Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([CH2:8][O:9][C:10](=[O:12])[CH3:11])[CH2:3][O:4][C:5](=[O:7])[CH3:6].CN(C)C1C=CC=CC=1.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>CCOCC.C(OCC)(=O)C>[C:5]([O:4][CH2:3][C:2]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([NH:1][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:8][O:9][C:10](=[O:12])[CH3:11])(=[O:7])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCC(N)(COC(C)=O)COC(C)=O
Reactant: CCCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Product: CCCCCCCCCCCCCCCCCCC(COC(C)=O)(COC(C)=O)NC(=O)CCCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2-Amino-1,3-diacetoxy-2-octadecylpropane (1.0 g) was dissolved in 50 ml of dry ether and 425 mg of N,N-dimethylaniline and 500 mg of pentanoyl chloride were added thereto. The mixture was stirred at room temperature under a nitrogen atmosphere for 6 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution. The organic layer was dried and the resultant mixture was concentrated. The concentrate was purified by silica gel column chromatography using hexane-ethyl acetate (5:1→2:1) as an eluent to give 1.036 g of colorless, oily 1,3-diacetoxy-2-octadecyl-2-(N-pentanoylamino)propane. IRν max (CHCl3): 3450, 3400, 2920, 2850, 1740, 1680, 1520, 1460, 1380, 1240, 1020 cm-1 1 H-NMR (CDCl3 /TMS) δ: 0.879 (3H, t, J=6.8 Hz), 0.918 (3H, t, J=7.4 Hz), 1.251 (34H, m), 1.6 (4H, m), 2.078 (6H, s), 2.150 (2H, t, J=7.2 Hz), 4.271 (2H, d, J=11.6 Hz), 4.330 (2H, d, J=11.6 Hz), 5.599 (1H, s)
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1([N:15]=[C:16]=[N:17][CH:18]2[CH2:23]CCC[CH2:19]2)[CH2:14]CCC[CH2:10]1>>[CH:18]([NH:17][C:16](=[N:15][CH:9]([CH3:14])[CH3:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:23])[CH3:19]
Reactant: OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)N=C(NC(C)C)OCc1ccccc1

Procedure:
Synthesis is carried out from benzyl alcohol and N,N′-dicyclohexylcarbodiimide (Mathias, Synthesis 1979, 561.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>C(O)C.C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Nc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1
Yield: 17 %

Procedure:
A mixture composed of 500 mg of N-(4-bromophenyl)methane-sulfonamide, 334 mg of 4-methoxyphenyl boronic acid, 55.5 mg of tetrakis-triphenylphosphinepalladium, 2 ml of a 2 M aqueous solution of sodium carbonate, 4 ml of toluene, and 1 ml of ethanol was heated under. reflux for 5 hours in an atmosphere of nitrogen. After the reaction mixture was poured into a saturated aqueous solution of sodium chloride, the product was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by silica gel column chromatography (using a 7:1 mixture of chloroform and tetrahydrofuran as the eluent) to obtain 94 mg of N-(4′-methoxybiphenyl-4-yl)methanesulfonamide.
Reaction SMILES: [AlH4-].[Li+].[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]1[CH:23]=[CH:22][C:16]([C:17](OCC)=[O:18])=[CH:15][CH:14]=1.C(Cl)Cl.CO>C1COCC1.O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]1[CH:23]=[CH:22][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(Nc2nc3ccccc3s2)cc1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: OCc1ccc(Nc2nc3ccccc3s2)cc1
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
A solution of lithium tetrahydroaluminate (0.1107 mol) in THF (100 ml) was added dropwise at 0° C. under N2 flow to a suspension of ethyl 4-(2-benzothiazolylamino)-benzoate (0.1107 mol) in water. The mixture was brought to RT and stirred for 30 minutes. The mixture was hydrolized by adding water (8 ml) dropwise and then CH2Cl2 (50 ml), and a little CH3OH was added. The precipitate was filtered and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE. The precipitate was filtered off and dried, yielding 8 g (86%) of 4-(2-benzothiazolylamino)benzenemethanol (interm. 8).
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].C(OC(=O)C(=COCC)C(OCC)=O)C.CC[O-].[Na+].C(O[C:37]([C:39]1[C:40](O)=[N:41]C(C2C=CC(CCCC)=CC=2)=N[CH:44]=1)=O)C.P(Cl)(Cl)(Cl)=O.C(OC(C1C(Cl)=NC(C2C=CC(CCCC)=CC=2)=NC=1)=O)C>C(O)C>[C:40]([C:39]1[CH:37]=[N:11][C:10]([C:9]2[CH:8]=[CH:7][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:14][CH:13]=2)=[N:12][CH:44]=1)#[N:41]
Reactant: CCCCc1ccc(-c2ncc(C(=O)OCC)c(O)n2)cc1
Reactant: CCCCc1ccc(C(=N)N)cc1
Agent: CCCCc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
The starting material can be obtained according to the procedure of A. R. Todd and F. Bergel, J. Chem. Soc. 1937, 366 from p-n-butylbenzamidine hydrochloride and ethoxymethylenemalonic acid diethyl ester with sodium ethylate in ethanol and subsequent treatment of the obtained 2-(p-n-butylphenyl)-4-hydroxy-5-pyrimidinecarboxylic acid ethyl ester (melting point 198.0°-198.8° C) with phosphorus oxychloride. The melting point of 2-(p-n-butylphenyl)-4-chloro-5-pyrimidinecarboxylic acid ethyl ester is 64.9°-65.3° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].CC(C)=O.C(OC(C)C)(C)C.[C:26]1([CH:32]([C:36]([O:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.[OH-].[Na+]>[CH:39]([O:38][C:36]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:34])=[O:37])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)C(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)OC(C)C
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 0.05 h

Procedure:
Following a procedure analogous to that of Goldman et al. (loc. cit.), 7-aminodesacetoxycephalosporanic acid (7-amino-3-methylceph-3-em-4-carboxylic acid; 74.9 g., 0.35 mole) is dissolved in well-stirred water (200 ml.) by the slow addition of sodium hydroxide (approximately 75 ml. of 4 N) to a pH of 7.5. To this solution is added 200 ml. of acetone. Keeping the temperature at 10° to 15° C., the isopropyl ether solution of 2-phenyl-2-benzhydryloxycarbonylacetyl chloride prepared above is added with continued strong stirring over 3 minutes. The pH is maintained near 6.5 by the addition of 4 N NaOH (about 160 ml.). Organic solvents are removed by evaporation in vacuo. The aqueous layer is diluted with an equal volume of ethyl acetate and the pH adjusted to 2. The ethyl acetate layer is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 7-(2-benzhydryloxycarbonyl-2-phenylacetamido)-3-methylceph-3-em-4 -carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:11]3[CH:33]=[CH:34][CH:35]=[CH:36][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[CH:33]=[CH:34][CH:35]=[CH:36][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2c(-c3ccc(O)cc3)nc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccccc1-c1ccc(Cn2c(-c3ccc(O)cc3)nc3ccccc32)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(4-hydroxyphenyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Cl:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([O:16][C:7]2[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:14]([Cl:15])=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[CH:19]=1
Reactant: BrC1C=CCCC1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Temperature: 110 °C

Procedure:
A mixture of 2.5 g methyl 4-acetylamino-5chlorosalicylate, 2 g of 3-bromocyclohexene, 2 g K2CO3 and 30 ml DMF are combined and heated at 110° C. overnight. The reaction mixture is then poured into water, filtered, dried and then extracted into ether. The ether solution is treated with charcoal, filtered and evaporated to dryness to obtain methyl 2-(cyclohexen -3-yloxy)-4-acetylamino-5-chlorobenzoate. This is then purified by recrystallization from ether/hexane. (M.P. 100°-102° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](S(O)(=O)=O)=[CH:6][CH:7]=1.O.[CH2:13]([NH:20][C:21]1[C:22]([NH2:28])=[CH:23][C:24]([Br:27])=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.COC(OC)(OC)C1C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:20]1[C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][C:22]=2[N:28]=[C:13]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(Br)ccc1NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: COC(OC)(OC)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2c(c1)nc(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
p-TsOH.H2O (311.7 mg, 1.606 mmol) was added to a DCM (50 ml) solution of N1-benzyl-4-bromobenzene-1,2-diamine (4451 mg, 16.06 mmol) and trimethyl orthobenzoate (3096 μl, 17.66 mmol) and the resulting mixture was stirred at rt under an atmosphere of Nitrogen for 40 h. The reaction mixture was then concentrated in vacuo to give a yellow solid which was triturated with 40% MeOH/water (375 mL), filtered, washed with saturated NaHCO3 (20 ml)+H2O (80 ml) twice and 40% MeOH/H2O (2×50 ml), and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm=5.44 (s, 2H, 7.05-7.08 (m, 3H), 7.30-7.36 (m, 4H), 7.44-7.50 (m, 3H), 7.66-7.68 (m, 2H) and 7.99 (dd, 1H, J=0.4 & 1.6 Hz). MS (ES+): m/z 363.20 and 365.26 [MH+].
Reaction SMILES: C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[C:13]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])([CH3:15])[CH3:14].[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:23]=1[CH3:37].CO>C1COCC1>[Br:21][C:22]1[CH:27]=[C:26]([Br:28])[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=2[F:36])[C:23]=1[CH2:37][CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:20]
Reactant: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1c(Br)cc(Br)nc1-c1ccc(F)cc1F
Temperature: -50 °C
Reaction time: 0.17 h

Procedure:
To a −78° C. solution of the lithium bis(trimethylsilylamide) (14 mL) in mL of THF was added t-butylacetate (2 mL). After stirring for 10 min, 4,6-dibromo-2-(2,4-difluorophenyl)-3-methylpyridine (1.0 g) dissolved in 3 mL THF was added dropwise. The mixture stirred at −78° C. for 1.5 h, then warmed to −50° C. The reaction mixture was then recooled to −78° C. and 3 mL of methanol was added. The solution stirred for 24 h at rt. The crude mixture was purified by flash chromatography, eluting with 50% ethyl acetate/hexanes. Mass spectrum m/z (ESI) 478.3 (M+1).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[CH2:18][C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>S1(CCCC1)(=O)=O>[O:21]=[C:19]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH2:1][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]=2[CH2:18]1
Reactant: O=C(O)Cc1ccc(Cc2ccccc2)c(CC(=O)O)c1
Solvent: O=S1(=O)CCCC1
Product: O=C(O)Cc1ccc2c(c1)CC(=O)c1ccccc1C2
Temperature: 0 °C
Yield: 37 %

Procedure:
To a mixture of 15 g of polyphosphoric acid and 10 ml of sulfolane was added 1.5 g of 2-benzyl-5-carboxymethylphenylacetic acid, and the mixture was heated at 100° to 110° C. for 2 hours with stirring. After the reaction, the reaction mixture was cooled, and dissolved in ice water. The solution was extracted with ethyl acetate, and washed with water. The ethyl acetate layer was extracted with a 2% aqueous solution of sodium hydroxide. The aqueous layer was acidified with 10% hydrochloric acid. The precipitated solid was extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The ethyl acetate was then distilled off. Recrystallization of the residue from a mixture of ethyl acetate and n-hexane afforded 0.52 g of 10,11-dihydro-10-oxo-5H-dibenzo[a,d]cycloheptene-2-acetic acid as a colorless crystalline powder having a melting point of 163° to 165° C.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][C:20]=1[CH3:21])[C:17]1[N:13]([CH:14]=[C:15]([C:22]3[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2)=O.Cl.[NH:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]1)[NH2:33]>C(O)(=O)C>[CH:27]([N:26]1[C:22]([C:15]2[N:16]=[C:17]3[C:18]4[CH:19]=[C:20]([CH3:21])[C:7]([C:5]5[N:32]([CH:34]6[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]6)[N:33]=[CH:3][CH:4]=5)=[CH:8][C:9]=4[O:10][CH2:11][CH2:12][N:13]3[CH:14]=2)=[N:23][CH:24]=[N:25]1)([CH3:28])[CH3:29]
Reactant: CN1CCC(NN)CC1
Reactant: Cc1cc2c(cc1C(=O)/C=C/N(C)C)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc2c(cc1-c1ccnn1C1CCN(C)CC1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 100 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A mixture of (2E)-3-(dimethylamino)-1-{13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (110 mg, 0.30 mmol) and 4-hydrazinyl-1-methylpiperidine hydrochloride (42 mg, 0.24 mmol) in acetic acid (2.0 mL) was stirred at 100° C. for 1 hour under nitrogen atmosphere. After concentration, the residue was purified by preparative HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 264 (30 mg, 21% yield). LCMS (ESI): RT=5.04 min, m/z: 473.3 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.00 (s, 1H), 7.94 (s, 1H), 7.58 (d, J=1.5 Hz, 1H), 6.92 (s, 1H), 6.27-6.26 (m, 1H), 5.85 (t, J=13 Hz, 1H), 4.55 (t, J=20 Hz, 4H), 3.76 (s, 1H), 2.86 (s, 2H), 2.19-2.11 (m, 8H), 1.78 (s, 2H), 1.74 (d, J=14.5 Hz, 2H), 4.51 (d, J=7 Hz, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]3[CH2:16][CH:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][C:26]1[CH:28]=[CH:29][C:23]([S:20]([O:19][CH2:18][CH2:17][C@H:15]2[CH2:16][C@@H:14]2[CH:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=3)[CH2:9][CH2:10]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCC1CC1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title compound was synthesized using 2-{2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol from Example 2b-S (slow) (41.2 mg, 0.146 mmol) was in 1.46 mL dichloromethane. TEA (0.0408 mL, 0.296 mol), DMAP (1.786 mg, 0.015 mmol) and TsCl (33.5 mg, 0.175 mmol) were sequentially added. The mixture was stirred at room temperature for 3 hour. Another 0.02 mL of TEA, 1 mg of DMAP and 14 mg of TsCl were added. Reaction mixture was stirred at room temperature for 30 min. The mixture was poured in to ice water. The aqueous phase was extracted with ethyl acetate for 3 times. The combined organic layers were washed with water and brine, then dried over Na2SO4 and concentrated. The residue was purified by column chromatography using gradient elution (0 to 50% ethyl acetate in hexane) to give the titled compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=[CH:6][N:5]=1.[CH2:13]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C@@H:22]1Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:9]2[N:10]=[CH:11][N:12]([C@@H:22]3[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:21]3[O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][N:5]=1
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Clc1nccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc2c1ncn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
A solution of 2.4 g of sodium hydride, 15.4 g of 4-chloro-1H-imidazo[4,5-c]pyridine, and 200 ml of dry dimethylformamide (DMF) is stirred at 50° C. for 5 minutes, cooled, and added to 43.9 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride. The solution is kept at ambient temperature for two hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate-water. Chromatography of the dried ethyl acetate layer over silica gel with 4:1 benzene-ethyl acetate provides 49.6 g of syrupy 4-chloro-1-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)imidazo[4,5-c]-pyridine.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C@@H:13]([C:14](OC)=[O:15])[CH2:12][O:11][C:10]1=[O:18])#[N:2].[BH4-].[Na+]>C(O)C>[OH:15][CH2:14][C@H:13]1[CH2:12][O:11][C:10](=[O:18])[N:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2]
Reactant: COC(=O)[C@H]1COC(=O)N1CCCCCCC#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCCCCCN1C(=O)OC[C@@H]1CO
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of ester 2-2 (560 mg) in ethanol (5 mL) at 0° C. was added NaBH4 (38 mg) and the mixture was stirred at the temperature for 1 h and quenched with half saturated NaCl. The mixture was concentrated in vacuo to remove the ethanol and the residue was extracted with ethyl acetate (3×). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the desired alcohol 2-3 (480 mg). 1H NMR (400 MHz, acetone-d6): δ 4.33 (t, 1H), 4.20–4.12 (m, 2H), 3.96 (m, 1H), 3.79 (m, 1H), 3.65 (m, 1H), 3.40 (m, 1H), 3.17 (m, 1H), 2.47 (t, 2H), 1.70–1.35 (m, 8H).
Reaction SMILES: ClC1C(CCCl)=C(C2C=CC=C(OC)C=2)N=C(N2CCOCC2)N=1.CN(C)C1C=CC(N)=CC=1.C[O:36][C:37]1[CH:38]=[C:39]([C:43]2[C:44]3[CH2:57][CH2:56][N:55]([C:58]4[CH:63]=[CH:62][C:61]([N:64]([CH3:66])[CH3:65])=[CH:60][CH:59]=4)[C:45]=3[N:46]=[C:47]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[N:48]=2)[CH:40]=[CH:41][CH:42]=1>>[CH3:65][N:64]([CH3:66])[C:61]1[CH:60]=[CH:59][C:58]([N:55]2[C:45]3[N:46]=[C:47]([N:49]4[CH2:50][CH2:51][O:52][CH2:53][CH2:54]4)[N:48]=[C:43]([C:39]4[CH:38]=[C:37]([OH:36])[CH:42]=[CH:41][CH:40]=4)[C:44]=3[CH2:57][CH2:56]2)=[CH:63][CH:62]=1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(N(C)C)cc2)c1
Agent: CN(C)c1ccc(N)cc1
Agent: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: CN(C)c1ccc(N2CCc3c(-c4cccc(O)c4)nc(N4CCOCC4)nc32)cc1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 4-dimethylaminoaniline, 4-(3-methoxy-phenyl)-7-(4-dimethylaminophenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine was obtained, and subsequently, further in the same manner as Example 1-A-09, the desired compound was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].I[CH3:32]>CN(C=O)C.O>[O:28]1[CH2:27][CH:26]=[C:25]([C:24]2[C:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([C:10]([C:2]4[N:3]([CH3:32])[C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)=[O:11])=[CH:17][CH:16]=3)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:30][CH2:29]1
Reactant: CI
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(C(=O)c2ccc(Oc3ncccc3C3=CCOCC3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (0.350 g, 0.881 mmol) in DMF (5 mL) was treated with iodomethane (0.083 mL, 1.321 mmol). The mixture was stirred at RT and after 4 hours, it was diluted with water and extracted (2×) with DCM. The organic portions were combined and washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate, reduced and purified by column chromatography on silica gel using a gradient of 30 to 80% EtOAc in hexanes to afford (4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)(1-methyl-1H-benzo[d]imidazol-2-yl)methanone as white solid. MS (ESI, pos. ion) m/z: 411.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][O:8][C:4]=2[CH:3]=1.BrC1C2[O:19][CH:18]=[CH:17]C=2C=CC=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.O>C1(C)C=CC=CC=1>[O:8]1[C:4]2[CH:3]=[C:2]([C:18](=[O:19])[CH3:17])[CH:10]=[CH:9][C:5]=2[CH:6]=[CH:7]1
Reactant: Brc1ccc2ccoc2c1
Reactant: Brc1cccc2ccoc12
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2ccoc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of a mixture of 6-bromobenzofuran and 7-bromobenzofuran (1.12 g, 5.68 mmol) in toluene (19 mL), tetrakistriphenyl phosphine palladium (650 mg, 0.57 mmol) and tributyl(1-ethoxyvinyl)tin (2.11 mL, 6.25 mmol) were added, and the mixture was stirred at 100° C. overnight. The reaction solution was added water at room temperature, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified by silica-gel column chromatography (hexane). The title compound (280 mg) was obtained as a yellow crystal.