Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].[NH4+].[Cl-]>O1CCCC1>[CH2:28]([Sn:23]([C:18]1[N:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30][CH3:31]
Reactant: c1ccnnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCC[Sn](CCCC)(CCCC)c1cccnn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
n-Butyllithium (2.76 mL, 6.9 mmol, 2.5 M in hexane) was added dropwise to a cooled (0° C.) solution of diisopropylamine (0.97 mL, 6.9 mmol) in tetrahydrofuran (2 mL) under a nitrogen atmosphere. After stirring for 30 minutes the reaction mixture was cooled to −78° C. and a solution of pyridazine (452 μL, 6.3 mmol) and tributyltin chloride (1.9 mL, 6.9 mmol) were added simultaneously while the temperature was kept below −70° C. The reaction mixture was stirred for 2 hours at −78° C.; subsequently, a saturated aqueous NH4Cl solution was added and the reaction mixture was extracted three times with ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated to dryness. The crude product was purified by LCMS to give tributylstannylpyridazine (197 mg, 0.53 mmol, 8% yield). This stannylpyridazine (183 mg, 0.49 mmol), (11β,16α,17β)-11-(4-bromophenyl)-17-cyclopropylcarbonyl-16-methylestra-4,9-dien-3-one (100 mg, 0.20 mmol) and bis(triphenylphosphine)palladium(II) chloride (3 mg, 0.004 mmol) were dissolved in dioxane (3 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and then cooled to room temperature. Water was added and the mixture was extracted three times with dichloromethane. The combined organic layers were dried through a phase separate filter and evaporated to dryness. Purification by LCMS followed by lyophilisation gave (11β,16α,17β)-17-cyclopropylcarbonyl-16-methyl-11-[4-(4-pyridazinyl)phenyl]estra-4,9-dien-3-one (78 mg, 0.16 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 0.33 (s, 3H), 0.85-2.84 (m, 26H), 4.48 (d, J=7 Hz, 1H), 5.81 (s, 1H), 7.33-7.37 (m, 2H), 7.60-7.64 (m, 3H), 9.21 (dd, J=5 and 1 Hz, 1H), 9.46 (dd, J=3 and 1 Hz, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.F[C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2)=[O:22]>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[C@@H:2]([NH:1][C:21]([O:23][C:24]12[CH2:33][CH:28]3[CH2:27][CH:26]([CH2:32][CH:30]([CH2:29]3)[CH2:31]1)[CH2:25]2)=[O:22])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(F)OC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)OC12CC3CC(CC(C3)C1)C2)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a mixture of (S)-methyl 2-amino-3,3-dimethylbutanoate (200 mg, 1.377 mmol) and DIEA (0.481 mL, 2.75 mmol) in DCM (2 mL) solution was add 1-adamantyl fluoroformate (334 mg, 1.515 mmol). The reaction mixture was stirred at rt overnight. The compound was purified by silica gel column chromatography (20% EtOAc/80% hexane) to give a colorless oil (358 mg, 68%) as product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:3]=12.[NH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([NH:20][CH:21]4[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]4)=[C:3]3[CH:10]=[CH:9]2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: COc1ccc(Cn2ccc3c(Br)ccnc32)cc1
Product: COc1ccc(Cn2ccc3c(NC4CCCN(C(=O)OC(C)(C)C)C4)ccnc32)cc1

Procedure:
Reaction of 4-bromo-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine with tert-butyl 3-aminopiperidine-1-carboxylate following the method of Example 13 affords the title compound.
Reaction SMILES: C(C1[O:6][C:7]2[C:13]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)(=[O:16])=[O:15])=[C:12]([Cl:24])[CH:11]=[CH:10][C:8]=2[N:9]=1)(C)(C)C.O.OS(O)(=O)=O.[OH-].[Na+]>O1CCOCC1>[NH2:9][C:8]1[C:7]([OH:6])=[C:13]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[C:12]([Cl:24])=[CH:11][CH:10]=1
Reactant: CN1CCN(S(=O)(=O)c2c(Cl)ccc3nc(C(C)(C)C)oc23)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2c(Cl)ccc(N)c2O)CC1
Temperature: 85 °C
Yield: 67.3 %

Procedure:
To a solution of 2-tert-Butyl-6-chloro-7-(4-methyl-piperazine-1-sulfonyl)-benzooxazole (2.44 g, 6.56 mmol) in 1,4-dioxane (20 mL) was treated with water (4 mL) and conc. H2SO4 (4 mL). The mixture was heated to 85° C. for 14 h. The reaction was cooled to room temperature, and then basified to pH=14 with 25% aq NaOH. washed. The mixture was extracted with ethyl acetate (3 times), dried with MgSO4, filtered, and concentrated to afford the title compound (1.35 g, 68%). EI-MS m/z 306(M+H)+.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:28]2[CH:29]=[C:30]([C:34]([NH2:37])([CH3:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)=[N:13]1)[CH3:11].C(N(CC)CC)C>ClCCl>[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)=[CH:15][C:14]([C:28]2[CH:29]=[C:30]([C:34]([NH:37][S:4]([CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:6])=[O:5])([CH3:36])[CH3:35])[CH:31]=[CH:32][CH:33]=2)=[N:13]1)[CH3:11]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CCn1nc(-c2cccc(C(C)(C)N)c2)cc1Oc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
2,2,2-trifluoroethanesulfonyl chloride (0.83 mL, 7.7 mmol, 1.5 equiv) was added to a solution of 2-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)propan-2-amine (2.0 g, 5.1 mmol, 1 equiv) and triethylamine (1.1 mL, 7.7 mmol, 1.5 equiv) in dichloromethane (51 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, and then the cooling bath was removed. After stirring for 20 minutes, the reaction mixture was partitioned between dichloromethane and citric acid solution (1 M). The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography on silica gel (hexanes, grading to 50% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (2.04 g, 74%) as a white solid. Calcd (M+1)+: 536.1. Found: 536.1. 1H NMR (600 MHz, cdcl3) δ 7.92 (s, 1H), 7.70 (d, J=7.3, 1H), 7.65 (d, J=8.7, 2H), 7.48-7.39 (m, 2H), 7.22 (d, J=8.6, 2H), 6.06 (s, 1H), 5.01 (s, 1H), 4.11 (q, J=7.3, 2H), 3.42 (q, J=8.9, 2H), 1.83 (s, 6H), 1.45 (t, J=7.3, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].O[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[NH:15].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[O:8][N:15]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:24][CH:23]=4)=[CH:20][CH:21]=3)[N:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N=C(NO)c1ccc(-c2ccc(OCCCC(=O)O)cc2)cc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2nc(-c3ccc(-c4ccc(OCCCC(=O)O)cc4)cc3)no2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
A solution of 4-cyanobenzoyl chloride (2.29 g, 13.8 mmol) in dioxane (10 ml) was added to a suspension of 4-(4′-(N-hydroxycarbamimidoyl)biphenyl-4-yloxy)butyric acid (3.23 g, 9.6 mmol) in dioxane (50 ml) and pyridine (2.5 ml, 31.6 mmol). The mixture was stirred at room temperature for 4 h, and then heated to 100° C. for 22 h. The mixture was concentrated to ½ of its original volume, diluted with water (100 ml), and acidified by addition of concentrated hydrochloric acid (3 ml). The product was isolated by filtration and washed with water (50 ml). The solid was suspended in MeCN (70 ml), heated to reflux, allowed to cool, filtered off, and dried under reduced pressure to yield 3.17 g (54%) of 4-(4′-{5-[4-cyanophenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyric acid as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18](O)[C:17]([F:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].P(Cl)(Cl)(Cl)(Cl)[Cl:23].P(Cl)(Cl)(Cl)=O>O>[Cl:23][C:18]1[C:17]([F:21])=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:19]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc(F)cc1F
Yield: 34.7 %

Procedure:
A mixture of 9.5 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinate, 26.5 g of phosphorus pentachloride and 46.9 g of phosphorus oxychloride was subjected to reaction at 70°-80° C. for 4 hours. Subsequently, the reaction mixture was gradually added to 285 ml of water, and the crystals thus deposited were collected by filtration and then washed with 57 ml of water. The crystals thus obtained were purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene] to obtain 3.5 g (yield 34.7%) of methyl 6-chloro-2-(2,4-difluorophenylamino)-5-fluoronicotinate having a melting point of 137°-139° C.
Reaction SMILES: C([O:8][C:9]1[C:38]([CH3:39])=[CH:37][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:40])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:10]([CH3:40])=[CH:11][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:37][C:38]=1[CH3:39]
Reactant: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc(C)c1O
Reaction time: 1 h

Procedure:
50 mg palladium/charcoal (10%) were added to 390 mg (0.7 mmol) 1-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one in 50 mL MeOH and the mixture was hydrogenated for 40 min in a 5 psi hydrogen atmosphere at RT. The catalyst was removed by suction filtering and the filtrate was evaporated down. The residue was triturated with some MeOH, suction filtered and washed with diethyl ether. The suction filtered catalyst was decocted with 120 mL MeOH for 1 h, filtered hot and the filtrate was evaporated down. The residue was triturated with a little MeOH, suction filtered and dried. The two batches of solid were combined and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:31][CH3:32])=[CH:4][C:5]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:34]([O-])=O.[Na+]>O1CCOCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:34][N:31]([CH3:32])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:27]([F:28])([F:29])[F:30])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: CNc1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethylcarbamate (1.130 mmol, 0.51 g) was dissolved in 1M Hydrochloric Acid (2.259 mmol, 2.259 ml) and dioxane (5 ml). Sodium nitrite (1.582 mmol, 0.109 g) in water (5.00 ml) was added to the reaction mixture and it was stirred at room temperature for 1 hr. The reaction mixture was filtered and the solid washed with water to afford tert-butyl 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethylcarbamate. (0.61 g)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH:12]([C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:13]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)c1ccccc1C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1C(C)Oc1cccc(Cl)c1
Yield: 88 %

Procedure:
A solution of 3-chlorophenol (8.2 g) in DMF (30 ml) was added dropwise to a stirred suspension of sodium hydride (1.3 g) in DMF (30 ml). An hour later, a solution of crude methyl 2-(1-bromoethyl)benzoate described above (12 g) in DMF was added with stirring. After stirring at room temperature for 2 hours, the resulting mixture was poured into water and extracted with ether. The ether extracts were washed successively with water (×2), aqueous sodium hydroxide (×2), and brine, then dried and concentrated to give methyl 2-[1-(3-chlorophenoxy)ethyl]-benzoate (14.84 g, 88% pure by GC), as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[C:26](OC)(OC)(OC)[O:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:26][O:27][C:28]1[O:25][C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[N:8][N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH3:13])[C:10]=3[C:2]=2[N:1]=1
Reactant: C[C@@H](Cn1ncc2ccc(O)c(N)c21)NC(=O)OCc1ccccc1
Reactant: COC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1nc2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c32)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step D (0.47 g) was combined with tetramethyl orthocarbonate (15 mL), p-toluenesulfonic acid hydrate (10 mg) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with triethylamine (1 ml) and the reaction mixture was evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a colorless oil (60 mg): LC/MS m/z 381.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=O)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH3:27])=[CH:21][CH:20]=1)[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl.O.[OH-].[NH4+]>[CH2:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]2[N:6]([CH2:5][CH2:4][N:3]([CH2:29][CH3:30])[CH2:1][CH3:2])[C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=3[N:16]=2)=[CH:20][CH:21]=1)[CH3:27]
Reactant: CCOc1ccc(CC(=O)Nc2cc([N+](=O)[O-])ccc2NCCN(CC)CC)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C

Procedure:
N-[2-(2-Diethylamino-ethylamino)-5-nitro-phenyl]-2-(4-ethoxy-phenyl)-acetamide 6a (295 mg, 0.712 mmol), Phosphorous pentachloride (148.3 mg, 0.712 mmol) were dissolved in anhydrous chloroform (10 mL) in a small, argon purged flask fitted with a condenser and magnetic stirbar. The solution was heated to reflux in an oil bath for 4 hours and cooled to room temperature overnight. The mixture was diluted with H2O and chloroform and 2M ammonium hydroxide solution added to adjust pH to 9-10. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with chloroform and the combined organic layers were washed with brine, dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using dry silica gel column chromatography eluting with 25 mL portions of solvent system (2.5% 2M NH3 in methanol/95% dichloromethane) to afford a yellow residue. Recrystallization from diethyl ether/hexanes at 0° C. yielded a pale yellow solid 7a {2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine. Yield: 177 mg (62.7%). 1H NMR (DMSO) : 0.71 (t, 6H, J=7.0), 1.29 (t, 3H, J=7.0), 2.37 (q, 4H, J=7.1), 2.50 (m, 2H), 3.98 (q, 2H, J=6.9), 4.25 (m, 2H), 4.32 (s, 2H), 6.87 (d, 2H, J=8.4), 7.19 (d, 2H, J=8.4), 7.71 (d, 1H, J=8.9), 8.14 (dd, 2H, J=8.9, 2.1), 8.45 (d, 1H, J=2.1); MS (ESI): 397 (MH+, 100%)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1([CH3:37])[CH2:29][C:28]2[CH:30]=[CH:31][CH:32]=[C:33]([C:34](O)=[O:35])[C:27]=2[O:26]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:33]2[C:27]3[O:26][C:25]([CH3:37])([CH3:24])[CH2:29][C:28]=3[CH:30]=[CH:31][CH:32]=2)=[O:35])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: CC1(C)Cc2cccc(C(=O)O)c2O1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2OC(C)(C)C3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,2-Dimethyl-2,3-dihydro-benzofuran-7-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:23])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(CC2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Yield: 59.2 %

Procedure:
To 15.0 g (0.045 moles) of 5-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]} methylene-2, 4-thiazolidinedione, in 375 ml of ethyl acetate, 3.0 g of 10% palladium on carbon was added. The mixture was heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 4.5 hours. An additional 3.0 g of 10% palladium on carbon was added and the mixture was again heated at 80° C. in the presence of 50 psi (345 KPa) of hydrogen for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated to afford a solid. The solid was recrystallized from toluene and dried at 60° C. to obtain 8.93 g (59% yield) of subtitled compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:4]=1[CH:5]([OH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:18]([N:26]=[C:27]=[S:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO.C(N(CC)CC)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:3]([CH2:2][NH:1][C:27]([NH:26][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[S:28])=[C:4]([CH:5]([OH:12])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:13]=1
Reactant: S=C=NCCc1ccccc1
Reactant: NCc1ccc(Cl)cc1C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: OC(c1ccccc1)c1cc(Cl)ccc1CNC(=S)NCCc1ccccc1

Procedure:
2-aminomethyl-5-chlorobenzhydrol (10 g; 0.04 mole) in 100 ml methanol and 2 ml triethylamine was treated dropwise with a solution of phenethyl isothiocyanate (8.6 g; 0.053 mole) in 25 ml of methanol. After 16 hours at room temperature the reaction mixture was evaporated and the residue was extracted with petroleum ether. The residual oil was recrystallized from diisopropyl ether to yield 1-(4-chloro-2-(α-hydroxybenzyl)benzyl)-3-phenethylthiourea as a white powder (M.Pt. 97° -- 101° ).
Reaction SMILES: [CH2:1]=O.[NH2:3][CH2:4][C@@:5]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1C=CC=CC=1>[Si:9]([O:8][CH2:7][CH2:6][C@:5]1([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[O:16][CH2:1][NH:3][CH2:4]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:11]
Reactant: C=O
Reactant: CC(C)(C)[Si](C)(C)OCC[C@](O)(CN)c1ccc(F)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC[C@@]1(c2ccc(F)cc2)CNCO1
Yield: 104.2 %

Procedure:
Paraformaldehyde (18.50 g, 0.617 mol) was added to a solution of (2R)-1-amino-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-fluorophenyl)butan-2-ol (128.92 g, 0.411 mol) in benzene (1000 mL), a water separator was mounted, and the mixture was stirred at reflux temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give 139.43 g of crude (5R)-5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-5-(4-fluorophenyl)-1,3-oxazolidine as a brown oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](OB(O)O)=[CH:27][CH:26]=1)[CH3:20].C(N(CC)CC)C>ClCCl>[CH2:19]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: COC(=O)C1=Cc2cc(O)ccc2S(=O)(=O)CC1
Reactant: CCOCCCc1ccc(OB(O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCCCc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To methyl 7-hydroxy-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.4 g), 4-(3-ethoxypropyl)phenylboric acid (0.65 g), cupric acetate (0.27 g) and molecular sieves 4A (0.8 g) suspended in dichloromethane (15 ml) was added triethylamine (1.0 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the filtrate was evaporated to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain methyl 7-[4-(3-ethoxypropyl)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.28 g) as colorless crystals.
Reaction SMILES: [Na].[CH:2]1[C:15]2[CH:14]([C:16]([NH2:18])=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(O)(=O)C>O1CCOCC1>[NH2:18][CH2:16][CH:14]1[C:15]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[O:7][C:8]2[C:13]1=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: NC(=O)C1c2ccccc2Oc2ccccc21
Agent: [Na]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCC1c2ccccc2Oc2ccccc21
Yield: 76 %

Procedure:
To a stirred suspension of sodium boronhydride (1.89 g, 50 mmol) and 9-xanthencarboxamide (2.25 g, 10 mmol) in dioxane (20 mL) was added acetic acid (3.0 g, 50 mmol) in dioxane (10 mL) over a period of 10 minutes at 10° C.; the reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness in vacuo, excess reagent was decomposed with water and the solution extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulphate. The chloroform layer was evaporated in vacuo and the residue was purified by silica gel column chromatography (ethylacetate:methanol, 9:1 as eluent) to give a white solid (1.6 g, 7.6 mmol) in 76.2% yield.