Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10]Br)=[O:4].COC(C1SC(C2C=CC(F)=CC=2)=C(C2C=CC(SC)=CC=2)C=1CBr)=O.FC1C=CC(C=O)=CC=1.[C-:61]#[N:62].[K+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[C:9]=1[CH2:10][C:61]#[N:62])=[O:4]
Reactant: [C-]#N
Reactant: COC(=O)c1sc(-c2ccccc2)c(-c2ccc(SC)cc2)c1CBr
Agent: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(SC)cc2)c1CBr
Agent: O=Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1sc(-c2ccccc2)c(-c2ccc(SC)cc2)c1CC#N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 3-bromomethyl-4-(4-(methylthio)phenyl)-5-phenyl-thiopene-2-carboxylic acid methyl ester (1 g, prepared by using the same procedure described for 3-bromomethyl-5-(fluorophenyl)-4-(4-(methylthio)phenyl)thiophene-2-carboxylic acid methyl ester of Example 8, Step 2 but substituting benzaldehyde for 4-fluorobenz-aldehyde) in DMSO (25 mL) in an ice bath was added powdered KCN. The mixture was stirred for 15 minutes at R.T., then H2O was added and the mixture was extracted with Et2O (2×), the organic layers were combined, washed with brine, dried over MgSO4, filtered and the solvent was evaporated under vacuum. Purification by silica gel chromatography afforded the title compound.
Reaction SMILES: CO.[C:3]([O:7][C:8](=[O:24])[NH:9][C@:10]1([C:15]([NH:17][S:18]([CH:21]2[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[O:16])[CH2:12][C@H:11]1[CH:13]=[CH2:14])([CH3:6])([CH3:5])[CH3:4].CCCCCCC>CCOC(C)=O.[Ru]>[C:3]([O:7][C:8](=[O:24])[NH:9][C@:10]1([C:15]([NH:17][S:18]([CH:21]2[CH2:22][CH2:23]2)(=[O:20])=[O:19])=[O:16])[CH2:12][C@H:11]1[CH2:13][CH3:14])([CH3:4])([CH3:5])[CH3:6]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: [Ru]
Solvent: CO
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
A hydrogenation vessel was charged with a MeOH (1000 mL) slurry of tert-butyl((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate (164 g, 0.50 mol) (U.S. Pat. No. 6,995,174) and 5% Ru/C (dry, 7.5 wt %, 12.4 g) and set stirring. The vessel was placed under nitrogen (20 psig) and vented to atmospheric pressure three times to remove residual oxygen. The vessel was then placed under hydrogen (50 psig). After 20 h, the vessel was vented to atmospheric pressure. The reaction slurry was then transferred out of the reaction and filtered through SOLKA FLOK (34 grams, wetted with 100 mL MeOH) to yield a clear, light brown solution. The SOLKA FLOK was rinsed with MeOH (200 mL×2). The combined MeOH solutions were concentrated under reduced pressure to yield crude product as a white solid (153 g). The crude product was slurried in EtOAc (800 mL), warmed to 40° C. and aged for 30 min. The solution was then seeded, aged for 30 min, and heptane (500 mL) was added via addition funnel over 30 min. The partially crystallized solid was cooled to RT and aged overnight after which additional heptane (500 mL) was added. After 1 h, additional heptane (250 mL) was added via addition funnel, and the white slurry aged for 1 h. The solution was filtered, and the solid was rinsed with heptane/EtOAc (500 mL, 4:1) and dried under reduced pressure to give tert-butyl((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)carbamate (125.9 g).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC([CH2:36][CH2:37][NH:38][C:39]([CH3:51])([CH3:50])[CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=O)=[CH:43][CH:42]=1)=O)(C)(C)C.C(OC(CCNC(C)(C)CC1C=CC(C(CCNC2C=C(OC)C=CC=2C2CCC3C=C(OC(=O)C(C)(C)C)C=CC=3C2)=O)=CC=1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:45][C:44]1[CH:48]=[CH:49][C:41]([CH2:40][C:39]([NH:38][CH2:37][CH3:36])([CH3:51])[CH3:50])=[CH:42][CH:43]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(Cc1ccc(C(=O)O)cc1)NCCC(=O)OC(C)(C)C
Agent: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCC(=O)c2ccc(CC(C)(C)NCCC(=O)OC(C)(C)C)cc2)c1
Product: CCNC(C)(C)Cc1ccc(CN(CC)c2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 43.1 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoic acid (125 mg) according to analogous synthetic method to Preparation Example 86, pivalic acid 6-{2-{{4-[2-(tert-butoxycarbonylethylamino)-2-methylpropyl]benzoyl}ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (94 mg) was used according to an analogous synthetic method to the above-mentioned Example 215 and Example 337 to provide the title compound (55 mg).
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>ClCCl.O>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.2 %

Procedure:
A solution of rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid (89 mg, 0.28 mmol) in dichloromethane (10 mL) was treated with BOP reagent (187 mg, 0.42 mmol), triethylamine (0.12 mL, 0.85 mmol), and 2-aminothiazole (42 mg, 0.42 mmol) at 25° C. The resulting brownish-orange solution was then stirred 16 h at 25° C., then was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (1×10 mL), 1N sodium hydroxide solution (1×10 mL), 1N hydrochloric acid (1×10 mL), and brine (1×10 mL), then were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) to provide rac-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-N-thiazol-2-yl-acetamide (99 mg, 92% yield) as a white foam: EI-HRMS m/e calcd for C17H16Cl2O2N2S (M+) 382.0309, found 382.0308.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17]([S:23]C)=[N:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:25]=1.[CH3:26][O:27][CH2:28][CH2:29]Br.CC(C)([O-])C.[K+].[SH-].[Na+]>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:23])[NH:18][C:19](=[O:22])[N:20]([CH2:29][CH2:28][O:27][CH3:26])[CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:25]=1
Reactant: CSc1nc(=O)[nH]cc1C1c2ccc(Cl)cc2C=Cc2sc(C)nc21
Reactant: COCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCn1cc(C2c3ccc(Cl)cc3C=Cc3sc(C)nc32)c(=S)[nH]c1=O
Temperature: 80 °C

Procedure:
A solution of the product of example 39 step (i) (0.120 g) together with 2-bromoethyl methyl ether (0.073 ml) and a 1M solution of potassium tert-butoxide in tetrahydrofuran (0.62 ml) in N,N-dimethylformamide (3 ml) was heated at 50° C. for 20 h. Sufficient sodium hydrosulphide was added to give a blue solution and the reaction mixture heated at 80° C. for 4 h. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by chromatography eluting with 1% methanol in dichloromethane, followed by trituration with ethyl acetate to give the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:13][CH2:12][C:11]1[CH:10]=[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(NCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc(NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Benzylamino-benzonitrile described in Preparation Example 87 (57 mg, 0.27 mmol) was dissolved at 0° C. in tetrahydrofuran (0.5 mL), and lithium aluminum hydride (52 mg, 1.35 mmol) was added. After stirring overnight at room temperature, water (52 μl), an aqueous solution of 5N sodium hydroxide (52 μl) and water (156 μl) were sequentially added at 0° C. The reaction solution was filtered through Celite pad, then, the solvent was evaporated in vacuo, and (3-aminomethyl-phenyl)-benzyl-amine (62 mg, 0.29 mmol) was obtained as an oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)=[CH:10][CH:9]=1)=[O:7])C.Cl>O1CCCC1.CO.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:16]1[CH2:15][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=2)[CH2:17]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C(=O)O)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 2 M sodium hydroxide solution (28.5 mL, 57.0 mmol) was added to a solution of tert-butyl 3-(4-(ethoxycarbonyl)phenyl)azetidine-1-carboxylate described in Production Example 26-4 (4.35 g, 14.2 mmol) in tetrahydrofuran (32 mL) and methanol (7 mL) at 25° C. The reaction liquid was stirred at 60° C. for 1 hour. 2 M hydrochloric acid (28.5 mL) was added to the reaction liquid, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (3.4 g, 86%).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])C.[CH2:29]([NH2:34])[CH2:30][CH2:31][CH2:32][CH3:33].[C-]#N.[Na+]>>[CH2:29]([NH:34][C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:27])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCN
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)o1
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)o1
Temperature: 25 °C
Yield: 86 %

Procedure:
5-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl]-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (0.050 g, 0.126 mmol) was added to the mixture of n-pentylamine (1 mL) and sodium cyanide (0.012 g, 0.251 mmol). The reaction mixture was stirred at room temperature over night. The mixture was evaporated to dryness, then diluted with 5 mL of water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and then concentrated. The title compound was obtained in 86% yield (0.047 g) after column purification. 1H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.64-7.52 (m, 2H), 7.33-7.31 (m, 1H), 6.91 (t, J=5.4 Hz, 1H), 4.09-3.98 (m, 1H), 3.87-3.6 (m, 3H), 3.58-3.45 (m, 2H), 3.42-3.36 (m, 2H), 3.30-3.27 (m, 2H), 1.63-1.5 (m, 2H), 1.33-1.29 (m, 4H), 0.87 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.6, 164.6, 153.9, 153.5, 133.9, 132.4, 129.6, 128.97, 127.1, 126.9, 126.8, 126.7, 125.4, 121.8, 46.0, 45.7, 45.6, 40.8, 39.7, 29.0, 28.9, 22.3, 13.9. MS (ES+) m/z 440 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.FC(F)(F)S(O[CH2:45][CH:46]([F:48])[F:47])(=O)=O.C(N(CC)CC)C>C1COCC1>[F:48][CH:46]([F:47])[CH2:45][N:29]1[CH2:30][CH2:31][CH:26]([N:25]([CH3:32])[C:23]([N:11]2[CH2:12][C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[CH:14][C:10]2([CH2:9][OH:8])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(F)F)CC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To 87 mg (0.16 mmol) of amine 7-2 in THF in a sealed tube was added 41 mg (0.19 mmol) of 2,2-difluoroethyl trifluoromethane sulfonate and 67 μL (0.48 mmol) of triethylamine. After stirring 2.5 h at 70° C., the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in 5 mL CH2Cl2 and 1 mL of trifluroacetic acid was added. After stirring for 30 min at room temperature, the solvents were removed by rotary evaporation, the residue was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 10-1 as a white solid. Data for 10-1: 1HNMR (500 MHz, CDCl3) δ 7.7-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.8 (m, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.7 (m, 1H), 3.0 (m, 2H), 2.9 (s, 3H), 2.75 (m, 2H), 2.3 (m, 2H), 1.9 (m, 2H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H29F4N3O2: 492.2269. Found: 492.2250.
Reaction SMILES: ClC1C=[CH:4][N:5](C(OC)=O)NC=1.[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[N:17][CH:18]=1.ClC1N=CC(C(Cl)=O)=NC=1.S(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O.CN>O1CCCC1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([NH:5][CH3:4])=[O:21])=[N:17][CH:18]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: COC(=O)N1C=CC(Cl)=CN1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cnc(Cl)cn1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CNC(=O)c1cnc(Cl)cn1

Procedure:
Methyl 5-chloro-2-pyridazinecarboxylate (CAS #33332-25-1) is hydrolyzed to the corresponding carboxylic acid, 5-chloropyrazine-2-carboxylic acid. This acid is then converted to the corresponding acid chloride, 5-chloropyrazine-2-carbonyl chloride, by treatment with either thionyl chloride or oxalyl chloride. This acid chloride is then treated with a 2 M solution of methylamine in tetrahydrofuran to provide 5-chloro-N-methylpyrazine-2-carboxamide. The procedure of Example 48 is then repeated, substituting 5-chloro-N-methylpyrazine-2-carboxamide in place of 6-chloro-N-methyl-3-pyridinecarboxamide to give (R)—N-methyl-5-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yloxy)pyrazine-2-carboxamide.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>CN(C=O)C>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: C[C@H]1CC[C@@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[C@H]2CC[C@@H](C)CC2)cc1

Procedure:
cis-4-Methyl-cyclohexanol (3.28 g, 28.7 mmol), NaH (1.09 g, 27.3 mmol, 60% suspension in mineral oil) and DMF (50 mL) were combined and sonicated as in general procedure L. The mixture was charged with 4′-fluoroacetophenone (2.18 mL, 17.8 mmol) and heated. After aqueous workup, the crude residue was purified on a silica gel column (gradient, hexane→2% EtOAc-hexane) to obtain 1-[4-(cis-4-Methyl-cyclohexyloxy)-phenyl]-ethanone (976 mg).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:11]([Cl:13])[C:10]([F:14])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)(=O)CC>[Cu].C1(C)C=CC=CC=1>[Cl:13][C:11]1[CH:12]=[CH:2][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[F:14]
Reactant: CCOC(=O)c1cc(F)c(Cl)cc1Cl
Agent: [Cu]
Solvent: Cc1ccccc1
Solvent: CCC(=O)O
Product: CCOC(=O)c1ccc(Cl)c(F)c1
Temperature: 135 °C
Yield: 68.5 %

Procedure:
A 50-mL round-bottom flask was equipped with a magnetic stir bar, reflux condenser, thermometer, nitrogen inlet, and heating mantle attached to a temperature controller. The flask was charged with ethyl 2,4-dichloro-5-fluorobenzoate (5.09 g, 21.4 mmol) and copper powder (2.72 g, 42.8 mmol). Propionic acid (10 mL) was added, and the resulting mixture was heated to 135° C. The reaction was monitored by GC analysis and was judged to be complete when the starting material was no longer detectable (5 hours). Toluene (25 mL) was added as the reaction was cooled to room temperature. The resulting mixture was filtered, and the solids were washed with toluene. The filtrates were blue-green. The filtrates were combined and washed with 1M hydrochloric acid solution until the blue-green color disappeared. The resulting yellow organic layer was washed with water and dried over sodium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was dried under vacuum to give 2.97 g of ethyl 4-chloro-3-fluorobenzoate as a pale yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C1COCC1.[CH3:15][NH:16][CH3:17]>>[CH3:15][N:16]([CH2:2][C:3]1([CH3:9])[CH2:7][O:6][C:5](=[O:8])[NH:4]1)[CH3:17]
Reactant: CNC
Reactant: CC1(CCl)COC(=O)N1
Solvent: C1CCOC1
Product: CN(C)CC1(C)COC(=O)N1
Temperature: 25 °C
Yield: 32 %

Procedure:
A solution of 4-(chloromethyl)-4-methyloxazolidin-2-one (2.97 g, 19.9 mmol) in 2.0 M dimethylamine in THF (50 ml, 100 mmol) in a sealed tube was heated to 85° C. for 24 h, cooled to RT, and filtered through a coarse glass filter to remove precipitated dimethylammonium chloride. The filtrate was concentrated, and the residue purified by flash chromatography (3%→10% MeOH in CH2Cl2) to afford the oxazolidinone as a brown oil (1.02 g, 6.45 mmol, 32%), and the dihydrooxazole as a yellow oil (1.62 g, 10.2 mmol, 52%). Rf=0.5 in 10% MeOH in CH2Cl2. 1H NMR (CDCl3, 400 MHz) δ 1.35 (s, 3H), 2.33 (s, 6H), 2.37 (d, J=13.6 Hz, 1H), 2.43 (d, J=14.4 Hz, 1H), 4.02 (d, J=8.4 Hz, 1H), 4.18 (d, J=8.4 Hz, 1H), 5.2 (br s, 1H). ESI/APCI expected for C7H14N2O2: 158.11. Found: 159 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:19]2[CH2:21][CH2:20]2)[N:12]=1)([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(Br)n1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(C2CC2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
Combine [1-(6-bromo-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.64 g, 7.6 mmol), cyclopropyl boronic acid (850 mg, 9.9 mmol), potassium phosphate (6.1 g, 26.6 mmol), and palladium acetate (85 mg, 0.38 mmol). Add toluene (31 mL) and water (1.4 mL) followed by 1M tricyclohexyl phosphine in toluene (760 μl, 0.76 mmol); degas the mixture, purge with nitrogen, and heat at 100° C. for 6 hours, then stir at room temperature overnight. Add tri tert-butylphosphine (153 mg, 0.76 mmol) and palladium acetate (85 mg, 0.38 mmol), degas and heat at 85° C. overnight. Filter the reaction and purify the filtrate over silica (120 g) eluting with 0% to 25% EtOAc:hexanes to give [1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester as an oily yellow solid (1.3 g, 62%). MS (m/z): 277.4 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[N:2]1.CS(Cl)(=O)=O.[C:14]([N:18]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH2:19])([CH3:17])([CH3:16])[CH3:15].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CC(C)=O.C(N(CC)CC)C>[C:14]([N:18]([C:20](=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1)[NH:19][C:6]([C:4]1[N:3]=[N:2][NH:1][CH:5]=1)=[O:8])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1cccc(C(=O)N(N)C(C)(C)C)c1
Reactant: O=C(O)c1c[nH]nn1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)N(NC(=O)c2c[nH]nn2)C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
1,2,3-triazole-4-carboxylic acid (1.0 g) and triethylamine (0.9 g) were dissolved in 40 ml methylene chloride and cooled in an ice bath. Methanesulfonylchloride (1.0 g) was added dropwise. After addition was complete, the reaction mixture was stirred for 0.5 hours. N'-t-butyl-N'-(3-methylbenzoyl)hydrazine (1.84 g) in 10 ml CH2Cl2 was added dropwise. The resulting mixture was allowed to stand for 14 hours. Aqueous sodium bicarbonate was added. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give a yellow oil. Chromatography on silica gel using acetone as eluant afforded N'-t-butyl-N-1,2,3-triazole-4-carbonyl-N'-(3-methylbenzoyl)hydrazine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([OH:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[CH2:30][O:31][CH3:32]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:19][CH2:30][O:31][CH3:32])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1COC(C)=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
To a solution of (±)-cis-4-acetoxymethyl-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (45.0 mmol, 12.3 g) in anhydrous DCM (100 mL) at room temperature was added N,N-diisopropylethyl amine (180 mmol, 31.4 mL). The reaction mixture was cooled to 0° C. using an ice bath. To this was added chloromethylmethyl ether (135 mmol, 11.4 mL) dropwise over 15 minutes. After completion of addition, the reaction was stirred for 12 hours while coming to room temperature. All volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (250 mL) and washed with water (3×50 mL) and brine (50 mL). The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on 110 g SiO2 cartridge using ethyl acetate/hexanes gradient to give (±)-cis-4-acetoxymethyl-3-methoxymethoxy-piperidine-1-carboxylic acid tert-butyl ester (13.3 g).