Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].BrC1C=CC(O[C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=CC=1.CC(C)([O-])C.[K+].Cl[C:27]1[N:32]=[CH:31][N:30]=[C:29]([NH:33][S:34]([CH:37]=[CH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:36])=[O:35])[C:28]=1[C:45]1[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=1>COCCOC>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([O:3][CH2:2][CH2:1][O:4][C:27]2[N:32]=[CH:31][N:30]=[C:29]([NH:33][S:34]([CH:37]=[CH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:35])=[O:36])[C:28]=2[C:45]2[CH:46]=[CH:47][C:48]([CH3:51])=[CH:49][CH:50]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)C=Cc2ccccc2)cc1
Reactant: Brc1ccc(Oc2ccc(Br)cc2)cc1
Reactant: OCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCOc2ccc(Br)cc2)cc1
Reaction time: 1 h
Yield: 61.3 %

Procedure:
Ethyleneglycol-mono-(4-bromo-phenyl)-ether (112 mg) was dissolved in 1,2-dimethoxyethane (5 ml) and potassium tert.-butoxide (50 mg) was added and stirring continued for 1 h, followed by the addition of 2-phenyl-ethenesulfonic acid [6-chloro-5-p-tolyl-pyrimidin-4-yl]-amide (100 mg) and stirring was continued at 80° C. for 24 h. The reaction mixture was evaporated to dryness, water (20 ml) was added followed by acidification with 10% citiric acid and extraction with ethyl acetate (2×, 20 ml). The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The crude product was recrystallized from 2-propanol and 2-phenyl-ethenesulfonic acid {6-[2-(4-bromo-phenoxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (90 mg) was obtained as a white powder; tR=6.12 (LC); [M−H]+=565.75 (ES−).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]([O-])=O.[Na+].[C:13]([CH:15]([CH2:21][C:22]([O:24]CC)=O)C(OCC)=O)#[N:14].[OH-].[Na+]>N1C=CC=CC=1.O>[C:13]([C:15]1[CH:21]=[C:22]([OH:24])[N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:9]=1)#[N:14]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(C#N)C(=O)OCC
Reactant: Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1cc(O)n(-c2ccccc2)n1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
120 ml of water and 15 ml of 35% hydrochloric acid were added to 5.6 g (0.06 mole) of aniline to obtain a solution. The solution was ice-cooled to 0 to 5° C. Thereto was drop-wise added, with stirring, 24 ml of water in which 4.2 g (0.06 mole) of sodium nitrite had been dissolved, after which stirring was conducted for 1 hour. Then, this aqueous diazonium salt solution was dropwise added to 120 ml of a pyridine solution containing 10.2 g (0.06 mole) of diethyl α-cyanosuccinate, with stirring under ice-cooling. After the dropwise addition, the mixture was stirred for 1 hour under ice-cooling and successively for 1 hour at room temperature, to give rise to a reaction. After the reaction, 240 ml of a 2% aqueous sodium hydroxide solution was added, followed by stirring for 2 hours. Then, the reaction mixture was drop-wise added to 240 ml of 35% hydrochloric acid under ice-cooling. The resulting crystals were collected by filtration, washed with 10 ml of water, and dried in a hot-air drier, to obtain 8.4 g of crude, reddish brown crystals of title compound. The crude crystals were recrystallized from diethyl ether-petroleum ether and dried in a hot-air drier, to obtain 5.7 g (yield: 51.3%) of a title compound as light yellow crystals.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(N)(C)(C)C.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][S:15]([NH:4][CH2:1][CH2:2][CH3:3])(=[O:17])=[O:16]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CCCN
Solvent: CC(C)(C)N
Product: CCCNS(=O)(=O)CCCCCl
Yield: 88 %

Procedure:
This was prepared in an analogous manner to that disclosed for Intermediate 41, using n-propylamine (commercially available, for example, from Aldrich) instead of t-butylamine, and 4-chloro-1-butanesulfonyl chloride (prepared according to White, E. H.; Lim, H. M. J. Org. Chem. 52, 1987, 11, 2162-2166) instead of 3-chloropropane sulfonyl chloride. Yield 88%. LCMS RT=2.54 min, ES+ve m/z 214 (M+H)+.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([OH:16])=O)=[O:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37].C(N(CC)CC)C>O1CCCC1>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([C:10]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:11]=1[CH2:12][CH2:13][C:14]([NH:35][C@H:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:37])=[O:16])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)NC(=O)CCc1cc(Cl)ccc1C(=O)CCCNC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (0.006 mol) of 2-(4-acetamidobutyryl)-5-chloro -hydrocinnamic acid and 1.09 g (0.007 mol) of 1,1'carbonyldiimidazole are stirred at room temperature for 1.5 hours in 20 ml of tetrahydrofuran and 1.04 g (0.007 mol) of ethyl L-alaninate hydrochloride and 0.94 ml (0.007 mol) of triethylamine are then added thereto. After stirring at room temperature for 2 hours, the mixture is extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Chromatography on silica gel with ethyl acetatemethanol (9:1) and then on aluminum oxide with ethyl acetate and subsequent crystallization from ethyl acetate/ hexane gives ethyl N-[2-(4-acetamidobutyryl)-5-chlorohydrocinnamoyl]-L-alaninate as white crystals with melting point 106°.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=2)[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cc1ccc(CCN(C)CCCC(C(N)=O)(c2ccccc2)c2ccccc2)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.56 g-see Preparation 3), methyl 4-(2-bromoethyl)phenylacetate (0.51 g-see Preparation 22), anhydrous potassium carbonate (0.6 g) and acetonitrile (20 ml) was heated under reflux for 5.5 hours. The mixture was partitioned between dichloromethane (70 ml) and 10% aqueous potassium carbonate (50 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a gum which was purified by column chromatography on silica eluting with dichloromethane containing hexane (50%) then with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.2 g.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])#[N:2].CO.[ClH:13].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>C(Cl)Cl>[ClH:13].[CH2:15]1[CH2:16][CH:14]1[CH2:17][NH:18][C:1]([CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10])=[NH:2]
Reactant: N#CCCN1CCOC1=O
Reactant: NCC1CC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: N=C(CCN1CCOC1=O)NCC1CC1
Temperature: -15 °C
Reaction time: 6 h
Yield: 55 %

Procedure:
A solution of N-(cyanoethyl)oxazolidinone 18 (30 g, 0.21 mol) in dry methanol (10.9 g, 0.34 mol) and dry CH2Cl2 (60 mL) was saturated with dry HCl at -15° to 0° C. The mixture was then stirred for 6 h at 0°-20° C. The mixture was evaporated and dried in vacuo for 1 h. The crystalline imidoester hydrochloride was dissolved in dry methanol (120 mL) and cooled to -15° C. To the stirred solution cyclopropylmethylamine (31.2 g, 0.44 mol) was added in drops over a period of 20 min while maintaining the temperature at -15 to 0° C. The mixture was then stirred at -10° C. for 45 min and evaporated. The residue was dissolved in methanol, treated with ether until turbid and was refrigerated for 6 days. The colorless crystalline material was collected and dried to give 59 (28.7 g, 55%), mp 86°-88° C. 1H NMR (DMSO--d6) δ 0.28 (m, 2, --CH--CH2), 0.55 (m, 2, --CH--CH2), 1.05 (m, 1, --CH), 2.68 [t, 2, --CH2 --C(N=)], 3.07 (d, 2, --NH--CH2), 3.54 [t, 2, --CH2 --CH2 --C(N=)], 3.67 (t, 2, --O--CH2 --CH2). 4.30 (t, 2, --OCH2).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2.[C:18](O)(=[O:22])[C@H:19]([CH3:21])[OH:20].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[OH:20][C@@H:19]([CH3:21])[C:18]([NH:1][C@@H:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]2[CH:14]=[CH:15][CH:16]=[CH:17][C:3]1=2)=[O:22]
Reactant: N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H](O)C(=O)N[C@@H]1C(=O)Nc2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A solution of 0.20 g (0.9 mmol) (S)-7-amino-5H,7H-dibenzo[b,d]azepin-6-one in 8 ml tetrahydrofurane was treated at 0° C. with 0.09 g (0.99 mmol) L-lactic acid, 0.14 g (0.9 mmol) 1-hydroxybenzotriazole hydrate, 314 μl (1.8 mmol) N-ethyldiisopropylamine and 0.18 g (0.9 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimid-hydrochlorid. After stirring at room temperature overnight the mixture was extracted with 1N aqueous hydrochloric acid/ethylacetate. Purification by chromatography on silicagel with ethylacetate/cyclohexane (0-100/100-0) yielded 0.19 g (70%) (S)-2-hydroxy-N—((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-propionamide as white solid; MS: m/e: 297.1 (M+H+).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([NH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:33]([Br:36])[CH:34]=[CH2:35].CN(C)C=O>CCOCC>[Br-:36].[CH2:35]([N:29]1[C:30]2[C:25](=[CH:24][C:23]([NH:22][C:20](=[O:21])[C@H:12]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:1]([O:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:2])=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH2:28]1)[CH:34]=[CH2:33]
Reactant: C=CCBr
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccc2ncccc2c1)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=CCN1CC=Cc2cc(NC(=O)[C@H](Cc3ccccc3)NC(=O)OCc3ccccc3)ccc21
Product: [Br-]
Yield: 39 %

Procedure:
A solution consisting of 100 mg (0.235 mmol) of 6-(N-carbobenzoxy-L-phenylalanylamino)quinoline (Brynes, et al., 1981), 204 1 of allyl bromide, and 0.5 ml of dimethylformamide was allowed to react at room temperature for 48 h and at 50° C. for 12 h. Crude product was isolated by precipitation with ether followed by two ether washes. The compound was purified by dissolving the solid in water at 50° C., filtering the undissolved material and lyophilizing to obtain pure XVI. Recrystallization from ethanol/ethyl acetate yielded 50 mg (39% yield): mp 160° C. decomposes, 219° C. melts;Rf(E)=0.08. Fast atom bombardment mass spectrum of XVI: calculated for MW (466)+Br-. Found 466 (M=).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH:13]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][N:12]23)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(Cl)Cl>[C:1]([N:23]1[CH2:22][CH2:21][CH:13]2[N:12]([CH:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14]2)[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1
Reaction time: 1 h

Procedure:
3.08 of acetyl chloride diluted with 10 ml of methylene chloride was added dropwise to a solution of 9.9 g (7 RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline in 100 ml of methylene chloride. The reaction mixture was stirred for 1 hour, then wasted twice with water, then dried with magnesium sulphate and concentrated to dryness to give (7RS,12aRS)-3-acetyl-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline (M.P. 145°-147°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[N:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccc(Cl)c(C2CC(=O)c3c(C)cnnc3C2)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=NNC(=N)N)c3c(C)cnnc3C2)c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
To a mixture of 7-(2-chloro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.4 g) and aminoguanidine hydrochloride (0.164 g) were added ethanol (8 ml) and concentrated hydrochloric acid (0.15 ml), and the mixture was stirred at 110° C. (bath temperature) for 1.5 hours. The reaction solution was cooled to room temperature, and the resulting crystals were filtered and dried to give 7-(2-chloro-5-methylphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 173) (0.261 g) as blue white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])=[CH:4][C:3]=1[S:17](Cl)(=[O:19])=[O:18].[CH3:21][NH2:22].Cl>O>[CH3:21][NH:22][S:17]([C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:19])=[O:18]
Reactant: CN
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1NS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: O
Product: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g), a 40% aqueous solution of methylamine (1 g) and water (20 ml) was stirred at room temperature and allowed to stand overnight at the same temperature. The resultant mixture was made acidic with 5% aqueous hydrochloric acid to precipitate an oily substance, which was then extracted with chloroform. The organic layer was washed with a 5% aqueous solution of hydrochloric acid and water in order and dried over anhydrous magnesium sulfate, followed by concentration. The residue was allowed to stand to give crystals, which were recrystallized from toluene to give 1.1 g of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide. M.P., 134.5°-135.5° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.ClC1S[CH:13]=[C:14](C(O)=O)[N:15]=1.S(Cl)(Cl)=O.C(N)C>O.CN(C=O)C>[Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:15][CH2:14][CH3:13])=[O:8])[N:6]=1
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: O=C(O)c1csc(Cl)n1
Agent: CCN
Solvent: O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1csc(Cl)n1

Procedure:
2-Chloro-4-thiazolecarboxylic acid chloride (prepared from 2-chloro-4-thiazolecarboxylic acid, thionyl chloride and a catalytic amount of DMF) was reacted with 70% ethylamine in water to yield 2-chloro-N-ethyl-4-thiazolecarboxamide. This compound was reacted with TMSCl using the method of step c of Example 248. Purification by flash chromatography with 3% ethyl acetate-hexane gave 2.5 g of the title compound as a light yellow oil in 55.6% yield. nD26 1.5313.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][CH:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccncc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 44 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridin-4-ylcarbamate (271 mg, 0.610 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.610 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 80° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 98.3 mg (44.1%) of the desired product as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4]Br.[Mg:7].[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][Br:20]>[Cu](Cl)Cl.[Li].O1CCCC1>[CH3:1][CH:2]([CH3:6])[CH2:3][CH2:4][Mg:7][Br:8].[Br:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:4][CH2:3][CH:2]([CH3:6])[CH3:1]
Reactant: [Mg]
Reactant: CC(C)CCBr
Reactant: BrCCCCCCCCCCCBr
Agent: Cl[Cu]Cl
Agent: [Li]
Solvent: C1CCOC1
Product: CC(C)CCCCCCCCCCCCCBr
Product: CC(C)CC[Mg]Br
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 3-methybutylmagnesium bromide is prepared by treating 15.1 g. of 3-methylbutyl bromide with 2.7 g. magnesium turnings in 50 ml. of dry tetrahydrofuran. The resultant Grignard reagent is added dropwise to a solution of 34.5 g. of 1,11-dibromoundecane and 0.2 g. of lithium copper chloride in 75 ml. of tetrahydrofuran. After 1 hour stirring at -10° C., the solution is evaporated, and the resultant oil is distilled in vacuo to yield the colorless 1-bromo-14-methylpentadecane.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4](F)[CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:61][P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>CN(C)C(=O)C>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:40]([C:35]5[C:34](=[O:43])[N:33]([C:27]6[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=6[F:25])[C:38]([CH3:39])=[CH:37][CH:36]=5)=[O:41])=[C:3]([F:61])[CH:4]=4)=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:21][CH2:20]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1F
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: F[P-](F)(F)(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2F)c(=O)n1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
To a solution of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.613 mmol) and 1-(2,4-difluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (244 mg, 0.919 mmol) in N,N-dimethylacetamide (2.0 mL) were added HATU (350 mg, 0.919 mmol) and N,N-diisopropylethylamine (160 μL, 0.919 mmol), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (284 mg, 81%) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1F
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 6 h

Procedure:
2.0 g (4.12 mmol) of ethyl[(Z)-2-cyano-1-(2,4-difluorophenyl)ethenyl]carbamate (Example 37A) and 916 mg (4.95 mmol) of 1-(propan-2-yl)piperidin-4-carbohydrazide (Example 38A) were dissolved in 24 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 6 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The mixture was extracted with ethyl acetate (three times 50 ml each) and the combined organic phases were freed from the solvent. The residue was purified by preparative HPLC (Method 11). This gave 660 mg (41% of theory) of the product.
Reaction SMILES: C([O:4][C:5]1([CH3:47])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5C=[CH:30][CH:29]=[CH:28][C:27]=5CCC=C)[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]([O:40][CH3:41])=[O:39])[CH2:7][CH2:6]1)C=C.[CH3:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].CCOC(C)=O>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:43]([O:42][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:47])([O:4][CH2:48][CH:49]=[CH:50][CH2:51][CH2:52][C:53]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:38]([O:40][CH3:41])=[O:39])([CH3:46])([CH3:44])[CH3:45]
Reactant: C=CCCc1ccccc1-c1cccc(-c2cc3nc(C)c([C@H](OC(C)(C)C)C(=O)OC)c(N4CCC(C)(OCC=C)CC4)n3n2)c1
Reactant: CCCCCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OC/C=C\CCc1ccccc1-c1cccc-3c1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=CCCc1ccccc1-c1cccc-3c1
Temperature: 75 °C
Reaction time: 2 h

Procedure:
(S)-Methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-(but-3-en-1-yl)-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (116 mg, 0.182 mmol) was dissolved in DCE (150 mL). The solution was heated to 75° C. in an oil bath under an N2 atmosphere. Once the reaction flask had reached 75° C. the Hoveyda-Grubbs Catalyst 2nd generation (11.45 mg, 0.018 mmol) was added. The yellow reaction mixture turned green. Stirring at 85° C. was continued for 2 h at which time the reaction appeared complete by TLC (4:1 hexane/EtOAc) and HPLC (˜4:1 mixture of E/Z isomers). The cooled reaction mixture was concentrated in vacuo and purified by Biotage chromatography (0-50% EtOAc/hexanes) to give 84 mg of the desired product as a colorless oil. LCMS (M+H).=609.