Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:14][OH:15])[C:3]1[CH:12]=[CH:11][C:6](C(OC)=O)=[C:5](F)[CH:4]=1.C(C1C=C(C=CC=1)[CH2:21][N:22]([CH2:30][CH2:31][OH:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])#N>>[NH2:1]/[C:2](=[N:14]\[OH:15])/[C:3]1[CH:4]=[C:5]([CH:6]=[CH:11][CH:12]=1)[CH2:21][N:22]([CH2:30][CH2:31][OH:32])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(C#N)c1
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Product: CC(C)(C)OC(=O)N(CCO)Cc1cccc(/C(N)=N/O)c1

Procedure:
Title compound was prepared following procedure described for Intermediate 1 step 2 but starting from tert-Butyl 3-cyanobenzyl(2-hydroxyethyl)carbamate obtained from step 2 (6 g, 0.0217 mol) (RT for 12 h). Reaction mixture was concentrated under reduced pressure and purified by column chromatography using silica gel and chloroform/methanol as a eluent to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.60 (s, 1H), 7.52-7.53 (m, 2H), 7.31-7.34 (m, 1H), 7.19-7.20 (m, 1H), 5.76 (s, 1H), 4.65-4.68 (m, 1H), 4.42 (s, 2H), 3.42-3.47 (m, 2H), 3.13-3.16 (m, 2H), 1.33-1.41 (m, 9H). LC/MS (Method A): 310.0 (M+H)+. HPLC (Method B) Rt 4.57 min (Purity: 94.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O>[O:35]1[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:34]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCOCC1)=N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 34 ml of a 10% aqueous potassium hydroxide and 2.5 ml of tetrahydrofuran is added 4.5 g of 1-chloro-2-morpholinoethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 7.5 g of 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 191°-193° C.
Reaction SMILES: C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:17][CH2:18][CH2:19][CH2:20]/[C:21](=[CH:25]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)/[C:22]([OH:24])=[O:23].[F:40][C:41]1[CH:50]=[CH:49][C:44]([C:45](=[O:48])[CH2:46]Br)=[CH:43][CH:42]=1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][CH2:18][CH2:19][CH2:20]/[C:21](=[CH:25]\[C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]2)=[C:28]([O:38][CH3:39])[CH:27]=1)/[C:22]([O:24][CH2:46][C:45]([C:44]1[CH:49]=[CH:50][C:41]([F:40])=[CH:42][CH:43]=1)=[O:48])=[O:23]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(/C=C(\CCCCl)C(=O)OCC(=O)c2ccc(F)cc2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
IPEA (0.14 mL) was added to a solution of 5-chloro-2-{1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methylidene}valeric acid trifluoroacetic acid salt (110 mg) and 4-fluorophenacyl bromide (85 mg) in DMF (3 mL), and the reaction solution was stirred at room temperature for 30 minutes. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 47 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:13]([CH3:16])([OH:15])[CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[OH:24]O.N>C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:11][C@H:12]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:13]([CH3:16])([OH:15])[CH3:14])[C:5]2[S:10](=[O:24])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1SCC2)c1ccc(F)cc1
Reactant: OO
Agent: N
Solvent: CC(=O)O
Product: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1S(=O)CC2)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
300 mg (R)-1-(2-chloro-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ylamino)-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol are placed in 2.0 ml acetic acid. The reaction mixture is cooled to +10° C. 127 μl hydrogen peroxide (35%) are added dropwise. The reaction mixture is stirred for 1 hour at +10° C. and then stirred into ice water. It is then made basic with an ammonia solution. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 50/50 to 0/100 then ethyl acetate/methanol 50/50). 70 mg of the product are obtained as an oil. Analytical HPLC-MS (method D): RT=1.17 min.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[Si](C)(C)C)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([S:19][CH3:20])[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1cnc2c(c1)cc([Si](C)(C)C)n2S(=O)(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: CSc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A mixture of 1-benzenesulfonyl-2-trimethylsilyl-5-methylthio-1H-pyrrolo[2,3-b]pyridine obtained in Example 33 (1) (0.60 g), tetrabutylammonium fluoride/tetrahydrofuran solution (1.0 M, 0.8 ml) and tetrahydrofuran (100 ml) was stirred under nitrogen atmosphere at −25° C. for 30 minutes. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate=5:1) to obtain 0.40 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.C(OCC)(=O)C.[ClH:37]>>[ClH:37].[C:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc3c2OCCNC3)cc1
Yield: 73.9 %

Procedure:
A solution (5 ml) of tert-butyl 9-phenyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (390 mg, 1.20 mmol) and ethyl acetate (1 ml) in 4N hydrogen chloride-ethyl acetate was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (232 mg, 73.9%) as a solid.
Reaction SMILES: [CH:1]1([C@H:6]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][CH3:29])=[C:17]3[CH2:16][CH:15]=[CH:14][CH2:13][CH2:12][C@@H:11]3[CH2:42][CH2:43][CH2:44][C@H:10]3[O:9][C:8](=[O:45])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.CO.[Rh]>[CH:1]1([C@H:6]2[C:35](=[O:36])[N:34]3[CH2:37][C@@H:31]([CH2:32][C@H:33]3[C:38]([O:40][CH3:41])=[O:39])[O:30][C:18]3=[N:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]([O:27][CH2:28][CH3:29])=[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[CH2:42][CH2:43][CH2:44][C@H:10]3[O:9][C:8](=[O:45])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCC=CC2
Agent: [Rh]
Agent: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CC/C=C/C2
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOc1c2c(nc3ccccc13)O[C@@H]1C[C@@H](C(=O)OC)N(C1)C(=O)[C@H](C1CCCC1)NC(=O)O[C@@H]1CCC[C@H]1CCCCC2
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of methyl (3aR,7S,10S,12R,21E,24aS)-7-cyclopentyl-19-ethoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,20,23,24,24a-tetradecahydro-10H-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxylate (Example 1, Step 4) (100 mg) in ethyl acetate (20 ml) and methanol (20 ml) was added 5% Rh/C (20 mg) and the mixture was stirred for 18 hours under hydrogen atmosphere. After exchanging the atmosphere for nitrogen, the reaction mixture was filtered and concentrated to give the desired product as a foam (100 mg). LRMS (ES+) M/Z (M+H)+ 622.1.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10](C1CCCCO1)[N:9]=[C:8]2[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28][CH2:27]2)[N:21]=1)=[O:4].Cl>CCOC(C)=O>[NH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:22]2[N:21]=[C:20]([C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([C:3]([N:2]([CH3:40])[CH3:1])=[O:4])[CH:6]=4)[NH:10][N:9]=3)[CH:25]=[CH:24][N:23]=2)[CH2:27][CH2:28]1
Reactant: CN(C)C(=O)c1ccc2c(c1)c(-c1ccnc(N3CCC(NC(=O)OC(C)(C)C)CC3)n1)nn2C1CCCCO1
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc2[nH]nc(-c3ccnc(N4CCC(N)CC4)n3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a solution of tert-butyl (1-(4-(5-(dimethylcarbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-yl)piperidin-4-yl)carbamate (0.4 g, 0.728 mmol) in EtOAc (8 mL) was added HCl (4 N in dioxane, 8 mL) and the reaction was stirred at RT for 3 h The mixture was quenched with water and neutralized with NaHCO3 and extracted with EtOAc. The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified with HPLC (5-50% MeCN in water with 0.1% TFA) to give 3-(2-(4-aminopiperidin-1-yl)pyrimidin-4-yl)-N,N-dimethyl-1H-indazole-5-carboxamide (150 mg, 52%) as an off white solid. MS (ESI, pos. ion) m/z: 366.2 (M+1); 1H NMR (300 MHz, DMSO-d6): −δ 13.88 (s, 1H), 8.53 (s, 1H), 8.48 (d, 2 H, J=5.1 Hz), 7.96 (s, 3H), 7.70 (d, 1 H, J=8.6 Hz), 7.52 (dd, 1 H, J=8.6, 1.4 Hz), 7.38 (d, 1 H, J=5.1 Hz), 4.77 (d, 2 H, J=13.6 Hz), 3.41 (bs, 1H), 3.09-3.20 (m, 2H), 3.03 (s, 6H), 2.03 (d, 2 H, J=10.5 Hz), 1.47-1.58 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:17]1[O:19][CH2:18]1.O>O1CCCC1.CCCCCC>[C:1]1([N:7]2[CH:11]=[CH:10][N:9]=[C:8]2[CH2:17][CH2:18][OH:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2ccnc2)cc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCc1nccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-Phenylimidazole (3.00 g) was dissolved in tetrahydrofuran. To the solution was added dropwise a solution of n-butyllithium (1.6 M) in hexane (16.9 ml) at −70° C. The mixture was stirred for 30 minutes at the same temperature, to which 50% solution (4.76 g) of ethyleneoxide in tetrahydrofuran. The mixture was warmed up to room temperature over 1 hour, and stirred 19 hours at the same temperature. To the reaction mixture was added water. The mixture was subjected to extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to column chromatography on silica gel (developing solvent: ethyl acetate-methanol 100:0→93:7) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:21]4[CH2:22][C:23]5[S:24][CH:25]=[CH:26][C:27]=5[C:20]=4[N:19](COCC[Si](C)(C)C)[N:18]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:21]4[CH2:22][C:23]5[S:24][CH:25]=[CH:26][C:27]=5[C:20]=4[NH:19][N:18]=3)=[CH:15][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sccc3-4)cc2)cc1OC
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1OC
Temperature: 100 °C
Yield: 80 %

Procedure:
6-(3′,4′-Dimethoxy-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.52 g, 1.0 mmol) was dissolved in MeOH and treated with concentrated HCl (0.3 mL, 10 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(3′,4′-Dimethoxy-biphenyl-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.3 g, 0.8 mmol) as brown solid in 80% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[OH2:15]>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:15])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: O
Solvent: CC#N
Product: O=C(CO)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (1 g) in acetonitrile (2.5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min) The same experiment is repeated five times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: N#N.C([O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[O:10][N:9]=1)=O)C.CC(C[AlH]CC(C)C)C>C1COCC1>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:11]1[O:10][N:9]=[C:8]([CH2:6][OH:5])[CH:12]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)c1cc(C(C)(C)O[SiH2]C(C)(C)C)on1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(CO)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-isoxazole-3-carboxylic acid ethyl ester (5.77 g, 20.22 mmol) in THF (200 mL) was treated at −78° C. with DiBAL-H (40.00 mL of a 1M solution in THF, 40.43 mmol). The reaction mixture was stirred at this temperature for 1 h before to be allowed to warm to rt. The reaction mixture was poured onto Rochelle's salt (200 mL) and stirred at rt for 1 h. The aq. layer was extracted with EA (2×200 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (70:30 hept-EA) gave the title compound as a yellow oil: TLC:rf (70:30 hept-EA)=0.28. LC-MS-conditions 02: tR=0.99 min; [M+H]+=244.35.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].I[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: N#Cc1ccc(I)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The sub-title compound was prepared in accordance with Example 8(b) from 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (see Example 8(a)) and 4-iodobenzonitrile.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3].[Br:18]Br>C(O)(=O)C>[N:1]([CH:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=[C:8]([Br:18])[C:7]=2[CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CC(N=[N+]=[N-])CC2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CC(N=[N+]=[N-])CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.8 %

Procedure:
A solution of N-(7-azido-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (1 g, 4.3 mmol) in acetic acid (40 mL) was treated dropwise with bromine (1 g, 6.5 mmol) and stirred at room temperature for 3 h. The solvent was evaporated and the solid residue was washed with ether, collected by filtration and dried to give the product (1.5 g) in 89% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=[O:20])[CH:13]=2)[CH:8]=[N:7]1.[CH2:32]1COCC1>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C@H:16]([CH:29]([CH3:31])[CH3:30])[CH2:17][C@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C@H:19]3[CH2:32][O:20]3)[CH:13]=2)[CH:8]=[N:7]1
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@@H](C=O)NC(=O)OC(C)(C)C)C(C)C)cc21
Reactant: C1CCOC1
Product: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@H]3CO3)C(C)C)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
A flame dried 100-mL, round-bottom flask was charged with sodium hydride (1.45 g, 60.0 mmol) and trimethyloxosulfonium iodide (8.0 g, 36 mmol). The flask was evacuated and refilled with N2, and dry DMSO (50 mL) was added. The mixture was stirred at rt for 2 h to give a solution of the sulfur ylid. A second 100-mL, round-bottom flask was charged with tert-butyl (2S,4S)-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methyl-1-oxohexan-2-ylcarbamate (830 mg, 1.92 mmol) and THF (10 mL). The flask was evacuated and refilled with N2, and the sulfur ylid solution (6.0 mL) was added through a cannula. The resulting mixture was stirred for 2-3 h at rt. The reaction mixture was quenched with brine and extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography to afford tert-butyl (1S,3S)-3-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-4-methyl-1-((S)-oxiran-2-yl)pentylcarbamate (410 mg, 48%). 1H NMR (400 MHz, CDCl3): 0.81-0.92 (m, 5H), 1.26 (m, 2H), 1.47 (s, 6H), 1.65 (m, 6H), 2.17 (m, 2H), 2.68 (m, 1H), 2.95 (m, 1H), 3.30 (s, 3H), 4.11 (m, 1H), 4.47 (m, 2H), 6.99 (m, 1H), 7.21 (m, 1H), 7.60 (m, 1H), 7.95 (m, 1H); MS: 446 (M++1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:17])[CH3:16])[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:18])[CH:15]([CH3:16])[CH3:17])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)C)c(N)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(=O)Nc1ccc(C(=O)O)cc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 5.9 %

Procedure:
A sample of ethyl 3-amino-4-(2-methylpropionylamino)benzoate (2.30 g, 0.0092 mol) was suspended in 1N NaOH (13.80 mL, 0.0138 mol). After stirring for 24 h at room temperature, the reaction was then heated at 50° C. for 6 h. The reaction was filtered and the filtrate acidified with 1N HCl forming an orange precipitate. The solid was collected by filtration and thin-layer chromatographic analysis (SiO2, 9:1 ethyl acetate:methanol) indicated formation of a new lower-running spot (Rf =0.1). This material was recrystallized from N-butanol. The residue was collected by filtration and then suspended in ether. The product was filtered and dried in vacuo at acetone reflux to give 0.12 g (5%) of the title compound as a beige solid, mp 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: FC(F)(F)c1cnc(Cl)cc1Nc1ccccn1

Procedure:
Method A was applied to a mixture of 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (45 mg, 0.15 mmol), 2-aminopyridine (28 mg, 0.30 mmol), Pd2(dba)3 (12 mg, 0.013 mmol), xantphos (8 mg, 0.014 mmol) and cesium carbonate (108 mg, 0.33 mmol) in dioxane (2.5 ml).
Reaction SMILES: [N:1]([C:4]1([CH2:20][C:21](OC(C)(C)C)=[O:22])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[O:11][C:10]2[C:5]1=[CH:6][C:7]([I:19])=[CH:8][CH:9]=2)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][C:4]1([CH2:20][CH2:21][OH:22])[C:17]2[C:12](=[N:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[O:11][C:10]2[C:5]1=[CH:6][C:7]([I:19])=[CH:8][CH:9]=2
Reactant: CC(C)(C)OC(=O)CC1(N=[N+]=[N-])c2cc(I)ccc2Oc2ncc(Br)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1(CCO)c2cc(I)ccc2Oc2ncc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
In a 1-L flask, the tert-butyl 2-(5-azido-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)acetate (7.27 g, 13.38 mmol) was suspended in THF (100 mL) and the suspension was cooled to 0° C. A THF solution of LAH (1 M, 20.08 mL, 20.08 mmol) was added. After 30 min, the reaction mixture was quenched with careful addition of water (0.75 mL), 4 M aqueous NaOH (2.2 mL), and water (0.75 mL). The mixture was filtered through Celite, rinsing with THF (60 mL), then with EtOAc (150 mL). The combined filtrate was concentrated. The residue was purified through silica gel (400 mL) which had been deactivated with Et3N (40 mL), using 100:100:1 EtOAc-hexane-Et3N, to afford 2-(5-amino-3-bromo-7-iodo-5H-chromeno[2,3-b]pyridin-5-yl)ethanol (2.24 g).
Reaction SMILES: [Na].CS([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH2:17](O)[CH2:18][OH:19]>COCCOC.O>[O:10]([CH2:9][CH2:8][CH2:7][O:6][CH2:17][CH2:18][OH:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCOc1ccccc1
Reactant: OCCO
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: OCCOCCCOc1ccccc1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
Sodium (2.80 g) was dissolved in 1,2-ethanediol (22.00 g) at ca 100° under nitrogen and 3-phenoxy-1-propanol methanesulphonate (25.5 g) in 1,2-dimethoxyethane (50 ml) was added dropwise at 100° under nitrogen. The mixture was stirred at 150° for 2 h and then carefully diluted with water (150 ml) and extracted with diethyl ether (2×150 ml). The combined organic extracts were washed with water (2×150 ml), dried and evaporated in vacuo to give the title compound (21.45 g) as an oil. T.l.c. System B (1:1) Rf 0.13.