Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:28])([CH3:27])[C:10]([NH:12][C@H:13]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:14]([NH:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])=[CH:35][CH:36]=1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
The acid (338 mg, 0.87 mmol) from Step D and 4-aminomethyl-2'-nitro-1,1'-biphenyl (200 mg, 0.87 mmol) and triethylamine (0.245 mL, 1.76 mmol) were dissolved in methylene chloride (8 mL) and stirred at room temperature. Benzotriazolyl-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (388 mg, 0.87 mmol) was added in a single portion. The reaction mixture was stirred together for 3.5 hours then the reaction was quenched by adding saturated aqueous sodium chloride (10 mL) and extracted with methylene chloride (3×20 mL). The combined extracts were dried over magnesium sulfate, filtered and evaporated under vacuum. The resulting thick gum was chromatographed on silica gel using ethyl acetate/hexanes (1:2 v/v) to give 297 mg (50%) of an orange semi-solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1.[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>ClCCl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:18][CH2:17][CH:14]2[CH2:16][CH2:15]2)(=[O:11])=[O:10])=[C:4]([F:13])[CH:3]=1
Reactant: NCC1CC1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1cc(F)c(Br)cc1F

Procedure:
According to general procedure C, 4-Bromo-2,5-difluorobenzenesulfonyl chloride (0.20 g, 0.68 mmol) and cyclopropylmethylamine were stirred together in dichloromethane (1 mL) for 16 hours. The reaction afforded 4-bromo-N-(cyclopropylmethyl)-2,5-difluorobenzenesulfonamide (0.17 g) after purification. HPLC purity 95.0% at 210-370 nm, 9.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C10H10BrF2NO2S−H+, 323.95109; found (ESI-FTMS, [M−H]1−), 323.95103
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][Si:15]([CH3:25])([CH3:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH:26]([P:29](Cl)(Cl)=[O:30])([CH3:28])[CH3:27]>CCCCCC.C1CCCCC1>[CH:26]([P:29]1(=[O:30])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][N:16]1[Si:15]([CH3:25])([CH3:24])[CH3:14])([CH3:28])[CH3:27]
Reactant: C[Si](C)(C)NCc1ccccc1
Reactant: CC(C)P(=O)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: CC(C)P1(=O)c2ccccc2CN1[Si](C)(C)C
Temperature: 26 °C
Reaction time: 16.5 h

Procedure:
Under a static nitrogen atmosphere at 0° C., a solution of n-butyllithium (8 g, 0.125 mol) in hexane was added to a solution of tetramethylethylenediamine (14.3 g, 0.123 mol) in 60 ml. of anhydrous cyclohexane with constant stirring. While maintaining the temperature of the reaction at 0° C., a solution of N-trimethylsilylbenzylamine (10.75 g, 0.06 mol) in 60 ml. of anhydrous cyclohexane was added to the reaction mixture to produce a suspension containing a dilithio compound. This suspension was stirred for 16.5 hours at 26° C. and then cooled to -72° C. using a solid carbon dioxide-acetone bath. A solution of isopropylphosphonic dichloride (10.3 g, 0.064 mol) in 60 ml. of anhydrous cyclohexane was rapidly added to the suspension causing the temperature of the reaction to increase to -10° C. The reaction mixture was allowed to cool to -72° C., after which time the solid carbon dioxide-acetone bath was removed and the reaction mixture was stirred for 1.5 hours at 26° C. The reaction mixture was cooled to 0° C. and then quenched with the rapid addition of 12 ml. of acetic acid. The reaction mixture was concentrated under vacuum and the resulting residue was partitioned between methylene chloride and water. The layers were separated and the methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to yield a red oil. The red oil was distilled at 180° C. and 0.2 mm to yield 1-isopropyl-2-trimethylsilyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:20][C:21]1[C:25]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[C:24]([CH3:29])[O:23][N:22]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1-c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 95 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (129 mg, 0.912 mmol), ethanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (120 mg, 57.7%) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:23]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[C:27]=2[CH:26]=[CH:25][CH:24]=1>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]5[C:27]=4[CH:26]=[CH:25][CH:24]=[N:23]5)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: OB(O)c1cccc2ncccc12
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5ncccc45)c3)cnc2c1F
Yield: 5 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and quinoline-5-boronic acid were coupled in the same way as in Example 30 to give 2-{8-fluoro-3-[4-fluoro-3-(quinolin-5-yl)phenyl]-imidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (7 mg, 5%): m/z (ES+) 416 [MH+].
Reaction SMILES: [C:1]1([C@H:7]2[N:10](CC3C=CC(OC)=CC=3OC)[C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[K+].[K+]>C(#N)C.O>[C:1]1([C@H:7]2[NH:10][C:9](=[O:22])[C@H:8]2[N:23]=[N+:24]=[N-:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](N=[N+]=[N-])[C@H]2c2ccccc2)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1c1ccccc1
Yield: 65.1 %

Procedure:
(±)-(cis)-4-Phenyl-1-(2,4-dimethoxybenzyl)-2-oxo-3-azidoazetidine (737 mg) is dissolved in 25 ml of acetonitrile and heated to 80°-83° C. under nitrogen. To the resulting solution are added over a 1 hour period 943 mg of potassium persulfate and 570 mg of potassium monohydrogen phosphate, both dissolved in 25 ml of water. After the addition, the mixture is further heated at 80°-83° C. for 7 hours. The mixture is cooled and the pH is adjusted to 6-7 by adding solid potassium monohydrogen phosphate. Most of the acetonitrile is removed under reduced pressure and the resulting mixture is extracted with 60 ml of chloroform. The chloroform layer is washed with water (60 ml), dried over anhydrous sodium sulfate and stripped of solvent to give a crude product as an oil. The crude product is chromatographed on 40 g of silica gel eluting with 1:1 petroleum ether-ethyl acetate. The combined fractions yield crystals and the product is recrystallized from petroleum ether-ethyl acetate to give 267 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].S(Cl)([Cl:41])=O>>[Cl:41][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Yield: 88 %

Procedure:
6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7. The solid was collected by filtration, washed with water and dried in a vacuum dessicator over phosphorus pentoxide to give 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g, 88%).
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([N:15](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:3][CH2:2]1.CO.C=O.[C:48]([BH3-])#N.[Na+]>C(O)(=O)C>[CH:1]1([N:4]([CH3:48])[CH:5]2[C:14]3[CH2:13][S:12][N:11]=[C:10]([NH2:15])[C:9]4=[N:30][N:31]([CH2:33][C:34]5[C:39]([CH3:40])=[C:38]([O:41][CH3:42])[C:37]([CH3:43])=[CH:36][N:35]=5)[N:32]=[C:7]([C:8]=34)[CH2:6]2)[CH2:2][CH2:3]1
Reactant: COc1c(C)cnc(CN2N=C3CC(NC4CC4)C4=C3C(=N2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(C)cnc(CN2N=C3CC(N(C)C4CC4)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 83.7 %

Procedure:
A mixture composed of di-tert-butyl {8-(cyclopropylamino)-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 60 (400 mg), methanol (2 mL), a 35% formalin solution (111 μL), acetic acid (156 μL) and molecular sieves 3A was stirred at room temperature for 40 minutes. Then, sodium cyanoborohydride (163 mg) was added, and the mixture was stirred at room temperature for 14 hours. The molecular sieves were separated off by filtration, and then the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with a saturated sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. Dichloromethane (2 mL) and trifluoroacetic acid (2 mL) were added to the resulting residue, and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue under ice-cooling, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound (233 mg, 84%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(O)(O)(=O)=O.[NH2:44][CH2:45][C:46]#[N:47].O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:26])[F:27])=[N:20][C:21]([C:22](=[O:23])[NH:47][CH2:46][C:45]#[N:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCN
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC#N)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), aminoacetonitrile sulfate (85 mg, 0.41 mmol), bis(2-oxo-3-oxazolidinyl) phosphonic chloride (0.206 g, 0.81 mmol) and triethylamine (0.37 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(cyanomethyl-carbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 4a (150 mg, yield 94.4%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].C1COCC1>O>[O:1]([C:8]1[C:9]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH:27]3[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]3)[N:23]=2)=[N:10][CH:11]=[C:12]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccccn4)cc3Oc3ccccc3)n2)CC1
Reaction time: 3 h
Yield: 54.5 %

Procedure:
3-Phenoxy-N-(3-(piperidin-4-yl)-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylthio) pyridin-2-amine (0.075 g, 0.16 mmol), TEA (0.090 mL, 0.65 mmol), and acetic anhydride (0.017 g, 0.16 mmol) were added to THF and stirred for 3 hr. Water was added and extracted with CH2Cl2. The organic layer was dried, filtered, and concentrated. The residue was purified by silica gel (5% MeOH in CH2Cl2) to provide the title compound (0.044 g, 54% yield). 1H NMR (d6-DMSO) δ 12.34 (s, 1H), 8.38 (m, 2H), 7.67 (dt, 1H), 7.48 (d, 1H), 7.42 (t, 2H), 7.21-7.11 (m, 5H), 4.32 (d, 1H), 3.84 (d, 1H), 3.19 (m, 1H), 3.05 (m, 1H), 2.76 (t, 1H), 2.01 (m, 5H), 1.74 (m, 1H), 1.59 (m, 1H).
Reaction SMILES: C([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3(O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)=[O:7])(C)(C)C.C([SiH](CC)CC)C.ClCCl>FC(F)(F)C(O)=O>[O:20]1[CH2:21][CH2:22][CH:17]([C:13]2[CH:12]=[C:11]3[C:16]([C:8]([C:6]([OH:7])=[O:5])=[N:9][NH:10]3)=[CH:15][CH:14]=2)[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)c1n[nH]c2cc(C3(O)CCOCC3)ccc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1n[nH]c2cc(C3CCOCC3)ccc12
Yield: 60 %

Procedure:
6-(4-Hydroxytetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid tert-butyl ester (1.0 mmol) was taken up in trifluoroacetic acid (5 mL), triethylsilane (2 mL), and dichloromethane (3 mL) and the mixture was refluxed for 16 h. The solvent was removed in vacuo and the residue was triturated with ethyl acetate to provide 6-(tetrahydropyran-4-yl)-1H-indazole-3-carboxylic acid (60%) as a tan solid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH3:35])[C:28](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[F:36][C:37]([F:42])([F:41])[C:38](O)=O>ClCCl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]([CH3:35])[CH2:28][C:19]4[CH:20]=[CH:15][CH:16]=[CH:17][C:38]=4[C:37]([F:42])([F:41])[F:36])[CH2:25][CH2:26]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Solvent: ClCCl
Product: CN(Cc1ccccc1C(F)(F)F)C1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
0.80 g of (R)-2-methyl-2-(4-(4-(N-methyl-N-tert-butoxycarbonylamino)piperidin-1-yl)phenoxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole was dissolved in 2 ml of trifluoroacetic acid and 2 ml of dichloromethane, followed by stirring at room temperature for 15 hours. Thereafter, the reaction solution was concentrated under a reduced pressure, and then, 2 ml of dichloromethane and 2 ml of triethylamine were added thereto. The mixture was stirred at room temperature for 5 minutes, and it was then concentrated under a reduced pressure. The residue was dissolved in 8 ml of dichloroethane, and then, 0.57 g of 2-trifluoromethylbenzaldehyde and 0.70 g of triacetoxy sodium borohydride were added thereto while cooled by ice. The mixture was warmed to room temperature, and the mixture was then stirred for 24 hours. Thereafter, an aqueous solution of potassium carbonate and dichloromethane were added to the reaction solution. The mixture was stirred, and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate, and then filtered. The obtained filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=9:1). The resultant product was then crystallized from ethyl acetate to obtain 0.47 g (yield: 52.4%) of light yellow powders, (R)-2-methyl-2-(4-(4-(N-methyl-N-(2-trifluoromethylbenzyl)amino)piperidin-1-yl)phenoxymethyl)-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Si:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36]Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>C1COCC1.CCCCCC>[C:1]1([C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:36][CH2:35][CH2:34][CH2:33][O:32][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCl
Reactant: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 82.4 %

Procedure:
t-Butylchlorodimethylsilane (8.3 g, 55 mmol) was added to a stirred mixture of 4-chlorobutanol (5.0 mL, 50 mmol), silver nitrate (12.8 g, 75.1 mmol), and pyridine (4.0 mL, 50 mmol) in 40 mL of dry THF. After 4 hr, the reaction mixture was filtered through Celite and evaporated to give a yellow oil. The material was purified by distillation to provide 4-chlorobutyl t-butyldimethylsilyl ether as a colorless oil (11 g, quantitative). To a solution of triphenylmethane (5.10 g, 20.8 mmol) in 25 mL of dry THF at -78° C., 13.1 mL (21 mmol) of 1.6M n-butyllithium was added dropwise under nitrogen. Shortly thereafter, 4.29 g (19.3 mmol) of 4-chlorobutyl t-butyldimethylsilyl ether was added. After addition of water and extraction with hexane, the product was purified by chromatography on silica gel with 1:3 dichloromethane-hexane, providing t-butyldimethylsilyl 5,5,5-triphenylpentyl ether as an oil (6.85 g). This material was dissolved in THF (30 mL) and 16 mL of 1.0M tetrabutylammonium fluoride in THF was added. After 3 hr, the mixture was acidified with 1N HCl, extracted with three portions of ethyl acetate, and the extracts dried over magnesium sulfate and evaporated in vacuo. The product was purified by chromatography on silica gel with a 10%-20% gradient of ethyl acetate in hexane, providing the title compound as a white solid, 3.83 g (63% overall).
Reaction SMILES: [CH2:1]([C:3]([OH:35])([CH2:33][CH3:34])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:30][CH3:31])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:32])[CH3:2].[CH3:36][O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](Br)[CH:45]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[CH3:36][O:37][C:38](=[O:47])[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44]([C:18]2[CH:17]=[CH:16][C:15]([C:12]([CH2:30][CH3:31])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:33][CH3:34])([OH:35])[CH2:1][CH3:2])=[C:7]([CH3:32])[CH:8]=3)[CH2:13][CH3:14])=[CH:20][CH:19]=2)[CH:45]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cncc(CC(=O)OC)c3)cc2)cc1C)CC
Temperature: 140 °C
Yield: 93.1 %

Procedure:
A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.10 mmol), (5-bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 36.2 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.8 mg, 0.0146 mmol) and potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with microwave heating at 140° C. for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (40 to 50% ethyl acetate/hexane) to give the title compound (46.5 mg, 88%).
Reaction SMILES: N#N.[Br:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[N:9]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: OCCO
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)n2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(6-bromo-pyridin-2-yl)-ethanone (1880 mg, 9.40 mmol) in ethylene glycol (10.00 mL, 179.32 mmol) was treated with trimethylorthoformate (2.10 mL, 19.16 mmol) followed by LiBF4 (180 mg, 1.88 mmol). The reaction mixture was heated at 95° C. for 5 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (50:50 hept-EA)=0.57.