Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:31][CH:32]([C:35]#[N:36])[C:33]#[N:34]>O1CCCC1>[NH2:36][C:35]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]([OH:10])=[N:31][C:32]=1[C:33]#[N:34]
Reactant: N#CC(N)C#N
Reactant: O=C=NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1nc(O)n(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 14 h
Yield: 107.5 %

Procedure:
Benzylisocyanate (25 g, 188 mmol) and N,N-diisopropylethylamine (23.5 ml, 130 mmol) were added to aminomalononitrile p-toluenesulfonate (45 g, 178 mmol) suspended in tetrahydrofuran. The mixture was stirred at room temperature for 14 hours and then the solvent was removed in vacuo. To the residue was added ethyl acetate and the solution was washed and the organic layer was dried on magnesium sulfate. The solvent was removed in vacuo. To the residue was added tetrahydrofuran and 1N aqueous sodium hydroxide. The solution was stirred at 50° C. for 20 minutes, and neutralized with 15% aqueous potassium hydrogen sulfide. The resulting crystals were filtered and dried to give the subject compound (41 g, 106%). The crude product was used for next reaction without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[N:8][CH:9]=[C:10]([NH2:13])[CH:11]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:15]1[C:23]([NH:24][S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])=[CH:22][CH:21]=[C:20]([F:31])[C:16]=1[C:17]([NH:13][C:10]1[CH:11]=[C:12]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[N:5][NH:6][C:7]2=[N:8][CH:9]=1)=[O:18]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Reactant: Nc1cnc2[nH]nc(C3CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4CC4)c3c2)c1Cl
Reaction time: 24 h
Yield: 66.3 %

Procedure:
3-Cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.0744 g, 0.427 mmol), 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (0.139 g, 0.470 mmol), EDCI (0.0901 g, 0.470 mmol), and HOBt (0.0635 g, 0.470 mmol) were dissolved in DMF (2 mL) and stirred for 24 hours. The reaction mixture was diluted with ethyl acetate and washed with water (4 X), saturated aqueous sodium bicarbonate solution (2×), and brine, dried over sodium sulfate and concentrated. The crude product was triturated with 1:1 DCM/Et2O to afford 2-chloro-N-(3-cyclopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-6-fluoro-3-(propylsulfonamido)benzamide (128 mg, 66% yield) as a solid. 1H NMR (400 MHz, d6-DMSO) 813.21 (s, 1H), 11.08 (s, 1H), 9.74 (s, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 7.59-7.63 (m, 1H), 7.40-7.46 (m, 1H), 3.11-3.15 (m, 2H), 2.29-2.31 (m, 1H), 1.79-1.80 (m, 2H), 0.95-1.00 (m, 7H); MS (APCI-neg) m/z=452.2, 454.1 (M+H).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]=[O:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>C1COCC1>[C:32]([O:36][C:37]([N:39]1[C:44]2[CH:45]=[CH:46][CH:47]=[C:48]([CH:49]([C:2]3[C:7]([N:8]([S:9]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=4)(=[O:11])=[O:10])[CH2:23][O:24][CH3:25])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=3)[OH:50])[C:43]=2[O:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(C=O)cccc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (2.92 g, 6.18 mmol) in THF (12 mL) under nitrogen atmosphere at −20° C. was added isopropylmagnesium chloride (2 M solution in THF, 6.5 mL, 13.0 mmol) via dropwise addition. The mixture was then stirred for 1 hour at 0° C. followed by the addition of a solution of 8-formyl-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (273.5 mg, 1.54 mmol) in THF (2 mL) at −20 ° C. The mixture was stirred at room temperature overnight, quenched with saturated aqueous NH4Cl solution (5 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts were washed with saturated aqueous NH4Cl solution (40 mL) and brine (40 mL), dried (Na2SO4), and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes to 90% EtOAc-hexanes) to obtain 8-({5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridin-2-yl}-hydroxy-methyl) -2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (590.2 mg) as yellow syrup. MS m/z: 678.0 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:36]=[CH:35][C:16]([CH2:17][O:18][CH:19]([C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=1.I[CH2:38][C:39]#[C:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45]>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][O:18][CH:19]([C:25]2[CH:26]=[CH:27][C:28]([N:31]([CH2:38][C:39]#[C:40][CH2:41][CH2:42][CH2:43][C:44]([O:46][CH3:47])=[O:45])[C:32](=[O:34])[CH3:33])=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:35][CH:36]=1
Reactant: COC(=O)CCCC#CCI
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(NC(C)=O)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.1 %

Procedure:
Sodium bis(trimethylsilyl)amide (0.31 ml of a 1.0 M solution in THF, 0.31 mmol) was added to a solution of the aryl amide 103 (100 mg, 0.282 mmol) in THF (1.3 mL) at 0° C. After 15 min a solution of the methyl 7-iodohept-5-ynoate (90 mg, 0.338 mmol) in THF (0.3 mL) was added and the reaction was warmed room temperature. After stirring for 16 h the reaction was the quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic portion was washed with brine, dried (MgSO4), filtered and the filtrate was concentrated in vacuo. Purification by FCC (silica gel, 3:2 hex/EtOAc) gave 35 mg (25%) of ester 104.
Reaction SMILES: C([O:8][C:9]1[C:22]2[S:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[C:12]([NH:23]CC2C=CC(OC)=CC=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.N1C=CC=CC=1>>[NH2:23][C:12]1[C:13]2[CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:21][C:22]=2[C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: COc1ccc(CNc2ccc(OCc3ccccc3)c3c2Cc2ccccc2S3)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Nc1ccc(O)c2c1Cc1ccccc1S2
Temperature: 150 °C
Reaction time: 12 h
Yield: 99.1 %

Procedure:
(4-Benzyloxy-9H-thioxanthen-1-yl)-(4-methoxy-benzyl)-amine (14.51 g, 33.00 mmol) was mixed thoroughly with solid pyridine hydrochloride (190 g, 165.00 mmol) before being heated to 150° C. and stirred at this temperature for a further 12 hours. Upon completion the reaction was cooled slightly before being poured into an beaker of ice/water. The brown precipitate was removed by filtration and the filtrate adjusted to pH 11 with NH3OH solution before being extracted with CH2Cl2 (3×100 ml). The combined organic phases were then washed with water (1×100 ml) and brine (1×100 ml) then dried using MgSO4, filtered and concentrated in vacuo to give the title compound as a thick brown oil (7.50 g, 99.1%) m/z (LC-MS, ESP): 229 [M+H]+, R/T=4.15 mins.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Reactant: c1nc[nH]n1
Product: Clc1ccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)=[O:29]
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ccccc2N)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-aminobenzoic acid, and by a method similar to that of Example 39, step A, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.[CH:20]1([CH2:26]O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14][CH2:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:13])[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1
Reactant: OCC1CCCCC1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)OCC2CCCCC2)C1
Reaction time: 16 h
Yield: 11.4 %

Procedure:
To a solution of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (200 mg, 0.7 mmol) and cyclohexyl methanol (80 mg, 0.7 mmol) in dichloromethane (10 ml) were added N,N′-dicyclohexylcarbodiimide (177 mg, 0.86 mmol) and 4-dimethylaminopyridine (105 mg, 0.86 mmol) and the contents were stirred at 25 deg C. for 16 h. The reaction mixture was concentrated to dryness to obtain the crude compound which was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to give 30 mg (11.3%) of cyclohexylmethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate as TFA salt. 1H NMR (DMSO) TFA SALT 10.39 (bs, 1H), 7.60 (s, 1H), 7.50 (d, 1H), 7.2 (d, 1H), 5.3-5.1 (dd, 2H), 4.70 (d, 1H), 4.30 (bs, 1H), 4.0 (d, 2H), 3.85 (bs, 1H), 3.50 (bs, 1H), 3.10 (s, 2H), 2.85 (s, 3H), 1.60-0.90 (m, 11H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15](Cl)[C:10]3=[N:9]2)=[CH:5][CH:4]=1.[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)([O-])C.[K+]>CN1CCCC1=O.C1COCC1>[F:29][C:2]([F:28])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:24](=[O:25])[N:11]3[N:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=4)=[C:15]([O:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:10]3=[N:9]2)=[CH:26][CH:27]=1
Reactant: OCc1ccccc1
Reactant: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=c1n(Cc2ccc(C(F)(F)F)cc2)nc2c(OCc3ccccc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(4-(trifluoromethyl)benzyl)-8-chloro-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (20 mg, 46 μmol), prepared as described in Example 361, in 1-methylpyrrolidone (1 mL) in a 1 dram vial was added benzyl alcohol (10.8 mg, 100 μmol), and 1M solution of potassium t-butoxide in THF (100 uL). The reaction vessel was capped and stirred at room temperature for 16 h. Reaction mixture was quenched with 100 uL of methanol, filtered through a Whatman 0.45 μm syringe filter and the crude product was purified using preparative HPLC (Xterra MS-C18, 30×50 mm); Eluted with 10% to 100% B, 8 min gradient, (A=water+0.1% TFA and B=acetonitrile+0.1% TFA); Flow rate at 30 mL/min. UV detection at 220 nm) to give the title compound 2-(4-(Trifluoromethyl)benzyl)-8-(benzyloxy)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. (4.9 mg, 16% yield), as a yellow crystalline solid. MS (M+H)=511; 1H NMR MeOD: δ 8.25 (1H, s), 7.60-7.7 (4H, m), 7.47-7.55 (4H, m), 7.13-7.31 (5H, m), 5.81 (2H, s), 5.39 (2H, s). Analytical HPLC purity: 99% at 2.31 min (retention time), (Xterra MS-C18, 4.6×50 mm); Eluted with 10% to 100% B, 4.5 min gradient, (A=water+0.1% TFA and B=acetonitrile+0.1% TFA); Flow rate at 2.5 mL/min. UV detection at 220 nm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH:21](OCC)[O:22]CC)[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:29])[NH:10][CH:11]([C:17](=[O:28])[NH:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:12]([OH:16])[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(CCNC(=O)C(NC(=O)OCc1ccccc1)C(O)C(C)C)OCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C(O)C(NC(=O)OCc1ccccc1)C(=O)NCCC=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a solution of [1-(3,3-diethoxy-propylcarbamoyl)-2-hydroxy-3-methyl-butyl]-carbamic acid benzyl ester (350 mg, 0.854 mmol) in anhydrous tetrahydrofuran (2 ml) was added 0.5N hydrochloric acid (2 ml). The resulting solution was stirred for 20 minutes at room temperature. The aqueous layer was basified to pH 8 with sodium bicarbonate solution, and extracted with ethyl acetate (3×40 mL). The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuo to provide [2-hydroxy-3-methyl-1-(3-oxo-propylcarbamoyl)-butyl]-carbamic acid benzyl ester (266 mg, 93%) as a white solid.
Reaction SMILES: [CH:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH:1]1([N:7]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=2)(=[O:9])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(NC1CCCCC1)c1cccc(CO)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN(C1CCCCC1)S(=O)(=O)c1cccc(CO)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A solution of N-cyclohexyl-3-(hydroxymethyl)benzenesulfonamide (1.744 g) in DMF (30 ml) under nitrogen was treated with sodium hydride (60% dispersion in mineral oil, 311 mg) and the mixture stirred at 20° C. for 0.5 h. 2-(Trimethylsilyl)ethoxymethyl chloride (1.15 ml) was added and the mixture was stirred for a further 2 h at 20° C. Phosphate buffer solution (pH 6.5, 50 ml) and water (50 ml) were added and the mixture was extracted with EtOAc. The combined extracts were washed with water and dried (Na2SO4). Solvent evaporation in vacuo gave a residue which was purified by flash chromatography on silica gel. Elution with EtOAc-petroleum ether (3:7) gave the title compound (1.917 g). LCMS RT=3.83 min.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:22]=[CH2:23].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:23][CH:22]([CH2:21][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: C=CCOc1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(OCC2CC(Cn3ccnc3)(c3ccc4ccccc4c3)N(C)O2)cc1

Procedure:
A mixture of compound 2 (13.0 g, 0.049 mol) and p-methoxyphenyl allyl ether (12.07 g, 0.073 mol) in 400 ml of toluene is refluxed for 48 hours, cooled, and the solvent removed in vacuo leaving a dark oil. Chloroform is added to the oil and carbon is added to decolorize the solution which is filtered through a bed of celite. The chloroform is evaporated and the oil that remained is purified by flash chromatography on silica gel (eluent comprised of 98% CHCl3 and 2% MeOH). The resulting tan solid (5.56 g, 26%) is recrystallized from ethyl acetate, m.p. 143°-145° C. (Found: C, 72.58; H, 6.46; N, 9.66. C26H27N3O3 requires: C, 72.71; H, 6.34; N, 9.78).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]([CH3:40])[C:23]([C:25]2([CH3:39])[CH2:28][CH2:27][N:26]2[C:29](=[O:38])[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](I)[CH:32]=2)=[O:24])=[CH:19][CH:18]=1>O1CCOCC1.O>[Cl:16][C:17]1[CH:42]=[CH:41][C:20]([CH2:21][N:22]([CH3:40])[C:23]([C:25]2([CH3:39])[CH2:28][CH2:27][N:26]2[C:29](=[O:38])[CH2:30][C:31]2[CH:32]=[C:33]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:34]=[CH:35][CH:36]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cccc(-c2ccccc2)c1
Temperature: 90 °C

Procedure:
To a solution of phenyl boronic acid (1.5 eq.) in Dioxane/H2O (9/1) were added Na2CO3 (4 eq.) and 1-[2-(3-iodo-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-methyl-amide, compound 8 (1 eq.). The flask was evacuated and backfilled with argon. Then Pd(PPh3)4 was added and the reaction was heated at 90° C. until completion. The crude was partitioned between water and EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with Heptane/EtOAc: 100/0 to 20/80) to afford 1-(2-biphenyl-3-yl-acetyl)-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-methyl-amide.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:16][CH:15]=1.[N:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[S:21][C:22]([C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)([OH:33])[CH3:32])=[CH:23][N:24]=2)=[CH:18][CH:19]=1
Reactant: Clc1ccc(-c2nccs2)cc1
Reactant: CC(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(Cl)cc2)s1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
To a solution of diisopropylamine (0.2 mL, 1.538 mmol) in dry THF (5 mL), was added 1.6M n-BuLi in hexanes (0.96 mL, 1.538 mmol) slowly at −78° C. The reaction mixture was stirred for 30 min, 2-(4-chlorophenyl)thiazole (0.2 g, 1.025 mmol) in THF (10.0 mL) added, the mixture stirred for 30 min, a solution of 1-(pyridin-4-yl)ethanone (0.17 mL, 1.538 mmol) in THF (5.0 mL) added, and the mixture was stirred for 2 hours at −78° C. The reaction mixture was quenched with saturated NH4Cl (50 mL) solution and extracted with EtOAc (2×100 mL). The organic layer was washed with water (2×50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (1% methanol in dichloromethane) to obtain 1-(2-(4-chlorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (0.1 g, 31% yield) in 99.9% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, 2H), 7.87 (d, 2H), 7.82 (s, 1H), 7.51-7.47 (m, 4H), 6.66 (s, 1H), 1.92 (s, 3H); LC-MS m/z calculated for [M+H]+ 317.04. found 317.4.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccccc1
Yield: 45.4 %

Procedure:
As described for Example 9, 0.314 g (1.0 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.155 g (1.1 mmol) of benzoyl chloride and 0.111 g (1.1 mmol) of triethylamine in 10 ml of dichloromethane for 1.5 hours at room temperature. The product is recrystallized from dichloromethane-hexane to give 0.19 g of crystals, m.p. 219°-221° C. Anal. Calc'd for C28H22N2O2 : C,80.4; H,5.3; N,6.7. Found: C,79.6; H,5.5; N,6.7.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=O>>[Cl:19][C:20]1[C:27]([Cl:28])=[C:26]([OH:29])[CH:25]=[CH:24][C:21]=1[CH:22]=[CH:15][C:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)=[O:16]
Reactant: O=Cc1ccc(O)c(Cl)c1Cl
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: O=C(C=Cc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
3-(2,3-Dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 2,3-dichloro-4-hydroxybenzaldehyde according to general procedure B. The evaporation residue is crystallized from acetonitrile.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([O:16][CH3:17])[CH:8]=1.Cl.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH2:22][CH2:21]1>>[O:18]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:20]2[CH2:25][CH2:24][CH:23]([C:26](=[O:27])[C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)[CH2:22][CH2:21]2)=[O:13])=[C:9]([O:16][CH3:17])[CH:8]=1
Reactant: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1ccc(C(=O)C2CCNCC2)cc1
Agent: Cl
Product: COc1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCC(C(=O)c2ccc(C)cc2)CC1
Yield: 10.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methoxybenzoic acid (285 mg) described in Preparation Example 19 and (piperidin-4-yl)(p-tolyl)methanone hydrochloride (252 mg) and by the reaction and treatment in the same manner as in Example 86, the title compound (52 mg) was obtained.