Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[N:29](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:50])([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][C:25]3[NH:29][N:28]=[N:27][N:26]=3)=[CH:17][C:16]=2[Cl:49])[CH3:14])[C:9]([F:11])([F:10])[F:12])[CH:5]=[CH:4][N:3]=1
Reactant: CC(c1ccc(OCCCc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(c1ccc(OCCCc2nnn[nH]2)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reaction time: 48 h
Yield: 86.8 %

Procedure:
2-(2-Chloro-pyridin-4-yl)-3-{2-chloro-4-[3-(1-trityl-(1H )-tetrazol-5-yl)-propoxy]-phenyl}-1,1,1-trifluoro-butan-2-ol (80 mg, from previous step) was dissolved in CH2Cl2 (2.5 mL). To the solution was added trifluoroacetic acid (1.25 mL) at RT and the mixture was allowed to stir for 48 hours; almost complete conversion was observed. The reaction mixture was concentrated in vacuo and diluted with ethyl acetate and water. The layers were separated and the organic extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of ethyl acetate in heptane) to give the desired compounds as a white solid (46 mg). MS (m/e)=476.1 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1.O1CCOCC1.Cl>>[ClH:27].[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][C@H:8]3[CH2:9][CH2:10][CH2:11][N:7]3[CH2:6][CH2:5][CH2:4][C:3]([OH:28])=[O:2])=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)CCCN1CCC[C@@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 49.5 %

Procedure:
Following the general procedure for Example 18, the product from step 1 (0.80 g 1.99 mmol) was treated with a 1:1 mixture of concentrated HCl dioxane (36 mL) to afford the title compound (0.21 g, 26%) as a white solid.
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[S:6]([Cl:10])(=[O:8])=[O:7])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1c(Cc2ccccc2)sc2ccccc12

Procedure:
2-Benzylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the method of Example 40B with DMF (5.4 mmoles, 0.41 ml), sulfuryl chloride (4.6 mmoles, 0.37 ml) and 2-benzylbenzo[b]thiophene. Flash chromatography (5% ethyl acetate/hexanes) provided 0.55 g (64%) of a yellow solid.
Reaction SMILES: [K+].[Br-].CC1SC=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1.[CH3:36][C:37]1[S:41][CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:45]2[O:62][C:60](=[O:61])[CH2:59][C@H:58]([OH:63])[C@@H:57]([CH3:64])[C:55](=[O:56])[C@H:54]([CH3:65])[C@@H:53]([OH:66])[C@@H:52]([CH3:67])[CH2:51][CH2:50][CH2:49][C:48](C)=[CH:47][CH2:46]2)\[CH3:44])[N:38]=1>CO>[CH3:36][C:37]1[S:41][CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:45]2[O:62][C:60](=[O:61])[CH2:59][C@H:58]([OH:63])[C@H:57]([CH3:64])[C:55](=[O:56])[C@H:54]([CH3:65])[C@@H:53]([OH:66])[C@@H:52]([CH3:67])[CH2:51][CH2:50][CH2:49][CH:48]=[CH:47][CH2:46]2)\[CH3:44])[N:38]=1
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: Cc1nc(/C=C/[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Solvent: CO
Product: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)[C@@H](C)C(=O)[C@@H](C)[C@@H](O)CC(=O)O1

Procedure:
colorless amorphous solid; [α]D22−11.6 (c 10.0, MeOH); UV (MeOH) λmax nm (ε) 212 (15500), 249 (12100); IR (KBr) νmax 3428, 2962, 2929, 2877, 2859, 1734, 1705, 1460, 1251, 982 cm−1; 1H NMR (CDCl3, 300 MHz) δ 6.99 (1H, s, H-19), 6.66 (1H, bs, H-17), 5.55 (1H, ddd, J=10.4, 9.2, 6.1 Hz, H-12), 5.38 (1H, ddd, J=10.4, 9.3, 6.2 Hz, H-13), 5.22 (1H, dd, J=8.8, 2.8 Hz, H-15), 4.42 (1H, dddd, J=9.4, 5.6, 4.2, 4.1 Hz, H-3), 3.93 (1H, d, J=5.6 Hz, 3-OH), 3.86 (1H, m, H-7), 3.15 (1H, bs, 7-OH), 3.12 (1H, dq, J=4.2, 7.0 Hz, H-4), 3.00 (1H, dq, J=6.9, 7.0 Hz, H-6), 2.70 (3H, s, H-21), 2.62 (1H, dddd, J=15.1, 9.3, 8.8, 0.8 Hz, H-14a), 2.58 (1H, dd, J=15.4, 9.4 Hz, H-2a), 2.38 (1H, dd, J=15.4, 4.1 Hz, H-2b), 2.31 (1H, ddd, J=15.1, 6.2, 2.8 Hz, H-14b), 2.08 (3H, d, J=1.3 Hz, H-27), 2.15 (1H, m, H-11a), 2.04 (1H, m, H-11b), 1.71 (1H, m, H-8), 1.59 (1H, m, H-10a), 1.43 (1H, m, H-9a), 1.31 (1H, m, H-9b), 1.26 (3H, d, J=7.0 Hz, H-24), 1.15 (3H, d, J=7.0 Hz, H-23), 1.11 (1H, m, H-10b), 1.00 (3H, d, J=6.9 Hz, H-25); 13C NMR, see Table 1; EIMS m/z 463 [M]+ (7), 324 (7), 306 (8), 290 (17), 168 (100), 164 (14), 139 (27); HREIMS m/z 463.2392 (calcd. for C25H37NO5S, 463.2392).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH:24]([CH2:28]Br)[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:24]([C:25]([NH2:27])=[O:26])[CH2:28]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNCCNc2cccc(Cl)c2)cc1OC
Reactant: NC(=O)C(Br)CBr
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2C(N)=O)cc1OC

Procedure:
In a manner similar to Preparation 1, react N-(3-chlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine (13.3 g, 41 mmol) with 2,3-dibromopropanamide (19.1 g, 166 mmol) to obtainthe title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8](OC)=[O:9])[O:5][N:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH2:8][OH:9])[O:5][N:4]=1
Reactant: COC(=O)c1cc(OC)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc(CO)on1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.23 g of methyl 3-methoxyisoxazole-5-carboxylate was dissolved in 30 ml of ethanol, and 0.60 g of sodium borohydride was then added ice-cooling. The mixture was stirred for 8 hours under ice-cooling. After water was added under ice-cooling, the reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.55 g of (3-methoxyisoxazol-5-yl)methanol.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[N:25]=[CH:24][CH:23]=[N:22]1)[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1nccn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
1H-1,2,4-Triazole (41 mg) was added an ice-cooled dispersion of 60% sodium hydride in oil (23 mg) in dimethylformamide (1 ml) and the resulting mixture was stirred for 10 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (76 mg) in dimethylformamide (0.8 ml), followed by heating for 5 hours at 50° C. and cooling. To the reaction mixture were added cold water (5 ml) and ethyl acetate (15 ml). The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was subjected to silica gel column chromatography (acetone/dichlormethane=1:2→1:1). The obtained oily substance was crystallized from isopropyl ether to give the title compound (Compound 8, 41 mg, 42%) as colorless crystals.
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Mg+2:5].S(=O)=O>>[S:1](=[O:2])([OH:4])[O-:3].[Mg+2:5].[S:1](=[O:2])([OH:4])[O-:3]
Reactant: O=S([O-])[O-]
Agent: O=S=O
Agent: [Mg+2]
Product: O=S([O-])O

Procedure:
In the present method, a sulfur dioxide-containing gas, such as a hot flue gas from the combustion of coal, is contacted, in a wet scrubbing unit, with an aqueous scrubbing solution containing magnesium sulfite and magnesium bisulfite. The initial aqueous scrubbing solution may be prepared by addition of magnesium hydroxide to water and, upon contact with the sulfur dioxide-containing gas, magnesium bisulfite and magnesium sulfite are formed as soluble magnesium salts. The magnesium sulfite reacts with sulfur dioxide to form magnesium bisulfite in aqueous solution according to the reactions:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[OH:11][C:12]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:13]=1[C:14]#[N:15]>CN(C)C1C=CN=CC=1.C1C=CC=CC=1>[C:14]([C:13]1[CH:16]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19][C:12]=1[O:11][C:8]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:9])#[N:15]
Reactant: N#Cc1cc(Oc2ccccc2)ccc1O
Reactant: CC1CCN(C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccccc1
Product: CC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2C#N)CC1
Yield: 105.2 %

Procedure:
4-Methyl-1-piperidinecarbonyl chloride (1.18 ml, 8.01 mmol) was added under a nitrogen atmosphere at room temperature to a solution of 2-hydroxy-5-phenoxybenzonitrile (1.53 g, 7.26 mmol) and 4-dimethylaminopyridine (0.976 g, 7.99 mmol) in 50 ml of benzene and the resulting solution refluxed for 1 hour. The reaction mixture was washed with 1N HCl. The benzene layer was separated, dried (anhydrous MgSO4) and the solvent removed under reduced pressure to give 2.57 g of a white crystalline solid. Recrystallization of this solid from diisopropyl ether-hexane gave the title compound as a white crystalline solid (1.59 g, 65%), mp 54°-58° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:29]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[C@@H:13]([OH:14])[CH2:12][N:11]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:10]2)=[O:7])=[CH:4][CH:3]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(=O)N[C@@H]2CN(C3CCCCC3)C[C@@H]2O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)N[C@@H]2CN(C3CCCCC3)C[C@@H]2O)cc1
Reaction time: 18 h

Procedure:
A solution of 6.0 g (0.02 mole) of cis-4-amino-N-(1-cyclohexyl-4-hydroxy-3-pyrrolidinyl)benzamide in 250 ml of tetrahydrofuran was mixed with 8 g of powdered anhydrous potassium carbonate and stirred while 1.6 g (0.02 mole) of acetyl chloride was added dropwise. The mixture was stirred for 18 hr. The tetrahydrofuran was removed and the residue was partitioned between water and chloroform. The chloroform was separated and in a short time the product precipitated. The precipitate was filtered and then triturated with boiling acetone, filtered and dried. The yield of product melting at 200.0°-203.0° C. was 5.1 g (74%).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:9][CH:8]=1)(=O)C.Cl>O.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:12]=1
Reactant: CC(=O)NCCc1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NCCc1ccc(O)cc1
Reaction time: 0.17 h
Yield: 84.7 %

Procedure:
A solution of sodium hydroxide(2.3 g, 58 mmol) in water(20 ml) was cooled to 0° C. A solution of N-(4-acetoxyphenylethyl)acetamide(6.4 g, 29 mmol) in methanol(40 ml) was added dropwise to the soultion, stirred for 10 minutes, adjusted to pH 1 with hydrochloric acid, and then extracted 3 times with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oily residue was solidified with ethyl ether, filtered, and dried to give 4.4 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C(C)=CC=CC=1C.O([Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>C(Cl)Cl.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:9][O:10][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: Cc1cccc(C)n1
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](OCc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a solution of (3,5-dichlorophenyl)methanol (10.0 g, 56.5 mmol) in methylene chloride (100 mL) at 0° C. was added 2,6-lutidine (16.4 mL, 141 mmol) followed by triisopropylsilyl triflate (19.7 mL, 73.4 mmol), and was stirred at 0° C. for 2 hours. The reaction was diluted with water and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel, eluting with hexane to provide the desired product (14.8 g, 79%). LC/MS: 333 (M+H)+, 1H NMR (CDCl3) δ 7.23 (s, 3H), 4.78 (s, 2H), 1.18 (m, 3H), 1.03 (s, 18H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([NH:30][C@@H:31]([CH2:35][CH3:36])[C@H:32]([OH:34])[CH3:33])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N1CCCCC1)C>C(Cl)Cl.CCOCC.CCCCCC>[C:11]([NH:30][C@@H:31]([CH2:35][CH3:36])[C:32](=[O:34])[CH3:33])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Agent: CCN1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)=O
Temperature: -45 °C
Reaction time: 1 h

Procedure:
To a stirred solution of DMSO (1.95 mL, 2.8 eq, 27.48 mmol) in DCM (30 mL) under an argon atmosphere at −45° C., was added oxalyl chloride (2 M in DCM, 6.85 mL, 1.4 eq, 13.70 mmol) dropwise. The reaction mixture was stirred at −45° C. for 1 h, after which time a solution (2R,3S)-3-(trityl-amino)-pentan-2-ol (3.39 g, 1 eq, 9.83 mmol) in DCM (20 mL) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 4 h, when TLC (hexane:ether; 80:20) indicated that the reaction had gone to completion. To the reaction mixture was added N-ethylpiperidine (6.71 mL, 5 eq, 48.84 mmol), and the solution allowed to warm to room temperature over 16 h. The reaction mixture was diluted with more DCM (50 mL) and washed with water (200 mL). The aqueous phase was extracted with DCM (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was dissolved in Et2O (100 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (50 mL), the solid precipitate removed by filtration and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil. Yield: 3.15 g (93%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.73 (t, 3H, J=7.50 Hz, —NHCH(CH2CH3)C(CH3)O), 1.45-1.62 (m, 5H, —NHCH(CH2CH3)C(CH3)O), 3.12 (d, 1H, J=8.53 Hz, —NHCH(CH2CH3)C(CH3)O), 3.31 (m, 1H, —NHCH(CH2CH3)C(CH3)O), 7.13-7.45 (m, 15H, 3×Ph).
Reaction SMILES: N1C=CC=CC=1.C(N1CCCOC(C[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C1)C1C=CC=CC=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:23]1([NH:22][C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN2CCCOC(CNc3ccccc3)C2)cc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)C1CC1
Temperature: 0 °C

Procedure:
Pyridine (3.64 mL, 45.0 mmol) was added to a solution of crude amine 80 (30.0 mmol) in CH2Cl2. The solution was cooled to 0° C. in an ice bath, then cyclopropyl carbonyl chloride (2.99 mL, 33.0 mmol) was added dropwise. The reaction was allowed to warm slowly to room temperature and stirred until the reaction was judged complete by TLC (3.25 h). CH2Cl2 and saturated NaHCO3 were added. The organic layer was removed and the aqueous layer extracted with CH2Cl2 (2×). The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oily residue was purified by alumina gel chromatography (96:2:2::Hexanes:CH2Cl2:2N NH3 in EtOH) to obtain 4-benzyl-1,4-ozazepan-2-ylmethyl)-N-phenylcyclopropanamide (85) as a pale yellow oil. 1H NMR (CD3OD) 7.46-7.24 (8H, m), 7.13 (2H, broad d, J=7.2 Hz), 3.90 -3.42 (5H, m), 2.92-2.76 (2H, m), 2.62-2.51 (1H, m), 2.30 (1H, dd, 13.7, 8.5 Hz), 1.40-1.20 (2H, m), 0.96-0.82 (3H, m), 0.61 (2H, dd, J=7.9, 2.8 Hz) ppm. 13C NMR (CD3OD) 175.84, 144.04, 140.20, 130.82, 130.54, 129.55, 129.08, 128.43, 77.04, 68.00, 63.63, 59.72, 55.83, 52.94, 31.28, 13.76, 9.34, 9.07 ppm. LRMS: 364.57.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C@H:40]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH3:41])[CH:34]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:19]3[CH:20]=[N:21][N:22]=[C:18]3[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:30])[F:32])[CH:24]=3)=[C:16]([C:33]3[CH:38]=[CH:37][N:36]=[C:35]([NH:39][C@H:40]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH3:41])[CH:34]=3)[N:15]=2)[CH2:12][CH2:13]1
Reactant: C[C@H](Nc1cc(-c2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1cc(-c2nc(C3CCNCC3)n3cnnc3c2-c2cccc(C(F)(F)F)c2)ccn1)c1ccccc1
Temperature: 25 °C

Procedure:
5-(1-(t-butoxycarbonyl)piperidin-4-yl)-7-(2-(1(S)-phenylethyl)amino-4-pyridyl)-8-(3-(trifluoromethyl)phenyl)-1,2,4-triazolo[4,3-c]pyrimidine (0.03 g, 0.05 mmol) and trifluoroacetic acid (1 ml) were combined in methylene chloride (5 ml) and maintained at room temperature for 24 hours. The solution was concentrated and the residue was partitioned between methylene chloride and 10% sodium carbonate. The organic layer was separated, dried over sodium sulfate, filtered and the solvent evaporated to give the product as a syrup; MS m/z (M+H)+ 544.1; C30H28F3N7 require 543.2.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:9]C(=O)OC(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C1C(=O)N([Br:37])C(=O)C1>O>[Br:37][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccnc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(Br)cnc1N
Temperature: 25 °C
Yield: 76 %

Procedure:
Following a literature procedure (Journal of Molecular Catalysis A: Chemical 2007, 267, 30) tert-butyl 3-ethylpyridin-2-ylcarbamate (820 mg, 3.68 mmol) was treated with 4.0 M HCl in dioxane (4 mL, 4 mmol) and the reaction was maintained at rt for 2 h. Water (2 mL) was added and K2CO3 was added until pH>10. The resulting suspension was filtered and the isolated solid was washed with EtOAc (2 mL). The organic filtrates were concentrated and the resulting residue was dissolved in acetonitrile (4 mL). A portion (2 mL) was treated with NH4OAc (100 mg), followed by NBS (280 mg, 1.57 mmol). The reaction was maintained at rt for 15 min. The reaction was then partitioned between EtOAc and water and the resulting layers separated. The aqueous portion was extract with EtOAc (2×5 mL) and the combined organic layers were concentrated. The resulting residue was purified by reverse phase HPLC. The collected fractions were basified to pH>10 by the addition of saturated aqueous Na2CO3 solution. Extraction with EtOAc (2×20 mL) followed by concentration provided 240 mg of 5-bromo-3-ethylpyridin-2-amine: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=2.4 Hz, 1H); 7.39 (d, J=2.4 Hz, 1H); 4.41 (br s, 2H); 2.42 (q, J=7.2 Hz, 2H); 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][OH:20])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])=[CH2:2]>CCO.[Pd]>[CH:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:18][C@H:17]3[CH2:19][OH:20])[CH2:12][CH2:11]2)=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Reaction time: 1 h

Procedure:
The product of step A (170 mg, 0.62 mmol) and 5% Pd/C (20 mg) were dissolved in EtOH (5 mL). The mixture was stirred under 1 atm of H2 for 1 hour. The mixture was filtered and the filtrate concentrated in vacuo, yielding the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]([O:24]CC)=[CH2:23])CCC.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl>CN1C(=O)CCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:22](=[O:24])[CH3:23])[C:10]=2[N:9]=[CH:8]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Brc1cccc2c1ncn2C1CCCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cccc2c1ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A mixture of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (1.6 g, 6 mmol), tributyl(1-ethoxyvinyl)stannane (2.4 g, 6 mmol), Pd(PPh3)4 (0.7 g, 0.6 mmol), K3PO4 (2.5 g, 12 mmol) in NMP (10 mL) was heated at 80° C. for 6 h. The mixture was cooled to RT, water was added and the mixture was extracted with EtOAc (50 mL×3). HCl (1.0 eq) was added to the combined extract and the resulting mixture was stirred for 30 min. The pH of the mixture was adjusted to ˜8 by addition of aqueous NH4OH solution (35%). The aqueous phase was extracted with EtOAc (50 mL×3). The combined extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether:EtOAc (10:1) to afford 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-4-yl)ethanone as a gray solid (0.8 g, 59%). MS (ESI): m/z=245.1 [M+1]+.