Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:22])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.CCCCCC.C(OCC)(=O)C.C(OCC)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:22])[C:18]2[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccccc1[N+](=O)[O-])C(=O)OCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 280 °C
Yield: 58.8 %

Procedure:
A solution of 2-[(2-Nitro-phenylamino)-methylene]-malonic acid diethyl ester (10 g, 32.44 mmol) dissolved in 20 ml of diphenyl ether in a 250 ml round bottom flask was heated and refluxed for 5 hrs at 280° C. with stirring. The reaction was monitered by TLC (n-hexane/ethyl acetate=3/1). After completing the reaction and cooling to room temperature, 200 ml of diethylether was added to the mixture and the resulting precipitate was collected by filtration, and the residue was washed with 200 ml of diethyl ether to give 8-Nitro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (6.5 g, 19.08 mmol, yield 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4([C:32]#N)[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].C[Mg]Br>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4([CH3:32])[CH2:24][CH2:23][N:22]([C:25]5[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(N2CCC(C#N)(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)ncn1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(C)(Nc3nc4c(-c5ccc(F)c(F)c5)cccn4n3)CC2)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
To a solution of 4-(8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-1-(6-methylpyrimidin-4-yl)piperidine-4-carbonitrile (Example 231) (50 mg, 112 μmol) in THF (2 mL) was added methylmagnesium bromide (1.4 M in toluene:THF, 240 μL, 336 μmol) dropwise at 0° C., and the resulting mixture was allowed to warm up to room temperature and stirred for 3 hours. Then the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification by chromatography (silica gel, 10 g, 0 to 10% methanol in dichloromethane) afforded the title compound (9 mg, 19%) as a light yellow solid.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:8]([O:25][CH3:26])[CH:7]=1)([O-])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[NH2:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:8]([O:25][CH3:26])[CH:7]=1
Reactant: CCCCCCCCCCCCOc1ccc(C=C[N+](=O)[O-])cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCCOc1ccc(CCN)cc1OC
Reaction time: 2 h

Procedure:
1-Nitro-2-(4-dodecyloxy-3-methoxyphenyl)ethene (5.7 g; 16 mmol) is suspended in THF ((100 ml) under a protective gas atmosphere. LAH solution (1M in THF; 56 ml, 56 mmol) is then slowly added dropwise. When the addition is complete, heating at reflux is carried out for 2 hours and stirring is then carried out for a further 16 hours at 25° C. Excess LAH is then decomposed with water (8 ml), 15% sodium hydroxide solution (8 ml) and again with water (24 ml). The suspension is stirred for a further 30 minutes at 25° C. and then filtration is carried out. The filtrate is concentrated to dryness by evaporation, and the brown residue is taken up in 10% aqueous hydrochloric acid (12 ml) and washed with tert-butyl methyl ether (3×10 ml). The aqueous phase is rendered alkaline with 15% sodium hydroxide solution (6 ml) and extracted with tert-butyl methyl ether (3×10 ml). The organic extracts are combined, washed with water and saturated sodium chloride solution, and dried over K2CO3. Filtration is followed by concentration to dryness by evaporation, and freeze-drying is carried out from tert-butyl alcohol/water (4:1) with the addition of hydrochloric acid.
Reaction SMILES: CC(C)=O.[C@@H:5]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10]2.[C:16]([O:21][CH2:22][CH2:23][OH:24])(=[O:20])[C:17]([CH3:19])=[CH2:18]>CN(C)C1C=CN=CC=1.O>[C:16]([O:21][CH2:22][CH2:23][O:24][C:11]([CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]1[C:14]([OH:13])=[O:15])=[O:12])(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: C=C(C)C(=O)OCCO
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(=O)OCCOC(=O)C1CCCCC1C(=O)O
Reaction time: 1 h

Procedure:
To acetone (1,000 mL) were added cis-1,2-cyclohexanedicarboxylic anhydride (308.3 g), 2-hydroxyethyl methacrylate (273.3 g), and 4-dimethylaminopyridine (4.9 g). This mixture was heated with refluxing for 5 hours, and the acetone was distilled off under reduced pressure. Thereafter, 1N hydrochloric acid (500 mL) and ethyl acetate (2,000 mL) were added to the residue to extract it. The resulting organic phase was washed twice with saturated aqueous sodium chloride solution (500 mL), and anhydrous magnesium sulfate (100 g) was then added thereto. This mixture was allowed to stand for 1 hour to dehydrate the organic phase. Subsequently, the magnesium sulfate was removed by filtration and the ethyl acetate was distilled off under reduced pressure to obtain a white solid. The solid was pulverized and then added to water (2,000 mL). After this mixture was stirred for 2 hours, the particles were taken out by filtration and dried. As a result, 2-[2-(methacryloyloxy)ethoxy-carbonyl]cyclohexanecarboxylic acid was obtained as a white solid (518.9 g).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH3:40])[C:12]([C:13]([N:15]([CH2:17][C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=3)[CH3:16])=[O:14])=[CH:11][N:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O1CCCC1>C(O)C>[F:31][C:28]([F:29])([F:30])[C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=1)[CH2:17][N:15]([CH3:16])[C:13](=[O:14])[C:12]1[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH3:40])=[CH:33][C:9]([C:7]2[S:8][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][CH:6]=2)=[N:10][CH:11]=1
Reactant: CC(=O)c1ccc(-c2cc(-c3ccccc3C)c(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(-c2ccc(C(C)O)s2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 95.4 %

Procedure:
A mixture of 50 mg (0.087 mmol) 6-(5-acetyl-thiophen-2-yl)-N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-4-o-tolyl-nicotinamide (Example 38), 7 mg (0.2 mmol) sodium borohydride in 1 ml ethanol and a small amount of tetrahydrofuran was stirred at room temperature for 2 h. The reaction was quenched by addition of water, followed by 1 N aqueous hydrochloric acid solution. The mixture was basified with sodium carbonate and extracted with 3 portions of ethyl acetate. The combined organic extracts were dried with sodium sulfate, filtered and concentrated to give 48 mg (96%) of the title compound as a slightly yellow solid.
Reaction SMILES: C(OC([N:8]1[CH:12]([CH2:13][O:14][C:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[O:17][N:16]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.CC(O)C.Cl>C(Cl)(Cl)Cl.CO>[ClH:24].[NH2:8][CH:12]([CH2:11][OH:10])[CH2:13][O:14][C:15]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[O:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1C(COc2noc3ccc(Cl)cc23)COC1(C)C
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: NC(CO)COc1noc2ccc(Cl)cc12
Yield: 159.7 %

Procedure:
To a solution of 7.68 g of 3-[(3-tert-butoxycarbonyl-2,2-dimethyloxazolidin-4-yl)methoxy]-5-chloro-1,2-benzoisoxazole in 77 ml of chloroform and 77 ml of methanol is added 16 ml of a 2-propanol solution (7.5N) of hydrogen chloride at 20°-25° C., and they are subjected to reaction at the same temperature overnight. The crystals precipitated are collected by filtration, to obtain 4.47 g of 3-(2-amino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole hydrochloride.
Reaction SMILES: C(OC(=O)CC1(C(N[CH2:19][CH:20]([CH2:28][C:29]2[CH:34]=[C:33]([Cl:35])[CH:32]=[C:31]([Cl:36])[CH:30]=2)[C:21]([O:23]C(C)(C)C)=[O:22])=O)CCCC1)C1C=CC=CC=1.CC1C(C)=C(C)C(C)=C(C)C=1>C(O)(C(F)(F)F)=O.CCOC(C)=O.[Pd]>[Cl:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([Cl:36])[CH:32]=1)[CH2:28][CH:20]([CH3:19])[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)OC(=O)C(CNC(=O)C1(CC(=O)OCc2ccccc2)CCCC1)Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: Cc1cc(C)c(C)c(C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(Cc1cc(Cl)cc(Cl)c1)C(=O)O
Reaction time: 2 h
Yield: 113.1 %

Procedure:
To a solution of tert-butyl 3-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentanecarboxamido)-2-(3,5-dichlorobenzyl)propanoate (130 mg, 0.237 mmol) in TFA (1.5 ml), pentamethylbenzene (351 mg, 2.370 mmol) was added at room temperature. After stirred for 2 hr, the reaction mixture was concentrated under reduced pressure. The obtained crude material was hydrogenated under hydrogen atmosphere (1 atm) with Pd/C in EtOAc for 0.5 hr at room temperature. The reaction mixture was filtered, and the filtered cake was washed with MeOH. The combined filtrate was concentrated under reduced pressure. The obtained residue was purified by RP-HPLC (SunFire, H2O (0.1% TFA)/CH3CN) to give 341-(carboxymethyl)cyclopentanecarboxamido)-2-(3,5-dichlorobenzyl)propanoic acid (62.5 mg); Retention time=0.71 minutes (condition B); MS (m+1)=402.0; 1H NMR (400 MHz, DMSO-6, mixture of rotamers) δ ppm 1.47-1.58 (m, 6H) 1.95-2.05 (m, 2H) 2.54-2.63 (m, 2H) 2.68-2.85 (m, 3H) 3.13-3.29 (m, 2H) 7.24 (d, J=1.8 Hz, 2H) 7.42-7.43 (m, 1H) 7.60-7.63 (m, 1H); HRMS (ES+) m/z for C18H22Cl2NO5 [M+H]+ calcd 402.0875. found 402.0854
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:14]=[C:13]([CH2:23]O)[CH:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:56]I>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:10]([C:11]3[CH:12]=[C:13]([CH2:23][I:56])[N:14]=[C:15]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:16]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: OCc1cc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)nc(NC2CCCC2)n1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2cc(CI)nc(NC3CCCC3)n2)cc1
Yield: 59.6 %

Procedure:
[6-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-(cyclopentylamino)-4-pyrimidinyl]methanol (215 mg, 0.49 mmol) was dissolved in a mixture of benzene (4 mL) and ether (8 mL). Imidazole (134 mg, 2.0 mmol) and triphenylphosphine (191 mg, 0.73 mmol) were added sequentially. A solution of iodine (179 mg, 0.71 mmol) in ether (5 mL) was added dropwise to the reaction mixture over 10 minutes. The resultant solution was stirred for an additional 20 minutes then diluted with 10 mL of ether. The mixture was filtered to remove solids. Concentration followed by flash chromatography (4:1 hexanes:ethyl acetate) provided 4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-cyclopentyl-6-(iodomethyl)-2-pyrimidinamine (160 mg, 60%) as a solid. Rf 0.47 (4:1 hexanes:ethyl acetate); 1H NMR (CDCl3) δ 8.38 (d, 1H), 7.67 (m, 2H), 7.28 (m, 1H), 7.18 (t, 2H), 7.03 (d, 1H), 6.38 (s, 1H), 5.19 (d, 1H), 4.35 (m, 1H), 4.02 (s, 2H), 2.10 (m, 2H), 2.67 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:12]
Reactant: O=C=NCCCl
Reactant: COCCCN
Solvent: C1CCOC1
Product: COCCCNC(=O)NCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of 3-methoxypropylamine (0.45 mL, 4.39 mmol) in THF (15 mL) was treated with 2-chloroethylisocyanate (0.35 mL, 4.10 mmol), stirred at RT for 3 h and concentrated to dryness to afford 1-(2-chloroethyl)-3-(3-methoxypropyl)urea (100% yield assumed) as a white solid. MS (ESI) m/z: 195.1 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]1.C(N(CC)CC)C.[Na+].[Cl-]>ClCCl>[CH:12]([CH:13]1[CH2:18][CH2:17][CH:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]1)=[O:11]
Reactant: N#CCC1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CCC1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 80.9 %

Procedure:
To a stirred solution of oxalyl chloride (0.24 mL, 0.0028 mol) in dichloromethane (15 mL) at −78° C. was added a solution of dimethyl sulfoxide (0.23 mL, 0.0032 mol) in dichloromethane (5 mL). After 10 min. a solution of [4-(hydroxymethyl)cyclohexyl]acetonitrile (0.38 g, 0.0025 mol) in dichloromethane (2 mL) was added to the reaction mixture. After 25 min., the reaction mixture was treated with triethylamine (1.7 mL, 0.012 mol), allowed to warm to room temperature, and then poured into 100 mL of saturated aqueous NaCl. The resulting mixture was extracted with two 100 mL portions of ether, dried (MgSO4), and then evaporated under reduced pressure. Chromatography of the residue on silica gel with 1:10 ethyl acetate/hexanes afforded 0.306 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 9.64 (s, 1H), 2.35 (d, 2H J=10.8 Hz) 1.10-2.4 (m, 10H) (major isomer).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[CH:33]=2)=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C(=O)C.CN(C)C=O>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:25]=[CH:24][C:23]([NH:22][C:7]([C:5]5[N:4]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=6)[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:44][CH:43]=4)=[CH:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)cc1
Reactant: Cc1cc(C(=O)O)n(-c2ccccc2)n1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)cc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.2 %

Procedure:
To a solution of 3-methyl-1-phenyl-1H-pyrazole-5-carboxylic acid (197 mg, 973 μmol) in tetrahydrofuran (2 mL) were added oxalyl chloride (80 μL, 973 μmol) and N,N-dimethylformamide under ice-cooling, and the mixture was stirred at room temperature for 1 hr. A solution of N-[6-(4-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 649 μmol) in N,N-dimethylacetamide (2 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was recrystallized from ethanol/water to give the title compound (138 mg, 29%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.OO.C(OCC)(=[O:24])C.CCCCCC>O>[Cl:19][C:14]1[CH:13]=[C:12]([CH:9]2[O:8][C:5]3=[N:6][CH:7]=[C:2]([OH:24])[CH:3]=[C:4]3[CH2:11][CH2:10]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(C)=O
Reactant: Clc1ccc(C2CCc3cc(Br)cnc3O2)cc1Cl
Agent: OO
Solvent: CCCCCC
Solvent: O
Product: Oc1cnc2c(c1)CCC(c1ccc(Cl)c(Cl)c1)O2
Temperature: -75 °C
Reaction time: 2 h

Procedure:
6-Bromo-2-(3,4-dichlorophenyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridine (1.5 g) was converted to the corresponding lithio intermediate according to the procedure described in Example 23 and then quenched at -90° C. with 1.3 ml of tri-n-butyl borate. The resulting dark solution was stirred at -75° C. for 2 hours and then allowed to warm to 0° C. The mixture was then acidified with 3N hydrochloric acid, the organic phase was separated, and the aqueous layer was extracted with ether. The combined organic layers were concentrated to give a light brown, tacky solid. To this material was added 25 ml of 30% hydrogen peroxide and the resulting mixture was warmed at 60° C. for 30 minutes. The mixture was then cooled and diluted with 75 ml of water and the resulting mixture was extracted with two 50-ml portions of methylene chloride. The methylene chloride extracts were combined, washed with aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a yellow solid. Column chromatography (silica gel, 3% ethyl acetate/hexane) gave 2-(3,4-dichlorophenyl)-3,4-dihydro-6-hydroxy-2H-pyrano[2,3-b]pyridine melting at about 218°-219° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: CN1CCN(c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)CC1

Procedure:
Prepared according to Procedure C from 4-(4-benzyloxyanilino)-6-chloropyrido[3,4-d]pyrimidine and 1-methylpiperazine; δH (CDCl3) 9.00 (1H,s), 8.58 (1H,s), 7.59 (2H, d), 7.28-7.40 (5H,m), 7.02 (2H,d), 6.59 (1H,s), 5.08 (2H,s), 3.60-3.74 (4H,m), 2.52-2.64 (4H,m), 2.40 (3H,s); m/z (M+1)+427.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].O.[OH-].[Li+].C1COCC1.Cl>O>[CH2:10]([C:9]1[CH:8]=[C:7]([C:12](=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])[CH3:11]
Reactant: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)O
Reaction time: 15 h

Procedure:
A mixture of 3-Ethyl-5-(3-hydroxy-benzylcarbamoyl)-thiophene-2-carboxylic acid methyl ester (140 mg, 0.44 mmol), lithium hydroxide monohydrate (180 mg, 4.38 mmol), THF (4 mL) and water (5 mL) was stirred 15 h, acidified with 1N HCl and extracted with EtOAc (×3). The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound, 145.4 (100%). MS m/e 305.9 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:37])[N:10]([CH2:28][C@H:29]([NH2:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11](=[O:27])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:13]=1[CH3:14].[CH2:38]([CH:43]=O)[CH2:39][C:40]([OH:42])=[O:41].N1C=CC=CC=1>CO>[OH:42][C:40]([CH2:39][CH2:38][CH2:43][NH:36][C@H:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][N:10]1[C:9](=[O:37])[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:13]([CH3:14])[N:12]([CH2:15][C:16]2[C:21]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:19]=[CH:18][C:17]=2[F:26])[C:11]1=[O:27])=[O:41]
Reactant: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](N)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: O=CCCC(=O)O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(-c2ccccc2Cl)c(=O)n(C[C@H](NCCCC(=O)O)c2ccccc2)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reaction time: 8 h

Procedure:
To compound 2b (0.03 mmol) in 1 mL MeOH, succinic semialdehyde (0.03 mmol) was added followed by addition of 8 M BH3:Pyridine (0.03 mmol). After overnight shaking, the compound 2-1 was purified by prep. LC-MS. MS (CI) m/z 618.2 (MH+) tR=1.005 (method 1)
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:15]([NH2:18])[CH2:16][OH:17]>C1COCC1>[OH:17][CH2:16][CH2:15][NH:18][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: NCCO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Yield: 95 %

Procedure:
To a solution of 4.70 g (21.9 mmol) of methyl 2-chloro-3-nitrobenzoate in 300 mL of THF was added dropwise 300 mL of 2-ethanolamine (80 mmol) and the mixture was refluxed over night. The reaction was concentrated to dryness, dissolved in ethyl acetate, and washed aqueous sodium hydrogen carbonate and water. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5.00 g (20.8 mmol, 95%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([OH:14])=O)[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([F:30])[CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.[OH-].[Na+]>[Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C:12]([NH:16][CH:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([C:26]#[N:27])([CH3:29])[CH3:28])=[C:21]([F:30])[CH:20]=3)[CH3:18])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:15]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(F)c1
Reactant: O=C(O)Cn1cnc2ccc(F)c(Cl)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2ccc(F)c(Cl)c21)c1ccc(C(C)(C)C#N)c(F)c1
Reaction time: 2 h

Procedure:
A mixture of (7-chloro-6-fluoro-1H-benzimidazol-1-yl)acetic acid (210 mg, 0.921 mmol) prepared according to scheme 12, 2-{4-[1-aminoethyl]-2-fluorophenyl}-2-methylpropanenitrile (190 mg 0.921 mmol)) prepared according to scheme 7 and Et3N (280 mg, 2.76 mmol, 0.39 mL) is stirred in MeCN (10.0 mL). HATU (350 mg, 0.921 mmol) is added, and after 2 hours of stirring, the mixture is diluted with 1N NaOH (40.0 mL) and then extracted 4 times with EtOAc (4×40.0 mL). The organic phases are combined and dried over MgSO4. The mixture is filtered and concentrated. The product is purified by a Gilson prep pump, flow rate: 30 ml/min, column: Synergi Polar (4u) 21.2×50 mm, mobile phase: A=water (0.1% TFA), B=MeCN (206 mg, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.38 (d, J=6.84 Hz, 3H) 1.71 (s, 6H) 4.85-5.00 (m, J=7.13, 7.13 Hz, 1H) 5.21 (s, 2H) 7.15-7.31 (m, 3H) 7.42 (t, J=8.30 Hz, 1H) 7.63 (dd, J=8.89, 4.39 Hz, 1H) 8.21 (s, 1H) 8.84 (d, J=7.81 Hz, 1H). The enantiomers are separated on a chiral AD column, eluting with 30% EtOH (0.1% DIEA) and hexanes 70% (0.1% DIEA), MS [M+H], calcd: 417.1. found: 417.3 [α]D=+154 (c=13, MeOH) and [α]D=−155 (c=15, MeOH).