Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.S(C1C=CC(C)=CC=1)(O[CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O.BrC1C=CC(OCCOCCOC)=C(C)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:4]([Cl:9])[CH:3]=1
Reactant: COCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: COCCOCCOc1ccc(Br)cc1C
Product: COCCOCCOc1ccc(Br)cc1Cl

Procedure:
Prepared from 4-bromo-2-chlorophenol and 2-(2-methoxyethoxy)ethyl tosylate by the method of Example 42 (b).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=[CH:9][N:8]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COCCCOc1ccnc(CCl)c1
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 2.60 g (0.022 mol) of thionyl chloride in 10 ml of chloroform was dropwise added to a solution of 3.64 g (0.018 mol) of 2-hydroxymethyl-4-methoxypropoxypyridine in 60 ml of chloroform under cooling with ice. The obtained mixture was stirred for one hour, neutralized with a saturated aqueous solution of sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure to obtain 3.23 g of the title compound as a crude product. 1H-NMR (CDCl3) δ; 1.80~2.20 (m, 2H), 3.31 (s, 3H), 3.49 ((t, J=6.2 Hz, 2H), 4.07 (t, J=6.2 Hz, 2H), 4.55 (s, 2H), 6.52~6.96 (m, 2H), 8.26 (d, J=5.3 Hz, 1H)
Reaction SMILES: [CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:10]([OH:22])[CH:9]=1)=[O:7])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[N:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](Cl)=[O:41]>>[CH:1]([NH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[C:10]([O:22][C:40](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][N:34]=2)[CH:9]=1)=[O:7])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2O)cc1
Reactant: O=C(Cl)c1ccccn1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: Cc1ccc(Oc2ccc(C(=O)CNC(C)C)cc2OC(=O)c2ccccn2)cc1

Procedure:
Following a procedure similar to that described above in Example 2A, when 3-hydroxy-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with picolinoyl chloride, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-(picolinoyloxy)-4-(p-toluyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:14]([C:15](=[O:21])[C:16]2[S:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:5]2[CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:22].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.BrN1C(=O)CCC1=O.Cl>C(Cl)(Cl)(Cl)Cl.CS(C)=O.O>[Cl:1][C:2]1[C:14]([C:15](=[O:21])[C:16]2[S:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:22]
Reactant: COC(=O)C1Cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2O1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc2cc(C(=O)c3cccs3)c(Cl)c(Cl)c2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylate (3.6 g., 0.01 mole) in carbon tetrachloride (100 ml.) containing a few crystals of benzoyl peroxide is treated with N-bromosuccinimide (1.8 g., 0.01 mole) then refluxed for one hour. The reaction mixture is cooled, filtered free of succinimide and the solvent distilled at reduced pressure to leave a yellow residual oil comprised of a mixture of methyl 2(and 3)-bromo-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate which is dissolved in dimethylsulfoxide (25 ml.) treated with 1,5-diazobicyclo(4.3.0)-5-nonene (1.3 g., 0.01 mole), stirred at 25° C. for two hours in an inert atmosphere, diluted with water (100 ml.) and acidified with hydrochloric acid to give methyl 6,7-dichloro-5-(2-thenoyl)benzofuran-2-carboxylate which melts at 184°-7° C. after recrystallization from acetonitrile-H2O.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=3)(=[O:36])=[O:35])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (1.52 g, 38.00 mmol) in anhydrous tetrahydrofuran (30 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (13.40 g, 38.00 mmol) in anhydrous tetrahydrofuran (120 ml) and stirred under a nitrogen atmosphere for 30 minutes. p-Toluene sulphonyl chloride (7.25 g, 38.00 mmol) was added portionwise and the mixture was allowed to warm to room temperature over 18 hours. The solvent was removed under reduced pressure The residue was dissolved in ethyl acetate and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound (10.75 g).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)=[O:4].S(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C@@H:3]2[CH2:2][O:4]2)=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(CCl)c1ccc(F)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc([C@@H]2CO2)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Under nitrogen atmosphere, 2-chloro-1-(4-fluoro-3-nitrophenyl)ethanone (5.4667 g) which can be prepared according to the method described in Reference example 64, etc. was dissolved in dehydrated THF (100 mL), added with 1 mol/L-(R)—CBS-toluene solution (7.5 mL; manufactured by Sigma-Aldrich Co.), followed by cooling to 0° C. To the resulting solution, BH32.SMe2 (10 mL; manufactured by Sigma-Aldrich Co.) was added dropwise over 10 minutes and the mixture was stirred at 0° C. for 2 hours. An aqueous solution of ammonium chloride was added to the reaction solution and extraction was carried out twice with ethyl acetate. The organic layer was washed once with brine, dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was added with 2-propanol (100 mL) and an aqueous solution of 1 mol/L-sodium hydroxide (25 mL; manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred at 0° C. for 10 minutes. The reaction solution was poured to water and extracted twice with ethyl acetate. The organic layer was washed once with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (“COLUMN-8”; n-hexane:ethyl acetate=88:12→67:33) to obtain the title compound (4.2885 g, optical purity; 92% ee).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].CCCCCC.C(Cl)(Cl)[Cl:26]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:26])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Agent: [Zn]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Temperature: 55 °C

Procedure:
4 (18 g, 67 mmol) in 250 mL glacial acetic acid, was treated with a single charge of 18 g of zinc dust. The mixture was heated at 55° C. for 45 minutes. Later 6 g more zinc dust was added. After heating for another 105 minutes, the yellow mixture was filtered through a pad of celite. The pad was washed with acetic acid and the filtrate was concentrated to a residue that was distributed between chloroform and water. The organic phase was washed with NaHCO3 (5%) to provide a pink precipitate which was filtered, dried over P2O5, dissolved in methanol, added silica gel and converted to a silica gel plug by removing the solvent under reduced pressure. The plug was transferred on top of a column packed with silica gel, ten times the weight of plug, eluted with hexane, chloroform, 5% ethylacetate in chloroform and 10% ethylacetate in chloroform. Fractions containing the product 5 (TLC) were pooled and evaporated to give a pink solid. The overall yield from 3 to 5 was 63%. TLC Rf 0.187 (hexane-chloroform 1:1); mp 140-142° C.; 1H NMR (DMSO-d6) δ 1.25-1.28 (t, 3H, CH3); 4.18-4.20 (q, 2H, CH2); 6.85 (bs, 2H, 2-NH2, exch); 6.92-7.09 (m, 3H, phenyl); 10.93 (bs, 1H, 9-NH, exch). Anal. Calculated (C11H11ClN2O2): C, 55.36; H, 4.65; N, 11.74; Cl, 14.85. Found: C, 55.39; H, 4.60; N, 11.65; Cl, 14.96.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH2:14])(=[O:13])=[O:12].C(N(CC)CC)C.Cl[C:23](OC1C=CC=CC=1)=[O:24].[NH2:32][C:33]1[N:38]=[C:37]([O:39][CH3:40])[CH:36]=[C:35]([O:41][CH3:42])[N:34]=1>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH:14][C:23]([NH:32][C:33]1[N:34]=[C:35]([O:41][CH3:42])[CH:36]=[C:37]([O:39][CH3:40])[N:38]=1)=[O:24])(=[O:12])=[O:13]
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NS(=O)(=O)c1c(Cl)nc2ccccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2c(Cl)nc3ccccn23)n1
Yield: 88 %

Procedure:
To 200 ml of dichloromethane are added 10.0 g (0.043 mole) of 2-chloroimidazo[1,2-a]pyridine-3sulfonamide and 8.85 g (0.0866 mole) of triethylamine, followed by adding dropwise 6.78 g (0.0433 mole) of phenyl chloroformate with stirring at 20° to 25° C. The mixture is further stirred at the same temperature for 30 minutes, and 4.20 g (0.0433 mole) of 2-amino-4,6-dimethoxyacid and 6.72 g (0.0433 mole) of 2-amino-4,6-dimethoxypyrimidine are added to the mixture in that order. The mixture is refluxed for 5 hours. After completion of the reaction, the dichloromethane is removed under reduced pressure and to the residue is added 50 ml of acetonitrile. The resulting crystals are collected by filtration, washed with three 10 ml portions of acetonitrile and water with water. The crystals were dried in vacuo over P2O5 to give 15.62 g (yield 87.9%) of the title compound.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][CH:17]=2)[N:9]=1.CC1C=CC(S(O[CH2:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1.O>CCCCCC.O1CCCC1>[CH:36]1([CH2:35][CH:15]([C:10]2[N:9]=[C:8]([O:7][CH3:6])[C:13]([CH3:14])=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][C:19]([S:22][CH3:23])=[CH:20][CH:21]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1nc(Cc2ccc(SC)cc2)ccc1C
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C(CC2CCCC2)c2ccc(SC)cc2)ccc1C
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.46 M n-butyllithium in hexane (1.11 mL) was added to a solution of 2-methoxy-3-methyl-6-[4-(methylsulfanyl)benzyl]pyridine obtained in Reference Example 2-1 (400 mg) in tetrahydrofuran (5 mL) in the presence of an argon gas at −78° C., and the mixture was stirred at −35° C. for 30 minutes. The reaction solution was cooled again to −78° C. and a solution of cyclopentylmethyl 4-methylbenzenesulfonate (549 mg) in tetrahydrofuran (3 mL) was added, after which the mixture was stirred at −78° C. to 0° C. for two hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by preparative TLC (hexane:ethyl acetate=19:1) to give 6-{2-cyclopentyl-1-[4-(methylsulfanyl)phenyl]ethyl}-2-methoxy-3-methylpyridine as a colorless amorphous (220 mg, 42%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C=O.[C:18](O)(=O)C>CO>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][CH2:18][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[N:7]=1
Reactant: CC(=O)O
Reactant: c1nc[nH]n1
Reactant: COc1cc(C)nc(N)n1
Agent: C=O
Solvent: CO
Product: COc1cc(C)nc(NCn2cncn2)n1

Procedure:
With stirring, a mixture of 13.9 g (0.1 mole) of 2-amino-4-methoxy-6-methylpyrimidine, 7 g (0.1 mole) of 1,2,4-triazole, 9.4 g (0.11 mole) of aqueous 35% formaldehyde and 1 g of acetic acid in 100 ml of methanol is refluxed for 11/2 hours. First a clear solution forms, from which the reaction product precipitates in crystalline form after a time. After the reaction mixture has cooled, the crystalline title compound is filtered with suction and dried. Yield: 14 g. Melting point: 191°-193° C.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[H-].[Na+].O.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl>O1CCCC1.CN(C)C=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1]
Reactant: COc1ccccc1CCl
Reactant: CN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1COCCCCCCN(C)C
Reaction time: 0.75 h

Procedure:
6-(Dimethylamino)hexanol (8.80 g, 60.6 mmol) was dissolved in an anhydrous 2:1 mixture of tetrahydrofuran and dimethylformamide (150 mL) and the solution was cooled in an ice bath. Sodium hydride (60% in oil, 3.23 g, 80.8 mmol) was added in portions and after 5 min. the water bath was removed. After 45 min., 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added. After 4 h, the reaction mixture was quenched with 1 M sodium thiosulfate and tetrahydrofuran was removed in vacuo. The reaction mixture was washed with ethyl acetate and the aqueous phase was basified with 3 M sodium hydroxide, followed by extraction with ether. The ether layer was dried over potassium carbonate, filtered and acidified with 4 M hydrochloric acid in dioxane. The reaction mixture was concentrated in vacuo and the residue was crystallized form ethanol/ether to give O-(2-methoxybenzyl)-6-dimethylaminohexanol as the hydrochloride salt (10.4 g, 85%). MS (M−Cl)+266.3.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH2:18][CH2:19][OH:20])[C:12]1[N:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]([CH2:18][CH2:19][O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:12]1[N:13]=[CH:14][CH:15]=[CH:16][N:17]=1
Reactant: CN(CCO)c1ncccn1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN(CCOc1ccc(C=O)cc1)c1ncccn1
Temperature: 120 °C
Reaction time: 6 h

Procedure:
A mixture of 4-fluorobenzaldehyde (12 ml) and 2-[N-methyl-N-(2-pyrimidinyl)amino]ethanol (10.05 g) in dry dimethyl sulphoxide (50 ml) containing anhydrous potassium carbonate (15 g) was stirred at 120° C. for 6 hours. The mixture was cooled to room temperature and added to water (200 ml). The aqueous solution was extracted with ethyl acetate (2×300 ml), the organic extracts washed with brine, dried (MgSO4) and evaporated. The title compound was obtained as an oil following chromatography on silica-gel in 2% methanol in dichloromethane.
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[Cl:14][C:15]1[C:16]([CH3:41])=[C:17]([NH:23][C@H:24]([CH2:39][OH:40])[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]2[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=2)=[O:26])[CH:18]=[CH:19][C:20]=1[C:21]#[N:22].O>CN(C=O)C>[Si:10]([O:40][CH2:39][C@@H:24]([NH:23][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[C:15]([Cl:14])[C:16]=1[CH3:41])[C:25]([NH:27][NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[N:37])=[CH:32][CH:31]=1)=[O:26])([C:7]([CH3:9])([CH3:8])[CH3:6])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(N[C@H](CO)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
Imidazole (1.3 g, 19.1 mol) and TBDMS-Cl (1.73 g, 11.46 mmol) were added sequentially to a pre-cooled (0° C.) solution of (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxypropanoyl)-4-cyanobenzohydrazide (1.52 g, 3.82 mmol) in DMF (145 mL). The reaction mixture was allowed to warm to room temperature and stirred for 20 h, whereupon the solution was poured into H2O (200 mL). The white precipitate was filtered, washed with H2O (35 mL) and taken up in CH2Cl2 (300 mL). This organic layer was washed with brine (1×160 mL), dried (Na2SO4), filtered and concentrated to provide the title compound (1.52 g, 78%). 1H NMR (400 MHz, acetone-d6, δ in ppm) 9.6 (br s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.80 (d, J=9 Hz, 2H), 7.41 (d, J=8 Hz, 1H), 6.63 (d, J=8 Hz, 3H), 5.45 (d, J=8 Hz, 1H), 4.29-4.23 (m, 1H), 4.05-4.02 (m, 2H), 2.21 (s, 3H), 0.79 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.C(OCC)(=O)C>C(Cl)(Cl)(Cl)Cl>[Br:8][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:9][CH2:10][CH2:11][CH2:12]2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)CCCN2
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1ccc2c(c1)CCCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.5 %

Procedure:
NBS (28 g, 158 mmol) was added to a solution of 1,2,3,4-tetrahydroquinoline (20 g, 150.16 mmol) in carbon tetrachloride (200 mL). The resulting solution was stirred for 3 h at 0° C., extracted with dichloromethane (3×50 mL) and concentrated in vacuo to give a residue, which was applied onto a silica gel column with 1% ethyl acetate in petroleum ether to give 6-bromo-1,2,3,4-tetrahydroquinoline as a yellow solid (11 g, 35%).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10](/[C:13](=[CH:22]\[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)/[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)=[O:15])=[CH:9][CH:8]=1.CN([CH:32]=[O:33])C.S(=O)(O)[O-]>C1COCC1.CCOC(C)=O>[CH:32]([C:19]1[S:18][C:17]([NH:16][C:14](=[O:15])/[C:13](/[C:10]2[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=2)=[CH:22]/[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:21][CH:20]=1)=[O:33]
Reactant: CN(C)C=O
Reactant: O=C(Nc1nccs1)/C(=C/C1CCOCC1)c1ccc(Br)cc1
Agent: O=S([O-])O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1cnc(NC(=O)/C(=C/C2CCOCC2)c2ccccc2)s1
Temperature: 20 °C
Reaction time: 1.83 h

Procedure:
n-BuLi (17 mL of a 1.6M solution in hexanes, 27.2 mmol) was added to a stirred solution of (E)-2-(4-bromophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylacrylamide (EXAMPLE 12, 4.00 g, 10.2 mmol) in anhydrous THF (100 mL) at −78° C. After 110 min, the mixture was treated with anhydrous DMF (5 mL, 64.6 mmol), before being allowed to warm to 20° C. over 30 min. The reaction was quenched with 1M HCl, then the THF was evaporated off under reduced pressure. The aqueous phase was extracted with CH2Cl2, then the CH2Cl2 extracts were dried (MgSO4), filtered, and concentrated. The residue was stirred with Na2S2O5 solution. The solid produced was collected and triturated with EtOAc. This material was then suspended in EtOAc, then saturated aqueous NaHCO3 was added with stirring. The layers were separated, then the aqueous phase was extracted with EtOAc and CH2Cl2. The combined organic layers were dried, filtered, concentrated, and subjected to column chromatography (CH2Cl2-THF, 93:7), to give EXAMPLE 125 (RTB=1.30 min; m/z (ES+)=371.2 [M+H]+) and EXAMPLE 126 (RTB=1.38 min; m/z (ES+)=343.4 [M+H]+). The EtOAc washings from the bisulfite addition complex were concentrated, then the residue was subjected to flash chromatography (CH2Cl2-THF, 24:1 to 93:7) to give EXAMPLE 124 (RTB=1.39 min; m/z (ES+)=315.3 [M+H]+) and an additional quantity of EXAMPLE 126.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10]P(=O)(OCC)OCC)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:21][O:22][CH2:23][O:24][C:25]1[C:29]([CH:30]=O)=[CH:28][N:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:26]=1.O>O1CCCC1>[C:1]([C:5]1[S:6][CH:7]=[C:8](/[CH:10]=[CH:30]/[C:29]2[C:25]([O:24][CH2:23][O:22][CH3:21])=[N:26][N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(Cc1csc(C(C)(C)C)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)(C)C)n1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of diethyl [(2-tert-butyl-1,3-thiazol-4-yl)methyl]phosphonate (2.2 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.48 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.3 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to give 2-tert-butyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow crystals (2.6 g, yield 71%). melting point: 112-113° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:36]#[C:37]Br>ClCCl.O>[C:37]([N:2]1[CH2:3][CH:4]([C:6]2[O:10][N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:29])=[C:15]([NH:17][C:18]([C:20]4[N:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]5=[N:22][CH:21]=4)=[O:19])[CH:16]=3)[N:7]=2)[CH2:5]1)#[N:36]
Reactant: N#CBr
Reactant: Cc1ccc(-c2noc(C3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 45 °C

Procedure:
To a stirring mixture of N-(5-(5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (21) (200 mg, 0.487 mmol), potassium carbonate (202 mg, 1.46 mmol) and cyanogen bromide (103 mg, 0.974 mmol) in dichloromethane:water (1:1, 15 mL) were heated at 45° C. for 1.5 hours. The reaction was cooled to room temperature and the layers were separated. The aqueous layer was washed with 3 times with DCM and dried over anhydrous sodium sulfate. The combined organics were concentrated. The resulting solid was washed with hexanes to give N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82). MS m/z 400.14 (M+1)+.