Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([Cl:4])C.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10].[O:15]1CCCOO1>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].O>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([O:15][CH2:2][Cl:4])=[O:10]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CC(Cl)Cl
Reactant: C1COOOC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: O
Product: O=C(OCCl)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 10 ml of dichloroethane were added 0.96 g of zirconium tetrachloride and 1 g of 3-bromobenzoyl chloride, and the mixture was stirred at room temperature for 20 minutes. At 10° C., 0.15 g of trioxane was added, and the mixture was stirred for 10 minutes, and further stirred at room temperature for 2 hours. Water was added slowly under ice-cooling, the resultant solution was extracted with chloroform three times, and the organic layers were combined, washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated to obtain 0.95 g of chloromethyl 3-bromobenzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:20][NH:21][CH3:22]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:21]([CH3:22])[CH3:20])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2Cl)C1
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A stirred solution of 5 g (0.016 mol) of 3-[2-chloro-4-(trifluoromethyl)phenoxy]-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 5.5 ml (0.048 mol) of 40% aqueous dimethylamine. After stirring for 16 h, the reaction mixture was diluted with 200 ml of water and the solid which precipitated was collected by filtration (4.8 g). The crude product was crystallized from benzene/ligroin to yield 4.3 g (83.3%) of fine white crystals, mp 106°-108° C.
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([O:9][CH2:10][CH3:11])[CH:6]=[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:4]=1.[Cl-].[NH4+].[CH2:18]([OH:20])[CH3:19]>O>[CH2:10]([O:9][C:7]1[CH:6]=[C:5]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:4]=[C:3]([O:20][CH2:18][CH3:19])[N:8]=1)[CH3:11]
Reactant: CCO
Reactant: CCOc1cc(C(Cl)(Cl)Cl)cc(Cl)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Product: CCOc1cc(C(Cl)(Cl)Cl)cc(OCC)n1
Reaction time: 72 h

Procedure:
A solution was prepared by dissolving 17.24 grams (0.75 mole) of sodium metal in 400 ml of ethanol. To this solution was rapidly added a solution prepared by dissolving 137.48 grams (0.5 mole) of 6-chloro-2-ethoxy-4-(trichloromethyl)pyridine in 300 ml of ethanol at 35° C. The mixture was heated to reflux at 72° for ~42 hours and thereafter a solution of 8.62 grams of sodium metal dissolved in 200 ml of ethanol was added thereto and the mixture refluxed for about an additional 5 hours. The mixture was diluted with 500 ml of water after first removing 500 ml of ethanol. The mixture was extracted twice with methylene chloride and the methylene chloride layers combined and washed with water (an emulsion formed and ammonium chloride was added thereto and the mixture allowed to set 3 days (week-end) for the emulsion to break). The methylene chloride layer was dried over sodium sulfate, treated with activated charcoal and filtered. The methylene chloride was removed by evaporation and 150 ml of methanol was added thereto. The mixture was chilled and the 2,6-diethoxy-4-(trichloromethyl)pyridine product which precipitated was separated. The product was recrystallized from 150 ml of methanol and dried over methylene chloride. The product melted at 45.5°-47.0° C. and was recovered in a yield of 46 grams (32 percent of theoretical). The product was found by analysis to have carbon, hydrogen, and nitrogen contents of 42.12, 4.17 and 4.92 percent, respectively, as compared with the theoretical contents of 42.20, 4.25 and 4.92 percent, respectively, as calculated for the above-named compound. The structure of the compound was confirmed by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1.BrCC1C[CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[C:14]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)=[N:13][CH:12]=[C:11]([S:22][CH2:23][CH:24]2[CH2:25][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:10]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(Sc2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Product: Cc1csc(Nc2ncc(SCC3CCNCC3)cc2Sc2ccccc2Cl)n1
Product: Cl

Procedure:
Prepared according to the method of Example 16 using methyl 3-(5-(2-chlorophenylthio)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. 1H NMR (d6-DMSO) δ 12.15 (bs, 1H), 10.05 (bs, 1H), 8.64 (m, 1H), 8.32 (m, 2H), 7.63 (m, 1H), 7.36 (m, 2H), 6.52 (s, 1H), 3.22 (m, 2H), 2.79 (m, 4H), 2.17 (s, 3H), 1.86 (m, 2H), 1.61 (m, 1H), 1.36 (m, 2H); Mass spectrum (esi) m/z=463.0 (M+H-2HCl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15](Cl)[N:14]=[C:13]([Cl:18])[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.O.[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:18][C:13]1[N:12]=[C:11]([NH:10][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:16]=[C:15]([NH:26][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:14]=1
Reactant: NC1CCCCCC1
Reactant: COc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Yield: 70.5 %

Procedure:
To a sample of compound 101 (20.02 g, 65.6 mmol) in acetone (200 mL) was added cycloheptylamine (8.3 mL, 65.5 mmol) in acetone (55 mL) slowly by addition funnel at rt. Then water (66 mL) was added followed by aqueous sodium hydroxide (26.2 mL, 2.5 N, 65.5 mmol) by addition funnel. The reaction mixture was heated at reflux under a nitrogen atmosphere for approximately about 3 hours. The reaction was cooled, diluted with ethyl acetate, washed 1 time with water, and finally 1 time with brine. The organic layer was separated and dried over potassium carbonate/sodium sulfate. The organic layer was filtered and concentrated in vacuo. The product (24.13 g) was purified by flash column chromatography (silica gel, 1:4 ethyl acetate:hexanes). The fractions were combined and concentrated in vacuo to afford 133 as a pale yellow solid (17.66 g, 70.5%), mp 146° C.; HPLC: Inertsil ODS-3V C18, 40:10:50 [KH2PO4 (0.01M, pH 3.2):CH3OH:CH3CN], 264 nm, Rt 58.8 min, 99.9% purity); MS (ESI): m/z 382 (M+H, 100), 241 (2.8), 226 (8.4), 139 (43.5), 116 (6).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(C(CC)C([NH:18][CH:19](C([O-])=O)[C:20]([O-:22])=[O:21])=O)C>>[NH2:18][CH:19]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])[C:20]([OH:22])=[O:21]
Reactant: CCC(CC)C(=O)NC(C(=O)[O-])C(=O)[O-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCl
Product: NC(Cc1ccc(Cl)cc1[N+](=O)[O-])C(=O)O

Procedure:
The title compound was prepared from 4-chloro-2-nitrobenzyl chloride and diethylacetamidomalonate according to the procedures described by Davis, A. L.; et al, in Arch. Biochem. Biophys., 102, 48 (1963).
Reaction SMILES: COC1[N:8]=[C:7]2C=CN[C:6]2=CC=1.[CH2:12]([O:19][C:20]1[N:25]=[C:24]2[CH:26]=[CH:27][NH:28][C:23]2=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.BrCCCCBr.Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]Br>>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:28]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:27]3=[C:26]([CH2:6][CH2:7][NH2:8])[C:24]=2[N:25]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: BrCCCCCBr
Reactant: COc1ccc2[nH]ccc2n1
Reactant: c1ccc(COc2ccc3[nH]ccc3n2)cc1
Solvent: BrCCCCBr
Product: NCCc1c2n(c3ccc(OCc4ccccc4)nc13)CCCCC2

Procedure:
The procedure is as for Preparation 8, in Step A replacing 5-methoxy-1H-pyrrolo[3,2-b]pyridine by 5-benzyloxy-1H-pyrrolo[3,2-b]pyridine and 1,4-dibromobutane by 1,5-dibromopentane.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(CCCC)CCCC)CCC.[C:49]([Si:53]([CH3:71])([CH3:70])[O:54][C:55]1[CH:56]=[C:57](O)[CH:58]=[C:59]([O:61][Si:62]([C:65]([CH3:68])([CH3:67])[CH3:66])([CH3:64])[CH3:63])[CH:60]=1)([CH3:52])([CH3:51])[CH3:50].N(C(N(C)C)=O)=NC(N(C)C)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:65]([Si:62]([CH3:64])([CH3:63])[O:61][C:59]1[CH:58]=[C:57]([O:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:56]=[C:55]([O:54][Si:53]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:71])[CH3:70])[CH:60]=1)([CH3:68])([CH3:67])[CH3:66]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(O[Si](C)(C)C(C)(C)C)c1
Reactant: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1cc(OCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a solution of Compound 2 (4.3 g, 8.9 mmol) in toluene (20 ml), tributylphosphine (2.35 g, 8.92 mmol) was added at room temperature; this was followed by stirring for 1 hour. This was gradually added to a solution of Compound 43 (3.3 g, 11.6 mmol) and 1,1′-azobis(N,N-dimethylformamide) (2.0 g, 11.6 mmol) in toluene (20 ml), and this was followed by overnight stirring at room temperature. Ethyl acetate (100 ml) was added; the resulting insoluble matter was removed by Celite filtration and washed with ethyl acetate. The combined organic phases were concentrated under reduced pressure; the residue obtained was purified by silica gel column chromatography (Yamazen YFLC Gel, eluent (n-hexane:ethyl acetate 3:1-2:1)) to yield Compound 44 (colorless oil 2.8 g, 39%).
Reaction SMILES: CN(C)[C:3](=[CH2:11])[C:4]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)=[O:5].Cl.[NH2:14]O>CO>[S:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4]1[O:5][N:14]=[CH:11][CH:3]=1
Reactant: NO
Reactant: C=C(C(=O)c1cccs1)N(C)C
Agent: Cl
Solvent: CO
Product: c1csc(-c2ccno2)c1
Yield: 97 %

Procedure:
A mixture of β-dimethylamino-1-(2-thienyl)-2-propen-1-one (1) (18.1 g, 100 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol) in anhydrous methanol (100 mL) is refluxed under nitrogen for 2 hrs. The reaction mixture is cooled, concentrated and partitioned between water and dichloromethane. The dichloromethane layer is dried with anhydrous sodium sulfate, filtered and concentrated to yield product (2) as a dark yellow-orange oil (14.7 g, 97 mmol, 97%).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[O:27][CH3:28])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:17]([CH3:26])=[CH:18][C:19]([N+:23]([O-:25])=[O:24])=[CH:20][C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[O:27][CH3:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(=O)CC1CCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1CCC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of 2-cyclopentyl-1-[5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-phenyl]-ethanone (200 mg, 0.52 mmol) and trifluoroacetic acid (0.34 mL) in CH2Cl2 (0.5 mL) was added triethylsilane (212 mg, 1.83 mmol). After stirring at RT for 18 h, the reaction mixture was poured into water (15 mL) and extracted with EtOAc (20 mL). The EtOAc extract was washed with sat'd sodium bicarbonate (2×15 mL), brine (15 mL), dried and concentrated. The residue was purified by preparative TLC (CH2Cl2:Hexanes=2:3) to give the title compound of Step B (186 mg) as an oil. MS (APCl−) Calc.: 369.2. Found: 468.3 (M−1).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.N1C=CC=CC=1>C(Cl)Cl>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ncccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 104.6 %

Procedure:
A solution of triflic anhydride (42.8 g, 0.15 mol) in CH2Cl2 (100 mL) was added dropwise to a 0° C. solution of 6-hydroxyquinoline (20.00 g, 0.138 mol) and pyridine (23 g, 0.277 mol) in CH2Cl2 (500 mL). The cooling bath was removed and the resulting solution was stirred at RT for 4 h. The reaction mixture was washed with water (3×300 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum to afford crude quinolin-6-yl trifluoromethanesulfonate (40 g, >100% yield) as an oil. 1H-NMR (400 MHz, DMSO-d6) δ 9.00 (d, 1H, J=2.8 Hz), 8.50 (d, 1H, J=8.0 Hz), 8.21 (d, J=2.8 Hz, 1H), 8.18 (d, J=9.2 Hz, 1H), 7.80 (m, 1H), 7.64 (m, 1H); MS (ESI) m/z: 277.9 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([S:40]([NH2:43])(=[O:42])=[O:41])[N:34]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:35]3[N:34]=[C:33]([CH3:32])[CH:38]=[C:37]([CH3:39])[N:36]=3)(=[O:41])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1cc(C)nc(S(N)(=O)=O)n1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1cc(C)nc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4,6-dimethylpyrimidine-2-sulfonamide: 1H-NMR (CDCl3) δ 7.46-7.23 (10H, m), 6.82 (1H, br.s), 3.54-3.47 (2H, m), 2.89-2.84 (2H, m), 2.58 (6H, s), 2.33 (3H, s), 2.27 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([C:17](=[O:20])[CH2:18]Cl)=[CH:10][C:11]=3[C:12]2([F:16])[F:15])=[CH:4][CH:3]=1.[C:21]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([OH:35])=[O:34])=[O:27])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[N:28]1([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:32][CH2:31][CH2:30][C@H:29]1[C:33]([O:35][CH2:18][C:17]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=3)[C:12]([F:16])([F:15])[C:11]=2[CH:10]=1)=[O:20])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(CCl)c1ccc2c(c1)C(F)(F)c1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OCC(=O)c1ccc2c(c1)C(F)(F)c1cc(Br)ccc1-2
Temperature: 60 °C
Yield: 88.2 %

Procedure:
A mixture of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone (2 g, 5.6 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.32 g, 6.1 mmol), potassium carbonate (1.55 g, 11.1 mmol) and potassium iodide (930 mg, 5.6 mmol) in acetone was heated to 60° C. After forty minutes, the reaction was cooled to room temperature and concentrated. The residue was dissolved in a mixture of ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous NH4Cl solution and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield (S)-2-(2-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl) 1-tert-butyl pyrrolidine-1,2-dicarboxylate (2.65 g, 88%).
Reaction SMILES: [CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](/[CH:15]=[CH:16]\O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>CC(O)=O>[CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14]([CH2:15][CH2:16][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(/C=C\O)c2cc(C3CCCCC3)sc2n1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nc(CCN2CCOCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of (Z)-2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethenol (120 mg) and AcOH (12 mL) were added morpholine (400 μL) and NaBH (OAc)3 (200 mg), followed by stirring at room temperature for 15 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain 6-cyclohexyl-2-methyl-4-[2-(morpholin-4-yl)ethyl]thieno[2,3-d]pyrimidine (53 mg).
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].B[O-].C(=O)C.[CH3:12][C:13]1[CH:18]2C(C)(C)C(C2)[CH2:15][CH:14]=1.B([O-])[O-].N(CCO)CCO>CCOCC.C1COCC1>[CH3:4][CH:3]([CH2:2][C@H:1]([OH:6])[CH2:18][C:13]([CH:14]=[CH2:15])=[CH2:12])[CH3:5]
Reactant: CC(C)CC=O
Reactant: CC1=CCC2CC1C2(C)C
Agent: B[O-]
Agent: CC=O
Agent: [O-]B[O-]
Solvent: OCCNCCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(=C)C[C@@H](O)CC(C)C
Temperature: 0 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
Isovaleraldehyde (2.15 g, 2.68 mL, 25 mmol) in ether (6 mL) was added dropwise to a rapidly stirred solution of B-Isoprenyldiisopinocampheylborane, dIpc2BIpn, maintained in THF/EE (1:2) at -100° C. Stirring was continued for 6 h, when the 11B NMR spectrum of an aliquot showed a peak at δ52 ppm, corresponding to a borinate indicating completion of the reaction. The reaction mixture was warmed to 0° C. and acetaldehyde (2.1 mL, 37.5 mmol) was added when one equiv of α-pinene was eliminated. 11B NMR showed a peak at δ 32 ppm corresponding to a boronate. The solvents were removed in vacuo and EE (20 mL) was added, followed by 1.1 equiv. of diethanolamine (2.6 mL, 27.5 mmol). Stirring was continued for 2 h and the precipitated boron components were filtered and the filtrate concentrated. Distillation (92°-94° C./19 mm Hg) provided 2.3 g (60%) of (+)-ipsenol, [α]D =+18.5° which corresponds to 100% ee. The spectral properties were identical to the sample obtained from example 9.
Reaction SMILES: BrC1C=CC([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)=CC=1.C1(NC2C=CC=CC=2N)C=CC=CC=1.[Br:37][C:38]1[CH:45]=[CH:44][C:41](C=O)=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:39]=[C:40]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH:41]=[CH:44][CH:45]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: Nc1ccccc1Nc1ccccc1
Product: Brc1cccc(-c2nc3ccccc3n2-c2ccccc2)c1

Procedure:
2-(3-Bromophenyl)-1-phenyl-1H-benzo[d]imidazole (m-BPBI) was prepared as the same procedure as 2-(4-bromophenyl)-1-phenyl-1H-benzo[d]imidazole from N-phenyl-o-phenylenediamine and 4-bromobenzaldehyde. The isolated yield of the compound was 85%. It has the same spectroscopic data as that as the bona fide compound.11
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)CCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:22][CH2:21][CH2:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)cc1

Procedure:
4-Acetylbenzoic acid (2.45 g, 14.9 mmol), beta-alanine t-butyl ester hydrochloride (4.0 g, 22 mmol), DIEA (3.9 ml, 22 mmol) and DMAP (100 mg) were dissolved in DCM (100 ml). EDC hydrochloride (3.5 g, 18 mmol) was added in portions. Additional EDC (0.7 g) was added one hour later to complete the reaction. After a total of 3 hours, the reaction was partitioned between ethyl acetate and 0.5 N HCl. The organic layer was washed with 0.5 N HCl 3×, 5% K2CO3 2×, brine 2×. Evaporation of solvent, and chromatography over SiO2 (10-20% ethyl acetate in DCM) afforded tert-butyl N-(4-acetylbenzoyl)-β-alaninate as a while solid. NMR (500 MHz, CD3OD) δ: 1.44 (s, 9H); 2.57 (t, J=7.0 Hz, 2H); 2.63 (s, 3H); 3.61 (t, J=7.0 Hz, 2H); 7.89 (d, J=8.5 Hz, 2H); 8.05 (d, J=8.5 Hz, 2H).
Reaction SMILES: N1C=CC=CC=1.CS([Cl:11])(=O)=O.[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]([Cl:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(Cl)c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 3.7 ml of pyridine and 2.2 ml of methanesulfonyl chloride was added dropwise to 35 ml of a solution of 3.5 g of 2-t-butoxycarbonylamino-1-phenylethanol [prepared as described in step (a) above] in methylene chloride and the reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was condensed by evaporation under reduced pressure, and the residue was dissolved in a mixture of ethyl acetate and water. The ethyl acetate layer was separated, washed with water and then washed with an aqueous solution of potassium hydrogen sulfate and with an aqueous solution of sodium bicarbonate. The resulting solution was dried over anhydrous magnesium sulfate. The solvent was then distilled off. The residue was subjected to silica gel column chromatography using a 15:85 by volume mixture of ethyl acetate and cyclohexane as the eluent, to give 0.75 g of the title compound as crystals melting at 57°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][NH:14][CH:15]=2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:16]#[N:17])=[CH:13][N:14]([CH3:21])[CH:15]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2c[nH]cc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cn(C)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a stirred solution of 4-(4-methoxycarbonylphenyl)-1H-pyrrole-3-carbonitrile (3.00 g) in N,N-dimethylformamide (25 ml) was added sodium hydride 60% oil dispersion: 559mg) at ambient temperature and the stirring was continued for half an hour at the same temperature. Iodomethane (1.99 g) was added to the mixture, and was stirred at ambient temperature for two hours. The reaction mixture was poured onto ice water and extracted with ethyl acetate and washed with 7% aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethanol to give 4-(4-methoxycarbonylphenyl)-1-methylpyrrole-3-carbonitrile (2.78 g) as pale yellow needles.