Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17]([C:19]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:20])[CH2:16][C@:14]2([C:29]2[S:30][C:31]([Br:34])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(NC1=N[C@@]2(c3cccs3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NC1=N[C@@]2(c3ccc(Br)s3)CN(C(=O)OCc3ccccc3)C[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 91.9 %

Procedure:
To a stirred clear and colorless solution of benzyl (4aR,7aR)-2-benzamido-7a-(2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazine-6-carboxylate (1.67 g, 3.50 mmol) in dimethylformamide (35 mL) at room temperature, under an atmosphere of nitrogen is added N-bromosuccinimide (747 mg, 4.20 mmol). The resulting pale yellow solution is stirred at room temperature for 50 minutes. The solution is diluted with ethyl acetate (150 mL) and washed with water (3×50 mL) and brine (50 mL). The organic phase is separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography eluting with a hexanes/ethyl acetate, gradient from 80:20 to 0:100, to give the title compound (1.79 g, 92%) as a white solid: ES/MS (m/z): 557.8 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C([O-])([O-])=O.[K+].[K+].[C:18]([O:21][CH2:22][CH2:23]Br)(=[O:20])[CH3:19]>CC(C)=O.C(OCC)C>[C:18]([O:21][CH2:22][CH2:23][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])(=[O:20])[CH3:19]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCCOC(C)=O
Yield: 75.2 %

Procedure:
A mixture of 4-hydroxy-3-methoxy-benzaldehyde (2.5 g, 16.4 mmol), K2CO3 (6.81 g, 49.3 mmol) and 2-bromoethyl acetate (5.49 g, 32.9 mmol) in acetone (50 mL) is refluxed for 48 h before it is diluted with diethyl ether (250 mL) and washed with water (2×200 mL). The washings are extracted with diethyl ether (200 mL). The combined organic extracts are dried over MgSO4 and concentrated. The remaining residue is purified by column chromatography on silica gel eluting with heptane/EA 1:1 to afford the title compound (2.94 g) as colourless solid. 1H NMR (CDCl3): δ 9.85 (s, 1H), 7.45-7.41 (m, 2H), 6.99 (d, J=7.6 Hz, 1H), 4.51-4.47 (m, 2H), 4.34-4.30 (m, 2H), 3.94 (s, 3H), 2.11 (s, 3′-1).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:49])([F:48])[CH2:44]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:16]([C:39]([F:42])([F:41])[F:40])=[N:17][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:19]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[C:1]([C:5]1[N:6]=[C:7]([N:43]2[CH2:47][CH2:46][C:45]([F:48])([F:49])[CH2:44]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:16]([C:39]([F:40])([F:41])[F:42])=[N:17][NH:18][CH:19]=3)[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3C(F)(F)F)nc2n1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c[nH]nc3C(F)(F)F)nc2n1

Procedure:
The crude 5-tert-Butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidine and triethylsilane in TFA was stirred at r.t. for 3 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield the title compound as white solid. MS (m/e): 431.3 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.C(OC(O)C)C.Cl.N1C=CC=CC=1.[CH3:24][NH:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)=[O:27]>>[CH3:24][NH:25][C:26]([N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH:37][C:6]3[C:5]([C:9]#[N:10])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=3)=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)=[O:27]
Reactant: N#Cc1cnc(N)cc1Cl
Reactant: CNC(=O)n1ccc2cc(N)ccc21
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)n1ccc2cc(Nc3cc(N)ncc3C#N)ccc21
Temperature: 130 °C
Reaction time: 3 h
Yield: 44.9 %

Procedure:
2-Amino-4-chloro-5-cyanopyridine (123 mg, 0.80 mmol) synthesized in Production example 215-3, ethoxyethanol (3 ml) and pyridine hydrochloride (186 mg, 1.60 mmol) were added to N1-methyl-5-amino-1H-1-indolecarboxamide (198 mg, 1.05 mmol) synthesized in Production example 218-2; and the reaction mixture was stirred at 130° C. for 3 hours. After allowing to be cooled to room temperature, the reaction mixture was partitioned between a saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, ethyl acetate in this order) to yield the title compound (110 mg, 0.359 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:12]([CH3:14])[CH3:13])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[Li+].[OH-].C(O)(C(F)(F)F)=O>CS(C)=O.O.C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:12]([CH3:13])[CH3:14])[S:9][C:10]=1[NH:11][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1nc(C(C)C)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)c1nc(C(C)C)sc1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.1 %

Procedure:
Combine a solution of 5-amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester (8.71 g, 40.6 mmol) and 2-fluoronitrobenzene (4.28 mL, 40.6 mmol) in DMSO (105 mL) and stir at rt under N2 as LiOH (1.95 g, 81.4 mmol, 2.0 eq.) or LiOH monohydrate (2 eq) is added in one portion. The reaction turns dark. Heat the reaction mixture to 55° C. for 3 h until complete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min). Cool to rt overnight, Cool the reaction to 0-5° C. with stirring as deionized water (315 mL) is added at such a rate to maintain the temperature below 20° C. Precipitate the product and the reaction color changes from brown to rust-orange color. Stir the slurry for 3-4 h at rt, filter by vacuum and rinse with minimal 3:1/H2O:DMSO, dry in a vacuum oven at 60° C. to afford 12.4 g (91%) of the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ 11.52 (bs, 1H), 8.23 (d, 1H, J=8.05 Hz), 7.80 (m, 2H), 7.21 (m, 1H), 4.36 (q, 2H, J=7.32 Hz, 6.95 Hz), 3.23 (dq, 1H, J=6.95 Hz), 1.34 (m, 9H); 13C NMR (75 MHz, DMSO-d6) δ 163.22, 161.85, 149.08, 136.99, 136.37, 136.10, 126.53, 126.48, 121.94, 117.05, 60.45, 32.47, 22.34(2), 14.24; IR (CHCl3) 2976, 2932, 2867, 1709, 1677, 1611, 1580, 1550, 1512, 1415, 1340 cm−; HRMS (ES) M/z calculated for C15H17N3O4S 336.1018, found 336.1009.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH2:18][CH:19]=[CH2:20])[C:12]3=[O:21])=[CH:7][CH:6]=1)(=O)C.Cl.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:16][CH:15]2[C:14](=[O:17])[N:13]([CH2:18][CH:19]=[CH2:20])[C:12]3=[O:21])=[CH:9][CH:10]=1
Reactant: C=CCN1C(=O)C2CC2(c2ccc(NC(C)=O)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCN1C(=O)C2CC2(c2ccc(N)cc2)C1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 2.2 g of 1-(4-acetylaminophenyl)-3-allyl-3-azabicyclo[3.1.0]hexane-2,4-dione, 8 ml of water and 8 ml of concentrated hydrochloric acid is stirred for 3 hours at 100° C. The mixture is diluted with a small amount of water, cooled in an ice-water bath, made alkaline with 30% sodium hydroxide solution, and extracted twice with ethyl acetate. The organic phases are washed repeatedly with water and once with a concentrated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. The filtrate is concentrated and the residue is crystallised from ethyl acetate/petroleum ether. The title compound is obtained in the form of pale beige-coloured crystals with m.p. 104°-106° C. and with Rf=0.57 on thin-layer silica gel plates in the system methylene chloride/methanol (10:1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]I>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: Cc1cc[nH]c(=O)c1Br
Solvent: ClCCl
Product: COc1nccc(C)c1Br
Reaction time: 144 h

Procedure:
A solution of 3-bromo-4-methyl-2-pyridone V-b (2.20 g, 11.7 mmol), in DCM (80 mL) was treated with MeI (7.29 mL, 117 mmol) and Ag2CO3 (6.47 g, 23.5 mmol). The flask was stoppered and stirred under argon for 6 days. The mixture was filtered and purified by column chromatography (SiO2, 10% EtOAc in cyclohexane) to afford the desired product V-c as a clear mobile oil (1.83 g, 80%). 1H NMR (300 MHz, CDCl3) δ 7.94 (d, J=5.0 Hz, 1H), 6.77 (d, J=5.1 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][OH:19])=[C:14]([NH:20][CH:21]([CH3:23])[CH3:22])[CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([NH:20][CH:21]([CH3:23])[CH3:22])[C:15]([CH:18]=[O:19])=[CH:16][N:17]=1
Reactant: CC(C)Nc1cc(Cl)ncc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)Nc1cc(Cl)ncc1C=O
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of DMSO (13.43 mmol, 3.5 equiv.) in dry DCM (30 mL), oxalyl chloride (11.51 mmol, 3 equiv.) was added at −78° C. After being stirred for 20 min, (6-chloro-4-(isopropylamino)pyridin-3-yl)methanol (75) (770 mg, 3.84 mmol) was added to the above reaction mixture at −78° C. and stirred for 2 h. The reaction mixture was allowed to warm up to −20° C. and added Et3N (19.19 mmol, 5 equiv.) dropwise over a period of 5 mins. The reaction mixture was allowed to warm up to 0° C. over 30 mins and quenched with ice-flakes followed by 10% NaHCO3 solution. The organic layer was separated, aqueous layer was extracted with DCM (twice). The organic layers were collected together, dried over Na2SO4, filtered and concentrated to give crude aldehyde. The crude material obtained was purified by column chromatography through silica gel and EtOAc: pet ether as eluent provided the desired compound, 6-chloro-4-(isopropylamino)nicotinaldehyde. LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.76 min; LCMS (ES-API), m/z 199.26 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:14]=[C:15]([NH2:17])[CH:16]=1)=[O:10].C(N(CC)CC)C>ClCCl.C(OCC)C>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:14]=[C:15]([NH:17][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[CH:16]=1)=[O:10]
Reactant: COC(=O)c1cc(N)cc(-c2ccccc2Br)c1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC(=O)Nc1cc(C(=O)OC)cc(-c2ccccc2Br)c1
Reaction time: 0.5 h

Procedure:
Butyryl chloride (55 mg, 0.52 mmol) was added to a solution of 5-amino-2′-bromo-biphenyl-3-carboxylic acid methyl ester (153 mg, 0.5 mmol) and triethylamine (76 mg, 0.75 mmol) in dichloromethane (5 ml) and the mixture left at room temperature for 30 minutes. The resulting solution was diluted with diethyl ether, washed with 1M hydrochloric acid and saturated sodium bicarbonate, dried (MgSO4) and evaporated to dryness to yield the title compound as a light yellow gum. (161 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([OH:13])=O)[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:42]([NH:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.CCN(CC)CC>>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:11]([NH:50][NH:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:13])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: NNCc1ccccc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: COC(=O)N[C@H](C(=O)NNCc1ccccc1)C(C)(C)C
Yield: 50 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using N-(methoxycarbonyl)-(L)-tert-leucine (J. Med. Chem., 41, 3387-3401, 1998) (1.56 g, 8.24 mmol), EDAC (1.74 g, 9.08 mmol), HOBT (1.22 g, 9.03 mmol), NMM (0.995 mL, 9.05 mmol), benzylhydrazine×2HCl (1.61 g, 8.25 mmol) and Et3N (2.53 mL, 18.0 mmol) which gave the title compound (1.21 g, 50%) as a light yellow solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:29]1[S:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:29]6[S:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][N:33]=6)[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: FC(F)(F)c1nnc(Cl)s1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCN(c4nnc(C(F)(F)F)s4)CC3)C2)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole following a procedure analogous to that described for Example 15. LC (method 3): tR=0.93 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([O-:4])=[O:3].[N:12]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.ClC1C=CC=CC=1>O>[N+:2]([C:5]1[CH:6]=[C:7]([NH:8][C:17]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[NH:18])[CH:9]=[CH:10][CH:11]=1)([O-:4])=[O:3]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: N#CN1CCCC1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: O
Product: N=C(Nc1cccc([N+](=O)[O-])c1)N1CCCC1

Procedure:
Samples of 3-nitroaniline hydrochloride, 15.5 g, and 1-pyrrolidinecarbonitrile, 9.6 g, were combined with 12 ml of chlorobenzene, and the mixture was warmed to reflux for three hours, and then allowed to cool. The resulting solid mass was taken up in 200 ml of hot water, and the chlorobenzene layer was separated. The aqueous layer was washed with 30 ml of chloroform and the combined organic layers were washed with 50 ml of water. The aqueous layers were combined, warmed, treated with charcoal and filtered hot. The filtrate was allowed to cool, and made strongly basic with 50% sodium hydroxide. This basic mixture was extracted with 200 ml of chloroform. The chloroform extract was concentrated on a steam bath to 150 ml, then diluted with hexanes to 300 ml, and stirred until yellow solids formed, giving 17 g of the N-(3-nitrophenyl)-1-pyrrolidinecarboximidamide. m.p. 117-118° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH3:36])[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].[CH3:41]N>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:38]([NH2:40])=[O:39])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][N:35]5[CH2:3][CH2:2][CH2:41][CH2:36]5)[CH:31]=[CH:30][C:29]=4[F:37])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CNC)ccc4F)cc23)CC1
Reactant: CN
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN5CCCC5)ccc4F)cc23)CC1
Yield: 62.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide trifluoroacetate, substituting pyrrolidine (44 μL, 0.524 mmol) for methanamine to afford 10 mg of the title compound (62.7%).
Reaction SMILES: B(F)(F)F.CCOCC.Cl[C:11](Cl)(Cl)[C:12](=N)[O:13][C@H:14]1[S:31][CH2:30][C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18].OC1C=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:17]([O:16][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:30][S:31][C@H:14]1[O:13][C:12]1[CH:37]=[CH:38][C:39]([C:40]#[N:41])=[CH:42][CH:11]=1)(=[O:19])[CH3:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Yield: 80 %

Procedure:
1 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride is added at -15° C., under an inert atmosphere, to a suspension of 250 mg (0.57.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 57 mg (0.48.10-3 mol) of 4-hydroxybenzonitrile and a molecular sieve (1 nm) in 10 ml of methylene chloride. The reaction medium is allowed to return gradually to 0° C. and, after a reaction time of 3 h, is neutralized with sodium bicarbonate. The reaction mixture is then washed with water and dried over magnesium sulfate, MgSO4, and the solvent is evaporated off under reduced pressure. 150 mg (yield: 80%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15](O)=[O:16])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:40])[CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:30](=[O:40])[CH2:31][C@H:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH2:33])=[O:16])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: N[C@H](CC(=O)NCc1ccccc1)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N[C@H](CC(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2)c1ccccc1
Yield: 81.9 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (154 mg, 0.53 mmol, 1.0 eq), L-β-phenylalanine N-benzylamide (286 mg, 1.06 mmol, 2.0 eq) and dichloromethane (1.5 mL), was treated with triethylamine (442 uL, 3.2 mmol, 6.0 eq), and a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (673 uL, 2.0 eq), to provide 229 mg (81%) of L-β-phenylalanine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(C=O)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(C=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 2-hydroxy-4-methoxybenzaldehyde (304 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-4-methoxybenzaldehyde.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.N1C=CC=CC=1.[Pd]>[CH2:20]([O:19][C:18]([NH:1][C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](N=[N+]=[N-])C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A mixture of cis-tert-butyl 3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 5.73 mmol) and 10% Pd/C (0.61 g, 0.57 mmol) in MeOH (20 mL) was charged 1 atmosphere H2 and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo. The residue obtained was dissolved in pyridine (10 mL) and benzyl carbonochloridate (1.61 mL, 11.46 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pyridine was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 3:1) to give cis-tert-butyl 3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.44 g, 22%) as a solid.