Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:14])=[C:10]([CH3:13])[CH:11]=2)[NH:6][C:5]=1[Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2cc(Cl)c(C)cc2c1CCN=[N+]=[N-]

Procedure:
3-(2-azidoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole was prepared according to method D Step IV with 3-(2-bromoethyl)-6-chloro-5-methyl-2-(triethylsilyl)-1H-indole (0.725 g; 1.87 mmol) and sodium azide (0.365 g; 5.62 mmol) in DMF (8 mL); the yield was quantitative as a brown oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][N:24]=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:24][CH:25]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: COc1ccc(Cl)nc1
Product: COc1ccc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)nc1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-5-methoxy-pyridine. MS (ESI): mass calculated for C23H23N3O2S, 405.52; m/z found 406.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.88 (d, J=2.7, 1H), 7.54-7.47 (m, 1H), 7.45-7.31 (m, 4H), 7.25-7.19 (m, 1H), 7.18-7.12 (m, 1H), 7.06-6.88 (m, 1H), 6.30-6.13 (m, 1H), 3.94-2.47 (m, 13H).
Reaction SMILES: N#N.Br[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:9][C@H:10]1[CH2:14][CH2:13][N:12]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:11]1
Reactant: F[C@H]1CCNC1
Reactant: OCCCCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCCN1CC[C@H](F)C1
Temperature: 100 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 4-bromo-1-butanol (187 mg, 1.20 mmol), (S)-3-fluoropyrrolidine (186 mg, 1.44 mmol) and K2CO3 (392 mg, 1.56 mmol) in CH3CN (8 mL) was heated to 100° C. under microwave irradiations for 25 min. The mixture was then filtered and the solvent removed under reduced pressure to give the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1.[CH3:15][CH2:16][O-:17].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:16][CH3:15])=[CH:9][CH:10]=2)[C:5]([O:13][CH3:14])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccc(F)cc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOc1ccc2c(Cl)ncc(OC)c2c1
Reaction time: 16 h
Yield: 53.4 %

Procedure:
1-chloro-6-fluoro-4-methoxyisoquinoline (533 mg, 2.52 mmol) was dissolved in DMSO (5 mL) then NaOEt (171 mg, 2.52 mmol) was added to the solution. The reaction was stirred for 16 h. The reaction was diluted with EtOAc and washed with 1N HCl, then brine. The organic layer was collected, dried over sodium sulfate and concentrated under vacuum. The crude material was purified by silica gel chromatography using DCM as eluent. The product fractions were collected and solvent was removed under vacuum to give 1-chloro-6-ethoxy-4-methoxyisoquinoline (320 mg, 54% yield). MS m/z 238.0 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:21]=[C:22]([CH3:24])[CH:23]=3)[CH:19]=O)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[N:3]=1.[C:40]([CH2:42]P(=O)(OCC)OCC)#[N:41].CC(C)([O-])C.[K+]>C1COCC1.CC(=O)OCC>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[CH:42][C:40]#[N:41])[CH:21]=[C:22]([CH3:24])[CH:23]=3)=[C:13]([CH:25]([CH3:27])[CH3:26])[C:12](=[O:28])[NH:11][C:10]2=[O:29])[CH:5]=[C:4]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)[N:3]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=CC#N)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a stirred solution of 3-{3-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy}-5-methyl-benzaldehyde (533 mg, 1 mmol) and diethyl cyanomethyl-phosphonate (162 μl, 1 mmol) in THF (10 ml) at 0° C. (ice bath) under nitrogen atmosphere, was added potassium t-butoxide (224 mg, 2 mmol). After stirring for 1 hr., the mixture was stirred for overnight at room temperature. The mixture was then diluted with EA, washed with aqueous saturated ammonium chloride solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA:hexanes (1:2); The fraction of Rf=0.19 was collected.) to afford 445 mg (80%) of a white foam. 1H NMR (300 MHz, CDCl3) δ 1.10 (6H, d, J=6.9 Hz), 2.32 (3H, s), 2.68 (1H, m), 3.79 (3H, s), 4.31 (2H, d, J=5.5 Hz), 4.73 (2H, s), 5.02 (1H, t, J=5.5 Hz), 5.81 (1H, d, J=16.6 Hz), 5.85 (1H, s), 5.98 (1H, s), 6.64 (2H, s), 6.86-6.89 (2H, m), 6.98 (1H, s), 7.20-7.24 (3H, m), 8.98 (1H, s).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[I-].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), potassium benzoate (1.91 g), potassium iodide (0.41 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was separated, was subjected to vacuum concentration and then to Kugelrohr distillation at 110-120° C. and at 1 mmHg and thereby yielded the target compound (2.41 g) in a yield of 77%.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:34])/[CH:23]=[C:24](/[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)\[CH3:25])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C([O-])(=O)C.[NH4+:39]>CO>[CH3:25]/[C:24](/[C:26]1[CH:27]=[C:28]([C:32]([NH2:33])=[NH:39])[CH:29]=[CH:30][CH:31]=1)=[CH:23]\[C:22](=[O:34])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1
Reactant: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: C/C(=C\C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)but-2-enamide (90 mg, 0.19 mmol) in 5 ml anhydrous methanol cooled in an ice bath was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (77 mg, 1 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-methyl-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzene-carboxamidine (15 mg, 20%) as a fluffy white powder after lyophilization. ES-MS (M+E+): 435.1
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23](OCC)=[O:24])(=[O:16])=[O:15])=[CH:10][CH:9]=1>O1CCCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[CH2:23][OH:24])(=[O:15])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NS(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(N[C@@H]1CCC[C@@H]1CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (9.36 mL, 9.36 mmol) was added dropwise to a solution of cis-ethyl 2-(4-chlorophenylsulfonamido)cyclopentanecarboxylate (2.07 g, 6.24 mmol) in 40 mL anhydrous tetrahydrofuran under nitrogen at 0° C. The reaction was then stirred for 1 h at room temperature, then quenched by the slow addition of 100 mL ethyl acetate. The reaction was partitioned between 600 mL ethyl acetate and 300 mL saturated ammonium chloride. The organic layer was dried on sodium sulfate and concentrated to yield 4-chloro-N-(cis-2-(hydroxymethyl)cyclopentyl)benzenesulfonamide (1.81 g, 100%). 1H NMR (400 MHz, CDCl3) δ ppm 7.77-7.85 (2H, m), 7.45-7.50 (2H, m), 5.38 (1H, d, J=7.05 Hz), 3.61-3.78 (3H, m), 2.04-2.15 (1H, m), 1.27-1.80 (7H, m). LC/MS R.T.=2.46 min; [M+H]+=290.10.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH3:33][O:34][C:35](=[O:38])[CH2:36][NH2:37].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([NH:37][CH2:36][C:35]([O:34][CH3:33])=[O:38])=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NCC(=O)OC)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (275 mg, 0.617 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and glycine methyl ester hydrochloride (120 mg, 0.956 mmol), WSCI.HCl (180 mg, 0.939 mmol) and 4-dimethylaminopyridine (150 mg, 1.23 mmol) were added, followed by stirring at room temperature for 2 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=20%-60%) to afford the desired product (270 mg, yield 85%) as a white solid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:17])C>>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
Experiments were carried out under such conditions that the mixing ratio of m-phenoxytoluene to acetic acid was varied. Using as catalysts 3 mol% of cobalt acetate tetrahydrate and 3 mol% of sodium bromide to m-phenoxytoluene and limiting the total volume of the reaction liquid to 150 ml, the experiments were carried out in the same manner as described in Example 17. The results obtained are shown in Table 21. No substantial intermediate oxidation product was obtained when the amount of acetic acide was zero. When the amount of acetic acid was 0.5 mol per mol of m-phenoxytoluene, m-phenoxybenzaldehyde was obtained at a rate of selection of 20 mol% at a conversion rate of 30%. However, this experiment showed bad reproducibility.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH:14]2[CH:18]([O:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH:16]([CH:28]=[CH:29][P:30]([O:35]CC)([O:32]CC)=[O:31])[O:15]2)=[C:7]([O:38]C(=O)N(C2C=CC=CC=2)C2C=CC=CC=2)[N:6]=1)(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.Br[Si](C)(C)C>CC#N>[C:1]([NH:4][C:5]1[NH:6][C:7](=[O:38])[C:8]2[N:9]=[CH:10][N:11]([CH:14]3[CH:18]([O:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH:16]([CH:28]=[CH:29][P:30]([OH:35])([OH:32])=[O:31])[O:15]3)[C:12]=2[N:13]=1)(=[O:3])[CH3:2]
Reactant: CCOP(=O)(C=CC1CC(OC(=O)c2ccccc2)C(n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(C)=O)nc32)O1)OCC
Agent: C[Si](C)(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CC(=O)Nc1nc2c(ncn2C2OC(C=CP(=O)(O)O)CC2OC(=O)c2ccccc2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
A suspension of compound 9.9 (128 mg, 0.173 mmol) in MeCN (5 mL) was treated with 2,6-lutidine (0.08 mL, 0.7 mmol) and bromotrimethylsilane (0.3 mL, 2.27 mmol) and stirred at room temperature for 2 h. The mixture was evaporated and co-evaporated with MeCN. The residue was dissolved in MeOH—H2O (1:1, 10 mL) and treated with NaOH (1 N, 3 mL). The mixture was stirred at room temperature for 16 h then at 45° C. for 1 h, and concentrated under reduced pressure. The residue was subjected to reverse phase HPLC eluting with 0-25% CH3CN in water to give the desired product 9.10 (32 mg, 48%). 1H NMR (D2O) δ 2.1 (m, 2H), 4.55 (m, 1H), 4.8 (m, 1H), 5.7 (d, 1H, J=1.5), 5.9 (m, 1H), 6.1(m, 1H), 7.7 (s, 1H). 31P NMR (D2O) d 17.17. LRMS (ESI) MH+ C11H14N5O6P requires 344.2. Found 344.0.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[CH:10][C:3]=1[NH:4][C@@H:5]([CH3:9])[C:6]([O:8][CH2:17][CH3:18])=[O:7]
Reactant: CCO
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](C)Nc1ccc(F)c(F)c1F

Procedure:
(2S)-2-(2,3,4-trifluoroanilino)propionic acid (219 mg; 99% ee) was dissolved in ethanol (2 ml) and hydrochloric acid (5 mol/l; 0.2 ml) was added thereto at room temperature. The liquid reaction mixture was heated under reflux for 6 hours and then the solvent was evaporated. To the obtained residue was added chloroform. Next, the organic layer was washed with a saturated aqueous solution of sodium chloride and water and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography (ethyl acetate-normal hexane=1:4) to give the title compound (246 mg) as a pale yellow oily substance. The optical purity of the product was 99% ee. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH2:7][CH2:6][CH2:5]2.[Li]CCCC.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.CCOC(C)=O>C1COCC1>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][CH2:7]2)=[CH:3][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: COc1cc2c(cc1Br)CCC2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1B(O)O)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A solution of 1.06 g (4.69 mmol) of 5-bromo-6-methoxyindane in 10 mL of THF was cooled to −78° C. and treated in a dropwise manner with 2.90 mL (4.64 mmol) of 1.6 M n-BuLi in hexanes. The mixture was stirred for 1 hr and was treated with 1.90 mL (8.2 mmol) of triisopropyl borate. The reaction was allowed to warm slowly to 0° C. and was stirred at this temperature for 0.5 hr. The reaction was quenched by the careful addition of 12 mL of aq 1N HCl. The layers were separated and the aqueous layer extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford 1.02 g. Flash chromatography (SiO2; 15% EtOAc in hexanes) gave 0.62 g (69%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.52 (s, 2H), 7.41 (s, 1H), 6.84 (s, 1H), 3.75 (s, 3H), 2.81 (t, J=7.3 Hz, 2H), 2.73 (t, J=7.3 Hz, 2H), 2.00-1.92 (m, 2H); IR (CHCl3) 3505 (br), 2945, 1612, 1570, 1487, 1465, 1417, 1297, 1252, 1161, 1129 cm−1; FDMS 192 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.[Li]CCCC.[NH4+].[Cl-]>C1COCC1>[C:2]([C:3]1[NH:5][C:6]2[C:7]([CH:12]=1)=[CH:8][CH:9]=[CH:10][CH:11]=2)([CH3:14])([CH3:13])[CH3:1]
Reactant: Cc1ccccc1NC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2ccccc2[nH]1
Temperature: 15 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30.0 g, 159 mmol) in dry THF (100 mL) was added dropwise n-BuLi (2.5 M, in hexane, 190 mL) at 15° C. The mixture was stirred overnight at 15° C., cooled in an ice-water bath and treated with saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography to give 2-tert-butyl-1H-indole (23.8 g, 88%).
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]2[C:29]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=3)=[C:28]([O:39][CH2:40][CH2:41][OH:42])[N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].CN(C1C=CC=CN=1)C>>[C:10]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]2[N:25]=[CH:26][N:27]=[C:28]([O:39][CH2:40][CH2:41][O:42][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:29]=2[O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)(=[O:22])=[O:21])=[CH:18][CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(Cl)N1CCOCC1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCO)c1
Agent: CN(C)c1ccccn1
Product: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOC(=O)N2CCOCC2)c1

Procedure:
In analogy to Example 1, part a), from 0.15 ml of morpholine-4-carbonyl chloride and 200 mg of p-tert-butyl-N-[6-(2-hydroxy-ethoxy) -5-(m-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide with the addition of 154 mg of dimethylaminopyridine at a reaction period of 12 hours there was obtained morpholine-4-carboxylic acid 2-[6-(4-tert -butyl-phenylsulfonylamino)-5-(3-methoxy-phenoxy)-pyrimidin-4-yloxy]-ethyl ester. MS: 587.4 (M+H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[CH:20]=[N:19][C:18]([I:21])=[CH:17][N:16]=1>C(O)(C)(C)C>[I:21][C:18]1[N:19]=[CH:20][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:16][CH:17]=1
Reactant: Brc1cnc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Temperature: 100 °C
Yield: 51.5 %

Procedure:
In a 5 mL round bottomed flask were mixed: 1,1-dimethylethyl 1-piperazinecarboxylate (110 mg, 0.590 mmol, available from Fluke), 2-bromo-5-iodopyrazine (140 mg, 0.491 mmol, available from Apollo) and Dipea (0.112 mL, 0.639 mmol) in Tert-Butanol (2 mL). The reaction was stirred and heated under reflux at 100° C. for 40 hr. The reaction mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic layer washed with brine (20 mL) before being dried through an hydrophobic frit and concentrated. The samples were dissolved in 1:1 MeOH:DMSO 2×1 mL and purified by MDAP. The solvent was evaporated in vacuo to give the required product 1,1-dimethylethyl 4-(5-iodo-2-pyrazinyl)-1-piperazinecarboxylate (98.6 mg) LCMS (Method C): Rt=1.20, MH+=391
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:22]([C:23]([OH:25])=O)[C:16]=3[N:15]=2)=[O:12])[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.S(O)(O)(=O)=O.[NH2:55][C:56]1[NH:57][CH:58]=[CH:59][N:60]=1>CN(C=O)C.CCN(C(C)C)C(C)C.[OH-].[Na+].[Cl-].[Na+].O>[NH:57]1[CH:58]=[CH:59][N:60]=[C:56]1[NH:55][C:23]([C:22]1[C:16]2[N:15]=[C:14]([NH:13][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:12])[NH:18][C:17]=2[CH:19]=[CH:20][CH:21]=1)=[O:25]
Reactant: Nc1ncc[nH]1
Reactant: O=C(Nc1nc2c(C(=O)O)cccc2[nH]1)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc2c(C(=O)Nc3ncc[nH]3)cccc2[nH]1)c1cc2ccccc2cn1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
332 mg (1.0 mmol) of above 2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid (0.33 g, 1.0 mmol) was reacted with 800 mg (2.0 mmol) of HBTU and 2-aminoimidazole sulfate (400 mg, 3.0 mmol) in 3.0 mL of DMF and 1.0 mL of DIEA as described in general procedure A. After cooling to room temperature, the reaction mixture was diluted with 0.6 mL of 5 N NaOH aq. solution and 4.0 mL of brine. The solid was collected by filtration and washed with 2 N NaOH aq. (3.0 mL), followed by H2O and EtOAc (3× of each), to give 224.0 mg of the crude compound. The crude was heated in 3.0 mL of DMF at 80° C. for 20 minutes. The filter cake was washed by another 1.0 mL of hot DMF. The combined filtrate was reheated to a clear solution, then cooled and addition of 2.0 mL of EtOAc, followed by 4.0 mL of H2O. The mixture was stirred, and a solid was gradually formed between EtOAc and DMF/H2O layers. The solid was collected by filtration and washed with H2O, EtOAc and MeOH (3× of each), then dried, to yield isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (83.0 mg, 21%). LCMS: 398.0 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.29 (s, 1H), 11.86 (s, 1H), 9.52 (s, 1H), 8.81 (s, 1H), 8.31 (t, 2H), 7.80-7.95 (m, 4H), 7.32 (t, 1H), 6.88 (s, 1H), 6.77 (s, 1H) ppm.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:14]([OH:24])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:22][CH:21]=1
Reactant: O[C@@H](CCCCCOCc1ccccc1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCC[C@H](O)COc1ccc(F)cc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of (2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8 g, 17.5 mmol) in ethanol (30 ml), 10% of Pd/C (100 mg) was added and stirred under H2 atmosphere at normal temperature and pressure for 3 hours. The reaction mixture was filtered through celite, washed with ethanol and concentrated. The residue was purified by silicia gel chromatography using EtOAc-hexane (1:1) to give (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.92 g, 93%); [α]D+12 (c 3.1, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.29-1.69 (m, 8H), 3.65 (t, J=6.8 Hz, 2H), 3.82-4.02 (m, 2H), 6.75-7.0 (m, 4H); HRMS (EI): calcd. for C13H19O3F (M+) 242.131823 found 242.131900.