Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([OH:34])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:43][CH3:44].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:21]([Cl:35])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[C:32]([O:34][CH2:43][CH3:44])=[O:33])[CH:23]=[CH:24][C:25]=1[Cl:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(-n2cccc2C(=O)O)c1Cl)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cccn1-c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 103.4 %

Procedure:
A mixture of 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-carboxypyrrole (1.12 g), potassium carbonate (360 mg) and iodoethane (490 mg) in N,N-dimethylformamide (10 ml) was stirred for 16 hours at 60° C. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 1M hydrochloric acid, water and brine and dried over magnesium sulfate. The solvent was evaporated to give 1-(3-tert-butyldiphenylsilyloxymethyl-2,4-dichlorophenyl)-2-ethoxycarbonylpyrrole (1.22 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[C:21]#[N:22])=[N:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][CH:7]=1.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][C:3]1[C:2]([NH:1][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:7][CH:6]=[C:5]([O:8][C:9]2[CH:16]=[CH:15][CH:14]=[C:11]([C:12]#[N:13])[CH:10]=2)[N:4]=1)#[N:22]
Reactant: N#Cc1cccc(Oc2ccc(N)c(Oc3cccc(C#N)c3)n2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Oc2ccc(NC(=O)c3ccccc3)c(Oc3cccc(C#N)c3)n2)c1
Reaction time: 3 h

Procedure:
To 3,3'-[3-amino-2,6-pyridinediylbis(oxy)]bis(benzonitrile) (1.0 g, 2.9 mmol) dissolved in acetonitrile (50 mL) was added benzoyl chloride (0.50 g, 3.5 mmol) and triethylamine (0.45 g, 0.60 mmol). After stirring for 3 hours, the reaction was partitioned between ether and water. The organic layer was separated, washed with water, saturated aqueous sodium bicarbonate, and brine, dried (MgSO4), and the solvent was removed in vacuo. Chromatography on silica gel with ethyl acetate/hexane (1/3) as eluent gave N-[2,6-bis(3-cyanophenoxy)pyridin-3-yl]benzamide; NMR (CDCl3) 8.95 (d,1), 8.25 (s,1), 7.9 (d,1), 7.2-7.7 (m,12), 6.8 (d,1) ppm.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[CH:8][C:7]([O:19][CH3:20])=[C:6]([O:21][CH3:22])[CH:5]=1.Cl.CC(C)=O>O>[CH3:22][O:21][C:6]1[CH:5]=[C:4]([C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[CH:8][C:7]=1[O:19][CH3:20])[CH:3]=[O:2]
Reactant: COc1cc(C(=O)c2ccnc(Br)c2)c(C(OC)OC)cc1OC
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
3,4-Dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde dimethyl acetal (13.9 g) and 2 M hydrochloric acid (1 ml) are added to a mixture of acetone (30 ml) and water (5 ml), and the mixture is stirred at room temperature for two hours. The mixture is evaporated to remove the acetone, and the remaining aqueous layer is extracted with chloroform. The extract is washed, dried, and concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=4:1) to give 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (8.65 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:12][CH2:11][CH2:10]2)[N:5]=[C:4]([CH:13]=[O:14])[C:3]=1[Cl:15].CC(=CC)C.P([O-])([O-])(O)=[O:22].[Na+].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]2[CH2:10][CH2:11][CH2:12]2)[N:5]=[C:4]([C:13]([OH:22])=[O:14])[C:3]=1[Cl:15]
Reactant: Nc1c(F)c(C2CCC2)nc(C=O)c1Cl
Reactant: O=P([O-])([O-])O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: Nc1c(F)c(C2CCC2)nc(C(=O)O)c1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A microwave vial equipped with a magnetic stir bar was charged with 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinaldehyde (209 mg, 0.914 mmol) and t-butanol (4.57 mL). The mixture was treated with water (1.523 mL), 2-methylbut-2-ene (0.8 mL, 0.914 mmol), sodium hydrogenphosphate (260 mg, 1.828 mmol), and finally sodium chlorite (248 mg, 2.74 mmol) was added in one portion. The mixture was heated to 70° C. in the microwave for 2 h. After stiffing at room temperature overnight, an aliquot of the reaction mixture was analyzed by LC-MS. LC-MS analysis showed one major product with the correct mass for the desired product. The reaction mixture was diluted with EtOAc (15 mL) and washed with 1 M HCl (1×5 mL), H2O (1×5 mL) and saturated NaCl (1×5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was triturated with Et2O and the Et2O removed giving 4-amino-3-chloro-6-cyclobutyl-5-fluoropicolinic acid (94 mg, 39.9%) as a yellow solid: 1H NMR (400 MHz, CDCl3) 11.60 (s, 1H), δ 4.94 (d, J=18.2 Hz, 2H), 3.86 (ttdd, J=9.1, 8.2, 2.1, 1.0 Hz, 1H), 2.35 (dddd, J=13.1, 6.9, 3.4, 1.8 Hz, 3H), 2.12 (m, 2H), 1.95 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −140.30; ESIMS m/z 243 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:28][C:29]([CH3:31])=O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH:29]([CH3:31])[CH3:28])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH2:16][CH2:15]1
Reactant: CC(C)=O
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Product: CC(C)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 65 %

Procedure:
The title compound was prepared from acetone and the amine of example 12, in 65% yield, using the procedure described in example 13.
Reaction SMILES: [NH2:1][CH:2]1[CH:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[NH:4][C:3]1=[O:15].C(=O)(O)[O-].[Na+].ClCCl.[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[O:24]([CH2:31][C:32]([NH:1][C@H:2]1[C@H:5]([S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[NH:4][C:3]1=[O:15])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC1C(=O)NC1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)COc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N[C@H]1S(=O)(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To an ice-cooled mixture of 7.6 g of 3-amino-4-phenylsulfonyl-2-azetidinone (mixture of cis and trans isomers), 5.1 g of sodium bicarbonate 100 ml of dichloromethane, and 50 ml of water was added dropwise with vigorous stirring 4.0 ml phenoxyacetyl chloride. After 90 minutes the resulting solid was removed by filtration and washed with water and dichloromethane. The solid was dissolved in tetrahydrofuran and precipitated with toluene to give 3.85 g of (3R-trans)-3-phenoxyacetylamino-4-phenylsulfonyl-2-azetidinone, melting point 192°-193° C., dec.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CCN(CC)CC.FC(F)(F)S(O[Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])(=O)=O>CN(C=O)C>[CH:32]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[O:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[S:5][C:4]3[CH:14]=[CH:15][CH:16]=[CH:17][C:3]=3[C:2]=2[Br:1])=[CH:12][CH:11]=1)([CH3:34])[CH3:33]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: Oc1ccc(-c2sc3ccccc3c2Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](Oc1ccc(-c2sc3ccccc3c2Br)cc1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
A solution of 3-bromo-2-(4-hydroxyphenyl)benzo[b]-thiophene (9.4 g, 30.8 mmol) in 50 mL of dry DMF was treated with Et3N (6.3 g, 61.6 mmol) and cooled to 0° C. To this was added in a dropwise manner 14.2 g (46.2 mmol) triisopropylsilyl trifluoromethanesulfonate. The cooling bath was removed and the reaction allowed to stir at ambient temperature for 2 h before pouring into 100 mL brine. This was extracted with EtOAc (2×50 mL). The combined extracts were washed with brine (2×100 mL), dried over MgSO4 and concentrated under reduced pressure to 4.8 g of an oil. The crude product was purified by chromatography (SiO2 ; hexanes) to recover 11.7 g (25.4 mmol, 82%) of the desired product as a white solid.
Reaction SMILES: C([CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1([CH3:14])[CH3:13])C.I[CH2:16][CH2:17][CH3:18]>>[CH3:14][C:4]1([CH3:13])[CH2:3][CH:12]([CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]1
Reactant: CCCI
Reactant: CCC1Cc2ccccc2NC1(C)C
Product: CCCC1CC(C)(C)Nc2ccccc21

Procedure:
This compound was prepared in a manner similar to that described for (R/S)-3-ethyl-1,2,3,4-tetrahydro-2,2-dimethylquinoline (EXAMPLE 348) but using iodopropane in place of iodethane. (R/S)-1,2,3,4-Tetrahydro-2,2-dimethyl-4-propylquinoline was obtained in 16% overall yield as a colorless oil. Data for (R/S)-1,2,3,4-tetrahydro-2,2-dimethyl-4-propylquinoline: 1H NMR (400 MHz, CDCl3) 6.98 (d, J=7.4, 1 H), 6.96 (t, J=7.4, 1 H), 6.61 (t, J=7.4, 1 H), 6.45 (d, J=7.4, 1 H), 3.60 (brs, 1 H), 2.87 (dd, J=16.6, 5.2, 1 H), 2.42 (dd, J=16.6, 10.7, 1 H), 1.66-1.49 (m, 3 H), 1.40-1.25 (m, 2 H), 1.21 (s, 3 H), 1.05 (s, 3 H), 0.92 (t, J=7.1, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][C:21]#[N:22])[CH:3]=1>[Ni]>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][NH2:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC#N
Agent: [Ni]
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCN
Reaction time: 5 h
Yield: 45.6 %

Procedure:
To a suspension of one teaspoonful of Raney nickel (well washed with methanol) in methanol (130 ml) was added 4-amino-5-chloro-2-cyanomethyl-N-[2-(diethylamino)ethyl]-benzamide (12.05 g, 37.1 mmoles) (prepared in Example 13), and the mixture hydrogenated at 40 psi for 5 hours. The catalyst was removed by filtration under nitrogen and the filtrate concentrated in vacuo. This was dissolved in methylene chloride and washed with 1N sodium hydroxide (4×25 ml). The washings were back extracted with methylene chloride and the organic phases combined, dried and concentrated in vacuo to give 5.56 g of the title product as a semi-solid. This was recrystallized from methanol-ether in the cold to give a sample, mp. 97°-99° C.
Reaction SMILES: C(C(C)=O)C.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)[CH3:27])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][CH2:46][Cl:47]>O>[Cl:47][CH2:46][CH2:45][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:24][O:25][CH3:26])=[CH:20][CH:21]=3)[S:16][CH2:15][C:14]2([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:32][CH:33]=2)[CH3:27])=[CH:9][CH:8]=1
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(O)cc2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2c2ccc(OCCCl)cc2)cc1
Yield: 47.8 %

Procedure:
To methyl ethyl ketone solution (3 ml) of (3RS,4RS)-4-(4-hydroxyphenyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-thiochroman (126 mg, 0.28 mmol) were added potassium carbonate (96 mg, 0.70 mmol) and 1-bromo-2-chloroethane (115 ml, 1.38 mmol), and the mixture was heated under refluxing for 70 hours. After adding water, the reaction solution was extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and the crude product thus obtained was then purified using silica gel plate (ethyl acetate:hexane=1:2) to obtain 69 mg (yield: 48%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20](Br)[CH2:21][CH3:22]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CCC(Br)CBr
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N1CCCC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To the mixture containing 2-methyl-5-nitrophenylamine and potassium carbonate (4 eq) in dimethyl formamide was added 1,2 dibromobutane (4 eq) and the resulting mixture was stirred at 70° C. for 16 hours. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was dried with sodium sulfate and concentrated and purified on silica gel to give (2-methyl-5-nitrophenyl)pyrrolidine.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([CH2:33][O:34][C:35]([NH:37][C:38]2[CH:43]=[CH:42][N:41]([CH2:44][C:45](O)=[O:46])[C:40](=[O:48])[N:39]=2)=[O:36])=[CH:31][CH:30]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:45](=[O:46])[CH2:44][N:41]2[CH:42]=[CH:43][C:38]([NH:37][C:35]([O:34][CH2:33][C:32]3[CH:49]=[CH:50][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[O:36])=[N:39][C:40]2=[O:48])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: COc1ccc(COC(=O)Nc2ccn(CC(=O)O)c(=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COC(=O)Nc2ccn(CC(=O)N3CCN(S(=O)(=O)c4nc5ccccc5s4)C(=O)C3)c(=O)n2)cc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(4-methoxybenzyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.70 (bs, 1H), 8.34 (m, 1H), 8.26 (m, 1H), 7.90 (d, 0.6H), 7.84 (d, 0.4H), 7.72 (m, 2H), 7.34 (d, 2H), 7.01 (t, 1H), 6.93 (d, 2H), 5.10 (s, 2H), 4.81 (s, 1.2H), 4.71 (s, 0.8H), 4.45 (s, 0.8H), 4.27 (s, 1.2H), 4.22 (t, 1.2H), 4.07 (t, 0.8H), 3.99 (t, 1.2H), 3.85 (t, 0.8H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@:11](O)([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:39])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@:11]([F:39])([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:21](=[O:32])[NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:25]=1[F:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@](O)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@](F)(CN2CCOCC2)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 1.5 h

Procedure:
To a solution of (2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-hydroxy-4-morpholin-4-ylmethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (85 mg, 0.18 mmol) in CH2Cl2 (10 mL) under N2 atmosphere at −78° C. was added DAST (47 μL, 0.359 mmol). The reaction mixture was then allowed to reach RT and further stirred for 1.5 h then poured into an aqueous saturated solution of NaHCO3 and extracted twice with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel (CH2Cl2/MeOH 8:2) to give the desired material. MS (LC/MS): 474.1/476.2 [M+H]+, 472.1 [M−H]−; tR (HPLC conditions f): 1.59 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][CH2:22]O>>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:22]
Reactant: O=C(O)Cc1ccc(Cl)c(OCc2ccccc2)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)Cc1ccc(Cl)c(OCc2ccccc2)c1

Procedure:
(3-Benzyloxy-4-chloro-phenyl)-acetic acid (8 g) was treated with hydrogen chloride (4N in 1,4-dioxane; 6 mL) in EtOH (100 mL) at 80° C. for 3 hours. After concentrating to dryness, the residue was purified by silica gel chromatography to give (3-benzyloxy-4-chloro-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].CO>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(diphenylmethyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 81% overall yield. mp 160-161°. FDMS m/e=441 (M+ of free base). α[D]589=−8.71 (c 0.89, methanol).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20])=[C:17]([O:30][CH2:31][C:32](=[O:34])[NH2:33])[CH:16]=2)=[CH:6][CH:5]=1.[C:37](OC1C=CC=CC=1)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([N:1]=[N:2][CH2:3][C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:29]=[CH:28][C:18]([C:19]([N:21]([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:26])[CH3:27])=[O:20])=[C:17]([O:30][CH2:31][C:32](=[O:34])[NH2:33])[CH:16]=2)=[CH:6][CH:5]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)Oc1ccccc1
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C=NN)cc2)cc1OCC(N)=O)C(C)C
Solvent: ClCCl
Product: CC(=O)N=NCc1ccc(OCCCCCOc2ccc(C(=O)N(C(C)C)C(C)C)c(OCC(N)=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 0.47 g (1.0 mmol) of 4-[5-[4-(aminoiminomethyl)phenoxy]pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide in 10 ml of methylene chloride is added 0.14 g (1.0 mmol) of phenyl acetate. The mixture is stirred at room temperature for 4 hours and then poured onto a silica gel column and eluted with ethyl acetate, and then 10% methanol/ethyl acetate to give 4-[5-[4[(acetylimino)aminomethyl]-phenoxy]-pentyloxy]-2-carbamoylmethoxy-N,N-bis(1-methylethyl)benzamide as a foam; CHN calculated for C29H40N4O8.0.5H2O:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([I:12])[N:11]=1)=[O:5])[CH3:2].[CH3:24][C:25]([CH3:30])([CH3:29])[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:26](=[O:27])[C:25]([CH3:30])([CH3:29])[CH3:24])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([I:12])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(I)c2snc(-c3ccc(Cl)cc3)c2c1O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(I)c2snc(-c3ccc(Cl)cc3)c2c1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-4-hydroxy-7-iodo-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (0.47 mmol) in CH2Cl2 (2.38 mL) was added trimethylacetyl chloride (0.57 mmol) and Et3N (0.71 mmol). The reaction mixture was stirred at r.t. for 2 h before the mixture was filtered. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2, gave the title compound (225 mg) as a white solid: MS (m/z) 544.9 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:31]#[N:32])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[F:33]C1N=C(C=O)C=CC=1>>[C:31](/[C:9](=[CH:8]\[C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:33])[N:7]=1)/[C:10]([NH:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16])=[O:11])#[N:32]
Reactant: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OCCN(CC)CC)cc1
Reactant: O=Cc1cccc(F)n1
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(F)n1)c1ccc(OCCN(CC)CC)cc1
Yield: 61 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 33 except that 6-fluoropicolinaldehyde was used instead of 6-bromopicolinaldehyde. This produced crude product which was purified by flash silica gel column chromatography, eluting with 4:96 methanol/dichloromethane, to give 34 (105 mg, 61%) as a yellow oil: MS (ES+) m/z 439.2 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1)#[N:2].C[Al]([NH2:19])Cl>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:7][CH:8]=1)(=[NH:19])[NH2:2]
Reactant: C[Al](N)Cl
Reactant: CC(C)(C)C(=O)Nc1ccc(C#N)cn1
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)Nc1ccc(C(=N)N)cn1
Temperature: 80 °C

Procedure:
A mixture of N-(5-cyanopyridin-2-yl)pivalamide (1.22 g, 6.00 mmol) and MeAl(Cl)NH2 (18 mL, 0.67M solution in toluene, 12.00 mmol) in 25 mL toluene is heated at 80° C. for 15 hours. The resulting N-(5-carbamimidoylpyridin-2-yl)pivalamide is used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[N+](C1C=CC([CH:39]2[S:43]/[C:42](=[N:44]\[C:45](=O)[O-:46])/[N:41]([C:48]3[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=3[CH:55]([CH3:57])[CH3:56])[C:40]2=[O:58])=CC=1)([O-])=O>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[N:15]=3)=[CH:12][CH:13]=2)[C:45](/[N:44]=[C:42]2\[S:43][CH2:39][C:40](=[O:58])[N:41]\2[C:48]2[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=2[CH:55]([CH3:56])[CH3:57])=[O:46])[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC2CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB27) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red-orange oil (0.127 g, 60%).