Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41](=[O:49])[C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)[C:25]3[N:29]=[C:28]([O:30]CC)[N:27](C(OC(C)(C)C)=O)[C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1.Cl>C(OCC)C.C(O)C>[CH3:16][C:17]1[C:21]([C:22]2[CH:23]=[C:24]([C:41]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)([OH:49])[C:2]3[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=3[F:10])[C:25]3[NH:29][C:28](=[O:30])[NH:27][C:26]=3[CH:40]=2)=[C:20]([CH3:50])[O:19][N:18]=1
Reactant: Fc1cc(F)c(Br)c(F)c1
Reactant: CCOc1nc2c(C(=O)c3ccc(F)cn3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCO
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccc(F)cn2)c2c(F)cc(F)cc2F)c2[nH]c(=O)[nH]c2c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To 1-bromo-2,4,6-trifluorobenzene (0.02 ml, 0.16 mmol) in diethyl ether (0.52 mL) at −78° C. was added n-butyllithium (0.12 mL, 0.18 mmol, 1.6 M in hexanes). After 30 minutes, tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(5-fluoropicolinoyl)-1H-benzo[d]imidazole-1-carboxylate (50 mg, 0.10 mmol) in diethyl ether (1 mL) was added drop-wise to the reaction. After 60 minutes, the reaction was warmed, quenched with saturated NH4Cl(aq) (10 mL), extracted with ethyl acetate (3×10 mL), dried over Na2SO4, and concentrated in vacuo. To the crude residue in ethanol (3.5 mL) was added hydrochloric acid (0.35 mL, 1.4 mmol, 4 M in 1,4-dioxane) and the mixture was heated to 70° C. in a microwave reactor for 45 minutes. Purification by reverse-phase HPLC (40-50% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-((5-fluoropyridin-2-yl)(hydroxy)(2,4,6-trifluorophenyl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:29])(=[O:28])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[F:30][C:31]([F:40])([F:39])[C:32]1[C:37]([OH:38])=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[S:22](=[O:28])(=[O:29])[NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:12][CH:11]=1)[C:6](=[O:7])[O:38][C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:31]([F:39])([F:40])[F:30])[CH2:2][CH2:3][CH3:4]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCN(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)C(=O)Oc1ccccc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A mixture of 171 mg (0.391 mmole) of N-butyl-N-[[2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl]carbamoyl chloride (from Step F), 63.9 mg (0.394 mmole) of α,α,α-trifluoro-o-cresol, 66 mg (0.48 mmole) of anhydrous potassium carbonate, and 3 mL of DMF was stirred under N2 at 90° C. overnight. The cooled mixture was partitioned between 20 mL of 2N HCl and 20 mL of EtOAc. The organic layer was washed with H2O (2×30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residual oil was flash chromatographed on silica gel (gradient elution with 20-35% EtOAc in hexane to yield 37.4 mg (17%) of the title compound as a yellow oil, homogeneous by TLC in 3:1 hexane-EtOAc; FAB-MS m/e 562 (M+1)+. The 1H NMR spectrum indicated the presence of two rotameric forms.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([OH:16])=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH2:24]([O:26][C:27]1[N:32]=[C:31]2[S:33][C:34]([NH2:36])=[N:35][C:30]2=[CH:29][CH:28]=1)[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:36][C:34]3[S:33][C:31]4[C:30]([N:35]=3)=[CH:29][CH:28]=[C:27]([O:26][CH2:24][CH3:25])[N:32]=4)=[O:16])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CCOc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 37.1 %

Procedure:
The compound of example A81 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.25 g, 0.73 mmol), 5-ethoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.157 g, 0.80 mmol), HOBt (0.148 g, 1.10 mmol), and EDCI (0.210 g, 1.10 mmol), N-methyl morpholine (0.22, 2.20 mmol) in DMF (5 mL) to provide the title compound (0.140 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH2:5]([O:7][C:8]([CH2:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][OH:23])=[O:9])[CH3:6].N1C=CC=CC=1.Cl.[C:31]1([N:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:5]([O:7][C:8]([CH2:10][O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][O:23][C:1]([NH:38][N:37]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:2])=[O:9])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCOC(=O)COc1cccc2c1CCCC2CO
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)COc1cccc2c1CCCC2COC(=O)NN(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a methylene chloride solution (1 ml) of phosgene dimer (0.027 ml) was added a methylene chloride solution (2 ml) of (5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methanol (0.12 g) and pyridine (0.1 ml) at -5° C., and the solution was stirred at room temperature for two hours. To the reaction mixture was added a solution of 1,1-diphenylhydrazine hydrochloride (0.10 g) and pyridine (0.05 ml) in methylene chloride (2 ml). The solution was stirred at room temperature for 3 hours, washed with 5% hydrochloric acid, water, and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (n-hexane-ethyl acetate) over silica gel to afford 2-[(5-ethoxycarbonylmethoxy-1,2,3,4-tetrahydro-1-naphthyl)methoxycarbonyl]-1,1-diphenyihydrazine (0.13 g) as colorless solids.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:24]=[CH:23][C:13]3[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=3[CH:11]=2)=[CH:4][CH:3]=1.[CH:25]1([CH2:28][CH2:29]O)[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1>[CH:25]1([CH2:28][CH2:29][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]3[CH:24]=[CH:23][C:13]4[CH:14]=[C:15]([CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[O:16][C:12]=4[CH:11]=3)=[CH:6][CH:7]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)NC(C)c1cc2ccc(CCc3ccc(O)cc3)cc2o1
Reactant: OCCC1CC1
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)NC(C)c1cc2ccc(CCc3ccc(OCCC4CC4)cc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
To a solution of N-(1-{6-[2-(4-hydroxyphenyl)ethyl]-1-benzofuran-2-yl}ethyl)acetamide (50.0 mg, 0.154 mmol) obtained in Example 165, 2-cyclopropylethanol (0.0529 mL, 0.616 mmol) and triphenylphosphine (161 mg, 0.616 mmol) in THF (1 mL) were added di(methoxyethyl) azodicarboxylate (144 mg, 0.616 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was directly purified by basic silica gel column chromatography (hexane:ethyl acetate=1:0 to 2:3), and the solvent was evaporated. The residue was triturated with a small amount of diisopropyl ether and hexane to give the title compound (25.9 mg, yield 43%) as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[OH-].[Na+]>>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc(-c2ccncc2)cc1[N+](=O)[O-]

Procedure:
To 160 ml. of nitric acid (90%) cooled to less than 0°C. in an ice-ethanol bath was slowly added with stirring 42 g. of 4-(4-acetamidophenyl)pyridine over a period of about twenty minutes. The reaction mixture was then stirred for 45 minutes, keeping the reaction temperature below 0°C. The reaction mixture was then poured onto ice and the mixture treated with 35% aqueous sodium hydroxide solution, adding ice to keep the mixture cool. The resulting yellow solid was collected, washed with water and air-dried to yield 43.7 g. of 4-(4-acetamido-3-nitrophenyl)pyridine, which was used directly in Example 4 without further purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[N:10][C:9]([C:12]2[S:16][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH:23]=C)=[N:8]1.[O:27]1CCOCC1.N1C(C)=CC=CC=1C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[N:20]1[CH:21]=[CH:22][C:17]([C:15]2[S:16][C:12]([C:9]3[N:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:26])([CH3:25])[CH3:1])[N:8]=3)=[C:13]([CH:23]=[O:27])[N:14]=2)=[CH:18][CH:19]=1
Reactant: C=Cc1nc(-c2ccncc2)sc1-c1ncn(COCC[Si](C)(C)C)n1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc(-c2sc(-c3ccncc3)nc2C=O)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To a solution of 4-[5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-4-vinyl-1,3-thiazol-2-yl]pyridine (1.43 g, 2.60 mmol) in a 3:1 mixture of 1,4-dioxane (17.5 mL, 224.6 mmol) and water (5.8 mL, 324.25 mmol) was added 2,6-lutidine (1.50 mL, 12.98 mmol) and the mixture was cooled to 0° C. Sodium metaperiodate (2.80 g, 12.98 mmol) was added followed by the addition of 4% osmium tetroxide in water (0.50 mL, 0.080 mmol) and the reaction mixture was slowly warmed to ambient temperature and allowed to stir overnight. Water (10 mL) was added. The resulting yellow precipitate was collected by filtration, washed with water, ether and MeOH. The filtrate was concentrated under reduced pressure and dried on the high vac to give the title compound (1.0 g, yield 99%). LCMS: (FA) ES+, 388. 1H NMR (400 MHz, d6-DMSO) δ: 10.70 (s, 1H), δ:9.05 (s, 1H), 8.79-8.80 (dd, J=1.5 Hz, 2H), 7.98-8.0 (dd, J=1.5 Hz, J=1.7 Hz, 2H), 5.64-5.66 (s, br, 2H), 3.64-3.68 (m, 2H), 0.870-0.90 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:10])[CH2:7][CH2:8][OH:9].Br[CH2:12][CH:13]=[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]>O>[CH3:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])=[CH:13][CH2:12][O:9][CH2:8][CH2:7][CH2:6][OH:10]
Reactant: OCCCO
Reactant: Cc1ccccc1C(=CCBr)c1ccccc1C
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccccc1C(=CCOCCCO)c1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of n-butyllithium in hexanes (15.2 ml, 2.5 M) was added dropwise under a nitrogen atmosphere to 1,3- propanediol (31 ml) on an ice-bath. When addition was complete the mixture was stirred 0.5 h at room temperature. 3-Bromo-1,1-bis(2-methylphenyl)-1-propene (11.5 g, 38 mmol, prepared in a similar way to the method described in Example 23) was added and the reaction mixture was stirred at room temperature for 48 h and at 75° C. for 36 h. Water (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml). The phases were separated and the organic phase was washed with water (2×50 ml), dried over magnesium sulphate and the solvent evaporated in vacuo. Flash chromatography of the residue on silica gel (300 g) using a gradient of n-heptane in ethyl acetate as eluent provided 3.5 g (31 %) of 3-(3,3-bis(2-methyl phenyl)-2-propen-1-yloxy)-1-propanol.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:28])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](N)=[CH:22][CH:21]=1)([OH:17])[CH2:9][C:8]2=[O:27])(=[O:3])[CH3:2].[ClH:29].N([O-])=O.[Na+].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36]>O.CC(C)=O>[C:1]([O:4][C:5]1[C:6]([CH3:28])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:36][CH:35]([Cl:29])[C:34]([O:38][CH2:39][CH3:40])=[O:37])=[CH:22][CH:21]=1)([OH:17])[CH2:9][C:8]2=[O:27])(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(O)(COc1ccc(N)cc1)O2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(O)CC(=O)c3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1

Procedure:
Following the same procedure as described in Preparation 18, 3.4 g of 6-acetoxy-2-(4-aminophenoxymethyl)-2-hydroxy-5,7,8-trimethylchroman-4-one (prepared as described in Preparation 44), 40 ml of acetone, 5 ml of 35% w/v aqueous hydrochloric acid, 1.2 g of sodium nitrite, 1.6 ml of water, 13 g of ethyl acrylate and 0.32 g of cuprous oxide were reacted, to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:15]([OH:17])=O)=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH2:18][C:19]1[CH:43]=[CH:42][C:22]2[CH2:23][CH2:24][C:25]3[C:26]([C:39]([NH2:41])=[O:40])=[N:27][N:28]([C:30]4[CH:38]=[CH:37][C:33]5[O:34][CH2:35][O:36][C:32]=5[CH:31]=4)[C:29]=3[C:21]=2[CH:20]=1>>[O:34]1[C:33]2[CH:37]=[CH:38][C:30]([N:28]3[C:29]4[C:21]5[CH:20]=[C:19]([NH:18][C:15]([C:3]6[C:2]([Cl:1])=[CH:7][CH:6]=[C:5]([N:8]7[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]7)[N:4]=6)=[O:17])[CH:43]=[CH:42][C:22]=5[CH2:23][CH2:24][C:25]=4[C:26]([C:39]([NH2:41])=[O:40])=[N:27]3)=[CH:31][C:32]=2[O:36][CH2:35]1
Reactant: NC(=O)c1nn(-c2ccc3c(c2)OCO3)c2c1CCc1ccc(N)cc1-2
Reactant: CN1CCN(c2ccc(Cl)c(C(=O)O)n2)CC1
Product: CN1CCN(c2ccc(Cl)c(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc5c(c3)OCO5)CC4)n2)CC1

Procedure:
The title compound was synthesized from 0.30 g of 3-chloro-6-(4-methylpiperazin-1-yl)-2-pyridine carboxylic acid, obtained by acidification of its K-salt from step 1, and the title compound of step 4 of Example 161 (0.217 g) by the same procedure used for Example 260. The title compound is a brown solid (0.23 g, 61%), m.p. 264–266° C. (decomposition). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (d6-DMSO): δ 2.70 (s, 3H), 2.72–4.30 (m, 12H), 6.02 (s, 2H), 6.92–7.12 (m, 4H), 7.22–7.36 (m, 3H), 7.42–7.53 (m, 2H), 7.77 (d, 1H, J=9 Hz), 10.32 (s, 1H). ESI mass spectrum for C30H29ClN7O4+: 586 (M+1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[CH2:10][CH2:9][CH2:8]2)(=[O:3])[CH3:2].[C:16]([OH:20])(=[O:19])[CH:17]=O.Cl>[OH-].[Na+]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[C:10](=[CH:17][C:16]([OH:20])=[O:19])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CCCC2=O
Reactant: O=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1ccc2c(c1)CCC(=CC(=O)O)C2=O
Reaction time: 16 h
Yield: 58.5 %

Procedure:
0.5N Aqueous sodium hydroxide solution (190 ml) was added to an aqueous solution(60 ml) of 6-acetamido-1-tetralone (5.00 g, 24.6 mmol) and glyoxylic acid (9.05 g, 98.5 mmol) under ice-cooling, which was stirred at 60 for 16 hours. After cooling, concentrated hydrochloric acid was added to the reaction mixture. The precipitated crystals were collected, which was washed with water, to give the titled compound (3.73 g).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[CH3:16][N:17]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:31]>>[CH3:16][N:17]1[C:25]2([CH2:30][CH2:29][N:28]([C:11](=[O:13])[CH2:10][CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:15])[F:14])[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:31]
Reactant: CN1C(=O)c2ccccc2C12CCNCC2
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Product: CN1C(=O)c2ccccc2C12CCN(C(=O)CCc1ccccc1C(F)(F)F)CC2

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and 2-methylspiro[isoindoline-1,4′-piperidin]-3-one. LC-MS Method 1 tR=1.65, min, m/z=417, 415.
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6]([C:8]1[N:9]=[N:10][N:11]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.Cl.C(Cl)Cl>CCO>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=1)[CH2:19][N:11]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([CH2:6][OH:5])[N:9]=[N:10]1
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add sodium borohydride (1.70 g, 0.045 mol) to a solution of 1-(3,5-bis-trifluoromethylbenzyl)-5-phenyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (5.0 g, 0.011 mol) in EtOH (70 mL) and heat the mixture to reflux. After 2 h, cool to RT and add the reaction mixture to 0.5 N HCl (200 mL) and methylene chloride (200 mL). Separate the layers and extract the aqueous layer with methylene chloride (50 mL). Dry the combined organic layers over MgSO4, filter, and concentrate to give [1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-methanol.
Reaction SMILES: [Na].[C:2]([C:5]1[C:26]([OH:27])=[CH:25][CH:24]=[CH:23][C:6]=1[O:7][CH2:8][CH:9]([OH:22])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[C:19](=[O:21])[CH3:20])(=[O:4])[CH3:3].[C:28](OCC)(=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl>O.C(Cl)(Cl)Cl.C(O)C>[C:19]([C:13]1[C:14]([OH:18])=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:10][CH:9]([OH:22])[CH2:8][O:7][C:6]1[C:5]2[C:2](=[O:4])[CH:3]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:27][C:26]=2[CH:25]=[CH:24][CH:23]=1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)cccc1OCC(O)COc1cccc(O)c1C(C)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cc(=O)c2c(OCC(O)COc3cccc(O)c3C(C)=O)cccc2o1

Procedure:
A solution of 69.0 parts of sodium in 1000 parts of ethanol was added to a mixture of 360.3 parts of 1,3-bis-(2-acetyl-3-hydroxyphenoxy)propan-2-ol, 146.1 parts of diethyl oxalate and 250 parts of ethanol. The reaction mixture was refluxed for five hours, then poured into a stirred mixture of 700 parts of chloroform, 3,000 parts of water and 285 parts of concentrated hydrochloric acid. The solid obtained was removed by filtration, the chloroform phase of the filtrate separated and the aqueous phase extracted with chloroform. The combined chloroform extracts were washed with water and concentrated to give a solid which was removed by filtration. Evaporation of the chloroform from the filtrate gave a residue which, after fractional crystallization from ethanol, gave 36.0 parts of slightly impure ethyl 5-(3-[2-acetyl-3-hydroxyphenoxy]-2-hydroxypropoxy)-4-oxo-4H-1-benzopyran-2-carboxylate, m.pt. 145°-148°.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[S-:9][C:10]#[N:11].[NH4+].Cl>C(O)C>[N:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:9][C:10]=1[NH2:11]
Reactant: N#C[S-]
Reactant: Nc1cccnc1Cl
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Product: Nc1nc2cccnc2s1
Temperature: 85 °C
Yield: 43.1 %

Procedure:
A suspension of 2-chloro-3-aminopyridine (3 g, 23 mmole), and ammonium thiocyanate (3.5 g, 46.5 mmole) in 23 mL of ethanol was acidified with conc. HCl to pH ˜1 (˜1.8 mL). The reaction mixture was heated to 85° C. for 3 days. At this point, the solvent was evaporated and residual water was removed aziotropically by the distillation of 2-propanol. The yellow residue was mixed with 12 mL of 7 M ammonium hydroxide and 7 mL of chloroform. The solid was isolated by filtration to yield 1.50 g (43%) of the product as a white powder. MS (m/z, ES+): 152 (M+1, 100%).
Reaction SMILES: IC.[C:3]([O-])([O-])=O.[K+].[K+].[O:9]=[C:10]1[C@@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12>CN(C=O)C>[O:9]=[C:10]1[C@@H:16]([N:17]([CH3:3])[C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:15][CH2:14][S:13][C@H:12]2[CH2:24][CH2:25][CH2:26][C@@H:27]([C:28]([O:30][CH3:31])=[O:29])[N:11]12
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)C(F)(F)F)C(=O)N21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](N(C)C(=O)C(F)(F)F)C(=O)N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Iodomethane (77 mg, 0.54 mmol) and K2CO3 (150 mg, 1.08 mmol) were added to a solution of (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoroacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (64 mg, 0.18 mmol) in DMF (1 mL). The reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between EtOAc and water. The organic phase was isolated, washed with saturated NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give (4S,7S,10aS)-methyl 5-oxo-4-(2,2,2-trifluoro-N-methylacetamido)octahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate (47.6 mg, 0.129 mmol, 72% yield) of a yellow oil. Anal. Calcd. for C14H19F3N2O4S m/z 368.3. found: 391.1 (M+Na)+.
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[Br:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1>>[Br:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][O:14][S:1](=[O:4])(=[O:3])[NH2:2])=[CH:9][CH:8]=1
Reactant: NS(=O)(=O)Cl
Reactant: OCCOc1ccc(Br)cc1
Product: NS(=O)(=O)OCCOc1ccc(Br)cc1
Yield: 69 %

Procedure:
The title compound was prepared by the procedures of Example 28 from sulfamoyl chloride and 2-(4-bromophenoxy)ethanol as white solid, mp 134°-137° C., in 69% yield.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[S:19][CH:20]=[CH:21][C:7]=2[C:6]1=[O:22].[Li+].[OH-].Cl>C1COCC1.CO.O>[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[S:19][CH:20]=[CH:21][C:7]=2[C:6]1=[O:22]
Reactant: COC(=O)c1ccc2c3sccc3c(=O)n(CCCO)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c3sccc3c(=O)n(CCCO)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
Methyl 5-(3-hydroxypropyl)-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylate (1.0 eq, 19 mg, 0.060 mmol) was dissolved in a 1:1:1 mixture of THF, MeOH and water (0.5 ml). LiOH (40 mg) was added and the resulting mixture stirred at room temperature for 1.5 hours. Water, MeOH and HCl were added and the solution purified by preparative HPLC. Genevac evaporation afforded 5-(3-hydroxypropyl)-4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carboxylic acid as a white solid (4 mg, 22% yield). LCMS (ES): 95% pure, m/z 304 [M+1]+. 1H NMR (CDCl3/CD3OD, 9:1, 400 MHz) δ 2.08 (qi, J=6.0, 2H), 3.61 (t, J=5.2, 2H), 4.62 (t, J=6.0, 2H), 7.53 (d, J=5.2, 1H), 7.77 (d, J=5.2, 1H), 7.93 (d, J=8.0, 1H), 7.99 (dd, J=1.2, J=8.4, 1H), 8.26 (d, J=0.8, 1H) ppm.