Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16](=[NH:18])[NH:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(=[O:25])[C:23]#[CH:24].C(O)C>C(O)(C)(C)C>[CH:1]1([C:7]2[CH:21]=[CH:20][C:10]([O:11][CH2:12][C:13]3([CH3:19])[O:17][C:16]4=[N:18][C:22](=[O:25])[CH:23]=[CH:24][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(COc2ccc(C3CCCCC3)cc2)CNC(=N)O1
Reactant: C#CC(=O)OCC
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC1(COc2ccc(C3CCCCC3)cc2)Cn2ccc(=O)nc2O1
Temperature: 80 °C

Procedure:
A suspension of 5-(4-cyclohexyl-phenoxymethyl)-5-methyl-oxazolidin-2-ylideneamine (1.11 g, 3.85 mmol) in 15 ml of t-butanol was heated to 80° C. All of the suspension dissolved. Ethyl propiolate (0.51 ml, 5.0 mmol) was added followed by 5 ml of ethanol. The reaction mixture was heated at reflux for 8 hrs. An off-white precipitate gradually came out of the solution. The reaction was cooled to room temperature and the solid isolated by filtration and washed with ether to provide the title compound as a white solid. Yield 0.75 g.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]=1[C:18]([O:20]C)=O)=O.O>C(O)(=O)C>[CH3:12][C:9]1[N:8]([CH2:13][C@H:14]2[CH2:16][C@@H:15]2[CH3:17])[C:7]2[C:18](=[O:20])[NH:2][N:3]=[CH:4][C:6]=2[C:10]=1[CH3:11]
Reactant: COC(=O)c1c(C=O)c(C)c(C)n1C[C@H]1C[C@@H]1C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C)n(C[C@H]2C[C@@H]2C)c2c(=O)[nH]ncc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Hydrazine hydrate (1.92 g, 38.4 mmol) was added to a solution of methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropylmethyl]pyrrole-2-carboxylate (7.96 g, 31.9 mmol) in acetic acid (38 ml) and the mixture was stirred at 90° C. for 1 hour. After this time, the reaction mixture was cooled to room temperature, poured into iced water and filtered. The crude crystals were washed with water and dissolved in a mixture of chloroform and methanol (9:1). The organic layer was separated, washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and to the residue was added a mixture of toluene and hexane. The precipitate was collected by filtration to afford the desired compound (7.02 g, 95.0%) as a pale yellowish white powder.
Reaction SMILES: [H-].[Na+].C1COCC1.[O:8]=[C:9]1[CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:14][CH2:13][C:12]2[CH:24]=[CH:25][CH:26]=[CH:27][C:11]=2[NH:10]1.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32]Br>CCOC(C)=O>[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:32][N:10]1[C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[CH2:13][CH2:14][CH:15]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:9]1=[O:8]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Yield: 137.3 %

Procedure:
72 mg of sodium hydride in suspension at 60% in oil (1.81 mmol) are introduced, at AT, into a 100 ml round-bottomed flask, with stirring and under an argon atmosphere, containing 20 ml of THF and 0.5 g of 2 (1.81 mmol). The medium is stirred for 1 h and then 0.75 g (3.62 mmol) of 3,5-difluorobenzyl bromide is added. The medium is left stirring at AT overnight. 50 ml of EtOAc are added and the organic phase is washed with 50 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 1 g of a white solid is obtained. After trituration with 20 ml of isopropyl ether and filter-drying, 0.62 g of product 3 (white solid) is obtained.
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([N:7]1[CH:11]=[CH:10][N:9]([C:12](=[O:14])[CH3:13])[C:8]1=[O:15])(=[O:6])[CH3:5]>CCOCC.C(OCCCC)CCC>[C:12]([N:9]1[CH:10]=[CH:11][N:7]([C:4](=[O:6])[CH3:5])[C:8]1=[O:15])(=[O:14])[CH3:13].[C:12]([N:9]1[C:8](=[O:15])[N:7]([C:4](=[O:6])[CH3:5])[CH:11]2[CH:10]1[CH2:3]2)(=[O:14])[CH3:13]
Reactant: C=[N+]=[N-]
Agent: CC(=O)n1ccn(C(C)=O)c1=O
Solvent: CCCCOCCCC
Solvent: CCOCC
Product: CC(=O)N1C(=O)N(C(C)=O)C2CC21
Yield: 20 %

Procedure:
A solution of diazomethane in ether (prepared from 200 g of N-nitrosomethylurea) is introduced in portions over the course of 3 days into a solution of 25.0 g (0.15 mol) of 1,3-diacetyl-4-imidazolin-2-one and 5.0 g of copper-I chloride in 250 ml of di-n-butyl ether at 80°-90°. The solution is then filtered, the residue is repeatedly eluted with benzene and the combined filtrates are concentrated in vacuo. Chromatography of the crude product on silica gel gives 10.3 g of unconverted 1,3-diacetyl-4-imidazolin-2-one and 3.6 g (about 20%) of 2,4-diacetyl-2,4-diaza-bicyclo[3,1,0]hexan-3-one as colourless crystals of melting point 134°-136° C. (from ether).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3cccnc3)c(=O)n2Cc2ccccc2)c1O
Yield: 50.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (65 mg, 0.17 mmol) and N-bromosuccinimide (31 mg, 0.18 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (10-80% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 466.17, 468.12 (M+1, 79/81Br).
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[N:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]O)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Cl:5][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]1[CH:10]=[CH:11][N:6]=[CH:7][CH:8]=1
Reactant: OCCCCCCc1ccncc1
Reactant: Cl
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: ClCCCCCCc1ccncc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (1.03 ml) is added to 4-pyridinehexanol hydrochloride (2.42 g) and the mixture is stirred at 20° C. for 30 minutes. Excess saturated aqueous NaHCOs and CHCl3 (20 ml) is added. The organic phase is washed with saturated NaHCO3, brine and water, dried (MgSO4) and the solvent evaporated to give crude material which is purified by flash chromatography on silica gel (CH3OH:CHCl3 =1:49 by vol.) to give 4-(6-chlorohexyl)-pyridine as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:4]=1[C:5]#[N:6].[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24].C(N(CC)CC)C>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][O:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:3]([F:2])[C:4]=2[C:5]#[N:6])[CH2:14][CH2:15]1)=[O:24]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#Cc1c(F)cccc1OCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2cccc(Cl)c2)CC1
Yield: 77 %

Procedure:
A mixture of 2-fluoro-6-(piperidin-4-ylmethoxy)-benzonitrile hydrochloride (200 mg; 0.7 mmol) (Example 123, Step 3) was stirred at room temperature with 3-chlorobenzoyl chloride (129 mg; 0.7 mmol) and triethylamine (0.3 mL; 2.1 mmol) for 16 hours. Reaction was cooled and quenched with dilute HCl and mixture extracted with ethyl acetate (2×20 mL). Combined organics washed with water, saturated sodium bicarbonate, brine and dried over Na2SO4. Crude material was purified by chromatography using 0.5-2% methanol/DCM gradient to afford 2-[1-(3-chloro-benzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile as a white solid. (200 mg; 77% yield).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([CH:50]([OH:52])[CH3:51])[CH2:11][O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55].C(N(CC)CC)C>ClCCl>[C:54](=[O:55])([O:52][CH:50]([C@:10]12[O:32][C@:13]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=4)[CH:34]=3)([O:12][CH2:11]1)[C@H:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:51])[O:56][CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)OC(=O)Cl
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)OC(=O)OC(C)C)(O3)C(OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 1m (0.4 g, 0.56 mmol, obtained from the synthetic method described in step 11 of example 1) in dichloromethane (30 mL) were added isopropyl chloroformate (1.0 mL, 8.34 mmol), triethylamine (1.55 mL, 11.1 mmol) and 4-dimethyl aminopyridine (cat. 5 mg) in turn at room temperature. The mixture was stirred at room temperature for 16 hours. The resulting mixture was quenched with 20 mL of saturated aqueous ammonium chloride, and then extracted with ethyl acetate (40 mL×2). The combined organic layers were washed with saturated brine (20 mL×2), dried over anhydrous brine and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 13a as a light yellow solid (244 mg, 54.2%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.41-7.30 (m, 10H), 7.24-7.11 (m, 5H), 7.08 (m, 2H), 6.90 (m, 2H), 6.76 (m, 2H), 5.01-4.80 (m, 3H), 4.79 (m, 3H), 4.32 (d, 1H), 4.21 (d, 1H), 4.05-3.81 (m, 5H), 3.82-3.71 (m, 2H), 3.66 (d, 1H), 1.40 (t, 3H), 1.29 (d, 3H), 1.26 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:32]1[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:23][C:24]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:25][CH:26]=3)[C:2]([N:32]3[CH2:36][CH2:35][C@@H:34]([OH:37])[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O[C@@H]1CCNC1
Reactant: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2Cl)[nH]1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
A mixture of 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(5-(dimethylcarbamoyl)-1H-pyrrol-2-yl)nicotinamide (Stage 73.1, 60 mg, 0.102 mmol), (R)-pyrrolidin-3-ol (17.82 mg, 0.205 mmol), DIPEA (71.5 μL, 0.409 mmol) and iPrOH (205 μL) in a sealed vial was subjected to MW irradiation at 140° C. for 1 h. The RM was purified by preparative SFC (Column NH2, isocratic 24% in 6 min.) to yield the title compound as a white solid. UPLC-MS (Condition 3) tR=1.03 min, m/z=520.1 [M+H]+, m/z=564.2 [M+FA−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.78 (m, 1H) 1.78-1.89 (m, 1H) 2.96 (d, J=11.74 Hz, 1H) 3.13 (br. s, 6H) 3.25-3.31 (m, 2H) 3.38-3.51 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=2.57 Hz, 1H) 6.11-6.21 (m, 1H) 6.57-6.66 (m, 1H) 7.33 (d, J=9.17 Hz, 2H) 7.82-7.92 (m, 2H) 8.04 (d, J=2.45 Hz, 1H) 8.71 (d, J=2.45 Hz, 1H) 10.15 (s, 1H) 11.66 (br. s, 1H).
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>C1COCC1>[Cl:12][C:13]1[CH:20]=[CH:19][C:16](/[C:17](/[NH2:18])=[CH:6]/[C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: Cc1nccs1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Product: N/C(=C\c1nccs1)c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 2.5 h
Yield: 31 %

Procedure:
A 2.5M solution of N-butyllithium (8.00 mL, 20.00 mmol) in hexanes, was added dropwise to 2-methylthiazole (1.983 g, 20 mmol) dissolved in THF (35.00 mL) over a period of 5 minutes under argon at −70° C. The resulting pale yellow slurry was stirred at −70° C. for 2.5 hour. 4-chlorobenzonitrile (2.75 g, 20.00 mmol) in THF (35.00 mL) was added dropwise to the suspension, which was stirred at −70° C. for 90 minutes after the end of the addition. The reaction mixture was allowed to warm to room temperature under stirring and darkened. The crude was concentrated to dryness and diluted with ethyl acetate then washed with water, dried over magnesium sulphate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 10 to 100% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford (Z)-1-(4-chlorophenyl)-2-(thiazol-2-yl)ethenamine (1.466 g, 31.0%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:15][C:16]([CH:18]=[CH2:19])=[O:17]>C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:19][CH2:18][C:16](=[O:17])[CH3:15])[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: C=CC(C)=O
Reactant: Fc1ccc(CC2CCNCC2)cc1
Solvent: CC(C)O
Product: CC(=O)CCN1CCC(Cc2ccc(F)cc2)CC1
Yield: 100.1 %

Procedure:
To a solution of 4-(4-fluorobenzyl)piperidine (0.50 g, 2.2 mmol) in isopropanol (5 mL) was added methylvinyl ketone (0.25 mL, 3.0 mmol). The resulting solution was stirred at reflux for 1 h then concentrated under reduced pressure to afford the title compound as a pale yellow oil (0.58 g, 99%): 1H NMR (CDCl3) δ1.15-1.35 (m, 2H), 1.38-1.56 (m, 1H), 1.603 (bd, J=12.6 Hz, 2H), 1.894 (t, J=11.7 Hz, 2H), 2.155 (s, 2H), 2.486 (d, J=6.9 Hz, 2H), 2.615 (s, 3H), 2.8-2.9 (m, 2H), 6.9-7.0 (m, 2H), 7.0-7.1 (m, 2H); IR (film) 2928, 1720, 1514, 1219 cm−1.
Reaction SMILES: C(=O)(O)[O-].[Na+].[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]([NH:23][NH2:24])=[O:22])[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N:41]#[C:42]Br>O.O1CCOCC1>[C:6]1([C:12]2([C:19]3[CH:28]=[C:27]([O:29][CH2:30][C:31]4[CH:40]=[CH:39][C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[N:32]=4)[CH:26]=[CH:25][C:20]=3[C:21]3[O:22][C:42]([NH2:41])=[N:24][N:23]=3)[CH2:17][CH:16]3[CH2:18][CH:13]2[CH2:14][CH2:15]3)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CBr
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
A solution of sodium bicarbonate (10.0 mg, 0.12 mmol) in water (267 μL) was added dropwise via syringe to a stirred solution of 4d (0.108 mmol) in dioxane (1.0 mL) at room temperature. A suspension of cyanogen bromide (13.0 mg, 0.12 mmol) in dioxane (120 μL) was added in 4 equal portions at 1 minute intervals. After approximately 45 min, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TiFA as modifier). Lyophilization of the purified fractions afforded the title compound 5b, m/z (ES) 489 (MH)+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.C(N(C(C)C)CC)(C)C.[CH2:15]([CH:17]1[O:19][CH2:18]1)[Cl:16]>C(#N)C>[N:1]1[N:2]([CH2:18][CH:17]([OH:19])[CH2:15][Cl:16])[N:3]=[N:4][CH:5]=1
Reactant: c1nnn[nH]1
Reactant: ClCC1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: OC(CCl)Cn1ncnn1

Procedure:
6.905 g of tetrazole (100 mmol) and 1.75 ml of diisopropylethylamine (10 mmol) and 11.73 ml of epichlorohydrine (150 mmol) in anhydrous acetonitrile (30 ml) was stirred at 60° C. for 4 hours. The obtained solution was evaporated, dried on highvac and purified on a column of silica in chloroform-methanol 100:8. The first fraction provided pure 3-(2-H-tetrazol-2-yl)-2-hydroxy-1-chloropropane, 6.215 g (colorless oil, 38% Y), the second fraction yielded 9.208 g of pure 3-(1-H-tetrazol-1-yl)]-2-hydroxyl-1-chloropropane (sticky gum; 57% Y).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:22]N1C(=O)CCC1=O.COC(C)(C)CC(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:19]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[CH2:20][CH3:21]
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: COC(C)(C)CC(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 69.9 %

Procedure:
To a solution of methyl 3-isobutyryl-2-propylindole-6-carboxylate (201 mg) in carbon tetrachloride (7 ml) was added N-bromosuccinimide (187 mg) and 2,2′-azobis (4-methoxy-2,4-dimethylvaleronitrile; (20 mg) and refluxed for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([N:21]=[C:22]([NH:24][C:25]([CH:27]4[CH2:29][CH2:28]4)=[O:26])[N:23]=3)[CH:20]=2)[CH:9]=1)(C)(C)C.COC1C=CC=CC=1.FC(F)(F)C(O)=O>>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([N:21]=[C:22]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[N:23]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a mixture of tert-butyl[3-({2-[(cyclopropylcarbonyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}oxy)phenyl]carbamate (1.79 g, 4.39 mmol) and methoxybenzene (0.5 mL) was added trifluoroacetic acid (8.0 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and 5% aqueous sodium hydrogen carbonate solution (200 mL) was added to the residue. The obtained precipitate was collected by filtration, and washed with water, diisopropyl ether and hexane to give the title compound (1.13 g, 83%) as a pale-yellow powder. The obtained compound was used for the next reaction without further purification.
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=[N:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+]>C1COCC1.O>[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:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(S(=O)(=O)Nc2ccc(C(=O)NN=C3C(=O)Nc4ccc(I)cc43)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
Into a suspension of methyl 3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate (166 mg, 0.26 mmol) in THF/H2O (2/1) (6 mL) was added NaOH (1.0 N, 1.3 mL). The resulting solution was stirred at rt for 1 hr and quenched with HCl (5 N, 1.3 mL). A yellow solid precipitated out. Filtration, washing with water (4×2 mL) and drying under vacuo at 60° C. for 18 hrs gave the title compound as a yellow powder (133 mg, 81%) in 99.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:16][CH:11]([OH:10])[CH2:12]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: OC1CCCNC1
Solvent: ClCCl
Product: OC1CCCN(Cc2cccc(Br)n2)C1

Procedure:
8] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 3-hydroxypiperidine (326 mg, 3.22 mmol) in dry CH2Cl2 (15 mL) to give 2-bromo-6-(3-hydroxypiperidinyl)methyl pyridine as pale yellow solid. MS m/z: 271.2 (M+H). Calc'd for C11H15BrN2O: 271.15.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:44]=[CH:45][CH:46]=1)[CH2:12][C@@H:13]1[C@@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:15][C@@H:14]1[CH2:42][OH:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:54][S:55]([O:43][CH2:42][C@H:14]1[CH2:15][C@@H:16]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C@H:17](/[CH:18]=[CH:19]/[C@@H:20]([O:26][Si:27]([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:28])[CH3:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@H:13]1[CH2:12][C:11]1[CH:44]=[CH:45][CH:46]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)(=[O:57])=[O:56]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](CO)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(C)(=O)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethysilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methanol (50 g, 0.075 mol) in dry CH2Cl2 (500 ml) was cooled to 0° C. under nitrogen and treated with triethylamine (31.3 ml, 0.225 mol), then with methanesulfonyl chloride (11.6 ml, 0.15 mol). The mixture was poured to saturated sodium bicarbonate aqueous and stirred for 30 minutes. The reaction mixture was phase separated and the aqueous layer was extracted with 500 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. Yield: 81%.