Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:24][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][C:10]=3[F:23])=[N+:2]=[N-:3].[CH2:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:26]#[CH:27]>C1C=CC=CC=1.CC1C([Ru+])(C)C(C)=C(C)C=1C.ClC1CCC=CCCC=1>[CH2:25]([C:26]1[N:1]([CH:4]2[CH2:24][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([O:19][CH2:20][CH2:21][CH3:22])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][C:10]=4[F:23])[N:2]=[N:3][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C#CCc1ccccc1
Reactant: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(N=[N+]=[N-])CC2
Agent: CC1=C(C)C(C)([Ru+])C(C)=C1C
Agent: ClC1=CCCC=CCC1
Solvent: c1ccccc1
Product: CCCOC(=O)Cc1c2n(c3c(F)cccc13)CC(n1nncc1Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of propyl (7-azido-4-fluoro-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate (1 eq) and prop-2-yn-1-ylbenzene (1.5 eq) in benzene (0.3M) at room temperature was added chloro(1,5-cyclooctadiene) (pentamethylcyclopentadienyl)-ruthenium(II) (0.1 eq). The reaction mixture was flushed with nitrogen then aged at 80° C. for overnight, cooled to room temperature, filtered through silica gel, washed with EtOAc and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc/Hexane (0 to 50%) to give the desired material as a brown oil. The racemic mixture was resolved by HPLC using a 50×400 mm Chiralpak AD column eluting with 15% MeOH, 15% EtOH, 69.75% Hexanes and 0.25% Et3N at 50 mL/min and 254 nm to afford the desired chiral ester with retention time of 9.6 and 11.6 min respectively.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=1)[CH:32]=[CH:33][C:34](O)=[O:35]>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:34](=[O:35])[CH:33]=[CH:32][C:31]1[CH:37]=[CH:38][CH:39]=[C:29]([O:28][CH3:27])[CH:30]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: COc1cccc(C=CC(=O)O)c1
Product: COc1cccc(C=CC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Yield: 50 %

Procedure:
Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine was reacted with 3-methoxycinnamic acid under the conditions described in example 86 to yield 50% of the desired product.
Reaction SMILES: Cl[C:2]1[C:3](C#N)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17].ClC1C=CC(S([C:38]2C3C(=CC=CC=3NS(C)(=O)=O)[N:40](CC(O)=O)[C:39]=2C)(=O)=O)=CC=1.ClC1C=CC(SC2C3C(=CC=C(C)C=3)NC=2C)=CC=1>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([S:16]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[CH:2][C:3]=3[NH:40][CH2:39][CH3:38])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH3:15])(=[O:17])=[O:18])=[CH:24][CH:23]=1
Reactant: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(NS(C)(=O)=O)cccc2n1CC(=O)O
Reactant: Cc1c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc2n1CC(=O)O
Agent: Cc1ccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c2c1
Product: CCNc1cccc2c1c(S(=O)(=O)c1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 2 part (d) using the by product from example 22 part (a). Product was purified using reverse phase preparative HPLC.
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:15]>>[Cl-:15].[CH2:1]([NH+:8]([CH3:12])[CH2:9][CH2:10][Cl:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: C[NH+](CCCl)Cc1ccccc1
Product: [Cl-]
Temperature: 35 °C

Procedure:
2-[benzyl(methyl)amino]ethanol was added dropwise to an excess of SOCl2 (50 eq.) and the mixture heated at 35° C. for 16 h. Volatiles were removed in vacuo and the residual oil triturated with Et2O to give the title compound as a white solid in quantitative yield. MS (ES+) m/z 184 (M+H)+; 186 (M+H)+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[I:38])[CH:33]=O)[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:25]([O:29][C:30]1[CH:31]=[C:32](/[CH:33]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:35]=[CH:36][C:37]=1[I:38])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCOc1cc(C=O)ccc1I
Solvent: Cc1ccccc1
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Yield: 87.3 %

Procedure:
65.1 g (195 mmol) of methyl (triphenylphosphoranylidene)acetate are added to a solution of 29.6 g (97 mmol) of 3-butoxy-4-iodobenzaldehyde in 360 ml of toluene. The reaction mixture is refluxed for 2 hours. The solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/dichloromethane mixture. 30.5 g (87%) of methyl(E)-3-(3-butoxy-4-iodophenyl)acrylate are obtained in the form of pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=1[CH2:4][N:5]1[C@@H:9]([CH3:10])[C@@H:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][C:6]1=[O:17].[CH3:24][O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1>>[CH3:24][O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:3]=2[CH2:4][N:5]2[C@@H:9]([CH3:10])[C@@H:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:7][C:6]2=[O:17])[C:31]([O:34][CH3:35])=[CH:32][CH:33]=1
Reactant: COc1ccc(Br)c(CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: COC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(OC)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4S,5R)-3-(2-bromo-5-methoxy-benzyl)-4-methyl-5-phenyl-oxazolidin-2-one and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:11](OC(=O)C)(=O)[CH3:12].Cl[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20])[C:11]([CH3:12])=[N:9][C:4]=2[C:3]=1[F:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)c(F)c1N
Reactant: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(F)c(Br)ccc2n1C(=O)OCC(C)C

Procedure:
Synthesized according to the method of reagent preparation 19 using 5 4-bromo-3-fluorobenzene-1,2-diamine and acetylation with acetic anhydride in tetrahydrofurane in step 1 then treatment with isobutyl chloroformate in step 3. MS (EI) for C13H14BrN2O2: 328, 330 (MH+, Br isotope pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:32])([CH3:31])[CH2:29][OH:30])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:30][CH2:29][C@@:28]([OH:32])([CH3:31])[CH2:27][N:20]2[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=[C:19]2[Cl:18])=[CH:4][CH:3]=1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@](O)(COC(=O)Nc1ccc(Cl)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 83 %

Procedure:
A THF solution (15 ml) of 4-chlorophenylisocyanate (1.3 g, 85 mmol) and triethylamine (0.1 ml) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.5 g, 6.5 mmol) in THF (30 ml) followed by stirring at room temperature for 19 hours. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-chlorophenylcarbamate (2.1 g, yield 83%) as a white solid.
Reaction SMILES: [N:1]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:12])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li][CH2:14]CCC.CI.[NH4+].[Cl-]>C1COCC1>[CH3:14][N:6]1[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: [Li]CCCC
Reactant: O=C1CCCc2ncccc2N1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCCc2ncccc21
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A solution of 1.0 eq of 96 in 30 mL of dry THF was cooled to −78° C. While stirring, 1.1 eq of n-BuLi (2.5 M in hexanes) was added dropwise. The reaction solution was warmed to 0° C. and stirred for 1 hr. The solution was then cooled to -78° C. and 1.2 eq of methyl iodide was slowly added. The mixture was stirred, as the solution warmed to rt. After 17 hrs, 50 mL of saturated NH4Cl was added and extracted with EtOAc (3×50 mL). The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to afford a dark orange colored solid as 97.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([OH:14])(=[O:13])[CH:11]=O.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[CH2:19]>>[Cl:9][C:8]1[C:2]([Cl:1])=[C:3]2[C:5]([CH:18]([C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[Cl:15])[CH2:19][CH:11]([C:10]([OH:14])=[O:13])[NH:4]2)=[CH:6][CH:7]=1
Reactant: Nc1cccc(Cl)c1Cl
Reactant: O=CC(=O)O
Reactant: C=Cc1ccccc1Cl
Product: O=C(O)C1CC(c2ccccc2Cl)c2ccc(Cl)c(Cl)c2N1

Procedure:
Compound 65 was prepared from 2,3-dichloroaniline, glyoxylic acid and 2-chlorostyrene by the automated process.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Li].[Cl-].[NH4+]>C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH3:9]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(O)c1cccc(Br)c1
Yield: 95.8 %

Procedure:
To a solution of 3.34 g (16.8 mmol) of 3'-bromoacetophenone in dry diethyl ether (68 ml) was added 1.4M diethyl ether solution of methyllithium (18.0 ml, 25.2 mmol) in an atmosphere of argon at 0° C., and the mixture was allowed to react for 30 min. To the solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography for separation and purification. Elution with dichloromethane-methanol yielded 3.47 g (16.1 mmol) of 3-(α-hydroxyisopropyl)-1-bromobenzene.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[ClH:26].[CH3:22][N:23]([CH3:27])[C:24]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:25]
Reactant: Cc1cc(C)nc(NCCN(C)C)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)N(C)C)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 144.9 %

Procedure:
2-(2-Dimethylaminoethylamino)-4,6-dimethylpyridine (7.73 g, 0.04 mole) and triethylamine (4.8 g, 0.048 mole) are dissolved in 200 ml of anhydrous benzene. Dimethyl carbamoyl chloride (4.85 g, 0.045 mole) is added, the mixture stirred at room temperature for 2 hours and then refluxed four hours. After cooling and dilution with 200 ml of diethyl ether, the triethylamine hydrochloride is filtered off and the filtrate concentrated under vacuum. For purification the crude product is taken up in 200 ml diethyl ether and filtered thru Super-Cel. On addition of ethanolic hydrogen chloride to the filtrate, the product crystallizes and is filtered off to obtain 11 g of solid, m.p. 204°. Recrystallization from 150 ml ethanol and 250 ml diethyl ether yields 10.29 g, m.p. 205°-206° C. (d).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][C@H:11]([NH:13][CH2:14][C@@H:15]([C:24]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[C:30]3[C:25]=2[CH:26]=[CH:27][C:28](=[O:42])[NH:29]3)[O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:12])[CH:7]=[CH:8][CH:9]=1.[C:43]1([C:75]2[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=2)[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([O:52][CH:53]1[CH2:58][CH2:57][N:56]([CH2:59][CH2:60][C:61](CNC2C=CC(CC(O)=O)=CC=2)=[O:62])[CH2:55][CH2:54]1)=[O:51].[O-]S(C(F)(F)F)(=O)=O.C([N:92]([CH2:96]C)[CH:93]([CH3:95])[CH3:94])(C)C>C(Cl)Cl>[CH2:35]([O:34][C:31]1[CH:32]=[CH:33][C:24]([C@@H:15]([O:16][Si:17]([C:20]([CH3:21])([CH3:23])[CH3:22])([CH3:19])[CH3:18])[CH2:14][NH:13][C@H:11]([CH3:12])[CH2:10][C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:15]([CH2:24][C:25]3[CH:30]=[CH:94][C:93]([N:92]([CH3:96])[C:61]([CH2:60][CH2:59][N:56]4[CH2:57][CH2:58][CH:53]([O:52][C:50](=[O:51])[NH:49][C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=5[C:75]5[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=5)[CH2:54][CH2:55]4)=[O:62])=[CH:95][CH:26]=3)=[O:16])[CH:9]=[CH:8][CH:7]=2)=[C:25]2[C:30]=1[NH:29][C:28](=[O:42])[CH:27]=[CH:26]2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H](Cc1cccc(CCN)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: O=C(O)Cc1ccc(NCC(=O)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Cc1cccc(CCNC(=O)Cc2ccc(N(C)C(=O)CCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Yield: 76.1 %

Procedure:
A mixture of 5-[(R)-2-{(R)-2-[3-(2-aminoethyl)phenyl]-1-methylethylamino}-1-(tert-butyldimethylsilanyloxy)ethyl]-8-benzyloxy-1H-quinolin-2-one (0.586 g, 1.00 mmol); [4-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionyl}methylamino)-phenyl]acetic acid (0.516 g, 1.00 mmol); 2-chloropyridium triflate on Wang resin (polymer-supported Mukaiyama reagent) (1.19 mmol/g loading; 1.68 g, 2.00 mmol); and N,N-diisopropylethylamine (522 μL, 3.00 mmol) in DCM (5.00 mL) was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-5% MeOH in DCM) to give the title compound (412 mg, 38% yield) as an off-white oil.
Reaction SMILES: C(O)C.[CH2:4]=[C:5]1[CH2:13][CH2:12][C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]1=O.O.[NH2:16][NH2:17]>O>[N:16]1[NH:17][CH2:4][CH:5]2[C:6]=1[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:12][CH2:13]2
Reactant: NN
Reactant: C=C1CCc2sccc2C1=O
Solvent: CCO
Solvent: O
Product: c1cc2c(s1)CCC1CNN=C21

Procedure:
To 20 mL of anhydrous ethanol was added 1.2 g of the product from Step A and 0.40 g of hydrazine hydrate. The reaction mixture was heated at reflux for 2 h, cooled, poured into cold water and extracted with ether. The ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and utilized without concentration or purification in Step C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.CSC.B>C1COCC1>[OH:12][CH2:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=C(O)CCCc1ccc(O)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: OCCCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
4-(4-Hydroxy-phenyl)-butyric acid (22.1 g, 123 mmol) is dissolved in THF (750 ml) and borane-dimethyl sulfide (23.3 ml, 245 mmol) is slowly added. The yellow suspension formed is heated at reflux for 3 hours until most of the solid slowly dissolves. The flask is removed from the heating mantle, and MeOH is slowly added until bubbling ceases and the residual solid has dissolved. The flask is cooled to room temperature and water (1 L) is added. The pH is corrected to 3 with AcOH, then the mixture is extracted with EtOAc (2×500 ml). The organics are washed with brine, dried (MgSO4) and concentrated. The crude product is slurried with silica (500 g) in 25% EtOAc/iso-hexanes (1 L). This is filtered, then flushed with 50% EtOAc/iso-hexanes (2 L) to elute the product. The organics are concentrated to give 4-(4-Hydroxy-butyl)-phenol as a brown oil which crystallizes on standing; 1H NMR (CDCl3): 1.55-1.72 (4H, m), 2.58 (2H, t, J=7.0 Hz), 3.1 (2H, br signal), 3.70 (2H, t, J=6.4 Hz), 6.77 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz).
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([CH3:9])=[C:6]([Br:8])[N:7]=1.[Na].[CH3:12][OH:13]>>[Br:8][C:6]1[N:7]=[C:2]([O:13][CH3:12])[C:3]([NH2:10])=[N:4][C:5]=1[CH3:9]
Reactant: Cc1nc(N)c(Br)nc1Br
Reactant: CO
Agent: [Na]
Product: COc1nc(Br)c(C)nc1N

Procedure:
A solution of 3,5-dibromo-6-methyl-2-pyrazinamine (Example 118b) (0.9 g) was added to a solution of sodium (0.39 g) in methanol (30 mL) was heated at reflux for 18 h. After removal of solvent in vacuo, the residue was partitioned between water and dichloromethane, and the organic phase dried (MgSO4), filtered and evaporated to give the title compound as a pale yellow solid (0.58 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1([CH3:24])[CH2:8][C:7]2[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=2[O:5]1.[C:25]1([CH:31]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:39]1([CH:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:32][CH:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][C:4]3([CH3:24])[CH2:8][C:7]4[C:9]([CH3:23])=[C:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([CH3:14])=[C:12]([CH3:13])[C:6]=4[O:5]3)[CH2:35][CH2:34]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCBr)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CCN1CCC(OC(c3ccccc3)c3ccccc3)CC1)O2
Temperature: 60 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
A suspension of tert-butyl [2-(2-bromoethyl)-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (1.2 g), 4-(diphenylmethoxy)piperidine (0.85 g), and potassium carbonate (0.44 g) in N,N-dimethylformamide (20 mL) was stirred at 60° C. for 15 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=98:2 to 95:5) to provide 1.6 g of the title compound. Yield 92%.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25]CC)=[O:24])[O:3]1.[Li+].[OH-]>C1COCC1.CO>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[S:14][C:15]([C:18](=[NH:21])[NH:19][OH:20])=[N:16][N:17]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([OH:25])=[O:24])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(C(=N)NO)s3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2nnc(C(=N)NO)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude ethyl 2-(1-hydroxy-6-(5-(N-hydroxycarbamimidoyl)-1,3,4-thiadiazol-2-yloxy)-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate was dissolved in a mixture of THF and MeOH (1:1, 5 ml) and then treated with aqueous LiOH solution (200 mg in 5 mL water). After stirring at room temperature for one hour, the reaction mixture was evaporated, acidified with 1N HCl to pH 3 and then concentrated. HPLC purification gave desired product as white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.4 (b, 1H), 10.3 (b, 1H), 9.20 (b, 1H), 7.41 (d, J=2Hz, 1H), 7.28 (d, J=1.6 Hz, 1H), 5.48 (dd, J=9.2, 2 Hz, 1H), 4.07 (b, 2H), 3.00 (dd, J=15.6, 2.4 Hz, 1H), 2.27 (s, 3H), 2.10 (dd, J=15.6, 9.2 Hz, 1H). MS (ESI) m/z=363 [M−H]+.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1.Br[C:22]1C=C[S:24][C:23]=1C1N(C)C2=NC=C(C(F)(F)F)C=C2N=1.[Na].C(S)C.CN(C=O)C>O>[CH2:23]([S:24][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:19]([CH3:20])[C:10]2=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=[C:9]2[N:8]=1)[CH3:22]
Reactant: Cn1c(-c2sccc2Cl)nc2cc(C(F)(F)F)cnc21
Reactant: Cn1c(-c2sccc2Br)nc2cc(C(F)(F)F)cnc21
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCS
Product: CCSc1ccsc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 188 %

Procedure:
A mixture of 0.22 g of 2-(3-chlorothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.23 g of 2-(3-bromothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine, 0.21 g of ethyl mercaptan sodium salt (80%) and 4 ml of DMF was stirred at 100° C. for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.41 g of 2-(3-ethylthiothiophen-2-yl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (Compound of Present Invention (15)).
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[CH:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH:4]1[NH:5]2.[C:17]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[CH3:17][C:1]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:2]=1[C@H:3]1[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][C@H:4]1[NH:5]2
Reactant: c1ccc2c(c1)CC1Nc3ccccc3C21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cc1cccc2c1[C@H]1c3ccccc3C[C@H]1N2
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A mixture of 0.6 g (0.00289 mol) of 5,5a, 6,10b-tetrahydroindeno[2,1-b]indole, 0.9 g (0.00723 mol) of K2CO3 and 1.03 g (0.00723 mol) of methyl iodide in 10 ml of acetonitrile was stirred for over the night at room temperature. The resulting mixture was filtered and evaporated. The resulting residue was dissolved in ether and then washed twice with water. Drying (Na2SO4) and evaporation gave 0.25 g (39%) of the title compound. 1H NMR (CDCl3) δ, 2.78 (3H, s), 3.2 (2H, d), 4.3 (1H, m) 4.66 (1H, d), 6.37 (1H, d), 6.68(1H, t), 7.06 (1H, t), 7.13-7.18 (2H, m),7.22-7.26 (1H, m) 7.3-7.37 (2H, m).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].I[CH2:30][CH2:31][CH3:32]>C1COCC1>[CH2:27]([O:26][C:24]([C:21]1([CH2:30][CH2:31][CH3:32])[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)=[O:25])[CH3:28]
Reactant: CCCI
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.5 %

Procedure:
To a solution of potassium hexamethyldisilazide (29.1 g, 146 mmol) in THF (200 mL) at −78° C. was added ethyl N-Boc-piperidine-4-carboxylate (25 g, 97 mmol). The reaction mixture was stirred at −78° C. for 30 minutes, then 1-iodopropane (14.2 mL, 146 mmol) was slowly added. The reaction mixture was stirred at −78° C. for a further 20 minutes, then warmed to room temperature and stirred for 1 hour. The reaction was quenched by addition of saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (0% to 50% EtOAc in hexanes) to afford 19.3 g (66%) of 4-propyl-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester as a yellow oil.