Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.O>CN(C)C=O>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][C:5]([CH2:4][CH2:3][C:2]([F:10])([F:11])[F:1])([C:8]#[N:9])[C:6]#[N:7])[CH:21]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: ClCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(3,3,3-Trifluoropropyl)malononitrile (407 mg) was dissolved in N,N-dimethylformamide (5 ml), and potassium carbonate (347 mg) was added thereto, and then, a solution of 3-(chloromethyl)pyridine (320 mg) in N,N-dimethylformamide (1 ml) was added dropwise to the mixture, followed by stirring overnight at room temperature. To the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 400 mg of 2-((3-pyridyl)methyl)-2-(3,3,3-trifluoropropyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (6)).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])CCC.CCCCCC.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1>O1CCCC1>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]([OH:33])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(O)c2ccc(Br)cc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
3-Bromophenoxy-tert-butyldimethylsilane (146 g, 0.51 mol, Example 1, infra) was dissolved in dry tetrahydrofuran under nitrogen and cooled to −78° C. A solution of 1.6 M n-butyllithium in hexane (318 mL, 0.51 mol) was added dropwise at a rate to maintain temperature below −70° C. The reaction was stirred for 30 minutes after the addition was complete, and the cold solution was transferred to another vessel containing a cold (−78° C.) solution of 4-bromobenzaldehyde (94.3 g, 0.51 mol) in 1000 mL of dry tetrahydrofuran under nitrogen. The transfer rate was monitored to maintain reaction temperature below −70° C. The reaction mixture was stirred for another 45 minutes at −78° C. and then quenched with 100 mL of saturated aqueous ammonium chloride. After warming to room temperature, the mixture was diluted with 2000 mL of diethyl ether and washed with 2000 mL of water followed by 500 mL of saturated sodium chloride. The ethereal solution was dried over sodium sulfate and the solvent removed to give 197.2 g of crude α-(4-bromophenyl)-3-(tert-butyldimethylsilyloxy)benzyl alcohol as a yellow oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Li].CS(O[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]1[CH2:30][CH:29]=1)(=O)=O>C1COCC1>[C:8]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH2:30][CH:29]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)OCCCCCCCC1=CC1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Li]C
Solvent: C1CCOC1
Product: C1=C(CCCCCCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Diphenylamine (0.42 g, 2.5 mmol) in 10 ml of THF was cooled to −78° C. and treated with 1.6 ml (1.4M, 2.2 mmol) methyllithium. 1-(7-Methanesulfonyloxyheptyl)-cyclopropene was added, the bath was removed, and the reaction mixture was allowed to warm to room temperature. The reaction was held for 5.5 hours, then quenched with water. Ether and water were added to the reaction mixture and the phases were separated. The ether phase was washed with water twice, washed with brine, dried over magnesium sulfate and stripped. The product was chromatographed to give 80 mg of 7-(diphenylamino)-1-heptylcyclopropene as a colorless liquid.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:9][CH:8]=1)(C)C.CO.[OH-].[K+]>C(Cl)Cl>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(C#C)cc1
Yield: 63 %

Procedure:
Subsequently, the obtained 1,4-bis(trimethylsilylethynyl)benzene (500 mg, 1.85 mmol) was added with dist. CH2Cl2 (15 mL), dist. MeOH (3 mL) and an aqueous solution of potassium hydroxide (KOH) (0.4 mL) of 50% by mass. The resultant mixture was stirred under a nitrogen atmosphere at room temperature for 18 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with CH2Cl2. After that, an organic layer was washed with sat. NaCl, and dried with MgSO4. The dried organic layer was filtered and concentrated to obtain a crude product. Subsequently, the obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=20/1) to obtain 1,4-diethynylbenzene (147 mg, 63% yield (in two steps)).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[N:6][N:5]2[C:16]=1[S:17]([N:20]=[CH:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:19])=[O:18].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[CH:11])=[N:6][N:5]2[C:16]=1[S:17]([N:20]=[CH:21][N:22]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][CH:24]([CH3:25])[CH3:26])(=[O:18])=[O:19]
Reactant: CC(C)CN(C=NS(=O)(=O)c1c(Cl)nc2ccc(C#C[Si](C)(C)C)nn12)CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc2nc(Cl)c(S(=O)(=O)N=CN(CC(C)C)CC(C)C)n2n1

Procedure:
N′-(2-Chloro-6-(trimethylsilylethynyl)imidazo[1,2-b]pyridazin-3-ylsulfonyl)-N,N-diisobutylformamidine (2.31 g, 4.63 mmol) was dissolved in a mixed solvent of tetrahydrofuran-water (10:1), and tetrabutylammonium fluoride hydrate (1.50 g, 5.04 mmol) was added to the solution with stirring under ice-cooling. After the mixture was stirred for 20 minutes under ice-cooling, the tetrahydrofuran was distilled away under reduced pressure, and the residues were dissolved in ethyl acetate. The ethyl acetate solution was washed twice with water, dehydrated over anhydrous magnesium sulfate, concentrated to dryness under reduced pressure to give the title compound as pale yellow crystals. The yield was 1.96 g (100%).
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:33])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:26]([CH2:27][C:28]([O:30]CC)=[O:29])[N:25]=[CH:24][CH:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1>Cl>[ClH:1].[C:28]([CH2:27][N:26]1[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:33])[CH2:19][CH2:18][CH:17]\2[SH:20])=[CH:23][CH:24]=[N:25]1)([OH:30])=[O:29]
Reactant: CCOC(=O)Cn1nccc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Product: O=C(O)Cn1nccc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 75.7 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(ethoxycarbonylmethyl)-1H-pyrazol-5-yl]methylidene}-4-sulfanylpiperidine hydrochloride (70 mg) in 3N aqueous hydrochloric acid solution (15 ml), and the resulting mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by a preparative HPLC [YMC-Pack ODS-A; YMC, mobile phase: 25 to 27% acetonitrile/water (0.02% aqueous hydrochloric acid solution)] to afford the title compound (50 mg, yield: 75%) as a pale yellow amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[C:6]=1[CH2:19][N:20]([CH2:31][C:32]([O:34][CH3:35])=[O:33])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO.[Cl-].[Na+].O>[CH3:35][O:34][C:32]([C:31]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:19][N:20]=1)[N:7]([CH2:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:33]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1Cc1nccs1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2nccs2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
5-Bromo-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1-thiazol-2-ylmethyl-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (41 mg, 0.070 mmol) was dissolved in 5 mL of MeOH. NaOMe solution (0.050 mL, 0.21 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, followed by addition of brine (10 mL), and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-3% MeOH/CH2Cl2) to give 28.6 mg of the title compound. MS: (+) m/z 396.07, 398.03 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].O[C:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH2:24])=[O:23])[C:14]=2[N:15]=[N:16][N:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH2:24])=[O:23])[C:14]=2[N:15]=[N:16][N:17]=1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: NC(=O)c1cccc2c(NCc3ccc(Cl)c(Cl)c3)nnnc12

Procedure:
Compound 2 was prepared following general synthetic scheme 7 wherein (3,4-dichlorophenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [350 (M+1)], 1H NMR (400 MHz, DMSO-d6): δ 9.37 (s, 1H), 9.31 (t, 1H), 8.54 (d, 1H), 8.49 (d, 1H), 8.05 (s, 1H), 8.00 (t, 1H), 7.70 (s, 1H), 7.60 (d, 1H), 7.40 (d, 1H), 4.90 (d, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1O)([CH3:4])([CH3:3])[CH3:2].[OH-:16].[K+].O=O>>[C:1]([C:5]1[CH:6]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:9]([OH:16])[C:10]=1[C:8]1[C:9]([OH:16])=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=1[C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: [OH-]
Agent: O=O
Agent: [K+]
Product: CC(C)(C)c1cc(O)c(-c2c(O)cc(C(C)(C)C)cc2C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
Into a 500 ml autoclave equipped with an induction stirring device were charged 200 g of 2,6-di-t-butylphenol and 1 g of a 50% aqueous potassium hydroxide solution. The reaction was carried out for 0.5 hour at 200° C., while applying a pressure of up to 7 kg/cm2 with oxygen to the reaction apparatus, whereupon 147.5 g of 3,3',5,5'-tetra-t-butylbiphenol and 11.0 g of 3,3',5,5'-tetra-t-butyldiphenoquinone were formed in the reaction mixture, leaving 31.7 g of unaltered 2,6-di-t-butylphenol.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][C:22]([N:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:25])=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:25][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](=[O:23])[CH2:21][CH2:20][NH:19][CH2:6][C:5]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Reactant: CN(C(=O)CCN)C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Nitro-5-phenoxy-benzaldehyde (2.14 g, 0.00882 mol) was added to a solution of 3-amino-N-cyclohexyl-N-methyl-propionamide (1.5 g, 0.00882 mol) in 100 mL of 1,2-dichloroethane, and the mixture was stirred at 80° C. for 1 hour. Sodium triacetoxyborohydride (2.87 g, 0.00882 mol) was added at room temperature, and the reaction mixture was stirred for 15 h. Additional sodium triacetoxyborohydride (1 g) was added, and the reaction mixture was stirred another 20 h at room temperature. To the reaction mixture was added 10% aqueous NaOH solution (50 mL), and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and concentrated to yield a residue which was purified by column chromatography over silica gel using 97:3 CH2Cl2:MeOH as the eluent. The product containing fractions were combined and evaporated to yield a side product (MW 638). The residue was further purified by column chromatography over silica gel using 97:3 CH2Cl2:MeOH. The product containing fractions were combined and evaporated to yield a residue. The fractions containing impure product were combined and evaporated to yield a second residue, which was purified by silica gel chromatography to yield additional desired product.
Reaction SMILES: [CH3:1][N:2]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([O:70]C(C)(C)C)=[O:69])[C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][CH2:12][N:13]([CH3:56])[C:14](=[O:55])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:54])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:53])[NH:42][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:38]=[CH:37][N:36]=2)[CH:16]=1)=[O:4]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][N:2]([CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][C:68]([OH:70])=[O:69])[C:3]([C@@H:5]1[CH2:10][O:9][CH2:8][CH2:7][N:6]1[CH2:11][CH2:12][N:13]([CH3:56])[C:14](=[O:55])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:54])[NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:25][C:24]=2[C:35]2[CH:40]=[C:39]([C:41](=[O:53])[NH:42][C@@H:43]3[C:52]4[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=4)[CH2:46][CH2:45][CH2:44]3)[CH:38]=[CH:37][N:36]=2)[CH:16]=1)=[O:4]
Reactant: CN(CCN1CCOC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)OC(C)(C)C)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN1CCOC[C@H]1C(=O)N(C)CCOCCOCCOCCC(=O)O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-methyl-1-((S)-4-(2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)ethyl)morpholin-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oate Example 242 (100 mg, 0.10 mmol, 1.00 equiv) in dichloromethane (4 mL), trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (5% CH3CN up to 28% in 1 min, up to 38% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 8.4 mg product was obtained. This resulted in 8.4 mg (7%) of 2-methyl-1-((S)-4-(2-(N-methyl-3-(4-(piperidin-1-yl)-2-(4-((S)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenylcarbamoyl)benzamido)ethyl)morpholin-3-yl)-1-oxo-5,8,11-trioxa-2-azatetradecan-14-oic acid as a yellow solid. LC-MS (ES, m/z): 962 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.93 (d, J=5.1 Hz, 1H), 8.65 (d, J=9.3 Hz, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 8.14-8.11 (m, 1H), 8.03-8.02 (m, 1H), 7.86-7.84 (m, 2H), 7.76-7.72 (m, 1H), 7.64-7.61 (m, 1H), 7.28-7.25 (m, 1H), 7.18-7.14 (m, 3H), 5.39 (m, 1H), 4.50-4.45 (m, 2H), 4.30-4.20 (m, 1H), 4.09-4.05 (m, 1H), 3.86-3.43 (m, 25H), 3.21 (s, 1H), 3.10-3.08 (m, 3H), 3.00 (s, 1H), 2.91-2.84 (m, 2H), 2.57-2.51 (m, 2H), 2.04-1.79 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][N:33]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:34][N:33]=1)=[O:31]
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc(O)cn1
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cn1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 5-hydroxy-pyridine-2-carboxylic acid methyl ester (commercially available). White solid (82%). MS (Turbo Spray): m/z=526.1 [M+H].
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH2:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:6]([CH3:21])[O:5][N:4]=1)[CH3:2].O1CCCC1.[CH3:27][NH:28][CH3:29]>O>[CH3:27][N:28]([CH3:29])[C:18](=[O:19])[CH2:17][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:7]1[C:3]([CH2:1][CH3:2])=[N:4][O:5][C:6]=1[CH3:21]
Reactant: CNC
Reactant: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1CC(=O)N(C)C
Temperature: 25 °C

Procedure:
A mixture of 11.2 g. (0.036 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetyl chloride in 100 ml. of tetrahydrofuran is added to a vigorously stirred solution of dimethylamine in water (25 ml. 40% dimethylamine in water) at 0° to 10° C. The resulting mixture is allowed to warm to room temperature and poured into ether-water. The organic layer is separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give N,N-dimethyl-2-(3-ethyl-5-methyl-4-isoxazolyl)-3-indole acetamide; m.p. 176° to 178° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:12][CH:13]2[CH2:15][CH:14]2[CH2:16][CH3:17])=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:20]([N:22]=[C:23]=[S:24])[CH3:21]>CN(C)C=O>[Cl:1][C:2]1[C:7](/[C:8](/[NH:12][CH:13]2[CH2:15][CH:14]2[CH2:16][CH3:17])=[C:9](\[C:10]#[N:11])/[C:23](=[S:24])[NH:22][CH2:20][CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCC1CC1NC(=CC#N)c1cccnc1Cl
Reactant: CCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=S)/C(C#N)=C(\NC1CC1CC)c1cccnc1Cl
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 3-(2-chloropyridin-3-yl)-3-[(2-ethylcyclopropyl)amino]acrylonitrile (0.15 g, 0.606 mmol, 1 eq.) in 2 ml of dimethyl formamide (DMF) was treated with NaH (60% in mineral oil, 0.029 g, 0.727 mmol, 1.2 eq.) and stirring allowed for 1 h. ethylisothiocyanate (0.105 g, 1.21 mmol, 2 eq.) was added and stirring continued overnight. The reaction was quenched with water and extracted with AcOEt. The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was purified by chromatography on silica gel to give (2Z)-3-(2-chloropyridin-3-yl)-2-cyano-N-ethyl-3-[(2-ethylcyclopropyl)amino]-prop-2-enethioamide (0.059 g, 27% yield) as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24](Cl)[N:23]=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].C1(C)C=CC=CC=1>[Cl:21][C:22]1[N:23]=[C:24]([N:20]=[C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:25]=[C:26]([CH3:28])[CH:27]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc(N=C(c2ccccc2)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Toluene (27 mL), sodium tert-butoxide (0.925 g, 9.63 mmol), and benzophenone imine (1.75 g, 9.63 mmol) were added to 2,6-dichloro-4-methylpyridine (1.3 g, 8.0 mmol). The flask was purged with argon 3 times before 2-dicyclophenylphosphino-2′-(N,N-dimethylamino)biphenyl (0.474 g, 1.20 mmol) and Pd2(dba)3 (0.367 g, 0.401 mmol) were added. The flask was purged 3 times with argon, sealed, and heated to 80° C. After 16 hours, the reaction mixture was cooled to room temperature, diluted with water, and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-40% acetone/hexanes, linear gradient) to afford 6-chloro-N-(diphenylmethylidene)-4-methylpyridin-2-amine. 1H NMR (500 MHz, CDCl3) δ 7.83-7.73 (m, 2H), 7.49 (t, J=7.6 Hz, 2H), 7.44-7.34 (m, 2H), 7.34-7.27 (m, 2H), 7.21-7.12 (m, 2H), 6.72 (s, 1H), 6.27 (s, 1H), 2.15 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)#[N:13].[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]#[N:13])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: OCc1cccc(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: N#Cc1ccc(COCc2cccc(F)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
3-(Fluoro)benzylalcohol (5.00 g, 39.6 mmol) in THF (50 mL) was added dropwise at 0° C. to a THF (100 mL) suspension of NaH (60%, 6.3 g, 158.4 mmol). The mixture was stirred at 0° C. (30 min). Then, a THF solution of 4-cyanobenzylbromide (9.30 g, 47.6 mmol) was added dropwise at 0° C. and the mixture was stirred at room temperature (16 h). A saturated aqueous solution of NH4Cl (40 mL) was added dropwise at 0° C. and the layers were separated. The aqueous layer was washed with CH2Cl2 (60 mL). The organics layers were combined, dried (Na2SO4) and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with EtOAc/hexanes (0/10 to 1/9) as the eluant to obtain 4-((3-fluorobenzyloxy)methyl)benzonitrile as a colorless oil (7.80 g, 81%): Rf=0.65 (hexanes/EtOAc 8/2); IR (nujol) 2863, 2229, 1719, 1595, 1451, 1450, 1360, 1258, 1100, 1018, 945, 862, 790, 687, 554 cm−1; 1H NMR (CDCl3) δ 4.59 (s, CH2O), 4.61 (s, CH2O), 6.97-7.14 (m, 3 ArH), 7.26-7.37 (m, 1 ArH), 7.47 (d, J=7.5 Hz, 2 ArH), 7.65 (d, J=7.5 Hz, 2 ArH); 13C NMR (CDCl3) δ 71.2 (CH2O), 71.9 (CH2O), 113.4 (CCN), 114.4 (d, J=21.6 Hz, C2′ or C4′), 114.7 (d, J=21.6 Hz, C4′ or C2′), 118.8 (CN), 122.9 (d, J=2.3 Hz, C6′), 127.7 (ArC), 130.0 (d, J=9.2 Hz, C5′), 132.2 (ArC), 140.2 (d, J=8.0 Hz, C1′), 143.5 (ArC), 162.9 (d, J=244.8 Hz, C3′); HRMS (M+Cs+)(ESI+) 373.9957 [M+Cs+] (calcd for C15H12FNOCs+373.9954); Anal. Calcd. for C15H12FNO2: C, 74.67; H, 5.01; F, 7.87; N, 5.81. Found: C, 74.53; H, 4.93; F, 7.75; N, 5.81.