Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1COCC1.[CH3:26][C:27]#[N:28].F[C:30]1[N:35]=[CH:34][C:33]([C:36]2[CH:50]=[CH:49][C:39]([O:40][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>C1COCC1>[O:46]1[CH2:47][CH2:48][N:43]([CH2:42][CH2:41][O:40][C:39]2[CH:49]=[CH:50][C:36]([C:33]3[CH:32]=[CH:31][C:30]([CH2:26][C:27]#[N:28])=[N:35][CH:34]=3)=[CH:37][CH:38]=2)[CH2:44][CH2:45]1
Reactant: CC#N
Reactant: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A 3 L three-necked round-bottomed flask was equipped with mechanical stirrer, thermometer and adapter, additional funnel, and nitrogen inlet (on top of addition funnel, positive pressure through a bubbler). With a rapid stream of nitrogen going through the bubbler, the stopper was removed and the flask was charged with KHMDS (415.8 g, 2.08 mol) and then anhydrous THF (1 L). To the stirred and cooled (ice/methanol bath, internal temperature of solution was −8° C.) KHMDS/THF solution was added dropwise a solution of MeCN (70 g) in THF (110 mL) over a period of 22 min followed immediately by the relatively rapid (4 min) addition of a solution of 5 (79.06 g, 0.262 mol) in THF (400 mL), after which time the internal temperature of the reaction mixture had reached 10° C. With continued cooling (1 h) the internal temperature was −6° C. and by TLC the reaction appeared complete. After an additional 30 min (internal temperature of −3° C.), the reaction mixture was quenched with saturated brine (1 L) and diluted with EtOAc (500 mL). After removing the aqueous layer, the organic solution was dried (Na2SO4), filtered, and evaporated to dryness (to an oil) followed by completely dissolving in IPA (150 mL), diluting with heptane (300 mL), adding seed crystals (prepared by dissolving ˜100 mg of crude oil in IPA (˜150 mg) and diluting with heptane (˜2.5 mL)), and allowing to stand overnight. After stirring to break up the crystalline solid, the solid was filtered, washed with 250 mL 2:1 heptane/IPA and then multiple washes with heptane and air dried to give 64.38 g (yield of 76%) of title product 6 as a crystalline tan solid (LC purity of 99.3%). Another 5.88 g of less pure material was obtained from the filtrate.
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(C(C)=O)C(C)C>[C:20]([O:12][C:2]1([CH3:1])[CH:3]2[CH2:11][CH:7]3[CH2:6][CH:5]([CH2:10][CH:9]1[CH2:8]3)[CH2:4]2)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)Cl
Reactant: CC1(O)C2CC3CC(C2)CC1C3
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: C=C(C)C(=O)OC1(C)C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A vessel was charged with 83.1 g of 2-methyl-2-adamantanol and 101 g of triethylamine, and 200 g of methyl isobutyl ketone was added thereto to form a solution. To the solution was added dropwise 78.4 g of methacrylic acid chloride(1.5 times the molar amount of 2-methyl-2-adamantanol), followed by stirring for about 10 hours at room temperature. After filtration, the resulting organic layer was washed with an aqueous solution of 5 wt % sodium bicarbonate and then washed with water twice. The organic layer was concentrated and then distilled under reduced pressure to obtain 2-methyl-2-adamantyl methacrylate represented by the following formula.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]CCCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].CCCCCC>C1COCC1>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: c1ccsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
Thiophene (2.0 g, 12 mmol) was dissolved in anhydrous THF (20 mL) and n-BuLi (9.52 mL, 23.8 mmol, 2.5 M in hexane) slowly added at −30° C. under nitrogen flow. After stirring for 1 hour, tributyltin chloride (7.75 mL, 23.8 mmol) was added. After heating to room temperature, followed by stirring for 3 hours, the reaction was terminated. The produced compound was extracted with n-hexane and distilled water, dried with anhydrous MgSO4 and filtered under reduced pressure. The final product tributyl-2-thienylstannane (2.5 g, yield: 46%) was obtained by column chromatography (neutral alumina, n-hexane). The product was used in the next step after removing the solvent.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[N:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCOCC.[Mg+2].[Br-].[Br-].[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][N:36]=[C:35]([CH3:38])[C:34]=2[CH:39]=[O:40])=[CH:29][CH:28]=1>C1COCC1>[CH2:1]([C:8]1[O:9][C:10]([CH:39]([C:34]2[C:35]([CH3:38])=[N:36][O:37][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([Br:26])=[CH:28][CH:29]=2)[OH:40])=[N:11][N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2nnco2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(Cc2ccccc2)o1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
2-Benzyl-[1,3,4]oxadiazole (0.500 g, 3.12 mmol) was dissolved in THF and cooled to −70° C. then n-butyllithium (1.5M in THF, 2.1 mL, 3.12 mmol) was added and the reaction stirred for 1.5 hours. Magnesium bromide ethyl etherate (0.631 g, 3.43 mmol) was added and the reaction was allowed to warm to −45° C. After 45 minutes 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde (0.415 g, 1.56 mmol) in THF (2 mL) was added and the reaction was allowed to stir overnight. The reaction was quenched with aqueous ammonium chloride then submitted to standard workup and purification via silica gel chromatography (0-60% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:14]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C=O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
A mixture of 2-hydroxy-4-methoxymethoxybenzaldehyde (17.1 g), benzyl bromide (19.33 g), anhydrous potassium carbonate (13.0 g) and N,N-dimethylformamide (200 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-4-methoxymethoxybenzaldehyde as a colorless oil (25.3 g, 99%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH3:10]>C1COCC1>[Br:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: N
Solvent: C1CCOC1
Product: Nc1nc(Cl)ncc1Br
Reaction time: 15 h

Procedure:
A solution of 5-bromo-2,4-dichloropyrimidine (25g, 110 mmol) in 200 mL THF is treated with 47 mL of ammonia (330 mmol, 7.0M solution in methanol). After stirring for 15 hours the solution is concentrated under reduced pressure and purified by short-filtration (SiO2, Hexanes: Ethyl acetate/1:1) to yield 21g (92%) of 1 as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=O.[NH2:15][C@H:16]([C:19]([OH:21])=[O:20])[CH2:17][SH:18].O>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:15][CH:16]([C:19]([OH:21])=[O:20])[CH2:17][S:18]1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=C(c1ccccn1)c1ccccn1
Solvent: O
Solvent: CCO
Product: O=C(O)C1CSC(c2ccccn2)(c2ccccn2)N1
Yield: 11 %

Procedure:
A mixture of 3.68 g of di-2-pyridyl ketone, 2.42 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 3.5 hours. After allowing the mixture to cool, the insoluble matter was filtered off, and the filtrate was concentrated to dryness under reduced pressure. The residue was washed in sequence with ethyl acetate and ether to give 0.63 g of 2,2-di(2-pyridyl)thiazolidine-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:8]1[NH:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(Cc2ccccc2)[nH]1

Procedure:
A mixture of Ethyl 5-benzylpyrrole-2-carboxylate (0.7 g, 3.05 mmol; Elder et al., Synthetic Communications, 19, 763-767 (1989)), ethanol (20 ml) and 1M sodium hydroxide (9.2 ml, 9.2 mmol) was stirred and heated under reflux for 3 h. The major part of the ethanol was removed and the remaining liquid was diluted with water, washed with ether, cooled in ice and acidified with concentrated hydrochloric acid. The mixture was extracted with ether. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to afford 0.567 g (92%) of an off white solid: mp. 130-134° C.; 1H NMR(CDCl3) δ 8.87 (1H, brs), 7.37-6.95 (5H, m), 6.97 (1H, m), 6.07 (1H, m), 4.00 (2H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:8]([C:7]1[C:2]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cccnc1-n1cccn1
Temperature: 25 °C
Reaction time: 96 h
Yield: 59.3 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (942 mg, 5.94 mmol), pyrazole (967 mg, 14.2 mmol) and powdered potassium carbonate (2 g) in DM[(10 mL) was stirred vigorously at room temperature for 4 days. The mixture was diluted with water, causing precipitation of a solid, which was filtered and dried, affording 670 mg (63%) of 3-nitro-2-(pyrazol-1-yl)pyridine. 1H NMR (CDCl3) δ6.51 (m, 1), 7.37 (dd, 1 J=5, 8), 7.76 (m, 1) 8.03 (dd, 1, J=2, 8), 8.40 (m, 1), 8.60 (dd, 1, J=2, 5).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 121.5 %

Procedure:
The reaction was prepared in 2 batches, with both batches purified together. The amounts of reactants and product reflect the sum of both batches. To 1,1-dimethylethyl 4-(2-hydroxyethyl)-1-piperidinecarboxylate (172 g, 750 mmol) in DCM (4 L) was added TEA (304 g, 1.50 mol). The mixture was cooled 0° C. and methanesulfonyl chloride (190 g, 827 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. The reaction was determined to be complete by TLC. The reaction was diluted with DCM and washed with saturated Na2CO3 and the aqueous layer was separated. The organic layer was dried (Na2SO4), and rotovapped down to provide the title compound of Step B (280 g, 911 mmol, 61%). 1H NMR (400 MHz, CDCl3) δ 0.95-1.15 (m, 2H), 1.38 (s, 9H), 1.47-1.68 (m, 5H), 2.53-2.70 (m, 2H), 2.94 (s, 3H), 3.95-4.10 (m, 2H), 4.21 (t, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH2:23]([O:22][C:20](=[O:21])[C:19]([O:17][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][C:13]=1[CH:14]=[O:15])([CH3:26])[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1C=O
Yield: 82.8 %

Procedure:
5-Benzyloxy-2-hydroxy-benzaldehyde (Kappe, T.; Witoszynskyj, T. Arch. Pharm., 1975, 308 (5), 339-346) (169 g, 741 mmol), ethyl bromoisobutyrate (164 mL, 1.11 mol), and cesium carbonate (240 g, 741 mmol) in dry DMF (600 mL) were heated at 80° C. for 15 h. Additional cesium carbonate (5 g) and ethyl bromoisobutyrate (20 mL) were added, and the reaction mixture was heated for 6 h. The reaction mixture was cooled, diluted with EtOAc (4 L), and washed with water (3×2 L). The organic layer was dried (Na2SO4) and concentrated to a brown oil. The crude product was recrystallized from EtOAc (150 mL) with hexanes until turbid to give the title compound as a pale yellow solid (210 g, 83%): mp 65° C.; 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=7.1 Hz), 1.62 (s, 6H), 4.23 (q, 2H, J=7.1 Hz), 6.81 (d, 1H, J=8.8 Hz), 7.10 (dd, 1H, J=4.6, 9.0 Hz), 7.30-7.43 (m, 6H); MS (ES) m/e 343.1 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)cn1
Solvent: ClCCl
Product: Fc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-methanol (945 mg, 7.43 mmol) described in Manufacturing Example 41-1-1 in methylene chloride (70 mL) was added dropwise thionyl chloride (813 μL, 11.1 mmol) at room temperature, which was stirred for 30 minutes. This reaction solution was partitioned by addition of water, sodium hydrogencarbonate and methylene chloride. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:diethyl ether=1:1) to obtain the title compound (761.1 mg, 70%).
Reaction SMILES: [C:1]([O:7]C)(=O)[CH2:2][C:3]([CH3:5])=O.Cl.[CH:10]1([NH:16][NH2:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+]>>[CH:10]1([N:16]2[C:1](=[O:7])[CH2:2][C:3]([CH3:5])=[N:17]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COC(=O)CC(C)=O
Reactant: NNC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC1=NN(C2CCCCC2)C(=O)C1
Temperature: 120 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 14.5 ml (0.134 mol) of methyl acetoacetate and 20.2 g (0.134 mol) of cyclohexylhydrazine hydrochloride was stirred at 120° C. for 2 hours, and then cooled. The reaction mixture was neutralized with 30 ml of a 4M aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. Hexane was added to the residue, and precipitated crystals were collected by filtration to obtain 19.0 g (79%) of the captioned compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:14]1([O:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[O:20]([C:21]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(C)CCO
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)CCOC(=O)Oc1ccccc1

Procedure:
To a 500 ml three-necked round-bottomed flask equipped with an internal thermometer, reflux condenser, mechanical stirrer, addition funnel, and argon inlet are added N,N-dimethylethanolamine (25.00 g, 0.281 mol), toluene (200 ml), and triethylamine (31.21 g, 0.309 mol). The mixture is treated with a solution of phenylchloroformate (43.91 g, 0.281 mol) dissolved in 50 ml of toluene over 15 min. After addition is complete, the mixture is heated to reflux for 3 h. The cooled mixture is washed with saturated sodium bicarbonate solution (2×100 ml) and water (100 ml). The organic phase is dried over MgSO4, filtered, and concentrated first by rotary evaporation at 50° C. (water aspirator vacuum) and then at 60° C. (0.05 mmHg) in a Kugelrohr oven to give 8 as a light yellow oil, 49.93 g (85%) that crystallizes on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(OCC)(=O)C.[N:15]#[C:16]Br.[OH-]>O>[NH2:15][C:16]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1O
Reactant: N#CBr
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc2ccccc2o1
Temperature: 45 °C
Reaction time: 12 h
Yield: 88.2 %

Procedure:
A mixture of 2.5 g 2-aminophenol (6-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of podium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (6-2).
Reaction SMILES: C([O:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1)C.[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC>[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[N:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[CH:5]=1
Reactant: CCOc1ccc2nc(S(N)(=O)=O)sc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Product: NS(=O)(=O)c1nc2ccc(O)cc2s1
Yield: 42.1 %

Procedure:
A stirred mixture of 6-ethoxy-2-benzothiazolesulfonamide (20 g.) and aluminum chloride (40 g.) in heptane (500 ml) was heated at reflux for 4 hours and cooled. The heptane was decanted from the reaction mixture which was then treated with ice water (500 ml.). After 1/2 hour the crude product was filtered, dissolved in warm dilute sodium hydroxide, filtered and acidified with concentrated hydrochloric acid to give 7.5 g of 6-hydroxy-2-benzothiazolesulfonamide which melts at 225°-228° C. after recrystallization from acetic acid.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1>[Pd]>[F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([NH2:10])[CH:3]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: Nc1cc(F)c(F)cc1N

Procedure:
Five grams of 4,5-difluoro2-nitroaniline is hydrogenated in the presence of Pd/C to give 4,5-difluoro-1,2-phenylenediamine, which is then converted to 5,6-difuoro-2-methylbenzimidazole using the method of Example 1. A solution of 5,6-difluoro-2-methylbenzimidazole and 10 equivalents of iodoethane in DMF is stirred at 100° C. for about 5 hours. After the reaction mixture has cooled to room temperature, the product is precipitated by the addition of diethyl ether. The precipitate is collected by suction filtration, and then resuspended in water, followed by brief stirring. The solid is collected again by suction filtration and dried at 50° C. under vacuum.
Reaction SMILES: CC1(C)[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19][I:20])[O:6][C@H:7]2[N:10]2[C:16](=[O:17])[NH:15][C:13](=[O:14])[C:12]([F:18])=[CH:11]2)[O:3]1>FC(F)(F)C(O)=O.O>[I:20][CH2:19][C@H:5]1[O:6][C@@H:7]([N:10]2[CH:11]=[C:12]([F:18])[C:13](=[O:14])[NH:15][C:16]2=[O:17])[C@H:8]([OH:9])[C@@H:4]1[OH:3]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(=O)[nH]c1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CI)[C@@H](O)[C@H]2O)cc1F

Procedure:
5'-Deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorouridine (4 g) was treated with trifluoroacetic acid/water (9:1, 30 ml) for 15 minutes at room temperature. The solution was evaporated to dryness, co-evaporated with ethanol (2 × 100 ml) and the residue was recrystallized from ethyl acetate. Yield = 1.865 g (88%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Cl:25]>C(OC(=O)C)C>[Cl:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc(OCCCCCCl)cc1
Reaction time: 8 h
Yield: 90 %

Procedure:
While 70 g of 4-hydroxybenzonitrile (7) were added to 500 ml of acetonitrile and stirred, 85.3 g of potassium carbonate and 77.4 ml of 1-bromo-5-chloropentane were added. Subsequently, the temperature was gradually increased and stirring under reflux was continued for 8 hr, and then stirring was further continued at room temperature for 18 hr. After the reaction was completed, the resultant reaction mixture was added with 500 ml of ethylacetate and then washed with water. Thereafter, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated compound was dissolved in 280 ml of methanol, stirred at 0° C. for 2 hr, and then filtered, thus obtaining 118 g (yield: 90%) of a title compound as a white solid.
Reaction SMILES: [CH3:1][OH:2].C[O-].[Na+].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[N:8]=1>CO>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:2][CH3:1])[N:8]=1
Reactant: Brc1cccc(Br)n1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1cccc(Br)n1
Temperature: 80 °C

Procedure:
250 ml of 28% sodium methoxide methanol solution was added dropwise into a mixture of 200 g of 2,6-dibromopyridine and 150 ml of methanol while heating at 80° C. stirring in an oil bath, followed by stirring under heating for 2 hours as it was. After cooling as it was, the mixture was extracted with diethyl ether-water, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 150 g of the target compound.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].C([Li])CCC.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1>[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C

Procedure:
Prepared in analogy to Example 44(a) from 1-(dimethylsulfamoyl)-imidazole, butyl lithium and tert-butyldimethylsilyl chloride in tetrahydrofuran to afford 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide, then treatment of this with butyl lithium and 2-ethyl-6-fluoro-benzaldehyde in tetrahydrofuran. White crystalline solid. MS (ISP): 442.1 ([M+H]+).