Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Al:5](CC(C)C)CC(C)C)C(C)C.[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([OH:22])=[O:21])(=[O:16])[CH3:15]>O1CCCC1>[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[C:14]([O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([O-:22])=[O:21])(=[O:16])[CH3:15].[Al+3:5]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Product: [Al+3]
Temperature: 0 °C
Yield: 88.7 %

Procedure:
3.96 g of tri-isobutyl aluminum were added into 50 ml of tetrahydrofuran and the solution was cooled to 0° C. under nitrogen gas current, a solution of 10.8 g of o-acetoxybenzoic acid dissolved in 100 ml of tetrahydrofuran was added dropwise little by little to the above solution. After completion of the dropwise addition, the reaction mixture was treated in the same manner as in Example 5, followed by drying under reduced pressure. Thus, 10 g of white aluminum tris-(o-acetoxybenzoate) were obtained. The resulting aluminum salt had a molecular weight of about 570, and the average degree of polymerization was found to be about 1. The infrared absorption spectrum of the salt was as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH3:17])=[N:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[CH:12][C:13]([CH:16]([OH:18])[CH3:17])=[N:14][CH:15]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a stirred solution of 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanone (100 mg, 0.4 mmol) in THF (2 mL) and methanol (2 mL) was added NaBH4 (3 mg, 0.8 mmol) at rt and the reaction was stirred at rt for about 5 min. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine solution (10 mL), organic layer was dried over Na2SO4 and concentrated under vacuum to obtain 1-(5-(4-nitrophenyl)pyridin-2-yl)ethanol as off white solid (100 mg, 100% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.88 (d, 1H), 8.31 (d, 2H), 8.19 (dd, 1H), 8.01 (d, 2H), 7.64 (d, 1H), 5.43 (d, 1H), 4.78 (t, 1H), and 1.38 (t, 3H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]1([CH3:20])[CH3:19].[C:21](Cl)(=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:11]([O:10][CH:5]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([O:1][C:21](=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:3]([CH3:20])([CH3:19])[CH2:4]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)ON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Yield: 60 %

Procedure:
Using 1-hydroxy-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, prepared as described by Kurumada T. et. al., loc.cit., and stearoyl chloride in a procedure otherwise similar to the preparation of the compound 101 gives a 60% yield of the compound 109 which is obtained in the form of colourless crystals; melting point: 85-89° C. (acetonitrile).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([CH:18]1[CH2:19][C:14]([N:13]([CH3:27])[CH3:12])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15][CH2:16][C:17]1=[O:20])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(=O)C(Cc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Diisopropylamine (2.1 ml, 15 mmol) was provided in dry THF (30 ml) in argon and mixed with a solution of butyl lithium in hexane (2.5M, 6 ml, 15 mmol) at −30° C. (bath temperature. The reaction mixture was cooled to −78° C. After this temperature was reached, 4-(dimethylamino)-4-phenylcyclohexanone (2.17 g, 10 mmol), dissolved in dry THF (10 ml), was added in drops within 15 min. The batch was left for 30 min at −78° C. Benzyl bromide (3.6 ml, 30 mmol), dissolved in dry THF (20 ml), was then added within 10 min. The reaction mixture was stirred for a further 15 min at 78° C. (?), then the cooling removed. After room temperature was reached, the batch was stirred for a further 18 h. For work up the batch was carefully mixed with water (1 ml), then saturated NH4Cl solution (40 ml) was added. The organic phase was separated and the aqueous solution extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with saturated NH4Cl solution (2×40 ml). The organic phases were then mixed with 1N HCl (50 ml) and thoroughly shaken out. The acid aqueous phase was separated, the organic phase washed with water (2×20 ml). The combined aqueous phases were washed with ethyl acetate (1×30 ml). The aqueous solution was then placed on 70 ml of 2N NaOH. An oil separated out of the alkaline solution. The formed mixture was extracted with ethyl acetate (3×30 ml). The combined organic phases were dried over MgSO4 and then concentrated to low volume. One of the possible diastereoisomers was isolated from the residue (2.27 g) by chromatographic purification [silica gel 60 (50 g); ethyl acetate (1000 ml)].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9](Cl)=[O:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14]1>>[C:20]1([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][C@H:13]([NH:12][C:9]([C:4]34[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]3)[CH2:2][CH2:3]4)=[O:10])[CH2:14]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)C12CCN(CC1)CC2
Reactant: N[C@H]1CCN(CCc2ccccc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccccc2)C1)C12CCN(CC1)CC2

Procedure:
1-Azabicyclo[2.2.2]octane-4-carbonyl chloride and (S)-3-amino-1-(2-phenylethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-phenylethyl)pyrrolidin-3-yl)-1-azabicyclo[2.2.2]octane-4-carboxamide.
Reaction SMILES: [C:1]1([C:7]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]([NH2:33])[CH3:32])=[CH:25][CH:24]=1.CN1CCOCC1>C(Cl)Cl.CN(C)C=O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:31]([NH:33][C:12]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11]2)=[O:14])[CH3:32])=[CH:27][CH:28]=1
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CC(N)C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(NC(=O)C1(c2ccccc2)CCCC1)C(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of phenylcyclopentanecarboxylic acid (Aldrich, 23 mg, 0.12 mmol) in methylene chloride (1 mL) at 0° C. was added a drop of dimethylformamide and oxalyl chloride (0.025 mL, 0.29 mmol). After stirring at room temperature for 1 h, the reaction mixture was concentrated on a rotary evaporator and dried under vacuum, and the resulting crude acyl chloride was used without further purification. The crude acyl chloride was dissolved in 1 mL of methylene chloride and was added to a suspension of N-[3-(4-chlorophenyl)-2-phenyl-1-methylpropyl]-amine hydrochloride (Reference Example 2) (diastereomer α, 30 mg, 0.10 mmol) and N-methylmorpholine (0.053 mL, 0.48 mmol) in 1 mL of methylene chloride. After stirring at room temperature overnight, the reaction mixture was loaded onto a silica gel column, which was eluted with 10% ethyl acetate to give the title compound. 1H NMR (400 MHz, CD3OD): δ 7.45 (d, 2H), 7.35-7.08 (m, 6 H), 6.97 (d, 2H) 6.90 (d, 2H), 6.59 (d, 2H), 4.19 (m, 1H), 2.74-2.45 (m, 5), 2.12-1.65 (m, 6H), 0.79 (d, 3H). LC-MS: m/e 432 (M+H)+ (4.4 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][CH2:12][C:11](=O)/[C:10]/2=[CH:15]\[N:16](C)C)[CH:5]=[CH:6][C:7]=1[F:8].O.[NH2:20]N>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[CH:15]=[N:16][NH:20][C:11]=3[CH2:12][CH2:13]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)/C=C1\C(=O)CCC1c1ccc(F)c(F)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Fc1ccc(C2CCc3[nH]ncc32)cc1F
Temperature: 80 °C
Yield: 28 %

Procedure:
To the mixture of (+/−)-(2Z)-3-(3,4-difluorophenyl)-2-((dimethylamino)methylene)cyclopentanone (8.5 g, 34 mmol) in ethanol (200 mL), is added hydrazine hydrate (15 mL) and the mixture is heated to 80° C., overnight. The mixture is cooled to room temperature and concentrated in vacuo. The residue is purified by preparative HPLC using a CXTH instrument with a DAISO 10 μC18 250×50 mm column, a 9 mL injection, a flow rate of 70 mL/min, a wavelength of 214 nm and a mobile phase of 10-80% acetonitrile in 0.1% TFA/H2O to give the title compound as a white solid (2.1 g, 28%). ES/MS m/z 221 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:19](=[CH:20][CH:21]=2)[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[C:46]6[CH:45]=[C:44]7[C:47]([CH3:55])([CH3:54])[C:48]8[C:53]([C:43]7=[CH:42][C:41]=6C6C5=CC=CC=6)=[CH:52][CH:51]=[CH:50][CH:49]=8)=[CH:30][CH:29]=4)=[CH:24][CH:23]=2)[C:17]2[CH:16]=[C:15]4[C:56]([CH3:64])([CH3:63])[C:57]5[C:62]([C:14]4=[CH:13][C:12]3=2)=[CH:61][CH:60]=[CH:59][CH:58]=5)O1.Cl[C:67]1[N:72]=[C:71]([C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)[N:70]=[C:69]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[N:68]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:91]1(C)[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:91]1([C:67]2[N:72]=[C:71]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[N:70]=[C:69]([C:79]3[CH:84]=[C:83]4[C:82](=[CH:81][CH:80]=3)[N:34]([C:31]3[CH:30]=[CH:29][C:28]([C:25]5[CH:24]=[CH:23][C:22]([N:18]6[C:17]7[CH:16]=[C:15]8[C:56]([CH3:63])([CH3:64])[C:57]9[C:62]([C:14]8=[CH:13][C:12]=7[C:11]7[C:19]6=[CH:20][CH:21]=[CH:9][CH:10]=7)=[CH:61][CH:60]=[CH:59][CH:58]=9)=[CH:27][CH:26]=5)=[CH:33][CH:32]=3)[C:46]3[CH:45]=[C:44]5[C:47]([CH3:55])([CH3:54])[C:48]6[C:53]([C:43]5=[CH:42][C:41]4=3)=[CH:52][CH:51]=[CH:50][CH:49]=6)[N:68]=2)[CH:96]=[CH:95][CH:94]=[CH:93][CH:92]=1
Reactant: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(B8OC(C)(C)C(C)(C)O8)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)c2ccccc2-c2cc3c4ccccc4n(-c4ccc(-c5ccc(-n6c7ccc(-c8nc(-c9ccccc9)nc(-c9ccccc9)n8)cc7c7cc8c(cc76)C(C)(C)c6ccccc6-8)cc5)cc4)c3cc21

Procedure:
6.0 g (7.0 mmol) of 4-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)-4′-(12,12-dimethyl-10,12-dihydro-10-azaindeno[2,1-b]fluoren-10-yl)biphenyl, 1.9 g (7.1 mmol) of 2-chloro-4,6-diphenyl-1,3,5-triazine and 0.83 g (7.8 mmol) of sodium carbonate are suspended in 400 ml of dioxane, 400 ml of toluene and 200 ml of water. 0.42 g (3.6 mmol) of Pd(PPh3)4 is added to this suspension. The reaction mixture is heated under reflux for 5 h. After cooling, the precipitated solid is filtered off with suction, washed with water and ethanol and dried. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield after sublimation is 5.2 g (5 mmol, 77%) with a purity of 99.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=O)[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:32])=O>C1(C)C=CC=CC=1>[Cl:32][C:17]1[C:16]2[C:11](=[CH:12][C:13]([CH3:20])=[CH:14][CH:15]=2)[N:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:18]=1
Reactant: COc1ccccc1-c1nc2cc(C)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nc(Cl)c2ccc(C)cc2n1
Temperature: 80 °C

Procedure:
To a mechanically stirred suspension of 2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1 L toluene was added diisopropyl ethylamine (100 mL), followed by phosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was distilled under reduced pressure to remove toluene, and the resulting residue was dissolved in 2.2 L CH2Cl2. Ice water was added, and the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate solution while maintaining the temperature below 20° C. The resulting organic layer was separated and the aqueous solution extracted with CH2Cl2, then the combined the organic layers were dried over sodium sulfate and distilled under reduced pressure. The crude product was dissolved 2:1 CH2Cl2/hexane, and the solution was passed through silica gel (2.5 kg, 60-120 mesh), followed by washing the silica bed with 2:1 CH2Cl2/hexane until the product eluted. The pure fractions were collected and combined, and the solvent was removed under reduced pressure. Hexane (500 mL) was added, and the mixture was stirred and filtered to give 4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white to off-white solid (77 g, 72%). mp 161-164° C. 1H NMR (CDCl3) δ 2.6 (s, 3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2 (d, 1H) ppm; 13C NMR (CDCl3) δ 22.23, 56.06, 112.2, 120.26, 120.69, 125.34, 127.94, 130.45, 131.08, 131.08. M/z (obs., [m+H]+)=285.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O1CCOCC1>[CH3:14][N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[N:4]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CI
Product: Cn1nnc(-c2ccc(C=O)cc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
With ice-cooling, a solution of 75.5 g (0.434 mol) of 4-(tetrazol-5-yl)-benzaldehyde (Example 25a) in 550 ml of DMF/dioxane 1:1 is added dropwise to 179.7 g (1.30 mol) of K2CO3 in 200 ml of DMF/dioxane 1:1; the mixture is stirred for 30 min and then 40 ml (0.64 mol) of methyl iodide are added. The mixture is stirred in an ice bath for 3 hours and, finally, at room temperature for 15 hours; the reaction mixture is poured into 2.8 litres of ice-water and stirred for 10 min; the title compound is filtered off and washed with water: m.p.: 137°-139° C.; 1H-NMR (CD3OD/CDCl3) d 10.05 (s, HCO), 8.29 and 8.03 (2d, J=8, each 2H), 4.43 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14].I[CH3:36]>CN(C=O)C>[CH3:3][O:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[S:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1)([O:17][CH3:36])[C:13]([F:15])([F:14])[F:16]
Reactant: CI
Reactant: COCCn1cccc1C(O)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCn1cccc1C(OC)(c1ccc(N(C)S(=O)(=O)c2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a suspension of 3.8 mg of NaH (0.10 mmol) in 3 mL of DMF at 0° C. was added 32 mg of N-(4-{1-[1-(2-methoxyethyl)-1H-pyrrol-2-yl]-2,2,2-trifluoro-1-hydroxyethyl}-phenyl)-N-methyl-benzenesulfonamide (Example 79, 0.068 mmol) and the reaction mixture was stirred at 0° C. for 35 min. 6 μL of iodomethane (0.089 mmol) was added and the reaction mixture allowed to warm to room temperature and stirred for 2.5 h. The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:EtOAc, 9:1) to give the title compound.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[OH2:11].[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[NH2:19])=[N:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(S)[nH]c2c1
Reactant: Nc1ccccc1CCl
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Product: O
Yield: 106.1 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.00 g of 2-mercapto-5-ethoxybenzimidazole instead of 2-mercaptobenzimidazole and 2.76 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in 250 ml of isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Crystallization during concentration of the dichloromethane extract gave 2.60 g of the title compound as the monohydrate: m.p. 87-89° C. Analysis. Calc'd. for C16H17N3OS*H2O: C, 63.76; H, 5.68; N, 13.94; S, 10.64. Found: C, 63,65; H, 5.74; N, 13.89; S, 10.89.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:24])=[O:23])=O)C1C=CC=CC=1.C(OCC)C>Br.C(O)(=O)C>[NH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][CH:16]=[C:17]2[S:22]([NH:25][C:26]1[C:31]([O:32][CH3:33])=[N:30][C:29]([Br:34])=[CH:28][N:27]=1)(=[O:23])=[O:24]
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(=O)OCc3ccccc3)cccc12
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(N)cccc12
Reaction time: 1 h
Yield: 13.3 %

Procedure:
5-(N-Benzyloxycarbonylamino)-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.7 g) was dissolved in 33% hydrobromic acid in acetic acid (14 ml) and the resulting solution was stirred for 1 hour. Diethyl ether (60 ml) was added and after 10 minutes further stirring, the mixture was filtered. The solid was dissolved in water (5 ml), basified to pH 8 by the addition of 1N aqueous sodium hydroxide and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (10 g), eluting with a gradient of 20-50% ethyl acetate in hexane to give 5-amino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.07 g); 1H NMR (d6 -DMSO): 3.82 (s,3H), 6.78 (d,1H), 7.35 (t,1H), 7.50 (t,1H), 7.78 (s,1H), 7.91 (d,1H), 8.25 (d,1H), 8.40 (d,1H); mass spectrum (+ve FAB, methanol/NBA): 409 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C.[Br:20][CH2:21][C:22](Br)=[O:23]>C(Cl)Cl.C(OCC)(=O)C.[Na+].[Cl-]>[Br:20][CH2:21][C:22]([NH:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])=[O:23]
Reactant: CC(C)(C)C(=O)c1occc1N
Reactant: O=C(Br)CBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1occc1NC(=O)CBr
Temperature: 0 °C
Yield: 94.6 %

Procedure:
The 3-amino-2-pivaloylfuran (1.33 g, 8.0 mmol) was dissolved in methylene chloride (15 ml) under nitrogen and the solution was cooled to 0° C. Triethylamine (1.34 ml, 9.6 mmol) was added followed by 2-bromoacetyl bromide (1.94 g, 9.6 mmol) added dropwise over 1/4 hour. The mixture was stirred at ambient temperature over night. The reaction was diluted with ethyl acetate (25 ml) and saturated NaCl (10 ml). The organic layer was separated, washed with saturated NaCl, dried over Na2SO4, filtered and concentrated in vacuo. A brown oil (2.18 g) was obtained in theoretical yield.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19].C(N(CC)CC)C.CN(C)[CH:33]=[O:34]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[C:14][C:16]1[CH:23]=[CH:22][C:21]([O:34][CH3:33])=[CH:20][C:17]=1[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCCCCOCc1ccccc1
Reactant: CN(C)C=O
Reactant: O=Cc1ccccc1Br
Solvent: CCN(CC)CC
Product: COc1ccc(C#CCCCCOCc2ccccc2)c(C=O)c1

Procedure:
6-Benzyloxy-1-hexyne (5.60 g) and 2-bromo-benzaldehyde (2.90 g) were reacted in dimethylformamide (30 ml), in the presence of dichloro-bis-triphenylphosphinepalladium (0.40 g), cuprous iodide (0.20 g) and triethylamine (2.5 ml) in nitrogen atmosphere at 50° C. for 6 hr. The resulting reaction solution was evaporated, and ethyl acetate and water were added to the resulting residue. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 2.60 g of the title compound as a pale yellow oil.
Reaction SMILES: ClCCl.[CH3:4][C:5]([NH:15][CH:16]([CH3:20])[C:17](=O)[CH3:18])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](Cl)=[O:30].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH3:6][C:5]([N:15]1[CH:16]([CH3:20])[C:17]([CH3:18])=[C:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])[C:29]1=[O:30])([C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]([Cl:14])[CH:8]=1)[CH3:4]
Reactant: O=C(Cl)Cc1ccccc1F
Reactant: CC(=O)C(C)NC(C)(C)c1cc(F)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(c2ccccc2F)C(=O)N(C(C)(C)c2cc(F)cc(Cl)c2)C1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To 20 ml of dichloromethane were added 3.0 g of N-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-N-(1-methyl-2-oxopropyl)amine and 3.5 g of pyridine, and 3.0 g of (2-fluorophenyl)acetyl chloride was then added dropwise thereto at 5° to 10° C. After stirring at room temperature for 1 hour, a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with dichloromethane. After dried over anhydrous sodium sulfate, the solution was concentrated by evaporation, and the resulting oil was dissolved in 20 ml of ethyl acetate. Next, 10 ml of a 28% methanol solution of sodium methylate was added thereto, and after stirring under reflux for 15 minutes, the temperature of the solution was returned to room temperature and water was then added, followed by extraction with ethyl acetate. Afterward, the solution was washed with 12% hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, and then dried over anhydrous sodium sulfate. Next, the solution was condensed by an evaporator, and then subjected to silica gel chromatography to obtain 2.2 g of 1-[1-methyl-1-(3-chloro-5-fluorophenyl)ethyl]-4,5-dimethyl-3-(2-fluorophenyl)-3-pyrroline-2-one.