Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1(C(O)=O)[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].ClC1C=CC=CC=1C1C2C=C(Cl)C=CC=2NC(=O)C(C(O)=O)N=1.C(OF)(F)(F)F>N1C=CC=CC=1>[F:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21]
Reactant: O=C(O)C1(F)N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Agent: FOC(F)(F)F
Agent: O=C(O)C1N=C(c2ccccc2Cl)c2cc(Cl)ccc2NC1=O
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1F

Procedure:
3.7 g. of 3-fluoro-5-o-chlorophenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one-3-carboxylic acid, obtainable from 5-o-chlorophenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one-3-carboxylic acid and CF3OF, in 50 ml. of pyridine are boiled for 1 hour with 0.5 g. of CuO. The mixture is cooled, poured onto ice and filtered to give 3-fluoro-5-o-chlorophenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 211° (decomposition).
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([Br:12])=[CH:5][C:4]=1[F:13].C(=O)(O)[O-].[Na+]>CO>[Br:12][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([OH:2])=[C:4]([F:13])[CH:5]=1
Reactant: CCOC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(F)cc1Br
Reaction time: 4 h
Yield: 93.7 %

Procedure:
A solution of 4-bromo-2-fluoro-5-nitrophenyl ethyl carbonate (35 g, 113 mmole) in MeOH (200 mL) was treated with sodium bicarbonate (19 g, 227 mmole). The reaction mixture was stirred at 60 C for 4 hours. The methanol was evaporated under vacuum. Water (55 mL) was added to the residue and the aqueous layer was acidified to pH=5 by addition of a solution of 6N hydrogen chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (25 g, 93%) as a yellow solid. LC-MS (ES) (M+H)+ m/z=237.
Reaction SMILES: OS(O)(=O)=O.O[CH2:7][CH:8]([CH2:10]O)O.[Na+].[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.[OH-].[Na+].Cl>CCOC(C)=O.O>[N:26]1[C:27]2[C:28](=[CH:29][N:30]=[CH:31][CH:32]=2)[CH:10]=[CH:8][CH:7]=1
Reactant: OCC(O)CO
Reactant: Nc1ccncc1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: O
Product: c1cnc2ccncc2c1
Temperature: 135 °C

Procedure:
A sulfuric acid solution was prepared by adding H2SO4 (100 mL) to H2O (57 mL) cooled in an ice bath. To this solution was added glycerol (33 mL, 457 mmol), m-nitrobenzene sulfonic acid sodium salt (48 g, 212 mmol) and 4-amino-pyridine (10 g, 106 mmol). The reaction mixture was heated at 135° C. for 4 hours. The cooled reaction mixture was basicified with 2.5 N NaOH (500 mL) with cooling in an ice bath, and extracted into CH2Cl2 (3×200 mL). The organic fractions were combined, dried over Na2SO4 and concentrated. The resulting oil was purified by column chromatography (5% MeOH/CH2Cl2) affording 5.04 g (36%) as a dark orange oil. An analytical sample was prepared as the HCl salt from EtOAc yielding an orange low melting solid. MS EI m/z 130 M+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[S:16]1[CH:20]=[CH:19][CH:18]=[CH:17]1>ClCCl>[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([OH:10])=[O:15])=[O:9]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Aluminum chloride (58.7 g, 440 mmol, 2.2 equiv.) and dichloromethane (150 mL) were added to a round bottom flask. A solution of phthalic anhydride (29.6 g, 200 mmol, 1.0 equiv.) in dichloromethane (150 mL) was then added, and the mixture was stirred at room temperature for 30 minutes. Thiophene (15.8 mL, 200 mL, 1.0 equiv.) was added over 1 hour, after which the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was cautiously quenched with hydrochloric acid (0.2 M, 1 L), extracted with dichloromethane, and extracted with aqueous NaOH (1 N, 3×200 mL). The aqueous layer was acidified with concentrated hydrochloric acid; the solids were collected by filtration, and stirred in refluxing methanol. The suspension was filtered, and water was added to the filtrate to crystallize 1 as a colorless solid (20.7 g, 45%). 1H NMR (500 MHz, CDCl3) δ8.09 (dd, J=7.8, 0.85 Hz, 1H), 7.70 (dd, J=4.9, 1.1 Hz, 1H), 7.67 (td, J=7.5, 1.3 Hz, 1H), 7.58 (td, J=7.8, 1.3 Hz, 1H), 7.47 (dd, J=7.5, 0.90, 1H), 7.27-7.26 (m, 1H), 7.07-7.06 (m, 1H). m.p 144-145° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[CH2:9][CH3:10].Cl.[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=3)[N:20]=[C:19]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[CH2:9][CH3:10])[CH2:37][CH2:38]2)[CH2:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1cncc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)c1
Reactant: CCc1c(N)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-Chloro-5-ethyl-pyrimidin-4-ylamine (50.00 mg; 0.32 mmol; 1.00 eq.), 3-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-5-trifluoromethyl-pyridine hydrochloride (3) (155.08 mg; 0.32 mmol; 1.00 eq.), and Cs2CO3 (206.74 mg; 0.63 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2 days, purified by HPLC, title compound 81 mg, 41.5%. LC-MS: (M+1=501, obsd.=501).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([C:27]5[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCNCC4)oc3cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2cc3cc(C4CCN(c5ccc(C(F)(F)F)cn5)CC4)oc3cn2)CC1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine (50 mg), 2-chloro-5-trifluoromethyl-pyridine (25 mg), K2CO3 (40 mg), and N-methylpyrrolidinone (1 mL) is stirred at 60° C. overnight. After cooling to room temperature, water is added and the resulting mixture is extracted with ethyl acetate. The combined extracts are washed with brine, dried (Na2SO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:2) to give the title compound. LC (method 1): tR=1.05 min; Mass spectrum (ESI+): m/z=507 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CC(C)=O>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
In a 100 mL round bottomed flask benzyl 4-hydroxybenzoate (1.445 g, 6.33 mmol) and potassium carbonate (4.17 g, 30.1 mmol) in acetone (100 ml) were combined. Tert-butyl 2-bromoacetate (0.908 ml, 6.03 mmol) was added dropwise. The solution was stirred at 65° C. overnight. The solution was cooled then, the reaction mixture was filtered through a sintered glass funnel. The filtrate was concentrated to afford pale yellow oil, which was purified via silica gel chromatography (40 g, 30% EtOAc:Heptane) to afford benzyl 4-(2-tert-butoxy-2-oxoethoxy)benzoate (2.06 g, 5.90 mmol, 98% yield) as colorless oil. LC/MS (Table 1, Method a) Rt=4.31 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:18]1(O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:18]1([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCCCC1
Reactant: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(OC3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a solution of methyl 4-(4-hydroxyphenyl)benzoate (3.00 g) and cyclohexanol (1.58 g) in tetrahydrofuran (60 ml) was added dropwise diethyl azodicarboxylate (2.48 ml) at 0-10° C. under nitrogen atmosphere, and the mixture was stirred at ambient temperature for 4 hours. After concentration, to the residue was added ethyl acetate (50 ml) and n-hexane (10 ml), and the resulting precipitate was removed by filtration and discarded. To the filtrate was added silica gel (12 g) and the mixture was evaporated. The residue was purified by column chromatography on silica gel (80 g) eluting with a mixed solvent of 5% ethyl acetate in n-hexane to give methyl 4-(4-cyclohexyloxyphenyl)benzoate (1.79 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2]C(C1C(=O)C(C2C=CN=C(C(F)(F)F)C=2)=C(C)N(C(C2C=CC(Br)=CN=2)C)C=1)=O.[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:53])[N:39]([CH:54]([C:56]2[CH:61]=[CH:60][C:59](Br)=[CH:58][N:57]=2)[CH3:55])[CH:38]=1)=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([C:37]1[C:42](=[O:43])[C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]([F:52])[F:51])[CH:45]=2)=[C:40]([CH3:53])[N:39]([CH:54]([C:56]2[CH:61]=[CH:60][C:59]([C:1]#[N:2])=[CH:58][N:57]=2)[CH3:55])[CH:38]=1)=[O:36])[CH3:33]
Reactant: CNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2ccnc(C(F)(F)F)c2)c1=O
Reactant: CCNC(=O)c1cn(C(C)c2ccc(Br)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O
Product: CCNC(=O)c1cn(C(C)c2ccc(C#N)cn2)c(C)c(-c2cccc(C(F)F)c2)c1=O

Procedure:
Example 18 is prepared as described for Example 15, substituting preparation 15b with preparation 18b. ESI mass spectrum: [M+H]+=437; Retention time HPLC: 0.76 min (002_CA03).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].Br[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[K].CC(C)([O-])C>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([CH2:11][N:4]2[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:14]=1)#[N:17]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CC1(C)NC(=O)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K]
Product: CC1(C)NC(=O)N(Cc2ccc(C#N)cc2)C1=O
Yield: 98 %

Procedure:
Prepared analogously to Example 92a) from 5,5-dimethylhydantoin and 4-(bromomethyl)-benzonitrile in the presence of potassium-tert.-butoxide in a yield of 98% of theory.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9]P(=O)(OC(C)C)OC(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C.[ClH:27]>>[ClH:27].[C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)OP(=O)(NCCc1ccccc1)OC(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Product: NCCc1ccccc1

Procedure:
A solution of 1.425 g. (5 millimols) diisopropyl N-(2-phenylethyl)-phosphoramidate in 20 ml. diisopropyl ether saturated with hydrogen chloride is stirred overnight at ambient temperature. The precipitate of 2-phenylethylamine hydrochloride formed is filtered off, washed with diisopropyl ether and then dried in vacuo to give 0.75 g. (yield: 95%) of a crystalline solid, the physical and spectral characteristics of which are identical to those of the compound prepared in Example 2.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[N:6]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[CH3:26][O:27][C:28](=[NH:30])[NH2:29]>C(#N)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:5]([NH:30][C:28](=[NH:29])[O:27][CH3:26])[N:6]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC#N
Product: COC(=N)Nc1nc(OC)cc(OC)n1
Reaction time: 17 h
Yield: 171 %

Procedure:
54.5 g (0.25 mol) of 2-methylsulphonyl-4,6-dimethoxy-pyrimidine, 69 g (0.5 mol) of potassium carbonate and 1500 ml of acetonitrile are mixed with stirring. 33.85 g (0.1375 mol) of O-methyl-isourea sulphate are then added and the mixture is heated to boiling for 17 hours. After cooling, the solution is filtered off with suction and the mother liquor is concentrated. After taking up the residue in methylene chloride, the solution is washed three times with water, dried and concentrated again. 49.9 g of N-(4,6-dimethoxy-pyrimidin-2-yl)-O-methylisourea are obtained in the form of yellow crystals of melting point 91°-95° C. (90% purity; yield 85% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[NH2:16].[CH3:17][C:18]1[O:19][C:20](=O)[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>C(O)(=O)C>[CH3:17][C:18]1[N:16]([C:3]2[CH:4]=[CH:5][C:6]([C:8]#[C:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][C:2]=2[CH3:1])[C:20](=[O:19])[C:21]2[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:23]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: Cc1cc(C#Cc2ccccc2)ccc1N
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O

Procedure:
4-iodo-2-methylbenzenamine 24 (233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compounds (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[d][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC, the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 2,5-dihydroxy benzaldehyde (30c, 138 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4c) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11](=O)[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=1.C(O)(=O)C.[H][H].O>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH2:1][CH2:2][CH:3]([OH:16])[CH2:4][O:5][C:6]1[S:7][C:8]([CH2:11][N:12]([CH3:13])[CH3:14])=[CH:9][N:10]=1
Reactant: CN(C)C(=O)c1cnc(OCC(O)CN)s1
Reactant: [H][H]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CN(C)Cc1cnc(OCC(O)CN)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product from Example 11 (2.0 g, 8.2 mmol) can be added to a solution of borane dimethylsulfide complex (2.5 g, 33 mmol) in 25 ml of dry tetrahydrofuran at room temperature. After one hour, the mixture can be heated to reflux for 4 hours under nitrogen. The resulting suspension can then be cooled to 0° C., cautiously treated dropwise with 5 ml of glacial acetic acid and, after hydrogen evolution ceases, the solution can be heated to reflux for 8 hours. The mixture can then be cooled to 0° C., cautiously treated with water and concentrated in vacuo. The aqueous residue can be extracted with ether, basified with 10 N sodium hydroxide and reextracted with methylene chloride-ethanol. The methylene chloride extracts can then be combined, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product. The pure title compound can be obtained by chromatography on silica gel with 20% methanol in chloroform.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[OH-].[K+].Cl>O.CO>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCCCCOc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Yield: 86.2 %

Procedure:
4.9 g of compound (8) and 3.7 g of potassium hydroxide were added to a solvent mixture of 50 ml of water and 20 ml of methanol, and the mixture was refluxed for 5 hours. The reaction solution was poured to 200 ml water, and the mixture was adjusted approximately to pH 1 with concentrated hydrochloric acid. The solid matters formed therein were filtered, washed with water and dried, to obtain 4.0 g of compound (9) (Yield: 87%)
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([F:17])([F:16])[F:15])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]2)(=O)[CH3:2].ClCCl.C([SiH](CC)CC)C>O>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([C:14]([F:15])([F:16])[F:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]2)[CH3:2]
Reactant: CCOC(=O)C1=Cc2cc(C(C)=O)ccc2OC1C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=Cc2cc(CC)ccc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50 mL single-neck round bottom flask was charged with ethyl 6-acetyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate (1.465 g, 4.662 mmole), dichloromethane (4 mL), and triethyl silane (1.71 mL, 1.25 g, 10.72 mmole) and stirred at RT overnight. The crude reaction was poured into water and extracted several times with dichloromethane. The combined organics were washed with water, then with aqueous 10% sodium carbonate solution, dried over MgSO4, filtered and concentrated in vacuo to yield a colorless oil. This oil was purified by silica chromatography (9 hexane: 1 ethyl acetate) yielding the title compound as a clear, colorless oil (1.25 g, 89%): 1H NMR (acetone-d6/300 MHz) 7.84 (s, 1H), 7.30 (d, 1H, J=2.0 Hz), 7.26 (dd, 1H, J=8.3, 2.0 Hz), 6.93 (d, 1H, J=8.3 Hz), 5.79 (q, 1H, J=7.3 Hz), 4.37-4.24 (m, 2H), 2.60 (q, 2H, J=7.6 Hz), 1.32 (t, 3H, J=7.3 Hz), 1.20 (t, 3H, J=7.6 Hz). GCMS m/z 300 (M+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1.[CH2:30]=[CH:31][CH2:32]OC(C(Cl)(Cl)Cl)=N.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:32]([O:1][C@H:2]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C@@H:4]([C:5](=[O:29])[O:6][C:7]3[C@H:8]4[C@:20]([CH3:28])([CH2:21][CH2:22][C:23]=32)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]4)[CH2:3]1)[CH:31]=[CH2:30]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCO[C@H]1CC[C@]2(C)C3=C(OC(=O)[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Reaction time: 3 h
Yield: 57.4 %

Procedure:
Compound 2 (230 mg, 0.571 mmol) obtained in Example 2 was dissolved in dichloromethane (6.0 mL), and O-allyl-2,2,2-trichloroacetimidate (130 μL, 0.857 mmol) and boron trifluoride—ethyl ether complex (36.1 μL, 0.286 mmol) were added thereto at 0° C., followed by stirring for 3 hours. Subsequently, O-allyl-2,2,2-trichloroacetimidate (43.3 μL, 0.286 mmol) and boron trifluoride—ethyl ether complex (18.1 μL, 0.143 mmol) were further added thereto, followed by stirring for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel column chromatography to obtain (3S,5S)-3-allyloxy-7-oxa-8-cholesten-6-one (145 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12]>>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][N:14]([CH:11]([CH3:13])[CH3:12])[CH2:15][CH2:16]2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(C(=O)c2cccnc2Cl)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Step A of Example 9 using 2-chloro-nicotinic acid and 1-isopropyl-piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:11][C:5]1[CH:6]=[CH:10][CH:2]=[CH:3][CH:4]=1)=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(O)cc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 168.6 %

Procedure:
To a solution of 5-hydroxy-2-methylbenzoic acid (1.52 g) in DMF (25 mL) were added benzyl bromide (3.40 g) and potassium carbonate (4.14 g), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, and dried to give the title compound (2.80 g) as a white solid. This compound was used for the next step without further purification.