Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]([C:7]1[CH:16]=[CH:15][C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:9][CH:8]=1)[CH3:6])=[O:4].[OH-].[Na+].C(C1C=CC(C(=O)CC)=CC=1)C(C)C.S(=O)(=O)(O)O>CCCCCC.CO>[OH:4][C:3]([CH:5]([C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:15][CH:16]=1)[CH3:6])=[O:2]
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Agent: CCC(=O)c1ccc(CC(C)C)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
A 5.11 g. portion of the crude ibuprofen methyl ester prepared as described above was dissolved in 20 ml. of hexane and 12 ml. of methanol and cooled to 0° to 5° C. Then 6.0 g. (75 mmole) of a 50% sodium hydroxide solution was added and the resulting mixture was heated under reflux for 2 hours. On cooling, the mixture was transferred to a separatory funnel with about 50 ml. of 1 N sodium hydroxide solution and hexane. The hexane layer was extracted with about 10 ml. of 1 N aqueous sodium hydroxide and the combined aqueous layer was extracted with 50 ml. of fresh hexane. The neutral fraction isolated from the combined hexane extracts consisted primarily of p-isobutylpropiophenone. The aqueous layer was acidified with 50% aqueous sulfuric acid and extracted 3 times with 50 ml. portions of hexane. The combined hexane extracts were washed 3 times with 50 ml. portions of water and dried over sodium sulfate. Removal of solvent by vacuum evaporation gave crude ibuprofen as a pale yellow solid, weighing 4.20 g., having a purity of 96.7% by Glc analysis, again the impurities being about 1.4% p-isobutylbenzoic acid and 1.1% of the meta isomer of ibuprofen. The crude yield was 80.8% of theory. Recrystallization of the crude ibuprofen from hexane (2 ml./g.) gave 3.44 g. (70.3% chemical yield) ibuprofen.
Reaction SMILES: [CH2:1]([C:3]1([C:16](OC(C)(C)C)=[O:17])[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5][CH2:4]1)[CH3:2].[AlH4-].[Li+]>O1CCCC1.[OH-].[Na+]>[CH2:1]([C:3]1([CH2:16][OH:17])[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(C(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC1(CO)CCN(C)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred suspension of di-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (1.1 g, 3.7 mmol) in tetrahydrofuran (13 mL) was added lithium tetrahydroaluminate (1.0N solution in tetrahydrofuran, 15 mL, 15 mmol), and the mixture was stirred at ambient temperature for 6 hours. The mixture was diluted with a 1N sodium hydroxide solution (5 mL), filtered over Whatman filter paper, and the solids were washed with ethyl acetate (50 mL). The combined filtrate was separated, and the organic portion was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as a white solid, which was used in the next step without any further purification (506 mg, 57%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:20][CH3:21])[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:5][CH:4]=1.C(OC)(OC)OC.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.[BH4-].[Na+]>CO>[CH2:20]([N:8]([CH2:7][C:6]1[CH:22]=[CH:23][C:3]([CH2:2][NH:1][CH2:36][C:32]2[NH:31][CH:35]=[CH:34][N:33]=2)=[CH:4][CH:5]=1)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH3:21]
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CN)cc1
Reactant: O=Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CNCc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.7 %

Procedure:
The compound (219 mg) obtained in Example 23-6 was dissolved in anhydrous methanol (5.0 ml) and added with trimethyl orthoformate (112 μl) and 2-imidazole carboxaldehyde (72.4 mg) and the whole was stirred overnight at room temperature, under a nitrogen atmosphere. Subsequently, sodium borohydride (12.3 mg) was added thereto in an ice bath, and the whole was stirred at room temperature for 1 hour. After completion of the reaction, distilled water was added thereto and the whole was stirred for a while. The resultant was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer obtained was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (317 mg) as a yellow oily substance.
Reaction SMILES: C(O[C:6]([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C>O1CCCC1.CNC>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[C:20](=[O:21])[CH2:19][CH2:18][CH:17]4[CH3:22])=[CH:15][C:10]=3[C:9]([N:8]([CH3:40])[CH3:6])=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C)C)CC2)c(C)c1
Yield: 50.9 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 837 and 2 mol/L dimethylamine tetrahydrofuran solution (220 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (26 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C1COCC1>[Br:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:1]([CH2:10][C:9]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(Br)c2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cc(N(Cc2ccccc2)Cc2ccccc2)nc2ccccc12
Reaction time: 0.5 h
Yield: 185.2 %

Procedure:
A solution of 2-amino-4-bromoquinoline (244 mg, 1.09 mmol) in THF (5 mL) at 0° C. was treated with NaH (96 mg, 60% dispersion in oil, 2.4 mmol), stirred for 30 min, treated with benzyl bromide (0.335 mL, 2.4 mmol), stirred at room temperature for 3 days, poured into water (30 mL), extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo, purified by chromatography [SiO2; heptane-EtOAc (10:1)] and the resulting solid recystallised (MeOH) to give the product (407 mg, 99%) as a white crystalline solid: IR νmax (Nujol)/cm−1 3059, 3020, 2955, 2925, 2854, 1609, 1592, 1542, 1498, 1455, 1426 and 1358; NMR δH (400 MHz, CDCl3) 4.89 (4H, s), 7.15 (1H, s), 7.20-7.68 (11H, m),7.56 (1H, t, J 7.0 Hz), 7.69 (1H, d, J 8.7 Hz) and 7.94 (1H, d, J 8.4 Hz).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[N:13][CH:14]=1.C(Cl)(=O)C(C)(C)C.[Li].O1CCNC1=O.C([Li])CCC.[CH2:39]([C@@H:46]1[CH2:50][O:49][C:48](=[O:51])[NH:47]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[Cl-].[NH4+]>C1COCC1.C(N(CC)CC)C>[CH2:39]([C@@H:46]1[CH2:50][O:49][C:48](=[O:51])[N:47]1[C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:11]=[CH:10][C:9]([F:8])=[CH:14][N:13]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(O)/C=C/c1ccc(F)cn1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(F)cn1)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a solution of the compound (2.5 g) obtained in step 3 in THF (180 mL) were added at −78° C. pivaloyl chloride (12.9 g) and triethylamine (2.25 g) and the mixture was stirred for 2 hr. To this mixture was added at −78° C. a solution of oxazolidinone lithium anion (prepared by adding n-butyllithium (2.5M hexane solution, 5.34 mL) to (R)-4-benzyloxazolidin-2-one (1.73 g) in THF (180 mL) at −78° C. and stirring for 1 hr), and the mixture was stirred at room temperature for 18 hr. The reaction was discontinued by adding saturated aqueous ammonium chloride solution (200 mL), and the mixture was extracted with ethyl acetate (300 mL). The extract was dried, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (25% ethyl acetate/hexane) to give (4R)-4-benzyl-3-[(2E)-3-(5-fluoropyridin-2-yl)prop-2-enoyl]-1,3-oxazolidin-2-one (2.3 g, 80%) as a pale-yellow oil.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6](Cl)=[N:7][CH:8]=1.[CH2:13]([OH:15])[CH3:14]>>[Br:2][C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[C:6]([O:15][CH2:13][CH3:14])=[N:7][CH:8]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CCO
Agent: [Na]
Product: CCOc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Sodium (3.22 g) was dissolved in absolute ethanol (100 ml) and added dropwise to a suspension of 5-bromo-2-chloro-3-nitropyridine (30.2 g) in ethanol (100 ml) at 0° C. over 10 mins. The cold bath was removed and the reaction stirred at RT for 18 h. The reaction was evaporated to approximately half its volume then diluted with saturated ammonium chloride (aq) (600 ml). The reaction was stirred at RT overnight then the solids were filtered and rinsed well with water. The solids were dissolved in hot ethanol (100 ml) then diluted with hot water (500 ml) and stirred with cooling to RT for 2 hr. The solids were collected and rinsed well with water then suction dried and vacuum dried to give the title compound (26.4 g) as a dark brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[CH:11]([CH3:20])[C:10]2=[O:21])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:33][CH2:32][CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(O)C>[CH2:30]([O:29][C:27]([CH:26]1[CH2:32][CH2:33][N:23]([C:17]2[C:12]3[CH:11]([CH3:20])[C:10](=[O:21])[N:9]([C:5]4[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=4[CH3:22])[C:13]=3[N:14]=[C:15]([CH3:19])[N:16]=2)[CH2:24][CH2:25]1)=[O:28])[CH3:31]
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1nc(Cl)c2c(n1)N(c1c(C)cc(Br)cc1C)C(=O)C2C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2nc(C)nc3c2C(C)C(=O)N3c2c(C)cc(Br)cc2C)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A suspension of 7-(4-bromo-2,6-dimethylphenyl)-4-chloro-2,5-dimethyl-5,7-dihydropyrrolo[2,3-d]pyrimidin-6-one (7.5 g), ethyl isonipecotate (4.7 g), N,N-diisopropylethylamine (3.8 g) in ethanol (35 mL) was heated at reflux for 12 hours. The reaction mixture was stirred at room temperature to afford a solid. The solid was collected by filtration and washed with cold ethanol to give 1-[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid ethyl ester (7.7 g).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(N(CC)CC)C.[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>O1CCOCC1>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Temperature: 80 °C
Yield: 40.44 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 40.44% yield and used without further purification.
Reaction SMILES: O[CH:2]([C:4]1[O:5][C:6](=[O:27])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:16][CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[F:28][C:29]1[CH:30]=[C:31]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[N:43][C:44]=3[NH2:46])[NH:39][N:38]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>>[NH2:46][C:44]1[N:43]=[CH:42][N:41]=[C:40]2[N:39]([CH:2]([C:4]3[O:5][C:6](=[O:27])[C:7]4[C:12]([C:13]=3[C:14]3[CH:15]=[CH:16][C:17]([CH2:20][N:21]5[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]5)=[CH:18][CH:19]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:38]=[C:37]([C:31]3[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:29]([F:28])[CH:30]=3)[C:45]=12
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(CN2CCCCC2)cc1
Reactant: COc1cc(F)cc(-c2n[nH]c3ncnc(N)c23)c1
Product: COc1cc(F)cc(-c2nn(C(C)c3oc(=O)c4ccccc4c3-c3ccc(CN4CCCCC4)cc3)c3ncnc(N)c23)c1
Yield: 70.7 %

Procedure:
The title compound was made in a similar way as that of the example 134, step a, from 3-(1-hydroxyethyl)-4-(4-(piperidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (Intermediate B48, 720 mg, 1.981 mmol) and 3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G1, 565 mg, 2.17 mmol) to give 3-(1-(4-amino-3-(3-fluoro-5-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(4-(piperidin-1-ylmethyl)phenyl)-1H-isochromen-1-one (850 mg, 1.40 mmol, 71.0% yield) as a brown solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[O:5]CC1C=CC(Cl)=CC=1Cl.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C@@H:3]1[O:27][C@H:26]([CH2:28][O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[Cl:38])[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C@H:4]1[OH:5]
Reactant: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CO[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@H]1O
Reaction time: 27 h

Procedure:
To a solution of the product of Step 1 (171.60 g, 0.2676 mol) in 1.8 L CH2Cl2 that was cooled to 0° C., was added dropwise a solution of stannous chloride (31.522 mL, 0.2676 mol) in 134 mL CH2Cl2 while stirring. After the solution was kept at 3° C. for 27 hours, another 5.031 ml of SnCl4 (0.04282 mol) was added and the solution was kept at 3° C. overnight. After 43 hours the reaction was quenched by carefully adding the solution to 1.9 L saturated NaHCO3 solution. Tin salts were removed via filtration through celite after which the organic phace was isolated, dried with MgSO4 and evaporated in vacuo. The yield of raw, dark yellow oil was 173.6 g, which contains 2,4-dibenzoyl chloride. The crude oil was used directly in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:9]2=[O:14])([O-])=O.O.O.[Sn](Cl)Cl.O1CCCC1>>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]([CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1)[C:9]2=[O:14]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1CC1CCOCC1
Agent: Cl[Sn]Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc2c(=O)n(CC3CCOCC3)ccc12

Procedure:
5-Nitro-2-(tetrahydro-pyran-4-ylmethyl)-2H-isoquinolin-1-one (0.78 g, 0.0027 mol) and tin dichloride dihydrate (2 g, 0.01 mol) were stirred in tetrahydrofuran (10 mL, 0.1 mol) at room temperature for 24 hours. The mixture was partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3 solution, separated. The aqueous layer was extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4, and purified via flash chromatography (40 g of silica gel, 0-100% EtOAc/Hexanes) to give a yellow solid. MS m/z (M+H) 259.2.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[O:18]C)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(Cl)Cl>[CH2:5]([C:12]1[CH:13]=[C:14]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]#[N:29])=[CH:22][C:21]=2[CH2:30][CH:31]([CH3:33])[CH3:32])[CH:15]=[CH:16][C:17]=1[OH:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(O)c(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
2.20 ml (2.20 mmol, 3 eqv) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 279 mg (0.73 mmol) 3-(3′-Benzyl-2-isobutyl-4′-methoxy-1,1′-biphenyl-4-yl)propanenitrile (24) in 12 ml dry CH2Cl2 at 0° C. via syringe. After that, the solution was stirred for 2 h at 0° C. and then for 7 h at rt. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography, (Hexanes/EtOAc (2+1)) yielded 258.5 mg (0.70 mmol, 96%) 25 as a pale yellow oil: Rf (Hexanes/EtOAc (2+1)) 0.53; 1H NMR (500 MHz, CDCl3) δ 0.65 (d, 6H, J=6.62 Hz), 1.57 (m, 1H), 2.38 (d, 2H, J=7.25 Hz), 2.57 (t, 2H, J=7.41 Hz), 2.89 (t, 2H, J=7.41 Hz), 3.95 (s, 2H), 4.62 (s, br., 1H), 6.74 (d, 1H, J=8.04 Hz), 6.94-7.24 (m, 10H); LRMS (EI) m/z 369 (8), 335 (10), 293 (15), 161 (13), 160 (66), 91 (35), 86 (63), 84 (100); HRMS (EI) Calcd. for C26H27NO: 369.209264. Found: 369.209026.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]=[O:8])=[CH:5][N:6]=1.[CH2:9]([Mg]Br)[CH3:10].[Cl-].[NH4+]>C1COCC1.C(OCC)C.CCOC(C)=O>[Br:1][C:2]1[S:3][C:4]([CH:7]([OH:8])[CH2:9][CH3:10])=[CH:5][N:6]=1
Reactant: CC[Mg]Br
Reactant: O=Cc1cnc(Br)s1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)c1cnc(Br)s1
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-thiazole-5-carboxaldehyde (1.00 g, 5.21 mmol) in THF (10 mL) is added a 3 M solution of ethylmagnesium bromide (5.00 mL, 15.0 mmol) in diethyl ether. After 18 hours, the reaction is poured into saturated aqueous ammonium chloride (100 mL) containing crushed ice and diluted with EtOAc (100 mL). The organic phase is separated, washed with saturated aqueous sodium bicarbonate solution (100 mL), dried over sodium sulfate, filtered and concentrated. The compound is purified by silica gel chromatography eluting using a gradient of 0-100% EtOAc in hexanes to provide 1-(2-bromo-thiazol-5-yl)-propan-1-ol.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][N:11]=1.[P:18]([O:23]C)([O:21][CH3:22])[O:19][CH3:20]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][P:18]([O:21][CH3:22])([O:19][CH3:20])=[O:23])=[CH:12][N:11]=1
Reactant: COP(OC)OC
Reactant: BrCc1ccc(-c2nc3ccccc3s2)nc1
Product: COP(=O)(Cc1ccc(-c2nc3ccccc3s2)nc1)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
1.5 g (0.0049 mol) of 2-(benzothiazol-2-yl)-5-bromomethylpyridine was reacted with 3 ml of trimethyl phosphite in nitrogen gas streams at 130°-160° C. for 15 minutes. The reaction mixture was allowed to cool down to room temperature and the resulting crystals were recrystallized from ethyl acetate. By the above procedure was obtained 1.1 g (70%) of 2-(benzothiazol-2-yl)-5-dimethoxyphosphinylmethylpyridine as colorless needles, m.p. 151.5°-152.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1ccc(N)nc1
Product: COc1ccc(CCNc2ccc(C)cn2)cc1

Procedure:
Similarly prepared from 4-methoxyphenyl acetic acid and 2-amino-5-picoline.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:17])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:10]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(Cc1ccncc1)c1ccc(F)cc1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CC(C(=O)c1ccc(F)cc1)c1ccncc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium (400 mg, 17.40 mmol) was added to a stirred solution of 1-(4-fluorophenyl)-2-(4-pyridyl)ethanone (3.35 g, 15.58 mmol) (P. J. Gilligan et al., J. Med. Chem. 35, 4344, 1992) in ethanol (50 ml) at room temperature. After dissolution of the sodium, ethyl bromoacetate (1.93 ml, 17.40 mmol) was added dropwise at ice-bath temperature. After stirring for 4 h at room temperature, the reaction mixture was concentrated by evaporation. It was diluted with dichloromethane and made neutral by washing with diluted acetic acid followed by drying of the organic solution and evaporation. Flash chromatography (hexane-acetone=3:1,2:1) provided the title compound as a syrup. MS (m/z): 302.2 (M+H)+; C17H16FNO3 requir. 301.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[C:32](C1C=CC(CN[C@@H]2CN[C@H](C(N3CCSC3)=O)C2)=CC=1)#N.C=O.C([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH3:32])[CH2:10][C@H:9]1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(CN[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](NCc2ccc(C#N)cc2)C[C@H]1C(=O)N1CCSC1
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC#N
Solvent: CC(=O)O
Product: CN(Cc1ccc(C#N)cc1)[C@H]1C[C@@H](C(=O)N2CCSC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[(2S,4S)-1-tert-Butoxycarbonyl-4-(4-cyanophenylmethyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine [product of Example 63 (1), 1.35 g] and 37% formaldehyde solution (0.788 mL) were dissolved in acetonitrile (20 mL), and the mixture was stirred at room temperature for 30 min. Sodium cyanoborohydride (0.305 g) and several drops of acetic acid were added to the reaction mixture, and the reaction mixture was stirred for 1 hr. The reaction mixture was evaporated under reduced pressure. Saturated aqueous sodium hydrogencarbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[N-(4-cyanophenylmethyl)-N-methylamino]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (0.953 g) as white amorphous.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].[CH2:22]([NH2:30])[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH2:22]([NH:30][C:2]1[C:10]2[NH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19])[C:23]#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCC#CCN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)(F)F)nc12
Product: CCCCCC#CCNc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-2,5-bis(trifluoromethyl)benzimidazole is reacted with 2-octyn-1-ylamine to obtain 4-(2-octyn-1ylamino)-7-nitro-2,5-bis(trifluoromethyl)benzimidazole, m.w., 422.3.