Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=O)=O)=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42]>O1CCOCC1.O>[NH2:1][C:2]1[C:7]([S:8][CH2:39][CH2:40][C:41]([CH3:44])([OH:43])[CH3:42])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: CC(C)(O)CCBr
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(O)CCSc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 42 %

Procedure:
To a solution of 2-amino-5-bromopyridine-3-sulfonyl chloride (reagent preparation 25, step 1) (0.40 g, (1.47 mmol) in a mixture of 1,4-dioxane (8.0 mL) and water (1.0 mL) was added triphenylphosphine (1.64 g, 6.25 mmol) and the reaction mixture was stirred for 50 minutes at room temperature. Potassium carbonate (0.35 g, 2.50 mmol) was introduced, followed by 4-bromo-2-methyl-2-butanol (Tetrahedron Letters 2000, 41(38), 7337-7340) (0.31 g, 1.86 mmol) and the reaction mixture was stirred at 80° C. for 16 hours. After cooling to room temperature the reaction mixture was concentrated and the residue was partitioned between brine (50 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated. Gradient flash chromatography (25% to 50% ethyl acetate in hexane) provided 4-[(2-amino-5-bromopyridin-3-yl)thio]-2-methylbutan-2-ol (0.18 g, 42%); MS (EI) for C10H15BrN2OS: 292 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]2[O:16][CH:17]=[C:18]([C:20]([OH:22])=O)[N:19]=2)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:24](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15]2[O:16][CH:17]=[C:18]([C:20](=[O:22])[NH2:24])[N:19]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(NC1(c2nc(C(=O)O)co2)CC1)OCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)c1coc(C2(NC(=O)OCc3ccccc3)CC2)n1
Temperature: 60 °C
Yield: 83.3 %

Procedure:
To a solution of 2-(1-benzyloxycarbonylamino-cyclopropyl)-oxazole-4-carboxylic acid (0.20 g, 0.66 mmol) in DMF (3 mL) was added HATU (0.25 g, 0.66 mmol) and Et3N (0.16 g, 2.0 mmol). Ammonium hydrogen carbonate was then added and the reaction vessel sealed. The mixture was heated at 60° C. for 18 h. The reaction was allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×100 mL) and the combined extracts were washed with water, brine and dried with MgSO4. The mixture was filtered and concentrated to give [1-(4-carbamoyl-oxazol-2-yl)-cyclopropyl]-carbamic acid benzyl ester (0.17 g, 0.55 mmol).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](/[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)\[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\C(=O)O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (520 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at 40° C., for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate to obtain Z-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetic acid (321 mg, yield 66%) as colorless crystals. m.p. 156-157° C. (decomposition)
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[CH3:21][C:22]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[CH:25]=[CH:24][N:23]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:28]([OH:30])=[O:29].[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:28]([C:26]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:21])[CH:27]=1)=[O:29]
Reactant: Cc1cc(C(=O)O)ccn1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)ccn1
Product: O=CO
Yield: 120.7 %

Procedure:
To a solution of (3S)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 2) (80 mg, 0.259 mmol) in DMF (5 ml) was added 2-methyl-4-pyridinecarboxylic acid (35.6 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at room temperature overnight. DMF was evaporated in vacuo then DCM (5 ml) was added and washed with saturated aq. NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were collected and concentrated in vacuo giving the title compound (74 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](N(OC)C)=[O:21])=[CH:18][C:17]=1[S:28](=[O:31])(=[O:30])[NH2:29].C([Li])(C)(C)C>O1CCCC1>[Cl:15][C:16]1[CH:27]=[CH:26][C:19]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:18][C:17]=1[S:28]([NH2:29])(=[O:31])=[O:30]
Reactant: CON(C)C(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: CC1CCCN(c2ccc(Br)cc2)C1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC1CCCN(c2ccc(C(=O)c3ccc(Cl)c(S(N)(=O)=O)c3)cc2)C1
Reaction time: 0.17 h

Procedure:
A solution of 0.821 g of 1-(4-bromo-phenyl)-3-methyl-piperidine in tetrahydrofuran is cooled to −78° C. and treated with 0.3 g of 4-chloro-N-methoxy-N-methyl-3-sulfamoyl-benzamide. The mixture is stirred for 10 min and treated slowly with 4.31 mL of a solution of tert-butyl lithium (1.5 M) in tetrahydrofuran (3 mL). The orange solution is stirred at −78° C. for 15 min then at 0° C. for 1 hour. The reaction mixture is quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (2×50 mL). The organics are washed with water, a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is loaded on Celite and purified by silica gel chromatography (1:1 hexanes/ethyl acetate) to give 2-chloro-5-[4-(3-methyl-piperidin-1-yl)-benzoyl]-benzenesulfonamide as a light yellow syrup. MS (m/z): 393 (M+1). HPLC Reverse Phase (Nucleosil 100-5 C18, gradient 10->100% CH3CN in 5 min) room temperature=5.40 minutes.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C[C:15]([O-])([CH3:17])C.[K+].[SiH:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22]>C1(C)C=CC=CC=1>[CH2:21]([Si:20]([CH2:15][CH3:17])([CH2:23][CH3:24])[C:13]1[CH:12]=[CH:11][CH:10]=[C:8]([C:9]2[CH:5]=[CH:4][CH:3]=[C:2]([Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH:1]=2)[C:7]=1[OH:6])[CH3:22]
Reactant: CC(C)(C)[O-]
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: CC[SiH](CC)CC
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC[Si](CC)(CC)c1cccc(-c2cccc([Si](CC)(CC)CC)c2O)c1
Yield: 1 %

Procedure:
The title compound was prepared according to General Procedure by heating dibenzofuran (1, 840 mg, 5.0 mmol, 1 equiv.) with KOt-Bu (1.12 g, 10 mmol, 2 equiv.) and Et3SiH (4.0 ml, 25 mmol, 5 equiv.) in 20 ml of toluene for 20 hours at 100° C. After acidic aqueous work up, the crude reaction mixture was purified by chromatography on silica using hexanes and hexanes-ether (10:1) to give, among other isolated products, 20 mg (0.05 mmol, 1%) of 7. Data for (7): oily solid 1H-NMR (300 MHz, CDCl3): δ 7.53-7.44 (m, 2Har), 7.46-7.44 (m, 2Har), 7.36 (dd, J=1.5, 7.5 Hz, 1Har), 7.23 (dd, J=1.5, 7.5 Hz, 1Har), 6.98 (t, J=7 Hz, 1Har), 5.42 (s, 1H, OH), 1.01-0.96 (m, 18H, 6CH3) 0.91-0.77 (m, 15H, 6CH2). 13C NMR (75 MHz, CDCl3): δ 157.37, 139.45, 136.61, 135.87, 135.09, 133.86, 131.38, 129.57, 128.71, 127.55, 122.97, 120.36, 7.80, 7.57, 3.69, 3.46. HRMS: [C24H38OSi2] calculated 398.2461. measured 396.2470.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(C(F)(F)F)c2ccccc2c1=O
Yield: 83.8 %

Procedure:
The product of Example 11B (41 mg) and 2-(4-chlorophenyl)acetyl chloride (0.030 mL, 0.20 mmol) were treated using a method similar to that described in Example 1C to give the title compound (57 mg, 0.15 mmol) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.42 (dd, 1H), 8.19-7.97 (m, 3H), 7.41 (dd, J=3.3 Hz, 4H), 3.74 (s, 2H); MS (DCI) M/Z 399.2 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>S(Cl)(Cl)=O.C(Cl)Cl>[CH2:19]([C:13]1[CH:14]=[CH:15][C:16]([C:10](=[O:12])[CH2:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: N#Cc1cccc(CC(=O)O)c1
Reactant: CCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Temperature: 0 °C
Yield: 20.4 %

Procedure:
First, 3-cyanophenylacetic acid (3 g, 0.019 mol) is heated under reflux in thionyl chloride (50 ml) for 90 minutes. The excess thionyl chloride is then removed by distillation and the residual acid chloride added in one portion to a solution. 1-phenylpentane (2.76 g, 0,019 moles) in methylene chloride (10 ml). Anhydrous aluminum chloride (2.98 g) is added in small portions over 10 minutes. The reaction mixture is then heated under reflux for 1 hour, cooled and poured into a mixture of ice water (250 ml) and concentrated hydrochloric acid (50 ml). The mixture is extracted with ether (2×100 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica (hexane: ethyl acetate at 90:10 ) to yield 3-(4-pentylphenacyl) benzonitrile (1.13 g, m.p. 73° C.). This nitrile is heated under reflux in a mixture of 75% sulfuric acid (8 g) and acetic acid (8 g) for 90 minutes. The reaction mixture is then diluted with water (100 ml) and extracted with ether (2×75 ml). The ether extracts are dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane to provide 3-(4-pentylphenacyl)benzoic acid (0.97 g), m.p. 109°-111° C., which was identified by IR and NMR spectroscopy.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C1CCNCC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C(N1CCCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and piperidine. MS (ESI): 426.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28](B(O)O)=[CH:29][C:24]=2[CH:23]=[CH:22]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:2]3[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=4)[N:3]=3)=[CH:29][C:24]=2[CH:23]=[CH:22]1
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: OB(O)c1ccc2occc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4occc4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (100 mg, 0.34 mmol) in dioxane (5.0 mL) was added (1-benzofuran-5-yl)boronic acid (215.6 mg, 1.33 mmol), K3PO4 (280.6 mg, 1.33 mmol), Pd(PPh3)4 (25.56 mg, 0.02 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath under an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum to give a residue, which was purified by a silica gel column with 1% ethyl acetate in petroleum ether to afford methyl 2-(1-benzofuran-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate as a light yellow solid (105 mg, crude). LC/MS (ES, m/z): 376.0
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[NH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:34]([CH3:36])[C:32]([CH2:31][NH:30][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14])=[O:33]
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN(C)C(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCC(=O)N(C)C)ccc21
Yield: 37.5 %

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (45.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), 2-amino-N,N-dimethyl-acetamide (25.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 508; and 1H NMR (DMSO-d6, 400 MHz): δ 8.19 (1H, br. s), 7.88 (1H, br. s), 7.68 (1H, br. s), 7.55 (1H, br. s), 7.34-7.24 (2H, m), 7.13 (1H, m), 4.19-4.16 (2H, m), 4.12-4.10 (2H, d), 3.03 (3H, s), 2.88 (3H, s), 1.31-1.27 (3H, t), —NH proton signal was not observed.
Reaction SMILES: [CH2:1]([OH:9])[CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:10][C:11]([CH3:13])=O>>[CH3:10][C:11]1([CH3:13])[O:8][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])[CH2:1][O:9]1
Reactant: CC(C)=O
Reactant: OCCCCC(O)CO
Product: CC1(C)OCC(CCCCO)O1

Procedure:
15 g (112 mmol) of 1,2,6-hexanetriol were dissolved together with 0.5 g of FeCl3 in 1 1 of acetone and boiled under reflux for 7 h. The mixture was filtered, and excess acetone was removed by distillation, resulting in the product in pure form.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Si:13](Cl)([CH3:16])([CH3:15])[CH3:14].[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29](=[O:43])[CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:25]=2)[O:20]1>C1COCC1.C(OCC)C>[CH3:18][C:19]1([CH3:44])[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]([O:43][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:25]=2)[O:20]1
Reactant: COc1cc(CC(=O)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(C=C(O[Si](C)(C)C)c2ccc3c(c2)CCC(C)(C)O3)cc(OC)c1OC
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 74 %

Procedure:
i-Pr2NH (0.556 mL, 4.04 mmol), distilled from CaH, was added to THF (7 mL) and cooled to −78° C. A solution of n-BuLi (2.59 M in THF, 1.56 mL, 4.04 mmol) was added dropwise. After completion of addition the reaction mixture stirred at −30° C. for 35 minutes and then cooled down again to −78° C. TMS-Cl (0.546 mL) and 1-(2,2-dimethyl-chroman-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanone (1.20 g, 3.23 mmol) dissolved in THF (25 mL) were added dropwise to the stirring reaction mixture. After completion of addition the reaction mixture continued stirring at −78° C. for an additional 30 minutes before being warmed up to −30° C. After stirring at −30° C. for 1 hour the reaction was diluted with diethyl ether and warmed to room temperature. At room temperature the reaction mixture was concentrated and the resulting crude material was purified using silica gel chromatography (4:1 pentane: ethyl acetate to 1:1 pentane: ethyl acetate) to obtain the desired compound (879.1 mg, 74% yield based on recovered starting material).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][CH:23]=1)([CH3:3])[CH3:2].[CH3:30][O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][C:34]=1[CH3:41].[B][B][B][B][B][B][B][B][B][B].[CH2:53]=O>CO>[CH3:30][O:31][C:32](=[O:42])[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:29]([C:25]2[C:26]([CH3:28])=[N:27][C:22]([O:21][CH2:20][C:5]3[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[O:15][C:16]([F:19])([F:18])[F:17])[N:7]=[N:8][C:4]=3[CH:1]([CH3:3])[CH3:2])=[CH:23][CH:24]=2)[CH3:53])=[CH:35][C:34]=1[CH3:41]
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: C=O
Reactant: Cc1nc(OCc2c(C(C)C)nnn2-c2ccccc2OC(F)(F)F)ccc1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C(C)C)nnn3-c3ccccc3OC(F)(F)F)nc2C)cc1C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a room temperature solution of 6-[5-isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-ylamine (150 mg, 0.369 mmol) in MeOH (6 mL) is added 4-formyl-2-methyl-benzoic acid methyl ester (72 mg, 0.406 mmol), and the mixture is stirred for 10 min. Decaborane (14 mg, 0.0738 mmol) is added. After 2 h, formaldehyde (2.0 mL, 37 wt % in water) is added and the reaction is stirred for 10 minutes. A second portion of decaborane (14 mg, 0.0738 mmol) is added. After 2 h, the reaction is concentrated and the residue is chromatographed (SiO2 40 g, 0% to 20% EtOAc/Hexane to yield 4-[({6-[5-Isopropyl-3-(2-trifluoromethoxy-phenyl)-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-pyridin-3-yl}-methyl-amino)-methyl]-2-methyl-benzoic acid methyl ester (156 mg, 73%). 1H NMR (400 MHz, DMSO) δ 7.77-7.72 (m, 1H), 7.70 (d, 2H, J=7.9 Hz), 7.66-7.61 (m, 1H), 7.59-7.53 (m, 1H), 7.46 (d, 1H, J=8.8 Hz), 7.23-7.19 (m, 2H), 6.37 (d, 1H, J=8.4 Hz), 5.27 (s, 2H), 3.95 (s, 2H), 3.79 (s, 3H), 3.28 (sept, 1H, J=6.6 Hz), 2.47 (s, 6H), 2.32 (s, 3H), 1.28 (d, 6H, J=6.6 Hz).
Reaction SMILES: C[CH:2]([C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:15])[CH:3]=[CH2:4].[BrH:16].[C:17](O)(=O)C>>[Br:16][CH:4]([CH3:17])[CH2:3][CH2:2][C:5]1[C:10]([CH3:11])=[CH:9][CH:8]=[C:7]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:15]
Reactant: Br
Reactant: C=CC(C)c1c(C)ccc([N+](=O)[O-])c1O
Reactant: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(O)c1CCC(C)Br
Temperature: 113 °C
Reaction time: 1 h

Procedure:
A mixture of 155 ml of the crude 1B, 15 ml of glacial acetic acid and 135 ml of 48% hydrobromic acid was stirred at reflux (113° C.) for five hours, then concentrated at 30 Torr. and 80° C. for one hour. The residue was taken up in 500 ml of ether, dried (MgSO4), and filtered through Celite, and the solvent was evaporated from the filtrate. The residue was column-chromatographed on silica gel, using a 1:24 v:v mixture of THF and hexane as eluent. The product was recrystallized from ether/hexane to give 2-(3-bromobutyl)-3-methyl-6-nitrophenol (1C), as a light yellow solid, m.p.: 67°-69° C.
Reaction SMILES: Cl[CH2:2][N:3]([C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)[C:4](Cl)=[O:5].[F:14][CH:15]([F:33])[O:16][C:17]1[CH:32]=[CH:31][C:20]([CH2:21][NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[S:24])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[F:28][C:27]([F:29])([F:30])[CH2:26][N:25]=[C:23]1[N:22]([CH2:21][C:20]2[CH:31]=[CH:32][C:17]([O:16][CH:15]([F:14])[F:33])=[CH:18][CH:19]=2)[C:4](=[O:5])[N:3]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH2:2][S:24]1
Reactant: FC(F)Oc1ccc(CNC(=S)NCC(F)(F)F)cc1
Reactant: Cc1ccc(N(CCl)C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CSC(=NCC(F)(F)F)N(Cc3ccc(OC(F)F)cc3)C2=O)cc1
Yield: 55 %

Procedure:
0.69 g of N-chloromethyl-N-(4-methylphenyl)carbamoyl chloride and 1.00 g of 1-(4-difluoromethoxybenzyl)-3-(2,2,2-trifluoroethyl)thiourea were dissolved in 30 ml of toluene, and the solution was heated under reflux for 4 hours. After the reaction, toluene was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (10:1)]to give 0.80 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Br.[NH4+].[Cl-]>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:20][CH:22]3[CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: BrCC1CO1
Reactant: CCOC(=O)N1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [Cl-]
Agent: [NH4+]
Product: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC2CO2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
Ethyl 8-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.025 g, 0.097 mmol) was dissolved in anhydrous degassed THF and was cooled to −78° C. A solution of n-BuLi (0.082 mL, 1.78 M in hexanes) was added dropwise and the reaction was stirred at −78° C. for 30 min. Epibromohydrin (0.016 mL, 0.194 mmol) was added and the reaction was allowed to warm slowly to ambient temperature. After 3.5 h, epibromohydrin (0.008 mL, 0.097 mmol) was added and the reaction was stirred overnight at ambient temperature. Upon completion, saturated aqueous NH4Cl was added to quench the reaction and the mixture was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by chromatography (SiO2, 0-50% EtOAc/Hexane) to afford the desired product (15 mg, 49%).