Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[C:18](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1.O>C(#N)C>[CH3:18][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C
Temperature: 20 °C
Yield: 98 %

Procedure:
To a refluxing mixture of commercially available ethyl 5-nitro-1H-indole-2-carboxylate (420 g) and potassium carbonate (272.6 g) in acetonitrile (3360 mL) was added a solution of methyl p-toluenesulfonate (367.3 g) in acetonitrile (630 mL), and the resulting mixture refluxed for 18 hours. The mixture was then cooled to 20° C. over 3 hours and water (4200 mL) added over a 3 hour period. The product was granulated, filtered, washed with a 50/50 mixture of demineralized water and acetonitrile (630 mL), demineralized water (420 mL) and then with ethanol (420 mL), and dried, yielding the product ethyl 1-methyl-5-nitro-1H-indole-2-carboxylate (436.1 g, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][C@@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:19][C:20]1([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:30][O:29][C:27]([C:26]1[CH:31]=[CH:32][C:23]([C:20]2([NH:19][C:15]([C@H:9]3[CH2:10][C:11]([CH3:13])([CH3:14])[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:17])[CH2:21][CH2:22]2)=[CH:24][CH:25]=1)=[O:28]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: CC1(C)C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3CC(C)(C)CN3C(=O)OC(C)(C)C)CC2)cc1
Yield: 65.4 %

Procedure:
The title compound (D75) (94 mg) was prepared according to the general procedure for amides preparation (Method C) starting from (R)-1-(tert-butoxycarbonyl)-4,4-dimethylpyrrolidine-2-carboxylic acid (D41) (84 mg) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (79 mg). HCTU: 1.05 eq; Reaction time: 2 hrs.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5](OC)=[O:6].ClC1C=C(CO)C=C(C(F)(F)F)C=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: COC(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: OCc1cc(Cl)cc(C(F)(F)F)c1
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Yield: 35 %

Procedure:
The title compound was prepared from methyl 3-bromo-5-(trifluoromethyl)benzoate (Reference Example 37) by a procedure similar to the one described for (3-chloro-5-(trifluoromethyl)phenyl)methanol (Reference Example 30) to provide (3-bromo-5-(trifluoromethyl)phenyl)methanol (7.42 g, 35% (2 steps)) as a yellow oil.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51]([CH3:53])=[C:50]([C:54](=O)[CH3:55])[C:49]=2[CH:57]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+]>C(O)C>[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51]([CH3:53])=[C:50]([C:54]3[CH:55]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)[C:49]=2[CH:57]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1c(C)oc2ccc(OCc3ccccc3)cc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc2ccc(OCc3ccccc3)cc2c1-c1ccc2cc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)ccc2n1
Yield: 49 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5-benzyloxy-2-methyl-benzofuran-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (75 mg, 49% yield). MS: 608.25 (M+H+); HPLC Procedure A, retention time=17.24 min.
Reaction SMILES: C([O-])(=O)C.[K+].Cl.[CH2:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:8].[Br:14][C:15]1[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=1)[C:18]([C:20]1[CH:21]=[CH:22][C:23]([N+:28]([O-:30])=[O:29])=[C:24]([CH:27]=1)[CH:25]=O)=[O:19].[B-]C#N.[Na+]>C(O)C>[CH2:7]([N:9]([CH2:25][C:24]1[CH:27]=[C:20]([C:18](=[O:19])[C:17]2[CH:31]=[CH:32][CH:33]=[C:15]([Br:14])[CH:16]=2)[CH:21]=[CH:22][C:23]=1[N+:28]([O-:30])=[O:29])[CH2:10][C:11]([OH:13])=[O:12])[CH3:8]
Reactant: CCNCC(=O)O
Reactant: O=Cc1cc(C(=O)c2cccc(Br)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [B-]C#N
Solvent: CCO
Product: CCN(CC(=O)O)Cc1cc(C(=O)c2cccc(Br)c2)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
To a stirred mixture of 58.9 parts of potassium acetate, 100.5 parts of ethyl glycine monohydrochloride and 790 parts of ethanol, there were added 100 parts of 5-(3-bromobenzoyl)-2-nitrobenzaldehyde (prepared following the procedure described in Example 9 or Example 14. After stirring for 1/2 hour, there were added portionwise 9.4 parts of sodium cyanotrihydroborate. Stirring was continued for 1/2 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /C2H5OH 99:1). The eluent of the desired fraction was evaporated, yielding 71 parts (56.2%) of ethyl N-[[5-(3-bromobenzoyl)-2-nitrophenyl]methyl]glycine (interm. 66).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=[O:20])=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)c1cccs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1cccs1)C(=O)COc1ccc(F)cc1Br
Yield: 69.6 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (220 mg, 0.91 mmol) and thiophene-2-carboxylic acid N′-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 10-50% ethyl acetate/hexanes gradient to afford the product as a solid (263 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:17]>>[OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([C:11]([NH2:12])=[O:17])=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1oc2cc(O)ccc2c(=O)c1C#N
Reactant: O=S(=O)(O)O
Product: Cc1oc2cc(O)ccc2c(=O)c1C(N)=O

Procedure:
A slurry of 1 g of 7-hydroxy-4-oxo-2-methyl-4H-1-benzopyran-3-carbonitrile in 6 ml of conc. sulfuric acid was heated for 3 hours on the steam bath. The mixture was poured onto ice. The solid was filtered and recrystallized from ethanol, mp 289°-290°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12](=[O:14])[CH3:13].[BH4-].[Na+]>CCO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]([OH:14])[CH3:13]
Reactant: CC(=O)c1c(Cl)ccc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1c(Cl)ccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an EtOH (70 ml) solution of 1-(2-Chloronaphthalen-1-yl)-ethanone (3.98 mmol; prepared according to J. Org. Chem. 1946, 11, 163-169) was added sodium borohydride (232 mg, 6.09 mmol). The mixture was stirred at rt under an atmosphere of nitrogen for one hour. After that time, the mixture was quenched with saturated NH4Cl followed by water, extracted with EtOAc (3×50 ml). The extracts were washed with water (50 ml), brine (50 ml), and dried over MgSO4. After concentration in vacuo, a beige oil was obtained. It was purified by chromatography on silica gel (25 g) eluting with an EtOAc/hexane gradient to give the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=1.44 (d, J=6.4 Hz, 3H), 2.33 (d, J=3.6 Hz, 1H), 5.97-6.06 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 7.45-7.58 (m, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.81 (dd, J=1.6, 8.0 Hz, 1H), 8.75 (d, J=8.0 Hz, 1H). MS (ES+): 189.19/191.20 [MH+−H2O]. HPLC: tR=3.38 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl>ClCCl>[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(=O)c1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(OCOCC[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
While 30 mL solution of 2.72 g 4-hydroxyacetophenone and 5.2 mL diisopropyl ethylamine in dichloromethane was stirred under ice-cooling in a stream of nitrogen, 4.2 mL 2-(trimethylsilyl)ethoxymethyl chloride was added thereto. Then, the reaction solution was stirred at room temperature for 4 hours. The reaction solution was evaporated, then ethyl acetate and water were added to the residue, the organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 5.22 g of the title compound as a colorless oil.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][O:12][CH:13]3[CH:18]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[CH2:17][CH2:16][NH:15][CH2:14]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2ccc3c(c2)OCCO3)C1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Fc1ccc(C2CCNCC2OCc2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.7 %

Procedure:
A solution of 280 mg (0.63 mmol) of tert-butyl (3RS,4RS)-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethoxy)-4-(4-fluorophenyl)-piperidine-1-carboxylate in 5 ml of dry methylene chloride was treated with 808 mg (1.89 mmol) of anhydrous zinc bromide and the mixture was stirred at room temperature for 5 hours. Subsequently, the solvent was distilled off under reduced pressure, the residue was taken up in 10 ml of methanol, treated with 2 ml of 2N sodium hydroxide solution and the solid was separated. The filtrate was evaporated under reduced pressure and the residue was partitioned between methylene chloride and water. The organic phase was separated and evaporated under reduced pressure. There were obtained 220 mg (98% of theory) of (3RS,4RS)-3-(2,3-dihydrobenzo[1,4]dioxin-6-yl-methoxy)-4-(4-fluorophenyl)-piperidine as a yellowish solid; MS: 344 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[CH3:8].[CH2:27](I)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:7]([O:9][C:10](=[O:26])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([NH:25][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)[CH3:8]
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(N)cc2)cc1
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCNc1ccc(Oc2ccc(CC(=O)OCC)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A slurry of 3.45 g of anhydrous potassium carbonate in 50 ml of hexamethylphosphoramide (HMPA) containing 6.8 g of ethyl[p-(p-aminophenoxy)phenyl]acetate is heated to 50° C. A solution of 6 g of n-octyliodide in 10 ml of HMPA is added over 2 hours. The heating is continued for 24 hours. The mixture is diluted with 100 ml of H2O and extracted with two 100 ml portions of ether. The combined extracts are washed with two 100 ml portions of H2O, 100 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords a brown liquid, which yields, after silica gel chromatography (benzene, then CHCl3) and bulb-to-bulb distillation of the CHCl3 eluate, a pale yellow oil, b.p. 194° @ 0.05 mm.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH3:7][N:8]([CH3:26])[C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=O)=[CH:11][CH:10]=1.[Cl-].[NH4+]>C(OCC)C.C1C=CC=CC=1>[CH3:7][N:8]([CH3:26])[C:9]1[CH:25]=[CH:24][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[CH2:5])=[CH:11][CH:10]=1
Reactant: CI
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2)cc1
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 65 %

Procedure:
After adding 100 ml of benzene to a diethyl ether solution of methylmagnesium iodide prepared from 1.7 g of magnesium, 9.9 g of methyl iodide, and 100 ml of diethyl ether, 16.6 of 4,4'-bis-dimethylaminobenzophenone was gradually added thereto. After stirring at room temperature for 10 hours, the reaction mixture was decomposed by a saturated aqueous ammonium chloride solution, followed by stirring as it was for 2 hours. After separating and water-washing an organic layer, the solvent was distilled off, and the residue was recrystallized from ethanol to obtain 10.7 g of 1,1-bis(4'-dimethylaminophenyl)ethylene. The melting point was 121° to 122° C., and the theoretical yield was 65%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:24]1([C:30]#[CH:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([C:30]#[C:31][C:2]2[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C#CC1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(C#CC2CCCCC2)nc1
Yield: 25 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 25% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and cyclohexylacetylene. Purification by column chromatography using a gradient of 10-60% ethyl acetate in heptane as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl>C(O)C.[Fe]>[NH2:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cc(N)c(Cl)cc1Cl

Procedure:
8 g of 2',4'-dichloro-5'-nitro-acetophenone were boiled for 4 hours under reflux in 31 ml of ethanol, after addition of 6.1 g of iron turnings and 6.5 ml of concentrated hydrochloric acid. After evaporation of the solvent, the mixture was combined with water, extracted with ethyl acetate and the 5'-amino-2',4'-dichloroacetophenone was isolated by concentration of the ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](I)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1.[CH3:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]=1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:28]=[CH:29][C:20]=3[CH3:19])[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1cc(I)c2[nH]c(=O)[nH]c2c1
Reactant: Cc1ccc2ccccc2c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc2ccccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)[nH]c12
Temperature: 150 °C

Procedure:
In a 2-5 mL Smith Process Vial, 6-(3,5-dimethylisoxazol-4-yl)-4-iodo-1H-benzo[d]imidazol-2(3H)-one (100.0 mg 0.282 mmol), (2-methylnaphthalen-1-yl)boronic acid (176.0 mg, 0.946 mmol, 3.36 equiv), PEPPSI-iPr (19.2 mg, 0.028 mmol, 0.1 equiv) and Cs2CO3 (337.0 mg, 1.126 mmol, 4 equiv) were placed. The mixture was suspended in 1,4-dioxane (1.5 mL) and water (0.5 mL) under N2. The mixture was heated at 150° C. for 75 min using microwave reactor (Biotage Optimizer). After an aqueous work up, the crude product was purified by a silica-gel column chromatography (hexane/EtOAc 20:80) to give 6-(3,5-dimethylisoxazol-4-yl)-4-(2-methylnaphthalen-1-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([C:41](=[O:43])[CH3:42])[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)=[CH:29][C:22]=2[O:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([C:41](=[O:43])[CH3:42])[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[CH:29][C:22]=2[O:21]1)=[O:19]
Reactant: COC(=O)C1CCc2cc(C(C)=O)c(OCCCCCOS(C)(=O)=O)cc2O1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCc1c(OCCCCCOc2cc3c(cc2C(C)=O)CCC(C(=O)OC)O3)ccc2c1OCCC2=O
Yield: 90.9 %

Procedure:
A mixture of 0.8 g (3.88 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.6 g (3.88 mmol) of rac-6-acetyl-7-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester, 0.78 g (5.65 mmol) of anhydrous potassium carbonate, 0.082 g of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), and 20 mL of toluene was stirred and refluxed for 6 hr. After being cooled, the reaction mixture was diluted with ether and toluene and filtered with suction. The solids were washed with more toluene and ether and then the filtrate and washes were combined and concentrated in vacuo. The residue was dissolved in 1:1 ether-dichloromethane and washed with water and brine. Completion of the usual work-up afforded a solid residue which was purified by flash chromatography, eluting with 1:1 hexane-ethyl acetate. There was obtained 1.85 g (91%) of rac-6-acetyl-7-[5-[(3,4-dihydro-4-oxo- 8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester as a solid, mp 131°-133° C. This material was saponified using the procedure described in example 8 giving rac-6-acetyl-7-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid as an off-white solid, mp 148°-151° C., in 38.4% yield, after recrystallization from hexane-ethyl acetate.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:25]=[N:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]([CH:46]=[O:47])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CCCc1ccc(C=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 71 %

Procedure:
This compound was prepared using the same procedure as in Example 1.15 g of 5-n-propyl-1-[2′-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl-methyl]-2-pyrrolaldehyde (0.024 moles) and 30 mL of 4N HCl (0.120 moles) yield 6.3 g of product. Formula: C22H21N5O (m.w. 371.44). Yield 71%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)[CH:27]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH2:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]3[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=3)[CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: CCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-ethoxyphenyl)amino]piperidine (641 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl.[C@H:14]12[CH2:20][C@H:17]([NH:18][CH2:19]1)[CH2:16][O:15]2.C(N(CC)C(C)C)(C)C>CN(C)C(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=[C:2]([N:18]2[CH2:19][C@@H:14]3[CH2:20][C@H:17]2[CH2:16][O:15]3)[CH:7]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1nc(Cl)cc(N2C[C@@H]3C[C@H]2CO3)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 4,6-dichloro-2-methylsulfonyl-pyrimidine (3.41 g, 15 mmol) and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (2.03 g, 15.0 mmol) in N,N-dimethylacetamide (40.5 mL), was added N,N-diisopropylethylamine (6.60 mL). The resulting mixture was stirred at room temperature. After 30 min, the reaction mixture was concentrated to a solid. The crude material was purified by column chromatography using an 80 g column, with a gradient of 0% to 100% ethyl acetate in heptane. The combined fractions containing product were concentrated under reduced pressure to provide (1S,4S)-5-(6-chloro-2-methylsulfonyl-pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (3.03 g). 1H NMR (400 MHz, Chloroform-d) δ 6.30 (s, 1H), 3.98-3.81 (m, 3H), 3.45-3.35 (m, 2H), 3.28 (s, 3H), 2.16-1.98 (m, 2H), 1.95-1.86 (m, 1H).