Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:3]1.[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[C:20]([NH:22][NH:23][CH:24]([CH3:26])[CH3:25])=[O:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[C:20]([NH:22][N:23]([CH:24]([CH3:26])[CH3:25])[C:13](=[O:15])/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)=[O:21]
Reactant: Cn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1cccc(F)c1)C(=O)/C=C/c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-methyl-1H-indol-3-yl)acrylic acid (140.0 mg, 0.70 mmol), 3-fluoro-N′-isopropylbenzohydrazide (209.0 mg, 1.05 mmol) and HATU (399.2 mg, 1.05 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.18 ml, 1.05 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-3-fluoro-N′-isopropyl-N′-(3-(1-methyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained (37.0 mg, 13.9%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:34]=[CH:33][C:8]2=[N:9][N:10]([C:12]3[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[C:13]=3[OH:32])[N:11]=[C:7]2[CH:6]=1)=[O:4].[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43]C(O)[CH2:41][C:40]1([CH3:49])[CH3:48]>>[OH:35][C:36]([CH3:51])([CH3:50])[CH2:37][O:38][N:39]1[C:44]([CH3:46])([CH3:45])[CH2:43][CH:1]([O:2][C:3]([C:5]2[CH:34]=[CH:33][C:8]3=[N:9][N:10]([C:12]4[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:31])([CH3:30])[C:23]5[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=5)[C:13]=4[OH:32])[N:11]=[C:7]3[CH:6]=2)=[O:4])[CH2:41][C:40]1([CH3:49])[CH3:48]
Reactant: CC(C)(O)CON1C(C)(C)CC(O)CC1(C)C
Reactant: COC(=O)c1ccc2nn(-c3cc(C(C)(C)C)cc(C(C)(C)c4ccc(Cl)cc4)c3O)nc2c1
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccc3nn(-c4cc(C(C)(C)C)cc(C(C)(C)c5ccc(Cl)cc5)c4O)nc3c2)CC1(C)C

Procedure:
5-Methoxycarbonyl2-[2-hydroxy-3-(4-chloro-α,α-dimethylbenzyl)-5-tert-butylphenyl]-2H-benzotriazole (3.89 g, 0.0081 mol) and 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethyl-4-hydroxypiperidine (2.41 g, 0.0098 mol) are reacted together according to the procedure of Example 1. The title compound is obtained in a yield of 2.26 g (40.2%) as a yellow solid, melting at 80-90° C., whose structure is consistent with 1Hnmr and mass spectrometry. The compound has a molar absorptivity of 17,411 l/mole cm.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:26][CH:25]([N:27]([S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[Li+].[OH-]>C1COCC1>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH2:26][CH:25]([N:27]([S:34]([CH2:37][CH2:38][CH2:39][CH3:40])(=[O:36])=[O:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[O:24][N:23]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCC(COc2ccc(C3=NOC(N(CCC(=O)OC)S(=O)(=O)CCCC)C3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCOC(=O)N1CCC(COc2ccc(C3=NOC(N(CCC(=O)O)S(=O)(=O)CCCC)C3)cc2)CC1
Yield: 39 %

Procedure:
A solution of methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy)phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate more polar diastereomer (200 mg, 0.344 mmol) in THF (1 mL) was saponified using 0.5M LiOH (1 mL, 0.5 mmol) over 4 hours as per Example 1, Part F. The crude carboxylic acid was crystallized from EtOAc/hexanes, affording 77 mg (39%) of the desired material; mp: 137.3°-139.0° C.; 1H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.45 (d, J=9.5 Hz, 1H), 4.92 (m, 1H), 4.37 (m, 1H), 4.15 (b, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.47 (dd, J=16.5, 9.9 Hz, 1H), 3.08 (t, J=8.1 Hz, 2H), 3.01 (dd, J=16.5, 7.0 Hz, 1H), 2.74 (bt, J=12.1 Hz, 2H), 2.26 (m, 1H), 2.01 (m, 2H), 1.81 (m, 4H), 1.45 (s, 9H, overlapped with m, 1H), 1.24 (m, 3H), 0.91 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:13]([C:15]1[S:16][CH:17]=[C:18]([C:20]([N:22]2[CH2:27][C:26]3([CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[O:25][CH2:24][CH2:23]2)=[O:21])[N:19]=1)[CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:30]1[CH2:31][CH2:32][C:26]2([O:25][CH2:24][CH2:23][N:22]([C:20]([C:18]3[N:19]=[C:15]([CH2:13][CH3:14])[S:16][CH:17]=3)=[O:21])[CH2:27]2)[CH2:28][CH2:29]1
Reactant: O=Cc1cccc(CCO)c1Cl
Reactant: CCc1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 1.15 h
Yield: 107 %

Procedure:
To a solution of 2-chloro-3-(2-hydroxyethyl)benzaldehyde (1.1 molar equivalents) in DCM (12 volumes) was added to (2-ethylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone ((limiting reagent) (step b). Triethylamine (2 molar equivalents) was added and the mixture was stirred for 1.15 hr. Sodium triacetoxyborohydride (2.5 molar equivalents) was added portion-wise over 15 minutes maintaining the temperature below 25° C. The reaction mixture was stirred at ambient temperature for 22.5 hr. Saturated aq. sodium bicarbonate solution (8 volumes) was added slowly and the mixture was stirred vigorously for 1 hr; the aqueous was separated and extracted with DCM (5.3 volumes). The combined organics were washed with 20% brine solution (5.3 volumes), dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil. Yield 107% of theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([CH3:31])([CH3:30])[C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([C:28]3[NH:34][N:33]=[N:32][N:29]=3)([CH3:31])[CH3:30])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc(CCCCCC(C)(C)C#N)oc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc(CCCCCC(C)(C)c3nnn[nH]3)oc2-c2ccc(OC)cc2)cc1
Yield: 50.8 %

Procedure:
5 g of 7-[4,5-bis(4-methoxyphenyl)-2-oxazolyl)-2,2-dimethylheptanenitrile in 12 cm3 of dimethylformamide are treated with twice 2.7 g of sodium azide and twice 4.95 g of triethylamine hydrochloride according to the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 3.5 cm in diameter containing 120 g of silica gel (50 to 200μ). The column is eluted, collecting 50 cm3 fractions, with 0.5 liter of diisopropyl ether and then with 1.3 liters of a diisopropyl ether/ethyl acetate (70:30 by volume) mixture. The fractions emerging at between 0.85 liter and 1.3 liters are concentrated under reduced pressure (0.2 kPa). The solid is taken up with 30 cm3 of diethyl ether and drained, washed with 10 cm3 of diethyl ether and dried. 2.8 g (50%) of 5-{7-[ 4,5-bis(4-methoxyphenyl)-2-oxazolyl]-2-methyl-2heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 82° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][CH:9]1[C:8](=[O:12])[NH:7][C:6]2[CH:13]=[C:2]([CH:16]=[CH:15][C:14]([NH2:18])=[O:17])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1Oc2ccc(C=CC(N)=O)cc2NC1=O
Yield: 36 %

Procedure:
726 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is stirred in 1.5 ml of triethylamine with 0.267 g of acrylamide as well as 8 mg of palladium(II) acetate and 46 mg of tri-ortho-toluyl-phosphine for several hours at 100° C. The product is taken up in methanol and purified by column chromatography with an ethanol/ethyl acetate mixture. Yield 36%.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]#[N:19])[CH:16]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[C:5]([O:20][CH3:21])=[C:6]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]#[N:19])[CH:16]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CO
Product: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnn(CC#N)c1
Temperature: 25 °C

Procedure:
A mixture of [4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl]acetonitrile (0.10 g, 0.33 mmol), ammonium acetate (0.254 g, 3.29 mmol) and 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.82 mL, 0.82 mmol) in methanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C15H15ClN3O (M−NH2)+: m/z=288.1. found: 288.0.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[C:10]([C:19]([OH:21])=[O:20])=[N:11][C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:13][CH:14]=1>C1C=CC=CC=1.CO>[CH3:1][O:20][C:19]([C:10]1[C:9]([Br:8])=[CH:14][N:13]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[N:11]=1)=[O:21]
Reactant: CC(C)(C)c1ncc(Br)c(C(=O)O)n1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1nc(C(C)(C)C)ncc1Br
Reaction time: 48 h
Yield: 80.6 %

Procedure:
A 2.0 M hexanes solution of trimethylsilyldiazomethane (11.8 mL, 23.62 mmol) was added dropwise to a stirring solution of 5-bromo-2-tert-butyl-pyrimidine-4-carboxylic acid (6.12 g, 23.62 mmol) in 9:1 benzene/methanol (100 mL), and the reaction was stirred for 2 days. TLC analysis showed that the reaction was complete, so the mixture was concentrated in-vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (3×20 mL), dried over sodium sulfate, then concentrated in-vacuo. Purified over silica gel, eluting with 10% ethyl acetate/hexanes, to yield 5.2 g of a colorless oil as product. MS (ESI+)=273/275, (M+H)+. Yield=81%.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[NH:11][C:10]([C:12]3[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=3)=[CH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1)[NH2:27].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[ClH:2].[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:3]2[C:4]3[NH:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=4)=[CH:9][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOC(=O)c1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1ccc(-c2cc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3[nH]2)cc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
A mixture of ethyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and 1-methyl-2-pyrrolidinone (8 mL) was stirred at 140° C. for 5 hrs, poured into water (40 mL), and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The precipitated solid was collected by filtration, washed with water and suspended in methanol (15 mL). After stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60° C. The obtained solid was suspended in ethanol (10 mL) and 1N aqueous sodium hydroxide solution (1.5 mL) was added. After stirring at room temperature for 6.5 hrs, and at 60° C. for 3.5 hrs, the mixture was cooled to room temperature. 1N Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60° C. to give the title compound (498 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[CH:3]=1.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>ClCCl.CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([N:48]2[CH2:47][CH2:46][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49]2)=[O:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C(=O)O)c1cc(I)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(C)(C)c2cc(I)ccn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
2-(4-iodo-2-pyridyl)-2-methyl-propanoic acid (100 mg, 0.3435 mmol) was added to dichloromethane (5 mL) followed by the addition of [benzotriazol-1-yloxy(dimethylamino)methylene]-dimethyl-ammonium tetrafluoroborate (110.3 mg, 0.3435 mmol), diisopropyl ethyl amine (88.79 mg, 119.7 μL, 0.6870 mmol) and tert-butyl piperazine-1-carboxylate (83.18 mg, 0.4466 mmol). Some N,N-dimethylformamide (1 ml) was added to help dissolution. The mixture was stirred at ambient temperature for 1 hour. The mixture was diluted with dichloromethane, washed with water (×2). The extracted organic layer was dried over MgSO4, filtered and concentrated in vacuo to a solid. The residue was purified by column chromatography (ISCO Companion, 80 g column) loaded with dichloromethane and eluted with 100% diethyl ether. Product fractions were combined and concentrated in vacuo to give the sub-title product as an off-white solid (90 mg, 57.03% Yield). LC/MS m/z 460.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1[N:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl>CO>[ClH:1].[CH3:8][C:7]1[C:2]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]=[C:16]2/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Cl
Reactant: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccnc1-n1c(/C=C/c2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1-benzimidazole and 2-chloro-3-methylpyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.Br[C:22]1[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=1>>[CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[O:5][C:6](=[O:17])[NH:7][C:8]3[CH:13]=[CH:12][C:11]([C:22]4[CH:23]=[C:24]([C:27]#[N:28])[S:25][CH:26]=4)=[CH:10][C:9]2=3)[CH2:3][CH2:2]1
Reactant: N#Cc1cc(Br)cs1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Product: N#Cc1cc(-c2ccc3c(c2)C(C2CC2)(C2CC2)OC(=O)N3)cs1

Procedure:
The title compound was prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 4-bromo-2-thiophene carbonitrile. A white solid: mp 244-245° C.; 1H-NMR (DMSO-d6) δ 10.25 (s, 1H), 8.49 (d, 1H, J=0.87 Hz), 8.33 (s, 1H), 7.74 (d, 1H, J=1.44 Hz), 7.67 (dd, 1H, J=8.28, 1.54 Hz), 6.90 (d, 1H, J=8.28 Hz), 1.53 (m, 2H), 0.59-0.41 (m, 6H), 0.31-0.24 (m, 2H); MS (ESI) m/z 335 ([M−H]−, 100%); Anal. Calc. For C19H16N2O2S: C, 67.84; H, 4.79; N, 8.33. Found: C, 64.92; H, 4.66; N, 7.71.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Li])CCC.CN(C)CCN(C)CCN(C)C.[OH2:26].C1[CH2:31][O:30]CC1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:31]([OH:30])=[O:26])[C:5]([Cl:8])=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: O
Reactant: Clc1ccc(Cl)nc1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Product: O=C(O)c1cc(Cl)ncc1Cl
Reaction time: 2 h

Procedure:
At −75° C., 2,5-dichloropyridine (3.7 g) was added to a solution of butyl lithium (25 ml, 1M) and N,N,N′,N″,N″-pentamethyldiethylenetriamine (5.3 ml) in THF (50 ml) under a nitrogen atmosphere at −75° C. and the reaction mixture stirred for 2 h, poured onto dry ice, and water (50 ml) added. The aqueous phase was washed with diethyl ether; acidified to pH 2 and the white solid filtered off dried to give the product (2.5 g), a known compound, for the next reaction, without further characterization other than ascertaining that the compound was one spot by tlc with the expected molecular weight (M−1) of 190.
Reaction SMILES: [N:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:11]1[CH2:18][O:17][S:14](=[O:16])(=[O:15])[CH2:13][CH2:12]1>ClCCl>[OH:4][CH2:3][CH2:2][N+:1]([CH2:8][CH2:9][OH:10])([CH2:5][CH2:6][OH:7])[CH2:18][CH2:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15]
Reactant: OCCN(CCO)CCO
Reactant: O=S1(=O)CCCCO1
Solvent: ClCCl
Product: O=S(=O)([O-])CCCC[N+](CCO)(CCO)CCO
Temperature: 0 °C
Yield: 88.4 %

Procedure:
1.49 grams of triethanolamine was added to a 100 mL round bottom flask equipped with a stir bar. 40 mL of dichloromethane was added to the flask and the mixture stirred thoroughly. The solution was cooled to near 0° C. using an ice water bath. 1.36 grams of 1,4-butanesultone was dissolved in 8 mL of dichloromethane and the butanesultone solution added dropwise to the stirred triethanolamine solution. Following complete addition the ice water bath was removed and the solution allowed to warm to room temperature. The mixture was stirred for 16 hours during which a flocculent precipitate formed. The solid was filtered using a medium porosity glass fritted funnel. The white solid was washed using 30 mL of ethyl ether and the solid dried in a dessicator over Drierite® to give 2.52 grams of a white solid. The structure was confirmed by positive mode electrospray mass spectometry (M+Na)=308.3 m/z and 1H NMR.
Reaction SMILES: [OH:1][CH:2]1[CH2:22][CH2:21][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:21][CH2:22]1
Reactant: O=C(OCc1ccccc1)N1CCC2(CCC(O)CC2)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCC2(CC1)CCN(C(=O)OCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 265C (8.0 g) in dichloromethane (200 mL) was added Dess-Martin Periodinane (11.2 g). The mixture was stirred overnight. The mixture was diluted with ethyl acetate (400 mL) and washed with 2N aqueous NaOH, water, and brine.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([OH:16])=O.[N:17]1([C:23]([S:25][CH3:26])=[S:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]([N:20]1[CH2:21][CH2:22][N:17]([C:23]([S:25][CH3:26])=[S:24])[CH2:18][CH2:19]1)=[O:16]
Reactant: CSC(=S)N1CCNCC1
Reactant: COc1ccc(CC(=O)O)c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)N2CCN(C(=S)SC)CC2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.8 %

Procedure:
In 6.2 ml of methylene chloride were dissolved 310 mg (1.37 mmol.) of 2,3,4-trimethoxyphenylacetic acid and 289 mg (1.64 mmol.) of methyl 1-piperazinecarbodithioate. To the solution was added 395 mg (1.92 mmol.) of dicyclohexylcarbodiimide. The mixture was stirred at room temperature for 1 hour. A precipitated solid was removed by filtration, and to the filtrate were added methylene chloride and 1-N hydrochloric acid. The organic solvent potitoh was taken out, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. The residue was purified over a silica gel column. The obtained oil was crystallized from a mixture of ethanol and hexane, yielding 257 mg of the desired compound as a white crystalline product, m.p. 119°-120° C., yield 48.8%.
Reaction SMILES: [H-].[Na+].[N:3]1[O:7][N:6]=[C:5]2[C:8]([OH:12])=[CH:9][CH:10]=[CH:11][C:4]=12.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.O>CN(C)C=O>[N:3]1[O:7][N:6]=[C:5]2[C:8]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:10]=[CH:11][C:4]=12
Reactant: BrCC1CO1
Reactant: Oc1cccc2nonc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OCC2CO2)c2nonc2c1
Temperature: 50 °C

Procedure:
Sodium hydride (620 mg; 60% oil dispersion) was added in portions to benzofurazan-4-ol (1.74 g) in dimethyl formamide (30ml). The mixture was heated at 50° C. for 30 min. Epibromohydrin (1.6 ml) was added and the mixture was heated at 60° C. for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel (50% ethyl acetate/hexane) to give 1-(4-benzofurazanyloxy)-2,3-epoxypropane (1.6 g), mp 75° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[CH:18]=[CH:17][N:16]=1>C(O)C.[Pd]=O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([C:21]([NH2:23])=[O:22])[CH:18]=[CH:17][N:16]=1
Reactant: NC(=O)c1ccnc(C#CCCCCOCCCCCCBr)c1
Agent: O=[Pd]
Solvent: CCO
Product: NC(=O)c1ccnc(CCCCCCOCCCCCCBr)c1
Yield: 99.9 %

Procedure:
A solution of 2-[6-[(6-bromohexyl)oxy]-1-hexynyl]-4-pyridinecarboxamide (1.04 g) in ethanol (20 ml) was hydrogenated over pre-hydrogenated 10% palladium oxide on carbon (50% aqueous paste, 115 mg). The mixture was filtered through hyflo and the filtrate evaporated to give the title compound as a pale yellow solid (1.05 g), m.p. 73°-75°.