Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][C@H:7]([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH3:4].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C:23]3[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:26]([Cl:33])=[CH:25][N:24]=3)[N:21]=[CH:22][C:15]=12>O1CCCC1>[Cl:33][C:26]1[CH:27]=[C:28]([C:29]([F:32])([F:30])[F:31])[C:23]([N:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([O:12][C@@H:7]([CH2:6][O:5][CH2:3][CH3:4])[C:8]([O:10][CH3:11])=[O:9])[C:15]=3[CH:22]=[N:21]2)=[N:24][CH:25]=1
Reactant: CCOC[C@H](O)C(=O)OC
Reactant: FC(F)(F)c1cc(Cl)cnc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncc(Cl)cc1C(F)(F)F)C(=O)OC
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
60% Sodium hydride in mineral oil (0.316 g, 7.90 mmol) was added portionwise to (S)-methyl 3-ethoxy-2-hydroxypropanoate (Intermediate G4) (0.976 g, 6.59 mmol) in tetrahydrofuran (50 mL) cooled to 5° C. over a period of 1 minute under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. A solution of 4-chloro-1-(5-chloro-3-(trifluoromethyl)pyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate K3) (1.1 g, 3.29 mmol) was added portionwise over a period of 1 minute. The resulting mixture was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was cooled to 10° C., quenched with 1M citric acid (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (25 mL) and saturated brine (25 mL), dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 20 to 50% ethyl acetate in isohexane to give the product (1.1 g, 73%). 1H NMR (400 MHz, CDCl3) δ 1.25 (3H, t), 3.72 (2H, d), 3.81 (3H, s), 3.99-4.13 (2H, m), 5.84 (1H, dd), 8.22-8.24 (1H, m), 8.38 (1H, s), 8.57 (1H, s), 8.81-8.82 (1H, m); m/z (ESI+) (M+H)+=446; HPLC tR=2.52 min.
Reaction SMILES: [N+:1]([C:4]1[C:14]2[C:13](=[O:15])[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:14]2[C:13](=[O:15])[NH:12][CH2:11][CH2:10][NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: O=C1NCCNc2cccc([N+](=O)[O-])c21
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2c1C(=O)NCCN2

Procedure:
To a solution of 6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.2 g, 0.0011 mols) in methanol (8 mL) in a Parr bottle was added 10% palladium on carbon and the mixture subjected to hydrogen at 50 psi for 4 h. The reaction mixture was filtered through celite and washed with DMF and methanol. The filtrate was concentrated in vacuo to give 6-amino-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and carried on without purification. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 6.87 (d, 1H, J=7.6 Hz), 6.75-6.88 (m, 2H), 3.59 (t, 2H, J=6 Hz), 2.46 (t, 2H, J=6 Hz); MS (m/e) 178 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([CH2:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21].C(=O)(O)[O-].[Na+].BrBr.C[O-].[Na+].S1C=CC=C1CC(O)=O>O.C(O)(=O)C.C(O)C.C(O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([CH2:11][CH2:12][C:13]([N:18]2[CH2:25][CH2:24][CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:15])=[O:10])=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)c1ccc(C(=O)CCC(=O)O)cc1
Agent: BrBr
Agent: C[O-]
Agent: O=C(O)Cc1cccs1
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(C(=O)CCC(=O)N2CCC[C@H]2C(=O)O)cc1
Reaction time: 8 h

Procedure:
As for example 85, 14 g. of 3-(4-tert-butylbenzoyl)-propionic acid is reacted with 6.9 g. of N-hydroxysuccinimide in the presence of 12.36 g. of N,N-dicyclohexylcarbodiimide to give 15.5 g. of 3-(4-tert-butylbenzoyl)propionic acid, N-hydroxysuccinimide ester, m.p. 135°-138° C. The preceding compound is added to a solution of 8.05 g. of L-proline and 11.76 g. of sodium bicarbonate in 400 ml. of ethanol-water (1:1). The mixture is stirred overnight, filtered and the filtrate concentrated under vacuum. The mixture is acidified with concentrated hydrochloric acid and extracted with dichloromethane. The solvent is removed to give an amber gum which chromatographed on 150 g. of silica gel with hexane-ethyl acetate (1:1) containing 2% acetic acid as solvent. From the column is obtained 12.4 g. of glass. To a solution of 9.8 g. of the preceding glass in 150 ml. of acetic acid is added 4.8 g. of bromine. The mixture is stirred overnight, concentrated and poured into ice and water. The mixture is extracted with dichloromethane and the extract concentrated to give 12.1 g. of a glass. The preceding glass is added to a solution of 1.94 g. of sodium methoxide and 4.56 g. of thiolacetic acid in 50 ml. of ethanol. After stirring for 2 hours, 1 ml. of acetic acid is added and the mixture diluted with water. The mixture is extracted with dichloromethane, the extract washed with water, dried (MgSO4) and the solvent removed to give 12 g. of product as a yellow glass.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[NH:13]([C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16])[NH2:14]>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:14][NH:13][C:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=[O:16]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(=O)NN=C2C(=O)Nc3ccc(I)cc32)cc1
Temperature: 100 °C
Yield: 86 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl 4-(hydrazinocarbonyl)benzoate. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 334 mg of the title compound (86%) as a yellow solid in 98.3% purity by HPLC (Rt: 5.21, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Li]CCCC.[F:26][C:27]1[CH:38]=[CH:37][C:30]([C:31](N(OC)C)=[O:32])=[CH:29][CH:28]=1>C1COCC1>[F:26][C:27]1[CH:38]=[CH:37][C:30]([C:31]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)c3ccc(F)cc3)cn2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (50 g, 146.2 mmol) in anhydrous THF (700 mL) was dropwise added n-BuLi (2.5 M in hexane, 70 mL, 175 mmol) at −78° C. under nitrogen. The mixture was stirred at −78° C. for 1 h, followed by the addition of a solution of 4-fluoro-N-methoxy-N-methylbenzamide (30 g, 163.9 mmol) in anhydrous THF (100 mL). After stirred at −78° C. for another 2 h, the reaction mixture was quenched with saturated aqueous NH4Cl (250 mL) and extracted with ethyl acetate (200 mL*3). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was diluted with propan-2-ol (150 mL) and stirred at RT for 30 mins. The solid was collected via filtration, washed with propan-2-ol (100 mL) and petroleum ether (300 mL), and dried under vacuum to give the title compound (26 g, yield 46%) as a yellow solid. MS (ES+) C20H23FN4O3 requires: 386. found 331 [M−56+H]+; purity: 100% (UV214).
Reaction SMILES: C(N)(C)(C)C.[CH3:6][O:7][C:8](=[O:20])[C:9](=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:10][C:11]([OH:13])=[O:12].[H][H]>CO>[CH3:6][O:7][C:8](=[O:20])[CH:9]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: COC(=O)C(CC(=O)O)=C1CCCCC1
Solvent: CO
Solvent: CC(C)(C)N
Product: COC(=O)C(CC(=O)O)C1CCCCC1
Temperature: 0 °C
Yield: 109.4 %

Procedure:
The tert-butylamine salt of 2-cyclohexylidenesuccinic acid 1-methyl ester (0.91 g, 3.2 mmol) was placed in a 60 mL high pressure hydrogenation vessel and the vessel was purged with hydrogen (by pressurizing and venting three times with 10 bar of hydrogen). Methanol (9 mL, previously degassed by bubbling nitrogen for one hour at room temperature under stirring) was added through the solvent port and the vessel was then cooled to 0° C. A solution of [Rh(COD)(RR)Me-BPE]OTf (0.004 g, 0.0065 mmol, substrate/catalyst: 500/1) in methanol (1 mL) was added and the reactor was charged with 10 bar of hydrogen. The reaction was stirred at 0° C. for 20 hours, then the solvent was evaporated under reduced pressure and the residue was partitioned between HCl 2N (20 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over MgSO4, evaporated to give 0.75 g of 2-cyclohexylsuccinic acid monomethyl ester as a pale yellow oil (yield 82%). The enantiomeric excess of 2-(R)-cyclohexylsuccinic acid 1-methyl ester was 96% by GC.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([N+:25]([O-])=O)[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H][H]>C(OC(=O)C)C.[Pd]>[NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([NH2:25])[C:13]4[C:17]([CH:18]=3)=[N:16][N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH:14]=4)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12

Procedure:
6-(1H-Indol-4-yl)-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (714 mg, 1.97 mmol) was dissolved in ethylacetate (100 ml) and the compound was hydrogenated using the H-cube™ (available from THALESNano) using 10% Pd/C catalyst at 30° C. and under 30 bar pressure of hydrogen. Solvent was removed in vacuo. The title compound was isolated as an orange/brown solid (629 mg) which was used in subsequent reactions without further purification.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[OH:17]O>C(#N)C.[Pd]>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5]([CH3:6])=[O:17]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: OO
Agent: [Pd]
Solvent: CC#N
Product: CS(=O)CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 200 ml of acetonitrile is dissolved 37 g of BOC-(D)-Met-OH, followed by adding 19 ml of a 30% aqueous solution of hydrogen peroxide, and the mixture is stirred for 8 hours at room temperature. Palladium black is added to the reaction mixture, and then the mixture is stirred for one hour. Palladium black is filtered off, and then acetonitrile is distilled off. The residue is extracted with 300 ml of n-butanol. The n-butanol layer is washed with aqueous solution of NaCl, and then n-butanol is distilled off. The residue is recrystallized from diethyl ether and, then,AcOEt-diethyl ether to give 32 g of crystals, m.p. 125°-126° C., [α]D23 +7.2° (C=0.5, DMF), Rf1 =0.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:35]1[C:27]([NH:25][C@H:23]([C:15]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=2)[CH3:24])=[C:28]2[C:32]([NH:31][CH:30]=[N:29]2)=[N:33][CH:34]=1
Reactant: C[C@H](N)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 4-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester from Example 6 (202 mg), 6-chloro-9H-purine (91 mg, 0.586 mmol) and DIPEA (0.2 mL, 1.17 mmol) in n-butanol (1 mL) was stirred in a sealed tube for 3 h at 120° C. After cooling to RT, the crude reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether affording 112 as a pale brown solid (113 mg, 38% over two steps). LCMS: RT 3.24 min [M+H]+ 463.2. 1H NMR (CDCl3, 400 MHz): δ 8.54 (1H, s), 7.98 (1H, s), 7.78 (1H, d, J=7.55 Hz), 7.49 (1H, d, J=7.36 Hz), 7.28-7.07 (3H, m), 6.13 (1H, br), 4.89-4.78 (1H, m), 4.47-4.04 (2H, m), 2.97-2.78 (1H, m), 2.60-2.26 (3H, m), 1.99-1.62 (6H, m), 1.49 (9H, s)
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.ClC(OCC)=O.[CH2:24]([NH2:27])[CH2:25][NH2:26].Cl>C(Cl)(Cl)Cl>[ClH:8].[NH2:26][CH2:25][CH2:24][NH:27][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=1
Reactant: NCCN
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: NCCNC(=O)c1ccc(Cl)cc1
Yield: 85.6 %

Procedure:
23 ml (0.17 mol) of triethylamine are added dropwise at 0° to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloroformate in 200 ml of chloroform. After completion of the addition (0.5 hour), the solution obtained is added dropwise at 0° to a solution of 50 ml (0.75 mol) of ethylenediamine in 100 ml of chloroform. After completion of the reaction, 115 ml of concentrated hydrochloric acid are added dropwise at 0°. The acidic mixture is filtered and the neutral constituents remaining are removed by extraction with chloroform. The aqueous phase is then made alkaline with sodium hydroxide solution and extracted several times with chloroform. The chloroform extracts are dried and concentrated. The residue is converted into the hydrochloride which is recrystallized from ethanol/ether. There are obtained 15.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride, m.p. 212°-214°. The free base melts at 43°-45°.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]3[B:11]([OH:14])[O:12][CH2:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[OH:14][B:11]1[C:10]2[CH:15]=[CH:16][C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][S:27]([CH3:26])(=[O:29])=[O:28])=[CH:3][CH:4]=3)=[CH:8][C:9]=2[CH2:13][O:12]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-amino-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (50 mg, 0.21 mmol, 1.0 eq.) in DCM (3.0 mL) was added Et3N (35 μL, 0.25 mmol, 1.2 eq.), followed by methanesulfonyl chloride (18 μL, 0.31 mmol, 1.1 eq.). The mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with MeOH/DCM (0:100 to 10:90) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-phenyl]-methanesulfonamide as a white solid. LCMS (m/z) 342 (M+23); 1H NMR (DMSO-d6) δ: 9.72 (s, 1H), 7.65-7.79 (m, 1H), 7.21-7.26 (m, 2H), 7.01-7.05 (m, 2H), 6.91-6.94 (m, 1H), 6.89-6.91 (m, 1H), 4.88 (s, 2H), 2.94 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:26]=[CH:27][CH:28]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[O:3]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CBr)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.88 g, 4.54 mmol) in acetonitrile (20 mL) was added cesium carbonate (4.43 g, 13.61 mmol) and tert-butyl 3-(bromomethyl)phenylcarbamate (1.298 g, 4.54 mmol). The reaction was stirred at room temperature for 3 h. After this time, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phase was extracted with CHCl3. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated. The resulting residue was purified by (0-100% ethyl acetate:hexanes) to afford the title compound (1.06 g, 2.65 mmol, 59% yield) as a colorless oil. LCMS, [M+H]+=400.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16](OC)=[O:17])=[CH:12][C:11]=1[C:20]1[C@@:21]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:24]([CH:25]=1)[CH2:23][CH2:22]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][C:11]=1[C:20]1[C@@:21]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:24]([CH:25]=1)[CH2:23][CH2:22]2
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(CO)cc2C2=C[C@H]3CC[C@]2(C)C3(C)C)c1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a stirred solution of T10.5 (0.050 g, 0.1 mmol) in THF (4 mL) at 0° C. was added LAH in THF (0.3 mL, 0.3 mmol, 1.0M). The resulting mixture was stirred for 2 hours. 1N NaOH(aq) was added to the mixture to quench it. The reaction was then extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-20% EtOAc in hexanes) to yield T10.6 as a colorless oil (0.035 g, 75% yield).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([OH:11])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1cc(Br)c2occc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cc(OC2CCCCO2)cc2ccoc12
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Combine 7-bromo-5-hydroxybenzofuran (5.0 g, 0.0235 mol) with pyridinium para-toluenesulfonate (0.59 g, 0.1 equivalent) and dissolve in 60 mL dichloromethane under nitrogen. Add via syringe 3,4-dihydro-2H-pyran (3,2 mL, 1.5 equivalents) and stir at 20° C. overnight. Dilute with dichloromethane then extract with 1N sodium hydroxide and wash with brine. Dry over sodium sulfate, filtered, and then concentrate to afford the title compound as a brown oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16]Cl)=[CH:10][CH:9]=1.[CH3:19][CH:20]([CH3:36])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=1)=[O:22]>>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:18])[CH2:15][CH2:16][N:33]2[CH2:34][CH2:35][CH:30]([C:26]3[CH:25]=[C:24]([NH:23][C:21](=[O:22])[CH:20]([CH3:19])[CH3:36])[CH:29]=[CH:28][CH:27]=3)[CH2:31][CH2:32]2)=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(=O)c3ccc(Br)cc3)CC2)c1

Procedure:
Procedure K (KI) and Scheme E (K2CO3) using 1-(4-bromophenyl)-3-chloro-1-propanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 457.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:27]=O)=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:29]([N:31]([CH2:35][CH3:36])[CH2:32][CH2:33][NH2:34])[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:27]=[N:34][CH2:33][CH2:32][N:31]([CH2:35][CH3:36])[CH2:29][CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: CCN(CC)CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(C)NC(C=NCCN(CC)CC)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 96.3 %

Procedure:
A mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (970.9 mg), N,N-diethylethylenediamine (290.5 mg) and p-toluenesulfonic acid (catalytic amount) in dried benzene (20 ml) was refluxed under azeotropic dehydration for 4 hours. To the resultant solution was added diethyl ether and the solution was washed with water and dried. The solvent was removed to give red oil (1.1711 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-[2-(N,N-diethylamino)ethyl]iminomethyl-1,4-dihydropyridine-3,5-dicarboxylate.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[CH3:25][N:26]1[C:30]([SH:31])=[N:29][N:28]=[N:27]1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:31][C:30]3[N:26]([CH3:25])[N:27]=[N:28][N:29]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Cn1nnnc1S
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnnn3C)s2)c(C(=O)C2CCCC2)c1
Yield: 30 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(1-methyl-1H-tetrazol-5-ylsulfanyl)-thiazol-2-yl]-urea (133 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 1-methyl-1H-tetrazole-5-thiol (202 mg, 2 mmol) following the general procedure Y
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][CH2:21][C:15]1([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(C2(CNc3ccccn3)CCOCC2)cc1
Yield: 57.5 %

Procedure:
N-{[4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)tetrahydro-2H-pyran-4-yl]methyl}pyridin-2-amine (2.099 g, 5.27 mmol) and tetrabutylammonium fluoride (1M solution in THF, 5.80 ml, 5.80 mmol) were stirred in THF (20 ml) at room temperature for 24 hours until complete. THF was removed in vacuo and the residue partitioned between dichloromethane (75 ml) and sodium bicarbonate (50 ml). The organic layer was washed further with sodium bicarbonate (2×50 ml), then separated and dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on Biotage® silica gel eluting with dichloromethane:methanol:ammonia (100:0:0 to 90:10:1 by volume) to give the title compound (862 mg, 58%) as a solid. LRMS APCI+ m/z 285 [MH]+.