Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([N+:11]([O-])=O)[N:8]=[CH:7]1)[CH3:2].[C:21]([NH:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30][C:31](=[O:32])[C:26]=12)=[O:29])(=[O:23])[CH3:22]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[N:6]1[CH:10]=[C:9]([NH:11][C:28](=[O:29])[C:27]2[CH:33]=[CH:34][CH:35]=[C:25]([NH:24][C:21](=[O:23])[CH3:22])[C:26]=2[C:31]([OH:32])=[O:30])[N:8]=[CH:7]1)[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCCCCCC(C(=O)OCC)n1cnc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CCCCCCC(C(=O)OCC)n1cnc(NC(=O)c2cccc(NC(C)=O)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.7 %

Procedure:
Following the procedure of Example 2, 1.54 g of 4-nitro-α-hexyl-1H-imidazole-1-acetic acid ethyl ester were hydrogenated to the corresponding amine and allowed to react with 1.12 g of 3-acetamidophthalic anhydride in ethyl acetate. After stirring at room temperature, the solution was concentrated in vacuo and a small amount ethyl acetate added. After sitting overnight, the resulting solid was collected by filtration. Crystallization from hot ethyl acetate/methanol/ hexanes provided 0.54 g of the desired intermediate, m.p. 144'-145° C. NMR.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:8]=1[C:9](Cl)=O.[C:21](#[N:23])C>>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:8]=1[CH2:9][N:3]1[CH2:2][CH2:1][N:4]([CH2:9][C:8]2[CH:12]=[C:13]([O:16][C:17]([F:18])([F:19])[F:20])[CH:14]=[CH:15][C:7]=2[O:6][CH3:5])[C:21]1=[NH:23]
Reactant: COc1ccc(OC(F)(F)F)cc1C(=O)Cl
Reactant: NCCN
Reactant: CC#N
Product: COc1ccc(OC(F)(F)F)cc1CN1CCN(Cc2cc(OC(F)(F)F)ccc2OC)C1=N

Procedure:
The title compound was prepared in three steps as described in Procedure D. In the first step, ethylenediamine was reacted in acetonitrile with 2-methoxy-5-(trifluoromethoxy)benzoylchloride (2 eq) in the presence of TEA to give the dibenzoylated ethylenediamine upon aqueous work-up. After the last step (reaction with cyanogen bromide), the crude product was isolated upon aqueous work-up and purified by column chromatography to give the title compound as the hydrogen bromide salt. MS (ES+) m/z 494 ([M+1]+, 100); HR-MS: 494.1532 ([M+1]+, C21H22F8N3O4; calc. 494.15145).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:35]=[CH:36][C:37]=1[F:38].Cl>>[F:31][C:32]1[CH:33]=[C:34]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]4[CH2:30][CH2:29][CH2:28]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:44][CH2:43]2)[CH:35]=[CH:36][C:37]=1[F:38]
Reactant: Fc1ccc(CCCC2CCNCC2)cc1F
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)c(F)c3)CC2)[C@@H](c2ccsc2)C1
Yield: 65.1 %

Procedure:
The title compound was prepared from 21 mg (0.046 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-3-(cyclobutyl) propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 87, Step F) and 11.7 mg (0.046 mmol) of 4-(3-(3,4-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 119, Step C) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to provide 15.9 mg (77%) of the title compound: RF: 0.34 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 1.00-3.48 (m, 33H), 6.79-7.01 (m, 4H), 7.18 (m, 1H), 7.32 (m, 1H); ESI-MS 531 (M+H); HPLC A: 3.01 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O.[OH-].[Na+]>C(#N)C>[Br:22][C:3]1[N:4]=[CH:5][C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cncc(Cl)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cnc(Br)c(Cl)n1
Reaction time: 3 h

Procedure:
A mixture of 2-[6-chloro-2-pyrazinyl]-(1S,4S)-5-tert-butoxycarbonyl-2,5-diazabicyclo-[2.2.1]-heptane (10.6 g, 34.1 mmol), N-bromosuccinimide (6.06 g, 34.1 mmol) and acetonitrile (100 ml) was stirred for 3 hours. Aqueous sodium hydroxide (200 ml, 1 M) was added and the acetonitrile was evaporated. The mixture was extracted with ethyl acetate (2×200 ml). Chromatography on silica gel with ethyl acetate: petroleum (1:1) gave the title compound as free base. Yield 10.44 g (79%).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6]2)=C.C[CH:29]([OH:31])C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH:29]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][O:24]3)=[CH:17][N:16]=1)=[O:14])[CH2:6]2)=[O:31]
Reactant: CC(C)O
Reactant: C=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: O=Cc1ccc2c(c1)C[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cn1)C2
Reaction time: 3 h

Procedure:
A mixture of N-((R)-5-vinylindan-2-yl)-5-[(S)-1-(tetrahydrofuran-2-yl)methoxy]pyridine-2-carboxamide (0.60 g) and 2-propanol (5 ml) was admixed with a mixture of sodium periodate (0.775 g) and water (3 ml). Osmium(VIII) oxide (solution in tert-butanol; 16.7 mg) was added and the mixture was stirred vigorously for 3 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. This afforded the product with the molecular weight of 366.42 (C21H22N2O4); MS (ESI): 367 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[C:1]1([S:7]([N:10]2[C:16](=[O:17])[C:15]3[C:14](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:13][C:11]2=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Nc1ccccc1C(=O)O
Product: O=c1[nH]c2ccccc2c(=O)n1S(=O)(=O)c1ccccc1
Yield: 72.4 %

Procedure:
3.00 g (16.4 mmol) of benzenesulfonylisocyanate and 2.04 g (14.9 mmol) of 2-aminobenzoic acid were treated in the same way as in Example 1 to obtain 3.26 g of the above-identified compound (yield 72.4%). Properties: colorless crystal, Melting point: 211°-213° C., PMR (δppm, DMSO-d6): 7.13 (1H,d), 7.20 (1H,t), 7.61-7.70 (3 H,m), 7.78 (1H,t), 7.87 (1H,d), 8.17 (2H,d), 11.51 (1H,br).
Reaction SMILES: [C-:1]#[N:2].[K+].[O:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[CH2:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>Cl.O>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:7]2([C:1]#[N:2])[CH2:8][CH2:9][O:4][CH2:5][CH2:6]2)[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CCOCC1
Reactant: [C-]#N
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCN(Cc3ccccc3)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
6.5 g (99.8 mmol) potassium cyanide were added to a solution of 10.0 g (96.9 mmol) tetrahydropyran-4-one and 17.1 g (97.0 mmol) 1-benzyl-piperazine in 25 mL 4 M HCl and 50 mL water while cooling with ice and the reaction mixture was stirred for 40 h at RT. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N>N1C=CC=CC=1.O>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1)c1ccccc1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
A suspension of cytidine (9.72 g, 40.0 mmol) in pyridine (200 ml) was added to trimethylchlorosilane (25.6 ml, 200 mmol). After 15 minutes of stirring, benzoyl chloride (23.2 ml, 200 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then cooled on an ice bath, and water (40 ml) was added. Five minutes later, 28% aqueous ammonia (40 ml) was added, and the mixture was stirred at room temperature for 15 minutes. Then, the solvent was distilled off under reduced pressure, and acetone was added to precipitate a white solid. The precipitate was filtered off and recrystallized from water to give N4-benzoylcytidine (13.3 g, 96%). The N4-benzoylcytidine (13.0 g, 37.4 mmol), triphenylphosphine (28.0 g, 107 mmol) and lithium azide (13.0 g, 266 mmol) were suspended in dried DMA, and carbon tetrabromide (35.5 g, 107 mmol) was added to the suspension. After 3 hours of stirring at room temperature, ethyl acetate (1500 ml) was added, and the mixture was washed with water and a saturated aqueous solution of sodium chloride (1000 ml each). The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to give 5′-azido-5′-deoxy-N-benzoylcytidine (12.4 g, yield 89%). A solution of 5′-azido-5′-deoxy-N4-benzoylcytidine (10.0 g, 26.9 mmol) in methanol-DMF (1:1 v/v, 100 ml) was vigorously stirred with 10% palladium-on-carbon (about 1.0 g) in a hydrogen atmosphere. The resulting mixture was filtered, and the filtrate was evaporated under reduced pressure to give 5′-amino-5′-deoxy-N4-benzoylcyridine (9.04 g, yield 97%).
Reaction SMILES: [CH:1](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:20].[Na+].OO>C(O)C>[CH2:17]([O:16][C:14]([C:8]1([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:20]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)OC1c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
50 g of benzylidenemalonic acid, diethyl ester, (E. H. Kroeker, et al., J. Am. Chem. Soc., 56, 1171-3 (1934)) and 10 ml of 10% aqueous sodium bicarbonate were mixed with 100 ml of ethanol. 42 ml of 30% hydrogen peroxide was added dropwise over a 5-hour period at 70° C. Then 30 ml of 30% hydrogen peroxide was added over a one-hour period at 60° C. 100 ml of ethanol was added and the mixture was stirred for 8 hours at 60° C. The solvent was evaporated and the residue was extracted with methylene chloride. The solvent was evaporated from the separated extract and the residue was distilled to give ethyl 2-(ethoxycarbonyl)-3-phenyloxiranecarboxylate (6A), as a fraction boiling at 178°-180° C. at 0.05 Torr.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH3:10])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[S:13][CH2:14][CH3:15].[CH3:16][N:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[C:20]2[CH:32]=[CH:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]=2[C:18]1=[O:45]>>[CH2:14]([S:13][C:3]1[C:4]2[NH:8][C:7](=[O:9])[N:6]([CH3:10])[C:5]=2[CH:11]=[CH:12][C:2]=1[C:21]1[C:20]2[CH:32]=[CH:33][N:34]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:19]=2[C:18](=[O:45])[N:17]([CH3:16])[CH:22]=1)[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)cn(C)c(=O)c32)cc1
Reactant: CCSc1c(Br)ccc2c1[nH]c(=O)n2C
Product: CCSc1c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc2c1[nH]c(=O)n2C

Procedure:
This compound was synthesized according to the procedure of Example 10, Step 5, using 5-bromo-4-(ethylthio)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and 6-methyl-1-[(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one as the starting materials. LCMS calculated for C25H25N4O4S2 (M+H)+: m/z=509.1. found: 509.1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[C:3]([OH:5])=[O:4].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[NH2:1][C@H:2]([CH2:6][OH:7])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: N[C@H](CO)C(=O)O
Product: COC(=O)[C@H](N)CO
Product: Cl
Yield: 100 %

Procedure:
To a solution of (R)-2-amino-3-hydroxypropanoic acid (105 g, 1 mol) in methanol (1200 mL) was added thionyl chloride (87.6 mL, 142.8 g, 1.2 mol) dropwise at 0° C. After addition, the reaction mixture was heated at reflux for 12 h. Volatiles were evaporated to give the (R)-methyl 2-amino-3-hydroxypropanoate hydrochloride salt (155 g, yield 100%) as a solid that was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.51 (brs, 2H), 4.08 (s, 1H), 3.79 (m, 2H), 3.71 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][CH:20]([CH2:23][OH:24])[O:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][CH:20]([O:21][CH3:22])[CH:23]=[O:24])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13]
Reactant: COC(CO)CO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COC(C=O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Oleyl 2-O-methyl-rac-glycerate (Compound 76) To a solution of oxalyl chloride (87 (L, 1.0 mmol) in CH2Cl2 (7 mL) at −78° C. was added DMSO (71 (L, 1.0 mmol). After 20 min, alcohol Compound 42 (0.20 g, 0.91 mmol) was added followed, after another 20 min, by the addition of triethylamine (0.63 mL, 4.6 mmol). The reaction was warmed to room temperature over a 10 min period, filtered through a plug of silica-gel, which was washed with ethyl acetate (50 mL) and concentrated to give 3-O-t-butyldimethylsilyl-2-O-methyl-rac-glyceraldehyde Compound 73 (0.20 g, 100%) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1cc([N+](=O)[O-])c(O)cc1F
Temperature: -5 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of 1-(2-fluoro-4-hydroxy-phenyl)-ethanone (5 g, 32.5 mmol) in concentrated sulfuric acid (50 mL) at −5° C. was added KNO3 (3.29 g, 32.6 mmol) in portions and the mixture was stirred for 3 h at −5° C. The mixture was poured into ice water (120 mL) and the aqueous solution was extracted with EtOAc (3×50 mL). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 2-10% EtOAc in petroleum ether) to give 1-(2-fluoro-4-hydroxy-5-nitro-phenyl)-ethanone as a yellow solid (4.59 g, 71%). 1H-NMR (CDCl3, 400 MHz): δ 10.95 (s 1H), 8.79 (d, J=7.2 Hz, 1H), 6.92 (d, J=11.2 Hz, 1H), 2.63 (d, J=5.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([Cl:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([O:13][CH2:14][CH:15]([F:17])[F:16])[N:3]=1.[F-:18].[Cs+]>CS(C)=O>[Cl:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[C:4]([O:13][CH2:14][CH:15]([F:17])[F:16])[N:3]=[C:2]2[F:18]
Reactant: [F-]
Reactant: FC(F)COc1cc2c(Cl)cccc2c(Cl)n1
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1nc(OCC(F)F)cc2c(Cl)cccc12
Temperature: 140 °C

Procedure:
To a solution of 1,5-dichloro-3-(2,2-difluoroethoxy)isoquinoline (581 mg, 2.089 mmol) in DMSO (5 mL) was added CsF (349 mg, 2.298 mmol) and heated to 140° C. for 2 hrs. LC/MS showed the desired product. The reaction was diluted with ethyl acteate and washed with water, and brine. The organic phase was collected, dried over MgSO4, and concentrated under vacuum to give the crude product as a reddish brown solid. Crude material purified via silica gel chromatography (90 g column; 0-40% EtOAc:Hex) to get the product 5-chloro-3-(2,2-difluoroethoxy)-1-fluoroisoquinoline (450 mg, 82% yield) as a yellow solid. MS: MS m/z 262.1(M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.Cl[CH2:14][C:15]1[N:16]=[C:17](/[CH:20]=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[O:18][CH:19]=1>>[Br:28][C:25]1[CH:26]=[CH:27][C:22](/[CH:21]=[CH:20]/[C:17]2[O:18][CH:19]=[C:15]([CH2:14][O:1][C:2]3[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=3)[N:16]=2)=[CH:23][CH:24]=1
Reactant: OCCCCc1ccc(O)cc1
Reactant: ClCc1coc(/C=C/c2ccc(Br)cc2)n1
Product: OCCCCc1ccc(OCc2coc(/C=C/c3ccc(Br)cc3)n2)cc1
Yield: 91 %

Procedure:
Using 4-(4-hydroxyphenyl)-1-butanol (4.99 g) and (E)-4-chloromethyl-2-[2-(4-bromophenyl)ethenyl]oxazole (7.43 g), the same reaction as Reference Example 17-(i) was carried out to yield 4-[4-[2-(E)-[2-(4-bromophenyl)ethenyl]-1,3-oxazol-4-yl]methoxyphenyl]-1-butanol (9.70 g). Using the compound obtained (4.28 g), the same reaction as Reference Example 17-(ii) was carried out to yield the titled compound (4.47 g) as a white powder.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[O:3][CH2:4][CH2:5][CH2:6][C:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.C([Li:18])CCC>CCOCC.CCCCCC>[CH3:13][Si:2]([CH3:1])([CH3:12])[O:3][CH2:4][CH2:5][CH2:6][C-:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.[Li+:18]
Reactant: [Li]CCCC
Reactant: C[Si](C)(C)OCCCC1=CC=CC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C[Si](C)(C)OCCC[c-]1cccc1
Product: [Li+]
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 2.62 g (13.4 mmol) of (3-trimethylsiloxypropyl)-cyclopentadiene in ether, 5.36 ml of a 2.5 M (13.4 mmol) butyl lithium solution in hexane is added at −78° C. The immediate formation of a white solid is observed. The reaction is maintained under stirring for 2 hours; then, the white suspension is brought to dryness, the resulting solid is washed twice with hexane and a powdery white solid is obtained. (2.3 g, 11.4 mmol. Yield: 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12]O)[O:9]2)=[CH:4][CH:3]=1.[N:14]1[O:15][N:16]=[C:17]2[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=12.C1(S(Cl)(=O)=O)C=CC=CC=1.[C:37]1([C@H:43]([NH2:45])[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>N1C=CC=CC=1.O>[C:37]1([C@H:43]([NH:45][CH2:12][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([NH:1][S:23]([C:22]4[C:17]5[C:18](=[N:14][O:15][N:16]=5)[CH:19]=[CH:20][CH:21]=4)(=[O:25])=[O:24])=[CH:3][CH:4]=3)[O:9]2)[CH3:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc2c(c1)OC(CO)CC2
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Reactant: C[C@@H](N)c1ccccc1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H](NCC1CCc2ccc(NS(=O)(=O)c3cccc4nonc34)cc2O1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of (7-amino-3,4-dihydro-2H-chromen-2-yl)methanol (28.6 mg, 160 μmol) in pyridine is treated with 2,1,3-benzoxadiazole-4-sulfonyl chloride (39 mg, 180 μmol) at ambient temperatures, stirred for 1 h, treated with phenylsulfonyl chloride (23 μL, 180 μmol) stirred for an additional hour at ambient temperatures, treated with (1R)-1-phenyl-1-ethanamine (1.6 mmol, 206 μL), heated to 100° C. for 2 h, cooled to room temperature, diluted with water and extracted with ethyl acetate. The extracts are combined, dried over Na2SO4 and concentrated in vacuo. The resultant residue is purified by reverse phase preparative HPLC to give the title product, M+H 465, retention time 3.89 min.
Reaction SMILES: [C:1]1(=[O:44])[N:5]([CH:6]2[C:37](=[O:38])[N:8]3[C:9]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:10]([CH2:13][S:14][C:15]4[S:16][C:17]([CH3:20])=[N:18][N:19]=4)[CH2:11][S:12][C@H:7]23)[C:4](=[O:39])[C:3]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:2]12.C1C[O:48]CC1.O.S(=O)(=O)(O)O>C(OCC)(=O)C>[C:1]([C:2]1[CH:43]=[CH:42][CH:41]=[CH:40][C:3]=1[C:4]([NH:5][CH:6]1[C:37](=[O:38])[N:8]2[C:9]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])=[C:10]([CH2:13][S:14][C:15]3[S:16][C:17]([CH3:20])=[N:18][N:19]=3)[CH2:11][S:12][C@H:7]12)=[O:39])([OH:48])=[O:44]
Reactant: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N4C(=O)c5ccccc5C4=O)[C@H]3SC2)s1
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)c4ccccc4C(=O)O)[C@H]3SC2)s1
Reaction time: 0.25 h

Procedure:
A solution of benzhydryl 7-phthalimido-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylate (2 mmol.) in 25 ml. of THF and 8 ml. of water is cooled in an ice-water bath, and 660 mg. of Na2S. 9H2O are then added. The mixture is stirred for 15 minutes, and 10 ml. of water and 40 ml. of ethyl acetate are added. The layers are separated, and a neutral material is obtained from the ethyl acetate layer. The aqueous layer is acidified to pH 4.3 with 1N sulfuric acid and is extracted twice with ethyl acetate. The ethyl acetate extract is washed, dried, and evaporated to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:14]=1[O:15]C1N=CC=C2C=CNC=12>>[Br:1][C:2]1[C:3]([O:15][C:14]2[CH:25]=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:13]=2[F:12])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Clc1c(Br)cnc2ccsc12
Product: O=[N+]([O-])c1ccc(Oc2c(Br)cnc3ccsc23)c(F)c1
Yield: 61 %

Procedure:
Starting from the compound 271 and following the procedure described above for the synthesis of compound 260 (scheme 59, example 218, step 2), title compound 272 was obtained in 61% yield as an off-white solid. MS (m/z): 368.9(M+H).
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[CH2:2].[CH2:8]([Br:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CO>C(OCC)C>[Br-:20].[CH:1]([N+:3]1[CH:7]=[CH:6][N:5]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])[CH:4]=1)=[CH2:2]
Reactant: C=Cn1ccnc1
Reactant: CCCCCCCCCCCCBr
Solvent: CO
Solvent: CCOCC
Product: C=C[n+]1ccn(CCCCCCCCCCCC)c1
Product: [Br-]
Temperature: 60 °C
Reaction time: 15 h

Procedure:
(From Yuan & Antonietti, DOI: 10.1021/ma102858b.) A solution/suspension comprising 0.1 mol of 1-vinylimidazole, 0.1 mol of n-dodecyl bromide and 30 mL of methanol were loaded into a 100 mL reactor. The mixture was stirred at 60° C. for 15 h. After cooling the reaction mixture was added dropwise into 1 L of diethyl ether. The white precipitate was filtered off and dried at room temperature to yield a powder.