Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=3)=[C:23]2[N:22]=1)([CH3:14])[CH3:13].C1C=CC2N(O)[N:46]=[N:45]C=2C=1.O.O.NN.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH:12]([C@H:15]1[CH2:19][O:18][C:17](=[O:20])[N:16]1[C:21]1[CH:26]=[CH:25][N:24]2[N:27]=[CH:28][C:29]([C:30]3[CH:31]=[CH:32][C:33]([C:34]([NH:45][NH2:46])=[O:35])=[CH:37][CH:38]=3)=[C:23]2[N:22]=1)([CH3:14])[CH3:13]
Reactant: On1nnc2ccccc21
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)O)cc3)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NN)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.6 %

Procedure:
EDCI (2.39 g, 12.45 mmol) was added to a mixture of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (0.76 g, 2.1 mmol) and HOBT-H2O (0.95 g, 6.226 mmol) in DMF (10 mL) at ambient temperature, and the reaction mixture was stirred for 20 minutes at ambient temperature. A solution of hydrazine hydrate (0.31 mL, 6.2 mmol) in DMF and triethylamine (1.5 mL, 10.38 mmol) were added. The resulting mixture was stirred for 1 hour at ambient temperature. The reaction mixture was diluted with EtOAc, washed with aqueous NH4Cl, NaHCO3, and brine, dried over MgSO4, and concentrated under reduced pressure. The crude was purified by silica gel flash column chromatography (0-5% MeOH in dichloromethane) to afford 0.50 g (64%) of (S)-4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzohydrazide. LCMS (APCI+) m/z 381.4 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>C1COCC1>[C:35]1([O:34][C:32](=[O:33])[NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:15]([N:17]3[CH2:21][CH2:20][S:19][CH2:18]3)=[O:16])[NH:8][CH2:12]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (32 mg, 0.1 mmol) in anhydrous THF (5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.2 mmol), followed by phenyl chloroformate (17.22 mg, 0.11 mmol). The mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (3 mL) and trifluoracetic acid (0.075 mL) in dichloromethane (0.075 mL) were added. The mixture was stirred for 5 hours at room temperature, concentrated under reduced pressure and purified using RP-HPLC to provide the titled compound. MS (ESI) m/e 336 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.77 (m, 1 H) 2.69 (m, 2 H) 3.07 (m, 1 H) 3.17 (m, 2 H) 3.25 (m, 1 H) 3.52 (m, 2 H) 3.75 (m, 1 H) 3.88 (m, 1 H) 4.52 (m, 1 H) 4.66 (m, 2 H) 7.10 (d, 2 H) 7.21 (t, 1 H) 7.37 (t, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH:9]=O)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH3:11][C:12]([S@@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][O:2][C:3]1[C:4](/[CH:9]=[N:17]/[S@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: COc1cccnc1C=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxy-pyridine-2-carbaldehyde (2.95 g, 21.51 mmol) in DCM (26 mL) was added (S)-2-methylpropane-2-sulfinamide (5.3 g, 43.7 mmol) and copper(II) sulfate (6.95 g, 43.5 mmol). The suspension was stirred at rt under argon for 18 hours, filtered, and the solid washed with DCM (2×20 mL). The filtrates were concentrated, and the product thus obtained was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradient followed by DCM/MeOH to yield the desired product (S,E)-N-((3-methoxypyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide as a light-yellow solid after drying under high vacuum.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][C:3]#[CH:4].C(N(CC)CC)C.Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1COCC1.[Pd].[Cu]I.C(OCC)(=O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]#[C:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1ccc(C#N)cc1
Agent: [Cu]I
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CCC#Cc2ccccn2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
A dried 1 L of three-neck round-bottom flask was flushed with N2, connected to a N2 inlet, equipped with a thermometer and a magnetic stirrer. 4-But-3-ynyl-benzonitrile (49.38 g, 0.32 mol) was dissolved in 250 mL of THF, followed by the successive addition of triethylamine (TEA) (250 mL, 1:1 TEA/THF), bromopyridine (33.3 mL, 0.35 mol), Pd (pph3)2Cl2 (4.47 g, 6.0 mmol), and CuI (1.21 g, 6.0 mmol). The reaction mixture was heated up to 65° C. and kept stirring at that temperature. During the heating, it turned dark brown. After 2 h, the reaction was complete and cooled to room temperature, followed by the addition of water (200 mL) and ethyl acetate (200 mL). The organic layer was separated, washed with water (30 mL) and brine (30 mL), and dried over sodium sulfate. After a simple filtration to remove any catalyst residues and drying agents, concentration in vacuo left an oil, which immediately became solid after cooling. The solid was then filtered and washed with heptane to give 58.74 g (79.6% yield; purity: 98%) of 4-(4-pyridin-2-yl-but-3-ynyl)-benzonitrile. 1H NMR (CDCl3): δ (ppm) 8.54 (m, 1H); 7.59 (m, 3H); 7.39 (m, 2H); 7.31 (m, 1H); 7.19 (m, 1H); 3.01 (t, J=6.9 Hz, 2H); 2.75 (t, J=6.9 Hz, 2H). ESMS calcd. (C16H12N2): 232.1. found: 233.1 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([C@@H:24]([NH:38][C:39](=[O:55])[O:40][CH2:41][C:42]1([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C(N(CC)CC)C>ClCCl>[N:32]1([C:30]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]([NH:38][C:39](=[O:55])[O:40][CH2:41][C:42]2([CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]2)[C:12](=[O:11])[C:13](=[O:23])[NH:14][C@@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])=[O:31])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)C(=O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a −60° C. solution of 0.034 mL (0.39 mmol) of oxalyl chloride in 1 mL of dichloromethane was added 0.055 mL (0.78 mmol) of dimethylsulfoxide, dropwise. A solution of 110 mg (0.177 mmol) of (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate in 1 mL of dichloromethane was added dropwise and the reaction stirred for 10 min before 0.12 mL (0.89 mmol) of triethylamine was added dropwise. The reaction was let warm to room temperature and stirred for 15 min before being applied directly to a silica gel column eluting with 3:7 acetone:dichloromethane to afford 90 mg (82%) of (1-benzylcyclohexyl)methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate. 1H NMR (300 MHz, 80° C., DMSO-d6) δ 8.91 (m, 1H), 7.15-7.38 (m, 11H), 6.30 (m, 1H) 5.01 (qnt, J=7 Hz, 1H), 4.85 (m, 1H), 3.63-3.72 (m, 2H), 3.54 (t, J=5 Hz, 4H), 3.26 (t, J=5 Hz, 4H), 3.04 (m, 2H), 2.66 (s, 2H), 1.316-1.714 (m, 19H). ES-LCMS m/z 643 (M+Na). HRMS C35H48N4O6 m/z 621.3652 (M+H)Cal; 621.3641 (M+Na)Obs.
Reaction SMILES: [F:1][C:2]1[C:3]2[CH2:14][CH2:13][C:12](=[CH:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2>CO.[C].[Pd]>[F:1][C:2]1[C:3]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[C:4]=2[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH3:11])[CH:6]=2
Reactant: CCC(=O)NCC=C1CCc2c(F)cc3nn(C)cc3c21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)NCCC1CCc2c(F)cc3nn(C)cc3c21
Temperature: 25 °C
Reaction time: 7 h
Yield: 92 %

Procedure:
To a solution of N-[2-(5-fluoro-2-methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethyl]propanamide (83.2 mg, 0.290 mmol) in methanol (2.9 mL) was added palladium-carbon powder (8.3 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→15/85) to give the title compound (77.2 mg, yield 92%).
Reaction SMILES: [CH3:1][N:2](C)C=O.[CH3:6][O:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17](Br)[CH:18]=2)[N:13]=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1)=[O:9].[Cl-].[Na+]>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:6][O:7][C:8]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:1]#[N:2])[CH:18]=2)[N:13]=[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:11]=1)=[O:9]
Reactant: COC(=O)c1cc(-c2ccccc2)nc2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)nc2ccc(C#N)cc12
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
Zinc cyanide (0.3394 g, 2.89 mmol) and tetrakis(triphenylphosphine)palladium (0.1647 g, 0.143 mmol) were added to a dimethylformamide (14.0 mL) solution of 6-bromo-2-phenyl-4-quinolinecarboxylic acid methyl ester (0.9749 g, 2.85 mmol), and the mixture was heated with stirring at 150° C. for 10 minutes with microwave irradiation. To the reaction solution, water and a saturated aqueous solution of sodium chloride were added. The mixture was subjected to extraction with ethyl acetate and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, and the solvent was distilled off to obtain 6-cyano-2-phenyl-4-quinolinecarboxylic acid methyl ester (0.6614 g, 2.29 mmol) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl-].[Ca+2].[Cl-].C(O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][S:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[CH:7]=1
Reactant: Cc1ccc2ncc(CSc3ccc([N+](=O)[O-])cc3)n2c1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1ccc2ncc(CSc3ccc(N)cc3)n2c1
Yield: 88.2 %

Procedure:
A mixture of 6-methyl-3-[[(4-nitrophenyl)thio]methyl]imidazo[1,2-a]pyridine (3.0 g), reduced iron (2.80 g) and calcium chloride (0.56 g) in 15% water-containing ethanol (150 ml) was heated to reflux for 20 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→2:1), to give 4-[[(6-methylimidazo[1,2-a]pyridin-3-yl)methyl]thio]aniline (2.38 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16](O)=[O:17])[C:13](=[O:19])[C:12]3([CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]3)[N:11]([CH3:26])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:27][C:28]1[CH:29]=[C:30]2[C:43](=[CH:44][CH:45]=1)[CH2:42][C@:32]1([C:40]3[C:35](=[N:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C:33]1=[O:41])[CH2:31]2.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:27][C:28]3[CH:29]=[C:30]4[C:43](=[CH:44][CH:45]=3)[CH2:42][C@:32]3([C:40]5[C:35](=[N:36][CH:37]=[CH:38][CH:39]=5)[NH:34][C:33]3=[O:41])[CH2:31]4)=[O:17])[C:13](=[O:19])[C:12]3([CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20]3)[N:11]([CH3:26])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12COCCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12COCCOC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
75 mg (0.20 mmol) (R)-2-(3-(3,5-difluorophenyl)-1-methyl-5-oxo-8,11-dioxa-1,4-diazaspiro[5.6]dodecan-4-yl)-ethanoic acid, 55 mg (0.22 mmol) (R)-5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, 50 mg (0.26 mmol) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-hydrochloride, 35 mg (0.26 mmol) HOBT, 0.07 ml (0.50 mmol) TEA and 1.5 ml DMF were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation. The residue was stirred with 15 ml of a 1.25M methanolic hydrochloric acid for 1 h at 50° C. The mixture was concentrated by rotary evaporation and the residue was purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:13][CH:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:34](F)(F)C(O)=O>O.C(OCC)(=O)C>[CH3:34][C:10]1([O:13][C@@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:11]
Reactant: O=C(O)C(F)(F)F
Reactant: COC1O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 2,3,5-tri-O-benzyl-L-xylofuranoside (22.7 g, 56.30 mmol) is dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (200 mL) and stirred at 0° C. overnight. The mixture is put to dryness under reduced pressure. The oily residue is dissolved in ethyl acetate and washed three times with a saturated solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of cyclohexane and ethyl acetate yield methyl 2,3,5-tri-O-benzyl-L-xylofuranose as an oil (11.7 g, 53%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>[OH-].[Na+]>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=1
Reactant: Brc1ccccn1
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: COC(=O)c1ccc(Oc2ccccn2)cc1
Yield: 14.3 %

Procedure:
2-Bromopyridine (1.00 g), methyl 4-hydroxybenzenecarboxylate (1.92 g) and potassium carbonate (874.9 mg) were stirred at 150° C. for 6 hours. Aqueous 2 N sodium hydroxide solution (50 mL) was added to the reaction liquid, extracted with diethyl ether (100 mL), and the organic layer was washed with water (50 mL) and saturated saline water (50 mL) in that order, and then evaporated under reduced pressure to obtain a pale yellow residue. The resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 8/2) to obtain the entitled compound (208 mg) as a pale yellow solid.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)C1C=CC=CC=1.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>ClCCl>[CH2:24]([O:23][C:21]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@:10]([CH3:19])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:9]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)[C@@]1(C)CN(Cc2ccccc2)C[C@@H]1C
Solvent: ClCCl
Product: CCOC(=O)[C@@]1(C)CN(C(=O)OCc2ccccc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 53.7 %

Procedure:
To a solution of ethyl(3R*,4R*)-1-benzyl-3,4-dimethylpyrrolidine-3-carboxylate (2.75 g, 10.0 mmol) in dichloromethane (30 mL), benzyl chloroformate (2.14 mL, 15.0 mmol) was added at room temperature, and the mixture was stirred at room temperature for 6 hours. Benzyl chloroformate (2.14 mL, 15.0 mmol) was also added to the mixture, and the mixture was stirred at room temperature for another 14 hours. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate, 9:1→4:1→2:1) to obtain 1.64 g of the title compound (5.37 mmol, 2 steps, 54%) as a colorless transparent oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([O:14]CC2C=CC=CC=2)[C:10]1=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[N:11]([OH:14])[C:10]1=[O:22])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Yield: 98.5 %

Procedure:
10.5 g of (3S-trans)-3-(t-Butyloxycarbonylamino)-1-benzyloxy-4-methyl-2-azetidinone was dissolved in 250 ml of methanol and hydrogenated with 1.43 g of palladium on carbon (10%) as the catalyst. After 45 minutes the catalyst was filtered off and the filtrate was evaporated in vacuo. The crystalline title compound was dried (vacuum desiccator) at room temperature yielding 7.3 g of the title compound, melting point 161°-162° C., dec.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:16]([C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2cccc(F)c2)Oc2ccc(Br)cc21
Yield: 36.9 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (15 g, 0.07 mol), 3-fluorobenzaldehyde (8.7 g, 0.07 mol) and borax (26.7 g, 0.07 mol) in ethanol (90 mL) and H2O (150 mL) was refluxed for one day. The reaction mixture was cooled, diluted with an equal volume of H2O, and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to give 6-bromo-2-(3-fluorophenyl)chroman-4-one (8.3 g, 37%). 1H-NMR (CDCl3): 2.93 (d, 1H), 3.03 (m, 1H), 5.47 (d, 1H), 7.06 (d, 1H), 7.11 (m, 1H), 7.22 (m, 2H), 7.40 (m, 1H), 7.57 (d, 1H), 8.04 (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:23]4[CH2:27][CH2:26][CH2:25][CH:24]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.C([SiH](CC)CC)C>CO.[Pd]>[F:28][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:6][CH2:7]1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3=CCCC3)ccc12
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(C3CCCC3)ccc12
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 6-chloro-2-cyclopent-1-enyl-quinoline-5-carboxylic acid (4,4-difluoro-cyclo hexyl methyl)-amide (110.00 mg, 0.25 mmol, 1.00 eq) in methanol (15 mL, 136.36 V) was added palladium on carbon (10% w/w) (20 mg, 0.02 mmol, 0.08 eq) under argon atmosphere. Triethylsilane (0.40 mL, 2.49 mmol, 10 eq) was added to the reaction mixture and stirred for 30 min. The reaction mixture was filtered through a Celite bed and the filtrate was concentrated to provide a crude product which was purified by preparative HPLC to afford the title compound (18 mg, 0.04 mmol, 17.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.80 (t, J=5.80 Hz, 1H), 7.94-8.01 (m, 2H), 7.75 (d, J=9.01 Hz, 1H), 7.58 (d, J=8.72 Hz, 1H), 3.39-3.40 (m, 1H), 3.27 (t, J=6.21 Hz, 2H), 2.02-2.11 (m, 4H), 1.64-1.86 (m, 11H), 1.27-1.33 (m, 2H). m/z: 407 [M+H]+
Reaction SMILES: [F:1][CH2:2][CH2:3][OH:4].[H-].[Na+].F[C:8]1[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1>O1CCCC1>[F:1][CH2:2][CH2:3][O:4][C:8]1[C:9]([S:14]([NH2:17])(=[O:16])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)c1ncccc1F
Reactant: OCCF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ncccc1OCCF
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.76 ml of 2-fluoroethanol are added dropwise, with cooling, to a suspension of 6.54 g of sodium hydride (55.6% NaH in oil) in 120 ml of tetrahydrofuran so that the temperature does not exceed 20° C. When the dropwise addition is complete, the reaction mixture is stirred at room temperature for 15 minutes and then a further solution of 10.56 g of 3-fluoro-pyrid-2-ylsulfonamide in 60 ml of tetrahydrofuran is added dropwise over a period of 10 minutes. The reaction solution is then stirred for 10 minutes at room temperature and for 2 hours at reflux before it is cooled and concentrated. For purification, the oil remaining is chromatographed on a silica gel column using ethyl acetate/hexane 4/1. Evaporation of the eluant yields a light-coloured oil which crystallises spontaneously, yielding 5.88 g of title product which melts at 122°-123° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=O.Cl.[CH2:14]([O:21][C:22](=[O:31])[NH:23][C:24]1([C@H:27]([NH2:30])[CH2:28][CH3:29])[CH2:26][CH2:25]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]([NH:30][C@@H:27]([C:24]2([NH:23][C:22](=[O:31])[O:21][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:26][CH2:25]2)[CH2:28][CH3:29])[C:8]([F:12])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: CC[C@@H](N)C1(NC(=O)OCc2ccccc2)CC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 80 °C
Yield: 44.8 %

Procedure:
To a solution of 2,6-dichloro-5-fluoronicotinamide (233 mg, 1.22 mmol) in NMP (5.0 mL) was added (R)-benzyl-1-(1-aminopropyl)cyclopropylcarbamate hydrochloride salt (350 mg, 1.23 mmol) and DIPEA (0.434 mL, 2.44 mmol). After heated at 80° C. for 4 h, the mixture was diluted with EtOAc, organic layer was washed brine, dried and concentrated to give (R)-benzyl 1-(1-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)propyl)cyclopropylcarbamate (220 mg).