Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[OH:19])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:28][C:29]#[N:30]>C1COCC1.CN(C=O)C>[CH2:1]([C:5]1=[CH:6][N:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH2:28][C:29]#[N:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1O
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 4.5 %

Procedure:
To a solution of Example 135 (300 mg, 0.82 mmol) in THF/DMF (1:1, 4 mL) were added sodium hydride (39.2 mg, 0.98 mmol) and 2-bromoacetonitrile (65 μL, 0.98 mmol). The reaction was stirred at 40° C. for 4 hrs and at 80° C. for overnight. The reaction mixture was cooled to room temperature, quenched with saturated NaHCO3 (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in dichloromethane) to afford 15 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93 (t, J=7.3 Hz, 3 H), 1.20-1.48 (m, 2 H), 1.53-1.77 (m, 2 H), 1.63 (s, 9 H), 2.62-2.82 (m, 2 H), 5.22 (s, 2 H), 7.29 (d, J=9.1 Hz, 1 H), 7.58 (dd, J=8.7, 2.8 Hz, 1 H), 7.86 (d, J=2.8 Hz, 1 H), 8.67 (s, 1 H); MS (ESI+) m/z 406 (M+H)+; Anal. Calculated C20H24ClN3O2S: C, 59.17; H, 5.96; N, 10.35. Found: C, 59.18; H, 5.78; N, 10.37.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[OH:4].[H-].[Na+].[H][H].[CH2:36]1[O:39][C@@H:37]1[CH3:38]>C1COCC1.O>[F:31][C:2]([F:30])([F:1])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:36][C@H:37]([OH:39])[CH3:38])[CH:6]=1)([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[N:18]=[CH:17]2)[OH:4]
Reactant: C[C@@H]1CO1
Reactant: [H][H]
Reactant: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2ccccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccccc21
Temperature: 60 °C
Yield: 47.7 %

Procedure:
To a room temperature solution of 100 mg (0.23 mmol) of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-(1H-indol-3-yl)ethanol in THF was added 20.0 mg (0.50 mmol) of 60% NaH in mineral oil. After hydrogen evolution ceased, 14.5 mg (0.25 mmol) of (R)-(+)-propylene oxide was added. The reaction was then warmed at 60° C. for 5 hours. The reaction was then cooled to room temperature and diluted with water and extracted with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (20-40% ethyl acetate in hexanes). The major fractions were combined and concentrated to provide 53 mg (46.6%) of the title compound. MS m/z 484.47 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:12].O.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:14]([O:13][C:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCOC(=O)Oc1ccc(C=O)cc1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
Commercially available 4-hydroxybenzaldehyde (17.8 g, 0.15 mol) was dissolved in dry pyridine (100 ml) and to the solution was dropwise added under cooling, octyl chloroformate (25 g, 0.13 mol), followed by agitating the mixture at 50°-60° C. for about 2 hours, adding water and toluene thereto, sufficiently agitating the mixture, washing the separated toluene layer with 6N-HCl, then 2N-NaOH aqueous solution and further with water until the washing water became neutral, drying the layer with anhydrous sodium sulfate and distilling off toluene to obtain 4-octyloxycarbonyloxybenzaldehyde (33 g, 0.12 mol), dissolving this compound (33 g, 0.12 mol) in acetic acid (90 ml), dropwise adding to the solution, a solution of chromium oxide (25.2 g, 0.25 mol) dissolved in acetic acid (30 ml) and water (20 ml), at about 20° C., heating the mixture up to 40° C., keeping it for 8 hours, placing water therein, filtering off deposited crystals, washing with water and recrystallizing from ethanol to obtain 4-octyloxycarbonyloxybenzoic acid (31 g), adding thereto thionyl chloride (20 g), refluxing the mixture for about 2 hours, and removing excess thionyl chloride under reduced pressure to obtain 4-octyloxycarbonyloxybenzoic chloride (30 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:36]=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].[BH4-].[Na+].CCCCCC>C(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:36][C:35]1[CH:38]=[CH:39][C:40]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])=[C:33]([O:32][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCC=CCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCC=CCCCCCCCC
Reactant: CC(C)(C)OC(=O)NCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCC=CCCCCCCCCOc1ccc(CNCCCCNC(=O)OC(C)(C)C)cc1OCCCCCCCCC=CCCCCCCCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
To a vigorously stirred solution of the amine 9 (0.071 g, 0.38 mmol, 1.2 equiv) in CH2Cl2/MeOH (3:1, 5 mL) was added a solution of the aldehyde 8a (0.20 g, 0.33 mmol) in CH2Cl2/MeOH (3:1, 5 mL), dropwise over 20 minutes. The resulting mixture was stirred at it under an atmosphere of nitrogen overnight. 1H NMR showed the reaction to be complete when there was no aldehyde peak present. The solvent was removed in vacuo and the crude imine dissolved in CH2Cl2/MeOH (1:1, 10 mL). The solution was cooled to 0° C. and NaBH4 (60 mg, 1.58 mmol) was added in 15 mg portions over 30 minutes. TLC (10% EtAc/hexane) showed the reaction to be complete after stirring overnight. The solvent was removed in vacuo and the crude oil dissolved in CH2Cl2 (50 mL) and washed with sodium carbonate (10% aq, 3×40 mL). The CH2Cl2 layer was dried over Na2CO3, filtered, the solvent removed in vacuo and the oily residue purified by flash column chromatography (4% MeOH/CHCl3) to give the product 15 as a clear oil (0.18 g, 78%), Rf=0.2 (3% MeOH/CHCl3). 1H NMR (500 MHz, CDCl3) d 6.85 (s, 1H, aryl), 6.80 (m, 2H, aryl), 5.34 (t, 4H, olefinic), 4.78 (br s, 1H, NHCO), 3.97 (q, 4H, OCH2), 3.69 (s, 2H, benzylic), 3.13 (m, 2H, CH2) 2.63 (t, 2H, CH2NH), 2.01 (m, 8H, CH2C═C), 1.80 (m, 4H, CH2CH2O), 1.55 (m, 4H), 1.49-1.12 (m, 57H, 24×CH2, 3×CH3), 0.89 (t, 6H, CH3); 13C NMR (CDCl3) d 156.17, 149.34, 148.29, 133.15, 130.11, 130.00, 120.67, 114.18, 114.08, 79.23, 69.69, 69.52, 54.12, 49.22, 40.80, 32.28, 30.16, 29.92, 29.82, 29.71, 29.67, 28.81, 28.27, 27.68, 27.60, 26.44, 23.09, 14.54; Anal. (C52H94N2O4): C, H, N.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH3:20][O:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH:27]3[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][O:21][CH3:20])[CH2:25][CH2:26]3)[CH3:13])=[CH:8][C:6]=2[N:7]=1
Reactant: COCCN1CCC(=O)CC1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: COCCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)methylamine was reacted with 1-(2-methoxy-ethyl)piperidin-4-one using standard reductive amination conditions. The resulting crude solid was triturated with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-[1-(2-methoxy-ethyl)-piperidin-4-yl]-methyl-amine as an off white solid (32% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 343 as a solid (43% yield). NMR (CDCl3, 400 MHz), 0.95-0.99 (2H, m), 1.68-1.77 (2H, m), 1.81-1.84 (2H, m), 2.02 (2H, t, J=10.3), 2.37 (3H, s), 2.50-2.59 (3H, m), 3.06 (2H, d, J=11.5), 3.37 (3H, s), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.23 (2H, br s), 7.26 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=499
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]3[C:31]4[C:26](=[C:27]([F:33])[CH:28]=[CH:29][C:30]=4[F:32])[N:25]=[CH:24][N:23]=3)=[CH:15][CH:14]=2)[CH:3]=1.C(N(CC)CC)C.[H][H]>CCO.[Pd]>[F:32][C:30]1[CH:29]=[CH:28][C:27]([F:33])=[C:26]2[C:31]=1[C:22]([NH:21][CH2:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:4]3[CH:3]=[CH:2][N:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]=3)=[CH:18][CH:17]=1)=[N:23][CH:24]=[N:25]2
Reactant: [H][H]
Reactant: Fc1ccc(F)c2c(NCCc3ccc(Oc4cc(Cl)nc(C(F)(F)F)n4)cc3)ncnc12
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Fc1ccc(F)c2c(NCCc3ccc(Oc4ccnc(C(F)(F)F)n4)cc3)ncnc12
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of {2-[4-(6-chloro-2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-(5,8-difluoroquinazolin-4-yl)-amine (0.205 g, 0.46 mmol), 10% Pd on activated carbon (0.030 g) and triethylamine (0.60 mL, 4.3 mmol) in EtOH (15 mL) was charged with hydrogen to an initial pressure of 40 psi in a Parr bottle and shaken overnight. The catalyst was removed by filtration on Celite and the filtrate was concentrated in vacuo. The residue was purified on silica gel to give 0.087 g (42% yield) of (5,8-difluoroquinazolin-4-yl)-{2-[4-(2-trifluoromethylpyrimidin-4-yloxy)-phenyl]-ethyl}-amine as a white foam, 1H NMR (CDCl3): δ 8.71 (d, J=6.3 Hz, 1H), 8.69 (s, 1H), 7.32-7.40 (m, 3H), 7.16 (d, J=8.7 Hz, 2H), 6.97-7.04 (m, 2H), 6.68-6.82 (br, 1H), 3.97 (q, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H). LC/MS: 448.18 (M++1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCc2ccc(N)cc2CC1

Procedure:
3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (740 mg/3.4 mmol) was dissolved in anhydrous methanol (ca. 10 mL) and the solution added to a Parr flask. Palladium (10% on charcoal) was added carefully (WARNING: this addition should be done under a atmosphere of nitrogen to avoid ignition of methanol vapor in flask) and the mixture shaken under 40 psi of hydrogen for 2 hours. The mixture was then filtered and the colorless filtrate concentrated to afford 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo [d]azepin-7-ylamine (yellows upon standing). The material was typically used without further purification (680 mg/quantitative). 1H NMR (400 MHz, CDCl3) δ 6.9 (d, J=7.6 Hz, 1H), 6.4 (m, 2H), 2.9 (m, 4H), 2.7 (m, 6H), 1.1 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([O:18][CH3:22])=[O:17])=[CH:10][C:9]=1[F:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)NC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Nc1ccc(C(=O)NC(C)(C)C)c(F)c1
Temperature: 55 °C
Yield: 29.3 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (1.0 g, 3.3 mmol) and K2CO3 (1.38 g, 10 mmol) in DMF (10 mL) was stirred at RT for 10 minutes. Methyl iodide (710 mg, 5 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate (100 mL, 2 times), dried over Na2SO4, concentrated and purified with column chromatography to obtain 300 mg of methyl 2-(4-(tert-butylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:33][CH:32]=2)=[O:29])=[C:26](Cl)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C>[NH2:21][C:22]1[C:27]([C:28]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](=[O:41])(=[O:40])[NH:38][CH3:39])=[CH:35][CH:36]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2Cl)cc1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1
Temperature: 80 °C
Yield: 14 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (81 mg, 0.27 mmol), 4-(N-methylsulfamoyl)phenyl 4-amino-6-chloropyrimidine-5-carboxylate (135 mg, 0.39 mmol), DIEA (344 μl, 1.97 mmol) and cesium fluoride (150 mg, 0.99 mmol) were suspended in tert-butanol (10 ml) and the mixture was heated at 80° C. in a sealed tube for 24 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution and brine. After evaporation of the solvent, the residue was purified by reverse phase chromatography using SP1® Purification System to give 27 mg (14% yield) as a solid. Purity 99%.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N+:4]([O-])[CH:3]=1.[C-]#N.[Na+].[CH2:14]([N:16](CC)CC)C.C[Si](Cl)(C)C>CN(C=O)C>[C:14]([C:5]1[CH:6]=[CH:7][C:2]([C:1]([OH:10])=[O:9])=[CH:3][N:4]=1)#[N:16]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc[n+]([O-])c1
Agent: C[Si](C)(C)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)O)cn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 21.9 %

Procedure:
To a solution of the nicotinic acid N-oxide (51 g, 0.37 mol) in 1.2 L of DMF, NaCN (54 g, 1.1 mol) was added, followed by triethylamine (255 mL, 1.83 mol) and TMSCl (185 mL). The reaction mixture was stirred at 110° C. for 10 h, filtered and the filtrate was concentrated. The residue was dissolved in 100 mL of 2N HCl and extracted with methylene chloride. The organic layers were combined, concentrated and recrystallised from water to yield 12 g (22%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH2:10])=[O:4].C([O-])([O-])=O.[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:4]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)c1sccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1ccsc1C(=O)OC
Yield: 98.4 %

Procedure:
To a solution of 3-amino-thiophene-2-carboxylic acid methyl ester (2.39 g, 15.2 mmol) in benzene (51 mL) was added K2CO3(6.30 g, 45.6 mmol) followed by ethyl chloroformate (1.74 mL, 18.2 mmol). After heating at reflux for 12 h, the mixture was filtered and the filtrate was concentrated to afford the desired product (3.43 g), which was used in the next step without further purification. MS: 230.0. 1H NMR (400 MHz, CD3OD) δ ppm 7.82 (d, J=5.5 Hz, 1H), 7.66 (d, J=5.6 Hz, 1H), 4.23 (q, J=7.1, Hz, 2H), 3.86 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: O[C:2]1C=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.O=S(Cl)[Cl:13].Cl[CH2:16][Cl:17]>CN(C=O)C>[Cl:13][C:2]1[C:16]([Cl:17])=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(O)nc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(Cl)c(Cl)c1

Procedure:
2-Hydroxypyridine-5-carboxylic acid (4 g, 29 mmol) was dissolved 150 mL of dichloromethane, 50 mL of SOCl2, and five drops of DMF. The raction mixture was heated to reflux under a nitrogen atmosphere for sixteen hours. The reaction mixture was evaporated to an oily solid and used without further purification or characterization (see Preparation 3).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc2c1cnn2C1CCCCO1
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-bromomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (150 mg, 0.508 mmol) and sodium azide (132 mg, 2.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated in a 90° C.-oil-bath for 30 min, then allowed to cool, and poured into water (5 mL). The mixture was extracted with ether (2×10 mL), dried (MgSo4), filtered, evaporated, and dried under high vacuum overnight to give 4-azidomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (124 mg, 95%) as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:29].[CH2:30](N(CC)CC)C.[OH2:37]>ClCCl>[CH:30]([NH:1][C@@H:2]1[CH2:7][C@H:6]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]1=[O:29])=[O:37]
Reactant: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Reactant: CCN(CC)CC
Reactant: O
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](NC=O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To 460 mg (10 mmol) of formic acid, acetic anhydride (204 mg, 2 mmol) was added. The mixture was stirred at room temperature for 2 h. Then one fifth of the above solution was added to a mixture of benzyl (S)-1-((1S,2R,4R)-2-amino-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (60 mg, 0.149 mmol) in dichloromethane (3 ml) and triethylamine (62.3 μl, 3 eq) at 0° C. with stirring. The reaction was stirred for 1 h at room temperature and 1 ml of water was added to quench the reaction. The mixture was diluted with dichloromethane (60 ml) and washed with saturated NaHCO3 (20 ml). The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-formamido-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (50 mg, 78%). LC/MS found [M+H]+=431.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29](Cl)[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:24]=1>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:24]=1
Reactant: Fc1ccc(C(Cl)c2cccc(Br)n2)cc1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1ccc(C(c2cccc(Br)n2)C(c2cccnc2)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(pyridine-3-ylmethyl)pyridine (2.5 g, 14.69 mmol) in anhydrous THF (75 mL) under N2. The mixture was cooled to −78° C. and LDA (12.24 mL, 1.8 M) was added dropwise. The mixture was stirred @ −78° C. for 1 hr and 2-bromo-6-[chloro(4-fluorophenyl)methyl]pyridine (4.64 g, 15.42 mmol) was added. The mixture was warmed to 0° C. and stirred for 2 hr. The reaction was quenched with saturated aqueous NH4Cl and extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4) filtered, and concentrated. The resulting residue was purified by silica gel chromatography (1-3% MeOH in CH2Cl2) to give 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine. 1H NMR (500 MHz, CDCl3) δ 8.55 (d, 1H, J=2.0), 8.45 (d, 1H, J=2.0), 8.35-8.29 (m, 2H), 7.60 (dt, 1H, J=7.9, 1.9), 7.49 (dt, 1H, J=7.9, 1.9), 7.35-7.24 (m, 3H), 7.17 (d, 1H, J=7.8), 7.14-7.07 (m, 2H), 7.05 (d, 1H, J=7.6), 6.86 (t, 2H, J=8.7), 5.13 (d, 1H, J=12.2), 4.78 (d, 1H, J=12.0) LRMS m/z (M+H) Calcd.: 434.0, found: 434.0. The racemic mixture was separated by ChiralPak AD (30% iPrOH in Hexane+DEA 1 mL/L). The first peak was enantiomer A of 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine; HRMS m/z (M+H) Calcd.: 434.0663, found: 434.0648. And the second peak was enantiomer B of 2-bromo-6-[1-(4-fluorophenyl)-2,2-dipyridin-3-ylethyl]pyridine; HRMS m/z (M+H) Calcd.: 434.0633, found: 434.0646.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:20]([C:21]([O-:23])=O)=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH4+].S(Cl)(Cl)=O.[NH2:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>C(Cl)Cl.N1C=CC=CC=1>[Cl:39][C:37]1[CH:36]=[CH:35][C:33]2[N:34]=[C:30]([NH:29][C:21]([C:20]3[C:15]([NH:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:23])[S:31][C:32]=2[CH:38]=1
Reactant: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Reactant: Nc1nc2ccc(Cl)cc2s1
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(Nc1nc2ccc(Cl)cc2s1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Reaction time: 3 h
Yield: 11.1 %

Procedure:
A solution of ammonium 2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]pyridine-3-carboxylate (400 mg, 1.28 mmol) in methylene chloride (5 mL) was treated with thionyl chloride (0.112 mL, 1.54 mmol) and the mixture was heated at reflux. After 3 h, the mixture was cooled and then treated dropwise with a solution of 2-amino-6-chlorobenzothiazole (284 mg, 1.54 mmol) in pyridine (5 mL). After 1 h, the mixture was concentrated in the presence of silica gel. The residue was purified by column chromatography (SiO2: 1 to 4% [2 N ammonia in methanol]:chloroform) followed by recrystallization from methanol to yield 68 mg (11%) of the title compound.