Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.C(N(CC)CC)C.[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47](Cl)=[O:48]>ClCCl>[O:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[C:47]([N:22]1[CH2:21][CH2:20][C:19]([CH2:18][CH2:17][N:16]2[C@H:14]3[CH2:13][CH2:12][C@@H:11]2[CH2:10][CH:9]([N:8]2[C:7]4[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=4[N:5]=[C:4]2[CH3:3])[CH2:15]3)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:48]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)c2ccco2)CC1
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
To a stirred solution of endo 2-methyl-1-{8-[2-(4-phenylpiperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride II (0.35 g, 0.69 mmol) in dichloromethane (7 mL) and triethylamine (0.209 g, 2.07 mmol) was added 2-furoyl chloride (0.094 g, 0.72 mmol) at 0° C. The ice bath was then removed and the mixture allowed to stir for 30 min. The solvents were then removed in vacuo and the solid was added ethyl acetate and water. The insoluble precipitate was then filtered off and subsequently characterized as the desired product 19. Additional 0.18 g of the desired product 19 was obtained by extracting the organic layer with water (3×), drying with magnesium sulfate and evaporating solvents in vacuo. Following the SFC purification, on a portion of crude 19, 60 mg of the desired product 1-((1R,5S)-8-{2-[1-(2-furoyl)-4-phenylpiperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole 19 was obtained (calculated yield 86%). 1H NMR (400 MHz, CD3OD) δ 7.57 (1H, dist. d, J=1.1 Hz), 7.47 (1H, d, J=7.1 Hz), 7.43-7.29 (5H, m), 7.26-7.09 (3H, m), 6.89 (1H, d, J=3.6 Hz), 6.48 (1H, dd, J=1.8, 3.6 Hz), 4.08 (2H, m), 3.84 (2H, m), 2.60 (5H, m), 2.42 (3H, s), 2.30 (2H, m), 2.20 (2H, m), 2.05 (7H, m), 1.83 (2H, m). HRMS m/z (M+H)+Calc 523.3062; (M+H)+Obs 523.3073.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[CH:6][C:7](=O)[NH:8][N:9]=1)[CH2:2][CH3:3].P(Br)(Br)([Br:13])=O.O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:13][C:7]1[N:8]=[N:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCCc1ccc(=O)[nH]n1
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1ccc(Br)nn1
Temperature: 80 °C
Yield: 48 %

Procedure:
11.75 g of 6-propyl-3(2H)-pyridazinone were dissolved in 70 ml of absolute toluene while warming in a sulphonation flask under nitrogen, heated to 80° C. and treated dropwise while stirring well within 30 minutes with a solution of 24.4 g of phosphorus oxybromide in 24.4 g of absolute toluene. The mixture was subsequently stirred under reflux for a further 3 hours. After completion of the reaction, the mixture was poured into 200 ml of water and neutralized with solid sodium hydrogen carbonate. The phases were separated and the aqueous phase was back-extracted twice with 100 ml of tert.butyl methyl ether each time. The combined organic phases were washed with 100 ml of water and dried over sodium sulphate. After evaporation of the solvent, the dark brown crystalline residue (14.1 g) was sublimed at 40°-60° C. in a high vacuum, there being obtained 8.2 g (48%) of 3-bromo-6-propylpyridazine as white crystals of melting point 35°-36° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]([OH:16])=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1.[H][H].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.CCCCCC>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][C:10]2[CH2:11][CH2:12][O:13][C:9]=2[CH:8]=1
Reactant: BrCc1ccccc1
Reactant: OCCCc1cc2c(cc1O)CCO2
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCCc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.678 g, 16.95 mmol) was washed with petroleum ether then suspended in dry tetrahydrofuran (15 mL) and cooled in an icebath. A solution of 6 (3.00 g, 15.4 mmol) in dry tetrahydrofuran (16 mL) was added dropwise to the sodium hydride suspension. When the hydrogen evolution had ceased, benzyl bromide (3.03 g, 17.7 mmol) was added dropwise and the mixture allowed to stir at room temperature overnight. The reaction was diluted with hexane (20 mL), filtered, and the filtrate concentrated. The residue was taken up in ether (50 mL), washed with 2N HCl and brine, dried (MgSO4) and concentrated to give 7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([OH:27])=O)[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:46]([S:48]([NH2:51])(=[O:50])=[O:49])[CH3:47].C1CCN2C(=NCCC2)CC1>C1COCC1.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[C:11]3[CH:22]=[C:23]([C:25]([NH:51][S:48]([CH2:46][CH3:47])(=[O:50])=[O:49])=[O:27])[S:24][C:10]=3[C:9]=2[CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Reactant: CCS(N)(=O)=O
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)NC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
A solution (0.015 M) of 5-(4-chlorophenyl)-6-cyclohexyl-4-(2-morpholin-4-yl-2-oxoethyl)-4H-thieno[3,2-b]pyrrole-2-carboxylic acid in THF at RT was treated with CDI (1.1 eq.) and DMAP (1.1 eq.). After stirring for 1 h at RT, ethanesulfonamide (2 eq.) and DBU (2 eq.) were added. The mixture was heated to reflux for 5 h then cooled down and diluted with AcOEt. The organic phase was washed with aqueous HCl (0.1 N) and dried. Evaporation of the solvent under reduced pressure gave a residue which was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×100 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 50% A isocratic for 1 min then linear to 20% A in 9 min) to afford the title compound (17%) as a solid.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10]1)=O)(C)(C)C>O1CCOCC1.C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:9][CH2:10]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Fc1ccc(OC2CCNC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4N hydrogen chloride in dioxane (200 ml) is added to a solution of 3-(4-fluoro-phenoxy)-pyrrolidine-1-carboxylic acid tert-butyl ester 5 (39.43 g, 140 mmol) in ethanol (200 ml) and the mixture stirred at room temperature for 18 hours. The solvent is evaporated under vacuum and the residue basified using 4N sodium hydroxide solution (200 ml). The resulting product is extracted using DCM (3×100 ml). The organic extracts are dried (using MgSO4), filtered and evaporated to give the title compound as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24](O)=[O:25])[CH2:19]1.[NH2:32][CH2:33][CH2:34][OH:35].CCOC(C)=O.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[N:7]=[C:6]1[N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([C:24]([NH:32][CH2:33][CH2:34][OH:35])=[O:25])[CH2:19]1
Reactant: Cn1c(=O)c2c(nc(N3CCCC(C(=O)O)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: Cn1c(=O)c2c(nc(N3CCCC(C(=O)NCCO)C3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
A solution of 1-[7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperidine-3-carboxylic acid (30 mg, 0.066 mmol) in 1.0 mL of CH2Cl2 at room temperature was treated with polystyrene-carbodiimide (1.15 mmol/g, 104 mg, 0.12 mmol) and stirred for 30 min. The reaction mixture was treated with 2-aminoethanol (0.004 mL, 0.066 mmol), allowed to rotate overnight, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC chromatography eluting with 5:5:1/hexanes:EtOAc:MeOH to give 11 mg (33% yield) of the title compound: 1H NMR (CDCl3, 400 MHz) δ 7.26-7.14 (m, 2H), 7.00-6.93 (m, 1H), 6.17 (br s), 5.58 (d, 2H, J=1.5), 3.70 (t, 2H, J=5.1), 3.51 (s, 3H), 3.47-3.36 (m, 3H), 3.31 (s, 3H), 3.23 (br d, 1H, J=12.3), 3.12 (dd, 1H, J=12.8, 10.3), 2.97-2.88 (m, 1H), 2.42-2.32 (m, 1H), 1.94-1.86 (m, 1H), 1.82-1.45 (m, 4H); LRMS (ESI) m/z 493 (M+H+); TLC (hexanes:EtOAc:MeOH/5:5:1) Rf=0.12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:12]2C=CC=C[C:11]=2N=N1.[C-]#N.[K+].C(Cl)(=O)C>C1(C)C=CC=CC=1.CCO>[N:1]1[CH:11]=[C:12]([NH2:8])[N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=12
Reactant: c1ccc2[nH]nnc2c1
Reactant: Nc1ccccn1
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Nc1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of amino-pyridine derivative Gen-1 (1 eq.) in toluene are added the aldehyde RzCHO (1 eq.) and benzotriazole (1 eq.). The mixture is stirred at r.t. overnight. Additional aldehyde reagent (0.06 eq.) and benzotriazole (0.06 eq.) are added. After 4 h stirring, potassium cyanide (1.2 eq.) is added, followed by EtOH. The reaction mixture is stirred at r.t. for 5 days. The crude product mixture is then quenched with a 3 M NaOH solution. Solvents are evaporated carefully in vacuo. The residue is diluted with water and EtOAc. The aqueous layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product mixture is dissolved in EtOH and carefully added to a solution of acetyl chloride (2.1 eq.) in EtOH at 0° C. The resulting reaction mixture is stirred at r.t. overnight and then concentrated to dryness to afford the corresponding imidazo[1,2-a]pyridin-3-ylamine as hydrochloride salt.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=C)=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:29])([F:28])[F:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:34]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][C:13]=34)=[CH:21][C:20]([CH:24]=[O:34])=[CH:19][CH:18]=5)[C:8]=2[C:26]([F:27])([F:28])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)Cc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-6-vinyl-4H-indeno[1,2-c]isoxazole (Preparation 87C, 25 mg, 0.063 mmol) in THF (1 mL) were sequentially added NMO (50% in water, 0.016 mL, 0.076 mmol) and osmium tetroxide (4% in water, 0.012 mL, 1.902 μmol) at room temperature. The solution was vigorously stirred at room temperature for 1 hr before more osmium tetroxide (4% in water, 0.02 mL) was added. The mixture was stirred at room temperature overnight. Sodium periodate (17.63 mg, 0.082 mmol) in water (0.1 mL) was added. After the mixture was stirred vigorously at room temperature under nitrogen for 1 hr, water (2 mL) was added. The mixture was concentrated, the solid was filtered, washed with water (1×0.5 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4H-indeno[1,2-c]isoxazole-6-carbaldehyde as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.Cl.Cl.[NH:21]1[CH2:26][CH2:25][CH:24]([CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:21]3[CH2:26][CH2:25][CH:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH2:23][CH2:22]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CC(CN2CCOCC2)CCN1
Agent: Cl
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCOCC4)CC3)cc2n1
Yield: 43 %

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 4-piperidin-4-ylmethyl-morpholine, dihydrochloride salt using standard reductive amination conditions. The resulting crude solid was purified on silica using a gradient of 0%-40% methanol in ethyl acetate as the eluent to give 2-chloro-4-morpholin-4-yl-6-(4-morpholin-4-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine as a white solid (43% 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 methanol to give 329 as an off white solid (88% yield). NMR (CDCl3, 400 MHz), 1.26-1.34 (2H, m), 1.78 (2H, d, J=11.9), 2.09 (2H, t, J=10.8), 2.21 (2H, d, J 7.2), 2.38-2.43 (4H, m), 2.99 (2H, d, J=11.3), 3.70-3.73 (4H, m), 3.82 (2H, s), 3.88-3.90 (4H, m), 4.03-4.06 (4H, m), 5.21 (2H, br s), 7.28 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=511
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25](Cl)=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)[C:30]([O:32][CH3:33])=[O:31].Cl>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:24]=[CH:23][C:22]([C:25]([NH:28][C@@H:29]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=4)[C:30]([O:32][CH3:33])=[O:31])=[O:26])=[CH:21][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCOc1ccccc1-3
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
To a solution of 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl chloride (100 mg, 0.26 mmol) in chloroform (2 ml) was added methyl (S)-2-amino-3-(4-hydroxyphenyl)propionate (154 mg, 0.78 mmol). The mixture was stirred at room temperature for 12 hr, 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration, diethyl ether was added to the obtained residue, and the precipitated solid was collected by filtration. The solid was washed with diethyl ether to give methyl (S)-2-[(12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carbonyl)amino]-3-(4-hydroxyphenyl)propionate (102 mg, yield 82%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][CH2:29][C:30](=O)[CH2:31]Cl>>[Cl:28][CH2:29][C:30]1[N:26]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[S:27][CH:31]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(CCl)cs2)C1

Procedure:
250 mg (about 0.44 mmol) of the compound from Example 53A and 60 mg (0.52 mmol) of 1,3-dichloropropan-2-one were reacted according to the General Method 3. Yield: 150 mg (12% of theory).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1.C([O-])(=[O:25])C.[Cs+].CN(C=O)C>O>[OH:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([O:11][CH2:12][C@@H:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:14])[CH:3]=1
Reactant: C[C@@H](COc1cc(Cl)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1cc(O)c([N+](=O)[O-])cn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 10 h

Procedure:
A mixture of tert-butyl ((2S)-1-((4-chloro-5-nitropyridin-2-yl)oxy)propan-2-yl)carbamate (5.00 g), cesium acetate (7.23 g) and DMF (40 mL) was stirred at 0° C. for 10 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H][H].[CH3:17][NH2:18]>[Pd]>[CH3:17][NH:18][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: [H][H]
Agent: [Pd]
Product: CNC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 98 %

Procedure:
10% Pd/C (2 g) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20 g, 100 mmol) in methylamine (33% in ethanol, 10 mL) and the mixture was stirred at room temperature, under 60 psi of hydrogen, for 18 hours. The reaction mixture was then filtered through Arbocel® and the filtrate was concentrated in vacuo. The residue was azeotroped with dichloromethane (×3) and the dried under vacuum for 72 hours to afford the title compound as a solid in 98% yield, 21.1 g. LRMS APCI m/z 215 [M+H]+
Reaction SMILES: [CH:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:14][O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12])=[CH2:2].Cl[CH2:27]I.C([Zn]CC)C>ClCCl>[CH:1]1([O:3][C:4]2[CH:5]=[C:6]([CH2:14][O:15][Si:16]([CH:17]([CH3:18])[CH3:19])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:7]=[CH:8][C:9]=2[O:10][CH:11]([F:12])[F:13])[CH2:27][CH2:2]1
Reactant: C=COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OC(F)F
Reactant: ClCI
Agent: CC[Zn]CC
Solvent: ClCCl
Product: CC(C)[Si](OCc1ccc(OC(F)F)c(OC2CC2)c1)(C(C)C)C(C)C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of the alkene, 3-Ethenyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene, from Step 3 (67 g, 179 mmol) and chloroiodomethane (78 mL, 1.07 mol) in dichloromethane (1.5 L) at 5° C. (ice bath) was added diethyl zinc (55 mL, 537 mmol) in 5 mL portions over 1.2 h. During the addition, the internal temperature was maintained at <20° C. After the addition was complete, the mixture was stirred for 15 min and then the cooling bath was removed and stirring was continued for a further 2.5 h. The mixture was re-cooled to 5° C. (ice bath) and MeOH (2 mL) was added over 15 min, followed by the addition of water (30 mL) over 15 min and finally, the addition of 6N HCl (5 mL). The mixture was partitioned between ether (1 L) and water (500 mL). The aqueous layer was extracted with ether (500 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated. Flash chromatography of the residue (silica gel; hexane/ethyl acetate 98:2 to 95:5) provided 3-Cyclopropyloxy-4-difluoromethoxy-1-(triisopropylsilyloxy)methylbenzene (71 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1COCC1>[C:11]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=C1CCCC1
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1ccc(C2=CCCC2)c(F)c1
Temperature: 0 °C
Yield: 26.3 %

Procedure:
To a 0.497M solution of (2,4-difluorophenyl)magnesium bromide (32.4 g, 149 mmol) in THF at 0° C. was carefully added cyclopentanone (13.23 mL, 149 mmol). Upon the end of the addition, the reaction mixture was heated at reflux for 2 h. Ice (10 g) and 6N aqueous hydrochloric acid were added. The reaction mixture was extracted with ether. The combined organic extracts were washed with a saturated aqueous solution of sodium hydrogen sulfite, a saturated aqueous solution of sodium bicarbonate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum and the residue was purified by column chromatography on silica gel to give 1-cyclopentenyl-2,4-difluorobenzene (7.064 g, 39.2 mmol, 26.3% yield) as colorless oil. LC-MS (M+H)+=181.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.22-7.31 (1H, m), 6.75-6.85 (2H, m), 6.26-6.31 (1H, m), 2.68-2.74 (2H, m), 2.51-2.58 (2H, m), 1.93-2.02 (2H, m).
Reaction SMILES: C(OC(C1C=NN([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)C=1)=O)C.[CH3:30][O:31][C:32]([C:34]1[CH:38]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[NH:36][N:35]=1)=[O:33].[H-].[Na+].C(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C)C=O>[C:11]([N:36]1[C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:38][C:34]([C:32]([O:31][CH3:30])=[O:33])=[N:35]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: COC(=O)c1cc(C(=O)OC)[nH]n1
Agent: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)OC)n(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 98 %

Procedure:
This compound is a white microcrystalline solid that has been isolated following the methodology described in 2b for ethyl-1-tritylpyrazole-4-carboxylate, by reaction of with dimethyl-3,5-pyrazoledicarboxylate (1.411 g, 7.66 mmol) with sodium hydride (250 mg, 10.41 mmol) in dry dimethylformamide (20 mL), followed by treatment with trityl chloride (2.135 g, 7.66 mmol). Yield: 98% (3.200 g, 7.50 mmol).