml) at 0° C., and then stirred for one hour. To the reaction mixture was added water, and the ethyl acetate layer was separated, washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 ml), which was added to a solution prepared by adding sodium hydride (oily, 60%, 92 mg) to a solution of 1-[3-(4-hydroxyphenyl)propyl]imidazole (420 mg) in N,N-dimethylformamide (10 ml). After stirring for 2 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 2N-aqueous sodium hydroxide and then water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (95:5, v/v), crystals were obtained. Recrystallization from ethyl acetate-hexane gave 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(1-pyrrolyl)thiazole (530 mg, 70%), colorless prisms, mp 93-94° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[C:12]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])=[N:11][CH:10]=[CH:9][N:8]=1)([CH3:6])[C:3]([OH:5])=[O:4]>C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Au](Cl)(Cl)Cl.F[B-](F)(F)F.[Ag+]>[CH3:6][C:2]1([CH3:1])[C:7]2[C:12](=[N:11][CH:10]=[CH:9][N:8]=2)/[C:13](=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:24])[F:22])/[O:4][C:3]1=[O:5]
Reactant: CC(C)(C(=O)O)c1nccnc1C#Cc1ccccc1C(F)(F)F
Agent: Cl[Au](Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)C(=O)O/C(=C\c2ccccc2C(F)(F)F)c2nccnc21
Temperature: 55 °C
Yield: 34 %

Procedure:
A solution of gold chloride triphenylphosphine (0.444 g) and silver tetrafluoroborate (0.174 g) in carbon tetrachloride was stirred for 30 min. To this solution was added a solution of 2-methyl-2-[3-(2-trifluoromethyl-phenylethynyl)-pyrazin-2-yl]-propionic acid (0.50 g). The reaction mixture was flushed out with argon then heated to 55° C. for 48 hours. The reaction mixture was cooled to ambient temperature, filtered, concentrated and the residue purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give 8,8-dimethyl-5-[1-(2-trifluoromethyl-phenyl)-meth-(Z)-ylidene]-5,8-dihydro-pyrano[3,4-b]pyrazin-7-one (compound D1 of Table D) (0.170 g).
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].O.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.[CH:43]1([NH2:49])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH:43]1([NH:49][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCCCC1
Reactant: CCCCCCCCCCCC(=O)N[C@H](C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@H](C(=O)NC1CCCCC1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
61 mg (0.20 mmol) of N-lauroyl-L-valine and 39 mg (0.26 mmol) of N-hydroxysuccinimide monohydrate were dissolved into 3.0 mL of dried chloroform. 50 mg (0.26 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added thereto under argon atmosphere and in the ice bath, and stirred at 0° C. for 3 hours. 35 μL of triethylamine and 35 μL of cyclohexylamine were added thereto and stirred at room temperature overnight. Then, 20 mL of ethyl acetate was added thereto and washed with 25 mL of 0.2N hydrochloric acid, 20 mL of water and 20 mL of a saturated aqueous solution of sodium hydrogen carbonate. The mixture was then dried with anhydrous sodium sulfate and condensed under reduced pressure. The residue was purified with a thin-layer chromatography (silica gel, chloroform:methanol=20:1) to obtain 34 mg of N-lauroyl-L-valine cyclohexylamide (0.089 mmol, yield 44%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[CH:6]=[N:7][N:8]([CH2:10][C:11]#[N:12])[CH:9]=1.Br[CH2:14][CH2:15]Br.[Cl-].[NH4+]>CS(C)=O>[CH3:3][S:4][C:5]1[CH:6]=[N:7][N:8]([C:10]2([C:11]#[N:12])[CH2:15][CH2:14]2)[CH:9]=1
Reactant: CSc1cnn(CC#N)c1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CSc1cnn(C2(C#N)CC2)c1
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To sodium hydride (2.29 g, 57 mmol, 60% dispersion in mineral oil) was added petroleum ether (40 mL). The suspension was stirred for 10 min and the supernatant was removed. Petroleum ether (40 mL) was added again and the suspension was stirred for another 10 min. The supernatant was removed again after the suspension settled in order to remove the mineral oil. Dimethylsulfoxide (25 mL) was slowly added at 20° C. under nitrogen. A solution of 2-(4-(methylthio)-1H-pyrazol-1-yl)acetonitrile (1.46 g, 9.53 mmol) and 1,2-dibromoethane (2.46 mL, 28.5 mmol) in dimethylsulfoxide (23 mL) was added dropwise over a period of 15 minutes. Additional 1,2-dibromoethane (0.5 mL) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into a cold saturated aqueous solution of ammonium chloride (150 mL). The mixture was stirred for 10 min and then it was extracted with diethyl ether (100 mL×3). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (95:5 to 60:40 heptane:ethyl acetate) to afford 1-(4-(methylthio)-1H-pyrazol-1-yl)cyclopropanecarbonitrile (390 mg, 22.8%). 1H NMR (500 MHz, CDCl3) δ 1.79-1.83 (m, 4H), 2.36 (s, 3H), 7.52 (s, 1H), 7.58-7.60 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17]>>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:15][C:16]([OH:18])=[O:17]
Reactant: COc1ccc(C=O)c(Cl)c1OC
Reactant: O=C(O)CC(=O)O
Product: COc1ccc(C=CC(=O)O)c(Cl)c1OC

Procedure:
Similar procedure as described in example 9B was used, starting from 2-Chloro-3,4-dimethoxy-benzaldehyde and malonic acid to give 3-(2-Chloro-3,4-dimethoxy-phenyl)-acrylic acid. LC-MS: m/e 241 (M−1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:8]1=[O:27]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(CN2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.3 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.64 g, 1.3 mmol), and N,N-diisopropylethylamine (0.32 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.19 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.Cl.[NH2:13][CH2:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH2:14][CH2:15][CH:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
A procedure similar to the method described in step C.1 is carried out, starting from 2 g (8.42 mmol) of 5-bromo-2-chloro-3-nitropyridine, 3.14 g (10.11 mmol) of tert-butyl (S)-4-amino-2-tert-butoxycarbonylaminobutanoate hydrochloride and 2.31 g (16.85 mmol) of triethylamine in 30 ml of dioxane. This time the mixture is heated for 12 hours. This gives 3.71 g of the expected product, which is used as it is in the remainder of the synthesis.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([NH:11][N:12]([CH2:14][C:15]([NH:18][C@@H:19]([CH2:43][C:44]1[C:49]([CH3:50])=[CH:48][C:47]([OH:51])=[CH:46][C:45]=1[CH3:52])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21])=[O:17])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1c(C)cc(O)cc1C
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)CN(C)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 50.8 %

Procedure:
To the solution of 2-(2-(benzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 299 mg (1.26 mmol) and (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-3-(4-hydroxy-2,6-dimethylphenyl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-9) 404 mg (0.84 mmol) in dichloromethane 5 ml and dimethylformamide 5 ml, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 305 mg (1.26 mmol) was added and stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate 50 ml and washed with saturated sodium bicarbonate 50 ml, water 50 ml and brine 50 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Buch silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain the title compound 298 mg (50%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[S:11](Cl)(=[O:14])(=[O:13])[NH2:12]>>[C:4]([C:3]1[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=1[NH:1][S:11]([NH2:12])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1cc(Cl)ccc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-5-chlorobenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) 7.3 (S, 2H), 7.54-7.56 (d J=9.2 Hz, 1H), 7.74-7.77 (dd J=8.4 Hz, 2 Hz, 1H) 9.67 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNCC1
Reactant: CC(=O)c1ccc(Br)cc1
Product: CC(=O)c1ccc(N2CCCCC2)cc1

Procedure:
without solvents (e.g. B. G. Kresze and H. Goetz, Chern. Berichte 90, 2161, 2174 (1957)), reaction of p-bromoacetophenone with piperidine under reflux with 19% yields of 1-(4-piperidinophenyl)ethanone; or