Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[CH3:40][O:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:40][O:41][CH2:42][CH2:43][O:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(O)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: COCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(OCCOC)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (222 mg, 0.42 mmol), 2-methoxyethanol (0.1 mL, 1.26 mmol), diisopropyl azidocarboxylate (0.24 mL, 1.26 mmol), and triphenylphosphine (330 mg, 1.26 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction mixture was absorbed on silica gel and purified by flash chromatography on silica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 139 mg of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), 7.72 (d, 1H), 7.62 (s, 1H), 7.48 (d, 1H), 7.40 (d, 2H), 7.21 (d, 1H), 7.08 (d, 2H), 6.88 (d, 2H), 6.79 (d, 2H), 6.47 (d, 1H), 5.85 (dd, 1H), 4.13 (qt, 2H), 4.02 (m, 2H), 3.90 (m, 1H), 3.74 (m, 1H), 3.62 (m, 2H), 3.29 (s, 3H), 2.47-2.37 (m, 3H), 2.01 (m, 2H), 1.76 (m, 1H), 1.59 (m, 2H), 1.22 (t, 3H), 0.89 (t, 3H).
Reaction SMILES: [NH:1]1[C:5]([C@@H:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=3)=[CH:10][CH:9]=2)[CH3:7])=[CH:4][CH:3]=[N:2]1.CC[O:26]C(C)=O>>[F:23][C:20]([F:22])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C@H:6]([C:5]3[N:1]([OH:26])[N:2]=[CH:3][CH:4]=3)[CH3:7])=[CH:9][CH:10]=2)[S:16][CH:17]=1
Reactant: CCOC(C)=O
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ccn[nH]1
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1ccnn1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a solution of N-{4-[(1R)-1-(1H-pyrazol-5-yl)ethyl]phenyl}-4-(trifluoromethyl)-1,3-thiazol-2-amine (0.421 g, 1.24 mmol) in EtOAc (5 mL) m-CPBA (256 mg, 1.5 mmol) was added and the resulting mixture was stirred at room temperature overnight. The crude was diluted with EtOAc (10 ml), washed with water (2×10 ml) and dried over anhydrous Na2SO4. After solvent evaporation, the crude was purified by flash chromatography to give the pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]-1H-pyrazol-1-ol (7) (0.295 g, 0.65 mmol) as a white solid (67%). [α]D=−28 (c=0.82; CH3OH); 1H-NMR (CD3OD): δ 9.40 (bs, 1H, NH); 7.55 (d, 1H, J=2.5 Hz); 7.40 (d, 2H, J=7 Hz); 7.35 (d, 2H, J=7 Hz); 7.15 (s, 1H), 6.25 (d, 1H, J=2.4 Hz); 3.80 (q, 1H, J=7 Hz); 1.60 (d, 3H, J=7 Hz).
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH:7][CH3:8].[Br:9][C:10]1[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:13]2[N:14]=[C:15]([C:17]([O:19]CC)=O)[O:16][C:12]=2[C:11]=1[F:27].Cl>ClCCl>[Br:9][C:10]1[C:23]([CH3:24])=[C:22]([C:25]#[N:26])[C:13]2[N:14]=[C:15]([C:17]([N:7]([CH3:8])[CH3:6])=[O:19])[O:16][C:12]=2[C:11]=1[F:27]
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(Br)c(F)c2o1
Reactant: CNC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(Br)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution, 57.9 ml, 59.6 mmol) was dropwise added to a dichloromethane (100 ml) solution of dimethylamine hydrochloride (4.86 g, 59.6 mmol) with cooling in a water bath, taking 30 minutes, and stirred for 65 minutes at room temperature. Subsequently, a dichloromethane (30 ml) solution of ethyl 6-bromo-4-cyano-7-fluoro-5-methyl-1,3-benzoxazole-2-carboxylate (I-126) (6.50 g, 19.9 mmol) was dropwise added and stirred for 30 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, and the reaction liquid was extracted with chloroform. Next, the obtained organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with dichloromethane/methanol (100:1, v/v) gave the entitled compound (3.10 g, 48%) as a pale yellow solid. The fraction containing impurities was recovered and purified twice in the same manner to obtain the entitled compound (362 mg, 591 mg), and 4.05 g (62%) of the entitled compound was obtained in total.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][C:4]=1[F:12].[CH3:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([CH3:23])[C:21]=1[OH:22])[CH:17]=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH:10]=[CH:17][C:16]2[CH:19]=[C:20]([CH3:23])[C:21]([OH:22])=[C:14]([CH3:13])[CH:15]=2)=[CH:5][C:4]=1[F:12]
Reactant: COc1ccc(C(C)=O)cc1F
Reactant: Cc1cc(C=O)cc(C)c1O
Product: COc1ccc(C(=O)C=Cc2cc(C)c(O)c(C)c2)cc1F

Procedure:
This compound was synthesized from 4′-methoxy-3′-fluoroacetophenone and 3,5-dimethyl-4-hydroxybenzaldehyde according to general method 1 described earlier.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=O)[CH2:6][CH2:5]2.F[B-](F)(F)F.[F:29][CH2:30][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl-].[NH4+]>C(COC)OC.O>[F:29][CH:30]=[C:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][S:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:22])=[CH:8]1
Reactant: FC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: O
Product: CSC[C@]12CCC(=CF)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
500 ml of 19-methylthio-4-androsten-3,17-dione (Euoprean patent 100,566) in 10 ml of dimethoxyethane is added drop by drop at 0° C. to a suspension of 5.73 g of fluoromethyl triphenylphosphonium tetrafluoroborate in 40 ml of dimethoxyethane, which was stirred with 9.5 ml of butyllithium solution (1.6 m in ether) for 0.5 hour, instilled and stirred for another 15 minutes. Then saturated ammonium chloride solution is added, diluted with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated in a vacuum. After chromatography on silica gel with hexane/ethyl acetate, 331 mg of pure 3-fluoromethylene-19-methylthio-4-androsten-17-one with a melting point of 146°-147° C. [α]D +288.4° (CHCl3) as E:Z mixture is obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:22]([N:5]([CH2:4][CH:3]([O:2][CH3:1])[O:16][CH3:17])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(CNC(=O)OCc1ccccc1)OC
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=CCN(CC(OC)OC)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
A solution of benzyl N-(2,2-dimethoxyethyl)carbamate (50 g, 208.9 mmol) in toluene (180 mL) is treated with solid potassium hydroxide (51.6 g, 919.69 mmol) under nitrogen. After 10 minutes, benzyltriethylammonium chloride (0.8 g, 3.1 mmol) is added. After another 10 minutes a solution of allyl bromide (33 g, 272.8 mmol) in toluene (50 mL) is added drop wise over 10 minutes. The resultant mixture is stirred at 50° C. for 48 hours. The mixture is cooled to room temperature and quenched with water. The organic layer is separated, washed with brine, dried over magnesium sulfate, and concentrated to dryness to give the title compound (44 g, 75%). ES/MS (m/e): 280 (M+H).
Reaction SMILES: [C:1]([C:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[N:6]=1)([O:3][CH3:4])=[O:2].[Al]>O1CCCC1.C(OCC)(=O)C>[C:1]([CH:5]1[O:11][CH:10]2[CH:7]([C:8](=[O:26])[N:9]2[C:12](=[C:23]([CH3:24])[CH3:25])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[NH:6]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1=NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Agent: [Al]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C1NC2C(=O)N(C(C(=O)OCc3ccccc3)=C(C)C)C2O1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.8 %

Procedure:
A solution of 32.78 g of benzyl α-(3-carbomethoxy-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]hept-2-en-6-yl)-α-isopropylideneacetate in 500 ml of tetrahydrofuran containing 5% water is mixed with aluminium amalgam which has been prepared from 22.95 g of aluminium and 0.5% aqueous solution of mercuric chloride, and the mixture stirred at room temperature for 50 minutes. The reaction mixture is diluted with ethyl acetate and filtrated through a layer of Hyflo Super Cel. The filtrate is dried on sodium sulfate and concentrated under reduced pressure to yield the residue, which is crystallized from ether to yield 22.02 g of benzyl α-(3ξ-carbomethoxy-7-oxo-4-oxa-2,6-diaza-bicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 61% yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19](F)=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:12]=[C:11]([CH3:29])[N:10]=1.O>CS(C)=O.C(O)(=O)C>[CH3:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:24][C:23](=[O:25])[C:22]3[C:17](=[CH:18][C:19]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:20][C:21]=3[O:26][CH3:27])[N:16]=2)[CH:12]=[C:11]([CH3:29])[N:10]=1
Reactant: COCCO
Reactant: COc1cc(F)cc2nc(-c3cc(C)nc(C)c3)[nH]c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: COCCOc1cc(OC)c2c(=O)[nH]c(-c3cc(C)nc(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxyethanol (3 mL) in dimethyl sulfoxide (8 mL), sodium hydride (60% suspension in mineral oil, 0.40 g, 9.40 mmol) was added in portions and the reaction mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 2-(2,6-dimethyl-pyridin-4-yl)-7-fluoro-5-methoxy-3H-quinazolin-4-one (0.28 g, 0.94 mmol) and the reaction mixture was stirred at 90° C. for 16 hours. Water was added, acidified to pH approximately 4-5 with acetic acid, and the precipitated solid was filtered to give crude product, which was purified by preparative HPLC, to obtain the title compound as a white solid. Yield: 0.12 g (36%). MP 228.8-230.4° C. MS (ES) m/z: 356.05 (M++1). 1H NMR (400 MHz, CDCl3): δ 10.45 (s, 1H), 7.65 (s, 2H), 6.85 (d, J=1.6 Hz, 1H), 6.61 (d, J=1.6 Hz, 1H), 4.27 (t, J=4.8 Hz, 2H), 3.97 (s, 3H), 3.82 (t, J=4.8 Hz, 2H), 3.49 (s, 3H), 2.66 (s, 6H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([O:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:36][N:35]=3)=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (2.25 g), 2-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.88 g), anhydrous iron (III) chloride (1.07 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 1.54 g of desired compound (melting point: 139.0°-141.0° C.).
Reaction SMILES: [BrH:1].[NH+]1C=CC=CC=1.Br.[CH3:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17](=[O:19])[CH3:18]>C(O)(=O)C>[BrH:1].[Br:1][CH2:18][C:17]([C:16]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[O:10][CH3:9])=[O:19]
Reactant: COc1cnccc1C(C)=O
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Product: COc1cnccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of pyridinium hydrobromide perbromide (2.33 g, 0.0073 mol) in acetic acid (20 mL) containing 31% hydrobromic acid in acetic acid (1.85 mL) was stirred at room temperature for four hours. The mixture was cooled to 17° C. and a solution of 3-methoxy-4-acetylpyridine (1.02 g, 0.0062 mol) in acetic acid (5 mL) was added. The cooling bath was removed and after about thirty minutes a yellow solid was deposited. Ether (25 mL) was added and the crude α-bromo-3-methoxy-4-acetylpyridine hydrobromide (1.60 g) was collected by filtration washed with ether and air dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1)#[N:2].C([O-])([O-])=[O:29].[K+].[K+].OO>CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:29])=[C:4]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[CH:5]=1)[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2cc(N[C@H](CC3CCCCC3)C(N)=O)ccc2C#N)sn1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC3CCCCC3)C(N)=O)ccc2C(N)=O)sn1
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-cyclohexylpropanamide (241 mg, 0.629 mmol) in DMSO (2 mL), K2CO3 (300 mg, 2.17 mmol) and H2O2 (50% aq., 1.00 mL) were added. After being stirred at 90 C for 10 min, the mixture was purified by HPLC to give the titled compound (81 mg). MS 402.4 (M+H); UV 204.7, 298.3 nm
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Si](C)(C)C)[O:8][CH:7]=1)=[O:5])[CH3:2].S(Cl)([Cl:18])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:18])[O:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc([Si](C)(C)C)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1coc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
5-Trimethylsilyl-3-furancarboxylic acid (4.1 g) (synthesized in accordance with the method described in Tetrahedron Lett., 25, 4451 (1984)) was dissolved in tetrahydrofuran (100 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (3.0 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture as concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) as oil. 5-Trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) as oil. 5-Chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and 1N aqueous sodium hydroxide (12 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magensium sulfate and concentrated under reduced pressure. Precipaitated crystals were collected by filtration and washed with hexane to give 5-chloro-3-furancarboxylic acid (1.1 g) as crystals.
Reaction SMILES: [CH:1]([N:4]([CH:10]([CH3:12])[CH3:11])[C:5](=[O:9])[O:6][CH2:7]Cl)([CH3:3])[CH3:2].[OH:13][C@@H:14]([C@H:16]1[C:35](=[O:36])[N:18]2[C:19]([C:32]([O-:34])=[O:33])=[C:20]([S:22]/[CH:23]=[CH:24]\[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH2:30][OH:31])[CH2:21][C@H:17]12)[CH3:15].[Na+].C(OCC)(=O)C>CN(C)C(=O)C.[Cl-].[Na+].O>[OH:13][C@@H:14]([C@H:16]1[C:35](=[O:36])[N:18]2[C:19]([C:32]([O:34][CH2:7][O:6][C:5]([N:4]([CH:10]([CH3:12])[CH3:11])[CH:1]([CH3:3])[CH3:2])=[O:9])=[O:33])=[C:20]([S:22]/[CH:23]=[CH:24]\[C:25]3[S:29][CH:28]=[N:27][C:26]=3[CH2:30][OH:31])[CH2:21][C@H:17]12)[CH3:15]
Reactant: CC(C)N(C(=O)OCCl)C(C)C
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)C[C@H]12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)N(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Temperature: 30 °C
Reaction time: 3.5 h
Yield: 80.2 %

Procedure:
Chloromethyl N,N-diisopropylcarbamate (54 mg) and 75 mg of n-tetrabutyl ammonium bromide were added to 2 ml of a solution of 100 mg of sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-carbapen-2-em-3-carboxylate in N,N-dimethylacetamide, and the mixture was stirred at 30° C. for 3.5 hr. Ethyl acetate (10 ml) and 10 ml of semi-saturated brine were added to the reaction solution, followed by separation. The organic layer was washed three times with 10 ml of semi-saturated brine, was dried over anhydrous magnesium sulfate, and was filtered. Ethyl acetate was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=15:1) to give 108 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:30]([O:32][C:33]([CH3:35])=[CH2:34])=[O:31]>CCOC(C)=O>[Cl:22][C:5]1[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)=[CH:7][C:2]([NH:1][C:30](=[O:31])[O:32][C:33]([CH3:35])=[CH2:34])=[C:3]([F:23])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(Cl)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A bi-phasic mixture of Example A3 (250 mg, 0.710 mmol) in EtOAc (10 mL) and satd. NaHCO3 (15 mL) was treated with isopropenyl chloroformate 9120 mg, 0.984 mmol) and stirred at RT for 2 h. The layers were separated, the organic layer washed with water, then brine, dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl (4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (292 mg, 94% yield). MS (ESI) m/z: 436.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1>C(O)C.[Rh]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(=O)NCCCc1ccc(Cl)c2occc12
Agent: [Rh]
Solvent: CCO
Product: CC(=O)NCCCc1ccc(Cl)c2c1CCO2
Yield: 77.7 %

Procedure:
A solution of N-[3-(7-chloro-benzofuran-4-yl)-propyl]-acetamide (48 mg) in ethanol (15 ml) was hydrogenated over rhodium catalyst (5% on carbon; 15 mg) over 7 h. The catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography, eluting with dichloromethane/methanol 50:1 gave the title compound as a colourless solid (37.6 mg) mp 76-78°
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:63]([C:52]1[C:51]([NH:50][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:56][CH:55]=[CH:54][C:53]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)(=[O:64])[NH2:65]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2.4 g, 10 mmol) in DCM (40 mL) was added HATU (5.3 g, 14 mmol) and DIPEA (3.6 mL, 28 mmol) and the reaction mixture was stirred at room temperature for 1 h. 3-Aminobiphenyl-2-carboxamide (from Example 218) (1.5 g, 7.07 mmol) was added and the resulting mixture stirred for an additional 16 h. The reaction mixture was washed with water, the organic portion dried, filtered and concentrated under reduced pressure. The resulting residue was purified by ISCO chromatography (50% ethyl acetate in hexanes) to yield tert-butyl 4-(2-carbamoylbiphenyl-3-ylcarbamoyl)piperidine-1-carboxylate (1.0 g, 22% yield) as a white solid. LCMS Method T: retention time 1.71 min; [M+1]=423.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([N:13]=[N+]=[N-])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]([NH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cnc2c(c1)CCCC2N=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cnc2c(c1)CCCC2N
Yield: 98.2 %

Procedure:
To a solution of (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-azide (0.33 g, 1.6 mmol) in MeOH (16 mL) was added palladium on activated carbon, (10%, 50 mg) and the reaction mixture stirred under 1 atmosphere of hydrogen for 4 h. The mixture was filtered through celite, the cake washed with methanol and the solvent from the eluent removed in vacuo to give crude (3-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)-amine as a yellow oil (0.28 g, 96%). 1H NMR (CDCl3) δ 1.75 (m, 2H), 1.97 (m, 1H), 2.17 (m, 1H), 2.77 (m, 2H), 3.81 (s, 3H), 3.98 (t, 1H, J=4.5 Hz), 6.88 (d, 1H, J=1.5 Hz), 8.12 (d, 1H, J=1.5 Hz).