Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]>C(OCC)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[C:27](=[O:31])[CH:26]([CH3:32])[CH2:25][CH:24]([O:33][CH3:34])[CH:23]2[O:35][C:19]([OH:39])([CH:20]([CH3:38])[CH2:21][CH:22]2[O:36][CH3:37])[C:18](=[O:40])[C:17](=[O:41])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:42])[O:9][CH:8]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:7]([CH3:55])[CH:6]([OH:56])[CH2:5][C:4]1=[O:57])[CH3:2]
Reactant: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: CCOCC
Product: CCC1C=C(C)C(=O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 1.33 h

Procedure:
To 494.3 mg (0.6125 mmole) of 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone in 20 ml ethyl ether stirred at 22° C. was added 0.45 ml of Brown-Garg reagent (prepared from 5.0 g of sodium dichromate dihydrate and 3.75 ml. of conc. sulfuric acid diluted to 25 ml with water) in 3 increments of 0.15 ml at times of 0, 30 and 85 minutes. At 80 minutes stirring after the last addition the ether layer was decanted. The aqueous layer was washed well with ether, which was added to the ether decantate. Evaporation of the ether layer led to a crude residue which was purified first by preparative thin layer chromatography on silica gel using 5% methanol in methylene chloride as eluent and then by similar purification using ethyl acetate as eluent. The product, 53.6 mg, was identified as 17-ethyl-1,14-di-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16,20-pentaone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C.Br[C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=1[C:24]([OH:26])=[O:25]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)O)c(Oc2ccc(Br)cc2)c1
Temperature: 110 °C

Procedure:
4-Bromophenol (0.87 g, 5 mmol), Cs2CO3 (1.6 g, 5 mmol), CuOTf toluene complex (2:1) (0.0625 mmol, 5 mol % Cu, 33 mg), ethyl acetate (0.013 ml, 0.125 mmol) were added to a solution of 2-bromo-4-methylbenzoic acid (0.86 g, 5 mmol) in toluene (2 mL) in a sealed tube. The reaction mixture was purged with N2, and was heated to 110° C. until the aryl halide was consumed as determined by LC-MS (48 h). After cooling to rt, the mixture was filtered through a Celite plug. The Celite plug was washed with EtOAc. The mixture was acidified by 1N HCl, and extracted w/EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. This residue was purified via column chromatography on silica gel (gradient elution with 0-10% MeOH/DCM) to afford 2-(4-bromophenoxy)-4-methylbenzoic acid, MS m/z=309.1 [M+H]+. Calc'd for C14H11BrO3: 307.1.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1)[CH:2]([CH3:4])[CH3:3].[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH3:15][S:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:19][CH:18]=1
Reactant: CC(C)CNc1ccc2nc[nH]c2c1
Reactant: CSc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1ccc(CN(CC(C)C)c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from N-isobutyl-benzimidazol-5-amine (95 mg; 0.5 mmol; 1 eq.), 4-methylthiobenzylbromide (120 mg; 0.55 mmol; 1.1 eq.) and K2CO3 (76 mg; 0.55 mmol; 1.1 eq.) according to method 6; Yield: 0.066 g (40.6%); MS m/z: 326.4 [M+H]+; 1H-NMR (400 MHz, DMSO d6): δ 0.92 (d, 6H, 3J=6.6 Hz); 2.01-2.08 (m, 1H); 2.41 (s, 3H); 3.21 (d, 2H, 3J=7.1 Hz); 4.53 (s, 2H); 6.68 (br s, 1H); 6.70 (dd, 1H, 3J=2.1 Hz, 3J=8.7 Hz); 7.13-7.18 (m, 4H); 7.34 (d, 1H, 3J=8.7 Hz); 7.90 (s, 1H); 11.91 (br s, 1H); HPLC (METHOD [A]): rt 16.40 min (99.5%)
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13](CC3C=NC=CC=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28](C3SC=CC=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[CH3:37][N:38]1[CH:42]=[C:41](S(Cl)(=O)=O)[CH:40]=[N:39]1>>[CH3:37][N:38]1[CH:42]=[C:41]([S:28]([N:10]2[CH2:9][C:8]3[CH:36]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[NH:13][CH2:12][C@H:11]2[CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)(=[O:29])=[O:30])[CH:40]=[N:39]1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Agent: Cl
Product: Cn1cc(S(=O)(=O)N2Cc3cc(C#N)ccc3NC[C@H]2Cc2ccccc2)cn1

Procedure:
The title compound was prepared from Compound A of Example 23 and 1-methyl-1H-pyrazole-4-sulfonyl chloride following the procedure of Compound B of Example 23.
Reaction SMILES: [OH-].[K+].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]=[O:14])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[N+:15]([CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:19])#[C-:16]>CO>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([C@@H:13]3[O:14][CH:16]=[N:15][C@H:17]3[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccc2c(c1)OCCO2)N1CCCC1
Yield: 68.2 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (2.70 g, 48.1 mmol) in methanol (30 ml) was added a mixture of 1,4-benzodioxan-6-carboxaldehyde (8.20 g, 50.0 mmol) and the product from Example 1 (6.30 g, 45.6 mmol). The solution was stirred overnight with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried (magnesium sulfate). Concentration afforded crude product as a golden, glassy solid. Flash chromatography over silica (ethyl acetate) yielded 9.40 g (68%) of product as a colorless glassy solid. 1H NMR (CDCl3) δ 6.99 (s, 1H), 6.90-6.78 (m, 3H), 6.00 (d, J=7.3, 1H), 4.58, (d, J=7.3, 1H), 4.26 (s, 4H), 3.95-3.87 (m, 1H), 3.55-3.41 (m, 3H), 2.04-1.80 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:18])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2cc(Cl)ccc2C)C1=S
Yield: 56.6 %

Procedure:
A mixture of the crude N-ethyl glycine (9.23 g), 5-chloro-2-methylphenylisothiocyanate (9.18 g), triethyl amine (10 g) and chloroform (250 mL) was heated at reflux for 18 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (400 mL) and water (300 mL). The organic phase was washed with 1N HCl (2×300 mL), then evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (7.6 g) was obtained as a light pink solid, m.p. 152°-154° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.36; H, 4.79; N, 10.35. Mass spectrum (EI, M.+) m/z 268/270.
Reaction SMILES: Cl[CH:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(#N)C>[F:10][C:9]([F:12])([F:11])[C:5]1[CH:4]=[C:3]([CH:2]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:8]=[CH:7][CH:6]=1
Reactant: FC(F)(F)c1cccc(C(Cl)c2cccc(C(F)(F)F)c2)c1
Reactant: C1CNCCN1
Solvent: CC#N
Product: FC(F)(F)c1cccc(C(c2cccc(C(F)(F)F)c2)N2CCNCC2)c1
Temperature: 100 °C

Procedure:
To a solution of bis(3-(trifluoromethyl)phenyl)methanol (1.1 g, 3.4 mmol) in CH2Cl2 (10 mL) was added dropwise thionyl chloride (0.50 ml, 6.9 mmol) at rt. The reaction was stirred at 50° C. for 4 h, concentrated under vacuum, azeotroped with toluene, and dried under vacuum to give crude chlorobis(3-(trifluoromethyl)phenyl)methane. The crude chlorobis(3-(trifluoromethyl)-phenyl)methane was added to a solution of piperazine (0.81 ml, 10 mmol) in acetonitrile (10 mL), heated to 100° C. for 18 h and concentrated under vacuum. The residue was dissolved in CH2Cl2 (150 mL) and washed with 1N NaOH (150 mL). The organic layer was dried with K2CO3, filtered, and concentrated to give 1-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazine. The crude 1-(bis(3-(trifluoromethyl)phenyl)-methyl)piperazine was dissolved in acetonitrile (10 mL) and tert-butyl bromoacetate (0.55 mL, 3.4 mmol) and triethylamine (0.96 ml, 6.9 mmol) was added. The solution was stirred for 4 h, diluted with water, and extracted with CH2Cl2. The organic layer was washed with saturated NaCl solution, then dried over Na2SO4, and concentrated. The crude product was purified by ISCO using 0-50% EtOAc in haxanes to give tert-butyl 2-(4-(bis(3-(trifluoromethyl)-phenyl)methyl)piperazin-1-yl)acetate (0.86 g, 50% yield). MS (ESI, pos. ion) m/z: 503.1 (M+1), which was then converted to the title compound by proceeding as described in Example 4 above.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1.C[O-].[Na+:29]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O-:26])=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1.[Na+:29]
Reactant: O=C(O)CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C([O-])CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Yield: 56.5 %

Procedure:
To a stirred solution of 1 part of (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoic acid in 40 parts of methanol were added 2.94 parts of a sodium methoxide solution in methanol. The reaction mixture was evaporated. The precipitated product was filtered off and dried at 60° C., yielding 0.6 parts (56.5%) of sodium (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoate; mp. 215.9° C. (compound 121).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[NH:10]C(=O)O[C:7](=[O:12])[C:6]=2[CH:13]=1.[CH:15]([NH2:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[NH2:10][C:5]1[C:4]([CH3:14])=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:18][CH:15]([CH3:17])[CH3:16])=[O:12]
Reactant: Cc1cc(Br)cc2c(=O)oc(=O)[nH]c12
Reactant: CC(C)N
Solvent: c1ccncc1
Product: Cc1cc(Br)cc(C(=O)NC(C)C)c1N
Yield: 118.7 %

Procedure:
To a suspension of the benzoxazinedione of Step E, (4.0 g, 15.56 mmol) in pyridine (20 mL) was added isopropylamine (1.2 g, 20.23 mmol) and the reaction was heated to reflux for 2 hours. The reaction was then cooled, concentrated from toluene on a rotary evaporator and then dried under vacuum to afford a solid (5.01 g).
Reaction SMILES: [Li+].[OH-].[CH2:3]([O:10][C:11]1[C:43]([CH3:44])=[CH:42][C:14]([CH2:15][C@@H:16]([CH2:21][C:22](=[O:41])[N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:40])[CH2:25][CH2:24]2)[C:17]([O:19]C)=[O:18])=[CH:13][C:12]=1[CH3:45])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:3]([O:10][C:11]1[C:43]([CH3:44])=[CH:42][C:14]([CH2:15][C@@H:16]([CH2:21][C:22](=[O:41])[N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:35][CH2:34][C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[NH:31][C:30]3=[O:40])[CH2:25][CH2:24]2)[C:17]([OH:19])=[O:18])=[CH:13][C:12]=1[CH3:45])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(C)c(OCc2ccccc2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg (8.35 mmol) LiOH in 40 mL water was added to a solution of 2.43 g (4.16 mmol) methyl (S)-2-(4-benzyloxy-3,5-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoate in 80 mL THF and the reaction mixture was stirred for 1 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 100 mL water and acidified with 2 M HCl with stirring. The precipitate formed was separated off and dried at 40° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([C:21](OC)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>O.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C1COCCN1
Agent: COc1nc(Cl)nc(OC)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
Temperature: 20 °C
Reaction time: 4 h
Yield: 50.3 %

Procedure:
KOH (0.419 L, 4889 mmol) was added portionwise to methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (900 g, 2444 mmol) in water (5 L) at 20° C. over a period of 1 hour. The resulting suspension was stirred at 20° C. for 4 hours until saponification was complete. The reaction was filtered to remove insoluble particles and transferred into a vessel containing water (2 L) (vessel 1). Morpholine (0.639 L, 7333 mmol) was added and agitation continued. 2-chloro-4,6-dimethoxy-1,3,5-triazine (1931 g, 11000 mmol) and water (8 L) was charged to vessel 2 and the temperature adjusted to approximately 7° C., 4-methylmorpholine (134 mL, 1222 mmol) was charged at a rate to maintain the contents at 10° C. and the contents agitated for 4 hours. The contents of vessel 2 was transferred to vessel 1 and agitated at room temperature overnight. DCM (5 L) was then added and the mixture transferred to a 30 litre separator, extracted with a further portion of DCM and the organic extracts combined, dried (Na2SO4) and evaporated to dryness. The solid was stirred in ethyl acetate and filtered to give 8-bromo-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (520 g, 50.3%) as a slightly grey solid. Mass Spectrum: m/z [M+H]+=425.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].Cl.C(N=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1.N1C(C)=CC=CC=1C.[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47](O)=[O:48])=[N:43][N:44]=1>ClCCl>[Br:39][C:40]1[N:41]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:53]([CH:60]3[CH2:62][CH2:61]3)=[CH:52][CH:51]=2)[C:42]([S:45][CH2:46][C:47]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])=[O:48])=[N:43][N:44]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)C(C)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Alanine methyl ester hydrochloride (1.48 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.86 mmol), 1-hydroxy-7-azabenzotriazole (1.86 mmol) and 2,6-lutidine (0.43 mL, 3.71 mmol) are added to a solution of 2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetic acid (0.5 g, 1.24 mmol) in dichloromethane (6.18 mL). The mixture is stirred at room temperature for 18 hours and then purified by SGC (0-100% EtOAc/Hexanes).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:20](=O)([O-])[O-].[Cs+].[Cs+].C(I)C>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:20])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)c(C)c(NC2CCCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCI
Product: COC(=O)c1cc(Br)c(C)c(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 82.4 %

Procedure:
To a stirred solution of methyl 5-bromo-3-(cyclopentylamino)-2,4-dimethylbenzoate (0.3 g, 1.07 mmol) in DMF (5 mL), cesium carbonate (0.697 g, 2.14 mmol) and ethyl iodide (0.3 mL, 5.38 mmol) were added; resulting reaction mass was heated at 80° C. for 12 h. On completion, reaction mass was cooled to room temperature and filtered, residue was washed with ethyl acetate and filtrate was concentrated and then purified by column chromatography to afford desired compound (0.3 g, 82%).
Reaction SMILES: CC(C1N=C(C=CC2C=C(C=CC=2)C=O)SC=1)C.SCCC(OC)=O.[CH3:26][N:27]([CH3:33])[C:28](=[O:32])[CH2:29][CH2:30][SH:31].B(F)(F)F.CCOCC.CC(C1N=C(C=CC2C=C(C(SCCC(OC)=O)SCCC(OC)=O)C=CC=2)SC=1)C.[CH3:74][N:75]([CH3:105])[C:76](=[O:104])[CH2:77][CH2:78][S:79][CH:80](SCCC(OC)=O)[C:81]1[CH:86]=[CH:85][CH:84]=[C:83]([CH:87]=[CH:88][C:89]2[S:90][CH:91]=[C:92]([CH:94]([CH3:96])[CH3:95])[N:93]=2)[CH:82]=1>C(Cl)Cl>[CH3:26][N:27]([CH3:33])[C:28](=[O:32])[CH2:29][CH2:30][S:31][CH:80]([C:81]1[CH:86]=[CH:85][CH:84]=[C:83]([CH:87]=[CH:88][C:89]2[S:90][CH:91]=[C:92]([CH:94]([CH3:96])[CH3:95])[N:93]=2)[CH:82]=1)[S:79][CH2:78][CH2:77][C:76]([N:75]([CH3:74])[CH3:105])=[O:104]
Reactant: COC(=O)CCSC(SCCC(=O)N(C)C)c1cccc(C=Cc2nc(C(C)C)cs2)c1
Reactant: CN(C)C(=O)CCS
Agent: CC(C)c1csc(C=Cc2cccc(C=O)c2)n1
Agent: COC(=O)CCS
Agent: COC(=O)CCSC(SCCC(=O)OC)c1cccc(C=Cc2nc(C(C)C)cs2)c1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)c1csc(C=Cc2cccc(C(SCCC(=O)N(C)C)SCCC(=O)N(C)C)c2)n1
Reaction time: 1.5 h

Procedure:
To a solution of the aldehyde of Step 1 (430 mg), methyl 3-mercaptopropanoate (190 μL, 1 equiv.) and N,N-dimethyl 3-mercaptopropanamide (223 mg, 1 equiv.) in CH2Cl2 (10 mL), BF3.Et2O (620 μL, 3 equiv.) is added slowly and the mixture is stirred 1.5 hours. The reaction is quenched with 25% aqueous NH4OAc at 0° C. The products are extracted with EtOAc and separated by flash chromatography on silica using a gradient of EtOAc:toluene (from 10:90 to 40:60) and acetone:toluene 1:1. Three products are obtained: first, dimethyl 3,3'(((3-(2-(4-(1-methylethyl)-2-thiazolyl)ethenyl)phenyl)methylene)-bis (thio))bispropanoate; second, methyl 3-((1-((3-dimethylamino-3-oxopropyl)thio)-1-(3-(2-(4-(1-methyl-ethyl)-2-thiazolyl)ethenyl)phenyl)methyl)thio)-propanoate; and third, the title compound.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:6]=1)C.[C:26]1([C@H:32]([OH:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][N:7]2[C:8]3=[CH:9][N:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[CH:12]=[C:13]3[C:5]([CH2:4][O:34][C@@H:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:33])=[CH:6]2)=[CH:20][CH:21]=1
Reactant: C[C@@H](O)c1ccccc1
Reactant: COC(=O)c1cc2c(CN(C)C)cn(Cc3ccc(F)cc3)c2cn1
Product: COC(=O)c1cc2c(CO[C@H](C)c3ccccc3)cn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared as in example 116, step 1, using methyl 3-[(dimethylamino)methyl]-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate and (1R)-1-phenylethanol. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.48 (d, J=6.41 Hz, 3H) 4.01 (s, 3H) 4.48-4.59 (m, 3H) 5.34 (s, 2H) 6.97-7.05 (m, 2H) 7.10-7.17 (m, 2H) 7.23 (s, 1H) 7.29-7.42 (m, 5H) 8.47 (s, 1H) 8.72 (s, 1H)
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]=[O:23])[CH3:20]>C1COCC1>[CH2:19]([CH:21]([CH2:24][CH3:25])[CH:22]([C:11]1[N:7]([CH2:6][C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][CH:4]=2)[N:8]=[CH:9][N:10]=1)[OH:23])[CH3:20]
Reactant: Fc1ccc(Cn2cncn2)cc1
Reactant: CCC(C=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ncnn1Cc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 47 %

Procedure:
To a stirred solution of 1-(4-fluorobenzyl)-1H-1,2,4-triazole (0.500 g, 2.82 mmol) in THF (30 mL) at −78° C. was added a solution of n-butyllithium (2.5M in hexanes, 1.1 mL, 2.9 mmol) dropwise. The mixture was stirred at −78° C. for 1.5 h, then 2-ethylbutyraldehyde (0.42 mL, 3.4 mmol) was added. The solution was slowly warmed to room temperature and stirred 18 h. It was then quenched with saturated aqueous NH4Cl and extracted twice with EtOAc. The organic extracts were dried (MgSO4), filtered, concentrated in vacuo and purified by column chromatography (SiO2, EtOAc/hexane, 1:1) to yield an oil in 47% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([Cl:18])=[CH:4][CH:3]=1.[O:19]1CCC[CH2:20]1.C[O-].[Na+]>CO>[CH3:20][O:19][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([Cl:18])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cnc(Cl)s1)c1nc(OC)ccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.5 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridine-2-amine, prepared according to the example 11, and 20 mL of tetrahydrofuran were added in a 150 mL single neck flask equipped with a magnetic stirrer, after stirred at room temperature for 10 to 30 minutes, 0.25 g of sodium methoxide in 2.0 mL of methanol were added dropwise. The reaction mixture was stirred at the same temperature overnight, and then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.20 g of crude product which was purified by a silica gel column chromatography using a petroleum ether/ethyl acetate (15/1) as an eluent to obtain 0.42 g of 6-methoxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-chloropyridin-2-amine, having the content of 95.0% as a yellow viscous liquid, GC-MS (M+) (EI: 70 eV, m/z) calc: 317. found: 317. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.202 (t, J=7.2 Hz, 3H, CH3), 3.418 (q, J=7.2 Hz, 2H, CH2), 4.033 (s, 3H, CH3), 4.530 (d, J=0.6 Hz, 2H, CH2), 6.726 (d, J=8.1 Hz, 1H, Py H), 7.034 (s, 1H, Thiazole-H), 7.454 (d, J=8.1 Hz, 1H, Py H).