Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl>[F:23][C:2]([F:22])([F:1])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:37]([C:36]3[CH:40]=[CH:41][CH:42]=[C:34]([N+:31]([O-:33])=[O:32])[CH:35]=3)=[O:38])[CH2:20][CH2:21]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1ccc(CN2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a stirred mixture of 1,1,1,3,3,3-hexafluoro-2-(4-(piperazin-1-ylmethyl)phenyl)-propan-2-ol (3.21 mmol, 1.1 g) and triethylamine (3.21 mmol, 0.448 mL, 0.325 g) in dichloromethane at 0° C. was added 3-nitrobenzoyl chloride (3.21 mmol, 0.596 g). The reaction was stirred at 0° C. for 2 hours then was allowed to warm to room temperature and stir overnight. The reaction was purified by chromatography on silica (eluting dichloromethane to dichloromethane/methanol) and SCX column chromatography to give the title compound (850 mg). MS (ESI) m/z 492.3 [M+H]+
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C=CC(O)=CC=1)O.[CH2:21]=[C:22]1[O:26][C:24](=[O:25])[CH2:23]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:26]=[C:22]([CH3:21])[CH2:23][C:24]([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[O:25]
Reactant: C=C1CC(=O)O1
Reactant: C=C(C)C(=O)OCC(C)(C)CO
Agent: CN(C)c1ccncc1
Agent: Oc1ccc(O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(C)(C)COC(=O)CC(C)=O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
To a 2-L flask was charged neopentyl glycol (208.3 g, 2.0 moles), toluene (250 mL), hydroquinone (0.5 g) and sodium methoxide (25% in methanol, 8 g). The mixture was heated to 60-65° C. and methyl methacrylate (120 g, 1.2 moles) was added dropwise over 1 hour. The reaction was held at 70° C. for one hour under moderate vacuum to remove methanol and low boilers. Reaction was worked up by washing with 2×250 mL water and 1×100 mL saturated sodium chloride solution at 70° C. Toluene was evaporated and the resulting crude product (166 g) distilled to provide 3-hydroxy-2,2-dimethylpropyl methacrylate of 97% GC assay. To a 300 mL flask was charged 3-hydroxy-2,2-dimethylpropyl methacrylate (11.5 g, 0.064 moles), methylene chloride (20 g), DMAP (0.01 g), hydroquinone (0.05 g) and the mixture cooled to 0-5° C. To this was added dropwise diketene (5.4 g) at <3° C. Reaction allowed to warm to room temperature and stir overnight. Reaction cooled to 0-5° C. and additional diketene (2 g) added to complete reaction. Once reaction was complete, the dichloromethane was removed at 60° C. with house vacuum. Crude product distilled via Kugelrohr distillation to provide desired product of 92.6% assay with 1.6% starting material remaining (GC assay).
Reaction SMILES: Cl[C:2]1[NH:11][C:5]2=[N:6][C:7]([Cl:10])=[CH:8][CH:9]=[C:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[O:18]2)[CH2:14][CH2:13]1.O>CN1C(=O)CCC1>[Cl:10][C:7]1[N:6]=[C:5]2[NH:11][C:2]([N:12]3[CH2:17][CH2:16][C:15]4([C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19](=[O:26])[O:18]4)[CH2:14][CH2:13]3)=[N:3][C:4]2=[CH:9][CH:8]=1
Reactant: Clc1ccc2nc(Cl)[nH]c2n1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC2(CCN(c3nc4ccc(Cl)nc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2,5-dichloro-3H-imidazo[4,5-b]pyridine (0.07 g, 0.37 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.15 g, 0.74 mmol) in dry NMP (3 mL) at 100° C. for 14 hours. Pour the cooled mixture into water (10 mL) and extract twice with EtOAc (10 mL). Wash the combined extracts with brine (10 mL), dry, and evaporate in vacuo. Purify by preparative TLC (5% MeOH—CH2Cl2) to obtain 1′-(5-chloro-3H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a white solid.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[O:29]1[C:33]2[CH:34]=[CH:35][C:36](/[CH:38]=[CH:39]/[C:40](O)=[O:41])=[CH:37][C:32]=2[CH2:31][CH2:30]1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:40](=[O:41])/[CH:39]=[CH:38]/[C:36]4[CH:35]=[CH:34][C:33]5[O:29][CH2:30][CH2:31][C:32]=5[CH:37]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Reactant: O=C(O)/C=C/c1ccc2c(c1)CCO2
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc3c(c2)CCO3)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J, and trans-3-(2,3-dihydrobenzofuran-5-yl)prop-2-enoic acid, by the method of Example 1, step K, giving a solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C32H38N4O3: 527 (M+H). Found: 527
Reaction SMILES: COC1C=C(C(F)(F)[F:10])C=C([N+]([O-])=O)C=1.[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:26]([F:32])([F:31])C(F)(F)F)=[C:23]([OH:25])[CH:24]=1)([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:26]([F:31])([F:32])[F:10])=[C:23]([OH:25])[CH:24]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)C(F)(F)F)c(O)c1
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1

Procedure:
5-Nitro-2-trifluoromethyl-phenol was prepared from 1-Methoxy-3-nitro-5-trifluoromethyl-benzene similar to that described in the preparation of 5-nitro-2-pentafluoroethylphenol.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([O:23]C)=[O:22])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:25])[C:8](=[O:26])[C@H:7]2[CH2:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.Cl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]=[CH:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:25])[C:8](=[O:26])[C@H:7]2[CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)OC)c3)nc2N1C1CCCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(C(=O)O)c3)nc2N1C1CCCC1
Temperature: 100 °C

Procedure:
The title compound was prepared by dissolving (R)-methyl 1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-imidazole-4-carboxylate (Example 38, 0.51 g, 1.33 mmol) in 2 mL of acetic acid and 0.5 mL of concentrated aqueous HCl and heating the resulting solution to 100° C. for 4 hours. The solution was concentrated under vacuum and co-evaporated from toluene three times and the crude material was purified by preparative HPLC. 1H NMR (CDCl3) δ: 8.73 (s, 1H), 8.50 (s, 1H), 7.78 (s, 1H), 4.44-4.45 (m, 1H), 4.32-4.36 (m, 1H), 3.39 (s, 3H), 1.71-2.17 (m, 10H), and 0.92 ppm (t, J=7.6 Hz, 3H); LCMS: 371.1 m/z (M+H)+; ret. Time: 3.008 min (Analytical Method A).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([CH:40]([OH:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[C:33]([C:40](=[O:43])[CH2:41][CH3:42])[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:44])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCC(O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To 20 mL of a chloroform solution containing 165 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-(1-hydroxypropyl)-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 115 mg of Dess-Martin Periodinane was added, and stirred at room temperature for 2 hours. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution was added. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform:methanol=10:1], to give 115 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-2-oxo-5-propionylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].Br.[Br:12][C:13]1[S:17][C:16]([NH2:18])=[N:15][CH:14]=1>N1C=CC=CC=1>[Br:12][C:13]1[S:17][C:16]([N:18]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])=[N:15][CH:14]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ncc(Br)s1
Agent: Br
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 109.7 %

Procedure:
Phenyl chloroformate (1.4 ml, 11.0 mmol) was slowly added to a suspension of 5-bromo-thiazol-2-ylamine hydrobromide (1.3 g, 5.0 mmol) in 20 ml pyridine under an argon atmosphere. The reaction mixture was stirred for 3 h at room temperature and then concentrated under reduced pressure. The residue was suspended in water and acidified using conc. HCl to yield light brown crystals (2.3 g, 93%), m/e 419.2 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]([CH2:34][CH3:35])[C:25]4[C:30]([CH:31]=3)=[C:29]([Cl:32])[C:28]([Cl:33])=[CH:27][CH:26]=4)=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.Cl.O1CCOCC1>[ClH:32].[N:11]1([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]([CH2:34][CH3:35])[C:25]4[C:30]([CH:31]=3)=[C:29]([Cl:32])[C:28]([Cl:33])=[CH:27][CH:26]=4)=[O:22])=[CH:16][CH:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CCn1c(C(=O)Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc2c(Cl)c(Cl)ccc21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCn1c(C(=O)Nc2ccc(N3CCNCC3)cc2)cc2c(Cl)c(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 212.8 %

Procedure:
A mixture of 4-{4-[(4,5-dichloro-1-ethyl-1H-indole-2-carbonyl)-amino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (750 mg, 1.45 mmol) in 15 mL of methylene chloride and 2 mL of 4M hydrogen chloride in dioxane was stirred at room temperature for 24 hr. The solvent was removed to afford 4,5-dichloro-1-ethyl-1H-indole-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide hydrochloride salt (700 mg, 99% yield) as an off white solid. LCMS for C21H22Cl2N4O calcd. (m/e) 416, observed 417 (M+H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])[CH3:25]
Reactant: CCN
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Product: CCNC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)cn1
Yield: 85 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (100 mg, 0.32 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (93 mg, 85%), which was obtained as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:39][N:40](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>ClCCl.C1COCC1>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:40][CH3:39])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in dichloromethane (2 mL) were added HBTU (30 mg, 0.079 mmol) and methylamine (0.185 mL, 0.37 mmol, 2.0M soln in THF). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by chromatography (90% methylene chloride/7% MeOH/3% ammonia) afforded the title compound (32 mg, 78%). LC-MS m/z 535 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2.[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22].CO>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:24](=[O:25])[NH:23][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]=[CH:7]2
Reactant: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12
Reactant: CCCN=C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCNC(=O)Oc1ccc(-c2cc(C)c3[nH]c(=O)ccc3c2)cc1

Procedure:
A solution of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.30 g) and n-propylisocyanate (0.5 cm3) was heated under reflux in THF (10 cm3) under nitrogen for 50 hours. Methanol (10 cm3) was then added to dissolve solid material, followed by silica (Merck "MK 60.9385" [Trade Mark]) (10 g), and the volatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385") and eluted with chloroform:methanol, 19:1. Combination and evaporation of appropriate fractions in vacuo gave a solid which was recrystallised from propan-2-ol to afford the title compound, m.p. 224°-228°, (0.28 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][N:9]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][N:9]=1
Reactant: Cc1ccc(Nc2ccc(-c3ccncc3Cl)nc2)c(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Nc2ccc(-c3ccncc3Cl)nc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
The solid residue obtained in step A was dissolved in 3 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The solvent was evaporated and the solid residue was triturated with an isopropyl ether/hexane mixture. The solid was filtered off affording 0.16 g (yield 62%) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1>>[F:1][C:2]1[CH:3]=[C:4]([O:17][CH2:18][CH2:19][O:20][CH3:21])[C:5]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COCCOc1cc(F)cc(C(=O)OC)c1OCCOC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(CO)c1OCCOC
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of methyl 5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}benzoate (0.34 g, 1.13 mmol) at 0° C. was added a solution of lithium aluminum hydride in tetrahydrofuran (1M, 1.2 mL, 1.2 mmol) and the resulting mixture was stirred for one hour. It was then quenched with ethyl acetate (1 mL) and 5% sodium hydroxide solution (1 mL), diluted with ether (100 mL), and filtered. The filtrate was washed water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)methanol (0.30 g, 1.10 mmol, 97% yield), 1H NMR (400 MHz, CDCl3): 6.63-6.59 (m, 2H), 4.58-4.56 (d, 2H), 4.29-4.24 (m, 2H), 4.14-4.10 (m, 2H), 3.77-3.69 (m, 4H), 3.44 (s, 3H), 3.42 (s, 3H).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[C:15](N1C=CN=C1)(N1C=CN=C1)=[O:16].C(N(CC)CC)C>C1COCC1>[I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[O:12][C:15](=[O:16])[NH:14][N:13]=3)=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(-c2ccn3c(I)cnc3c2)o1
Reaction time: 3 h
Yield: 115.2 %

Procedure:
To a solution of 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (196 mg, 0.5 mmol) (prepared as described in Example 329 steps a-c) in THF (10 ml) was added carbonyldiimidazole (243 mg, 1.5 mmol) and triethylamine (0.35 ml, 2.5 mmol) and the reaction mixture left to stir for 3 h. The precipitate formed in the reaction was filtered off, washed with Et2O and dried to afford the desired product (189 mg). MS: [M+H]+=329.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19]Br)=[CH:16][CH:15]=1)#[N:13]>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:19][C:18]([C:17]3[CH:22]=[CH:23][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[O:21])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: Cc1[nH]c2ncccc2c1C
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccc(C#N)cc3)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) and p-cyanophenacyl bromide (248 mg, 1.1 mmol) in 3 ml CH3CN was refluxed for 1.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl4 affording 313 mg (85%) pure title compound as the hydrobromide salt.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:6]=1[F:17])[OH:4].C(=O)([O-])[O-].[K+].[K+].I[CH2:27][CH2:28][CH3:29]>C(#N)C>[F:19][C:2]([F:1])([F:18])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16]2)[C:6]=1[F:17])[OH:4]
Reactant: CCCI
Reactant: OC(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(c2cccc(C(O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 2,2,2-trifluoro-1-(2-fluoro-3-piperidin-4-ylphenyl)ethanol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and iodopropane (0.01 g). MS m/z (rel. intensity, 70 eV) 319 (M+, 4), 291 (14), 290 (bp), 220 (3), 149 (3).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(-c2sc(-c3ccccc3)cc2O)cc1
Solvent: c1ccncc1
Product: COc1ccc(-c2sc(-c3ccccc3)cc2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-Hydroxy-2-(4'-methoxyphenyl)-5-phenylthiophene (200 mg, 0.71 mmol) was dissolved in 2.0 mL of pyridine and treated with acetic anhydride (0.50 mL, 5.3 mmol). The solution was stirred 4 hours at 25° C., and then most of the acetic anhydride and pyridine were removed on a rotary evaporator at reduced pressure. The residue was dissolved in 40 mL of ethyl acetate and washed with 2×15 mL of 2N aqueous hydrochloric acid, 15 mL of saturated aqueous sodium bicarbonate, and 15 mL of saturated aqueous sodium chloride. The solution was dried over sodium sulfate, decanted, and evaporated. The residual oil (224 mg) began to crystallize upon standing overnight. This was combined with other material prepared by the same method and recrystallized twice from 3-4 mL of 7% ethyl acetate in hexane to give 3-acetoxy-2-(4'-methoxyphenyl)-5-phenylthiophene as very pale pink needles, m.p. 81°-82° C.
Reaction SMILES: Cl[C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH2:26][O:27][C:2]1[C:7]2[C:8](=[O:22])[C:9]3[CH:10]=[C:11]([C:16]4[CH:17]=[N:18][CH:19]=[N:20][CH:21]=4)[CH:12]=[CH:13][C:14]=3[O:15][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)CCO
Reactant: O=c1c2cc(-c3cncnc3)ccc2oc2ccnc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)CCOc1nccc2oc3ccc(-c4cncnc4)cc3c(=O)c12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A resealable tube was charged with 1-chloro-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one (0.320 g, 1.033 mmol), 3,3-dimethyl-1-butanol (0.260 mL, 2.066 mmol), cesium carbonate (0.842 g, 2.58 mmol), and acetonitrile (10.0 mL). The system was flushed with argon, the tube was sealed, and the mixture stirred at 100° C. for 5 h. The material was partitioned between dichloromethane and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a brown solid. This solid was purified via column chromatography on silica gel (RediSep 120 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford 1-(3,3-dimethylbutoxy)-8-(pyrimidin-5-yl)-10H-chromeno[3,2-c]pyridin-10-one as a white solid. MS m/z=376.2 [M+H]+. Calcd for C22H21N3O3: 375.4.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]1[O:17][C:16]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[CH:15]=2)[O:5]1.[F:18][C:19]1[CH:30]=[CH:29][C:22]([C:23]([CH2:25][CH2:26][CH2:27][Cl:28])=[O:24])=[CH:21][CH:20]=1.O>CN(C=O)C>[ClH:28].[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([CH2:25][CH2:26][CH2:27][N:12]2[CH2:13][CH2:14][C:8]3[CH:7]=[C:6]4[O:5][CH2:4][O:17][C:16]4=[CH:15][C:9]=3[CH2:10][CH2:11]2)=[O:24])=[CH:29][CH:30]=1
Reactant: c1c2c(cc3c1OCO3)CCNCC2
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCN1CCc2cc3c(cc2CC1)OCO3)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
The sodium hydride obtained by washing 1.95 g of the 54% dispersion (0.042 moles) with benzene was used to prepare the sodium salt from 4.54 g. of 2,3,4,5-tetrahydro-7,8-methylenedioxy-1H-3-benzazepine hydrochloride in 50 ml of DMF as described in Example 35. Treatment of the suspension with 4.41 g of 3-(4-fluorobenzoyl)propyl chloride (0.022 moles) for 24 hours at 55°-60° followed by decomposition with 200 ml of ice water gave an oil-water suspension. The base was recovered by extraction with benzene (3 × 50 ml), the combined extracts washed once with water, then dried, and the solvent distilled in the rotary evaporator. To the residual oil, 3N hydrochloric acid was added and the mixture digested for an hour. After cooling the salt was filtered off, mp 195°14 197°. Two further recrystallizations from water gave the above-named product as a buff colored salt, mp 209°-210°.