Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28](N(OC)C)=[O:29]>O1CCCC1>[F:25][C:26]1[N:37]=[CH:36][CH:35]=[CH:34][C:27]=1[C:28]([C:22]1[S:21][C:20]([N:16]2[CH2:17][CH2:18][CH2:19][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:12])[CH2:14][CH2:15]2)=[N:24][CH:23]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nccs2)CC1
Reactant: CON(C)C(=O)c1cccnc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ncc(C(=O)c3cccnc3F)s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.9 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.9 ml, 2.25 mmol) was added dropwise to a solution of tert-butyl-4-(thiazol-2-yl)-1,4-diazepane-1-carboxylate (570 mg, 2 mmol) in tetrahydrofuran (7 ml), cooled to −78° C. Thirty minutes later, a solution of 2-fluoro-N-methoxy-N-methylnicotinamide (370 mg, 2 mmol) in tetrahydrofuran (2 ml) added dropwise. The reaction mixture was stirred at −78° C. for one hour, then at 0° C. for an extra hour. It was quenched with a saturated sodium bicarbonate aqueous solution. The reaction mixture was diluted with ethyl acetate, then washed with brine. The organic was dried over magnesium sulfate, then concentrated in vacuo. The residue was purified by flash chromatography (40 g silica gel, pentane/ethyl acetate) to afford the title compound (300 mg, 38%). 1H NMR (CD3OD): 1.42 (9H, s), 1.90-2.00 (2H, MO, 3.45-3.50 (2H, m)<3.65-6.75 (2H, m), 3.80-3.90 (2H, m), 7.46-7.49 (1H, t), 7.67-7.69 (1H, d), 8.10-8.15 (1H, t), 8.39-8.40 (1H, d). MS (ES+): 407.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:23]([C:30](OCC)=[O:31])#[C:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(O)C>[C:25]([C:24]1[N:3]2[C:4]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])=[N:7][CH2:8][C:2]2=[N:1][C:30](=[O:31])[CH:23]=1)([O:27][CH2:28][CH3:29])=[O:26]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 27, 2-amino-7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine was heated in ethanol with diethyl acetylenedicarboxylate to give 1-carboethoxy-9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[C:15]([O:18][CH2:19][CH:20]([CH2:31][O:32][NH2:33])[CH2:21][CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])(=[O:17])[CH3:16].C(N(CC)C(C)C)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:33][O:32][CH2:31][CH:20]([CH2:19][O:18][C:15](=[O:17])[CH3:16])[CH2:21][CH2:22][P:23]([O:24][CH2:25][CH3:26])([O:27][CH2:28][CH3:29])=[O:30])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: CCOP(=O)(CCC(CON)COC(C)=O)OCC
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCC(CONc1nc(NC=O)nc(Cl)c1NC=O)COC(C)=O)OCC
Temperature: 100 °C
Reaction time: 3 h
Yield: 75.9 %

Procedure:
4,6-Dichloro-2,5-diformamidopyrimidine (0.390 g, 1.66 mmol), diethyl 3-(acetoxymethyl)-4-(aminooxy)-butylphosphonate (0.380 g, 1.275 mmol) and N,N-diisopropylethylamine (0.58 ml, 3.22 mmol) were dissolved in diglyme (15 ml) and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was then allowed to cool, N,N-diisopropylethylamine hydrochloride was filtered off and the filtrate was evaporated to dryness. The residue was chromatographed on silica gel (eluting with chloroform:ethanol 97:3) to give the title compound (0.480 g, 76%). 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7Hz (OCH2CH3), 1.75 (4H, m, CH2CH2P), 2.01 (4H, m, COCH3, CHCH2) 4.0 (8H, m, CH2OAc, NOCH2, (OCH2)2) 8.15 (1H, s, 5-NHCHO), 9.25 (1H, s, 2-NHCHO), 9.40 (1H, br.s, D2O exchangeable, NHOCH2) 10.80 (2H, br.s. D2O exchangeable, 2x NHCHO). Found: C,41.97, H,5.80; N,13.17%. C17H27N5O8PCl requires: C,41.17; H,5.49; N,14.12%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]([CH3:23])([CH3:22])[C:15](=O)[C:14]=2[C:13]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:10])=[O:9]>C(O)(=O)C.S(=O)(=O)(O)O.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][C:16]([CH3:22])([CH3:23])[CH2:15][C:14]=2[C:13]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:10])=[O:9]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(=O)C(C)(C)CC2
Agent: [Pd+2]
Agent: O=S(=O)(O)O
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1CC(C)(C)CC2
Yield: 5.2 %

Procedure:
A mixture of Example 362D (600 mg) and Pd(OH)2 on carbon (370 mg) in 50 mL of acetic acid and 0.6 mL of concentrated sulfuric acid was reacted under 60 psi pressure for 5 days. After insoluble was filtered off and the filtrate was concentrated in vacuo, the residue was purified by silica gel column chromatography eluting with 10% ethyl acetate in n-hexane to provide 30 mg of the desired product. MS (ESI(+)) m/e 409 (M+NH4)+; MS (ESI(−)) m/e 390 (M−H)−.
Reaction SMILES: [Na].[CH2:2]([S:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=1[C:12]([O:14]C)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CN(C)C=O>[OH:14][C:12]1[C:11]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:10]=2[S:9][C:2]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1SCc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: Oc1c(-c2ccccc2)sc2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hyride (50% dispersion in mineral oil) (0.49 g, 10.2 mmol) in N,N-dimethylformamide (30 ml) cooled to 0° C. in an ice-bath was added dropwise with stirring a solution of methyl 2-benzylthio-5-trifluoromethylbenzoate (2.5 g, 7.7 mmol) in N,N-dimethylformamide (10 ml). The reaction mixture was stirred at 75° C. for 1.5 hours under a nitrogen atmosphere, cooled and then poured into ice containing 1N hydrochloric acid. Extraction was effected with diethyl ether. The combined organic extracts were washed three times with water, once with saturated aqueous sodium chloride solution, dried (sodium sulfate) and evaporated. The residue was subjected to chromatography on a column of silica gel (Merck No. 7734) that was eluted with 10:1 hexane-ether. Fractions containing pure product were combined and evaporated to give a white solid that was recrystallized from toluene; yield 490 mg (22%), m/z 1294 (M+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1.I[CH2:16][CH3:17].CN(C=O)C.[H-].[Na+]>O>[CH2:16]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[N:4]1)[CH3:17]
Reactant: COc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-methoxy-5-nitro-1H-indazole (100 mg) and iodoethane (0.1 ml) were added to a DMF (1 ml) suspension containing sodium hydride (60% in oil) (23 mg), followed by stirring at room temperature for 0.5 hours. Water was added to the reaction solution. A solid precipitate was collected by filtration and purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1). 1-Ethyl-3-methoxy-5-nitro-1H-indazole (80 mg) was thus obtained.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:22][C:23]2([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH2:29][CH2:28][CH:27]=[CH:26][O:25][CH2:24]2)[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:3]1=[O:37]>CCO.[Pd]>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH2:12][N:13]([CH2:22][C:23]2([N:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24]2)[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])[C:3]1=[O:37]
Reactant: CN1CCN(C2(CN(Cc3cc4ccccc4n(C)c3=O)C(=O)C3CCCCC3)CCC=COC2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C2(CN(Cc3cc4ccccc4n(C)c3=O)C(=O)C3CCCCC3)CCCCOC2)CC1

Procedure:
N-[(1-methyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N-{[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methyl}cyclohexanecarboxamide (59 mg, 0.116 mmole) was hydrogenated at atmospheric pressure (H2 balloon) with 10% Pd/C (13 mg, 0.012 mmole) in EtOH at RT. After 16 hr the mixture was filtered through a pad of Celite washing with EtOH and concentrated to an off-white solid (57 mg, 96%). 1H-NMR (CDCl3, 500 MHz) d 7.58 (t, J=7.08 Hz, 1 H), 7.52 (d, J=6.59 Hz, 1 H), 7.39 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 7.21 (s, 1 H), 5.34 (d, J=19.78 Hz, 1 H), 4.58 (d, J=19.78 Hz, 1 H), 4.31 (d, J=14.41 Hz, 1 H), 4.01 (m, 1 H), 3.88 (dd AB, J=13.91 and 74.95 Hz, 1 H), 3.78 (s, 3 H), 3.37 (m, 1 H), 2.91 (d, J=14.65 Hz, 1 H), 2.80-2.26 (m, 12 H), 1.84-1.06 (m, 17 H). HRMS (M+H)+ calculated 509.3486. found 509.3491.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1[N+](=O)[O-]
Yield: 101.1 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 2-phenylphenol (3.5 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.6 g), sodium hydride (55 wt. %, 1.08 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.3 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:13]=3[CH:28]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].N[C@@H:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:31][OH:32]>C1(Cl)C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:16][C:12]3[CH:11]=[CH:10][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:1]5[O:32][CH2:31][C@H:30]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[N:2]=5)[CH:4]=4)=[CH:28][C:13]=3[C:14]=2[C:24]([NH:26][CH3:27])=[O:25])=[CH:18][CH:19]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C4=N[C@@H](c5ccccc5)CO4)c3)cc12
Yield: 24.2 %

Procedure:
Zinc chloride (9 mg, 0.067 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.135 mmol) and (S)-2-amino-2-phenylethanol (93 mg, 0.675 mmol) in PhCl (3 mL) rt. It was subjected to two interations of microwave irradiation at 200° C. for 1 hr. The material was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (16 mg, 23%). 1H NMR (500 MHz, CD3OD) δ ppm 8.33 (1H, s), 7.94-8.00 (4H, m), 7.91 (1H, d, J=7.94 Hz), 7.64-7.73 (2H, m), 7.61 (1H, t, J=7.78 Hz), 7.32-7.42 (6H, m), 7.26 (2H, t, J=8.55 Hz), 5.45 (1H, t, J=9.16 Hz), 4.94 (1 H, t, J=9.31 Hz), 4.36 (1H, t, J=8.24 Hz), 2.97 (3H, s). LC-MS retention time 1.76 min; m/z (MH+): 491. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% MeOH/95% H2O/10 mM ammonium bicarbonate, Solvent B=95% MeOH/5% H2O/10 mM ammonium bicarbonate, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Phenomenex Gemini C-18, 4.6×150 mm, 3 μm, Rt=18.32 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=18.10 min, purity=99%.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:12]1COCC1>>[CH3:12][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:1]([NH2:9])=[O:8]
Reactant: NC(=O)c1ccccc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1C(N)=O
Temperature: 60 °C
Yield: 91 %

Procedure:
Treat the product of step 5 (10.54 g, 23.3 mmol) in THF (170 mL) with 60% NaH (1.87 g, 47 mmol) followed by CH31I (1.9 mL, 30.5 mmol). Heat the reaction mixture at 60° C. for 30 min and then partition between Et2O (250 mL) and H2O (500 mL). Extract the aqueous layer with Et2O (500 mL), wash the combined organic layers with brine (250 mL), dry with MgSO4 and concentrate to give 9.9 g of the methyl benzamide product as a colorless oil (21 mmol, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH:11]1([CH:14]([OH:26])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH:3]=1)[O:26][CH:14]([CH:11]1[CH2:12][CH2:13]1)[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CN(CCC(O)C1CC1)C(=O)OC(C)(C)C
Product: CN(CCC(Oc1cc(Cl)ccc1C#N)C1CC1)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the method of Example 3 step (b) but using 4-chloro-2-fluorobenzonitrile and (3-cyclopropyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[N:27][C:28]#[N:29])SC)=[C:9]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].O.[NH2:36][NH2:37]>C(O)C>[NH2:29][C:28]1[N:27]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH2:19][C:10]2[NH:11][C:12]([CH3:18])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[C:30]([O:32][CH2:33][CH3:34])=[O:31])[NH:37][N:36]=1
Reactant: CCOC(=O)C1=C(COCCNC(=NC#N)SC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(COCCNc2nc(N)n[nH]2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl

Procedure:
N-{2-[(4{-2-Chlorophenyl}-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl)methoxy]ethyl}-N'-cyano-S-methyl-isothiourea (0.4 g) and hydrazine hydrate (0.15 ml) were dissolved in ethanol (20 ml) and heated under reflux for 3 hours. The solvent was then evaporated and toluene (10 ml) was added to the residue, and again the solution was evaporated to dryness. The residue was chromatographed on Merck "Kieselgel 60H" (Trade Mark), eluting with 2% methanol in methylene chloride, to give a beige solid. The solid was recrystallized from ethyl acetate plus a trace of ether to give the title compound, yield 0.1 g, m.p. 137°-138°.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:18][CH3:19])[C:11]([F:17])=[CH:12][CH:13]=2)[N:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:20]1([N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([F:17])[C:10]=3[O:18][CH3:19])[C:15](=[O:16])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]2)[CH2:21][CH2:22]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)ccc2c1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1c(F)ccc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C

Procedure:
A quantity of 28.6 g of ethyl-1-cyclopropyl-1,4-dihydro-7-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylate and 300 mL of a mixture of acetic acid, water, sulfuric acid (8/6/1) are refluxed for 2 hours. The reaction mixture is cooled at 0° C. and the desired product collected by filtration.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[O:15]=[C:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1>>[OH:15][C:16]1([C:7]2[N:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: COCCCn1cnc2ccccc21
Product: COCCCn1c(C2(O)CCCN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: -78 °C

Procedure:
1-(3-methoxypropyl)-1H-benzo[d]imidazole (137A) (9.62 mmoles; 1.83 g) was added to an oven dried 250 mL round-bottomed flask equipped with an addition funnel and for stirring under nitrogen. Et2O (75 mL) was added and the solution was cooled to −78° C. with an acetone/CO2(s) bath. N-BuLi (2.5M in hexanes, 10.1 mmoles, 4.0 mL) was added drop-wise via syringe and the resultant solution was allowed to stir at −78° C. for 45 minutes. Tert-butyl 3-oxopiperidine-1-carboxylate (10.1 mmoles, 2.01 g) in END (25 mL) was then added drop-wise to the reaction solution at −78° C. via addition funnel and allowed to stir for 1 hr. The reaction solution was then allowed to warm to rt and stir for ihr. The reaction solution was then poured into ice-water, extracted with ethyl acetate, and washed once with saturated aqueous sodium chloride. The organic layer was collected and subsequently dried with anhydrous Na.2SO4 and filtered. The filtrate was collected, concentrated, and dried in-vacuo. The residue was then partially purified by chromatography on silica gel (5-15% CH3OH/CH2Cl2) to afford tert-butyl 3-hydroxy-3-(1-(3-methoxypropyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (137E) as a mixture of products that was carried onto the next step without further purification. ESI-MS: m/z 390.4 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][O:6][CH2:7][C:8]([OH:10])=O.[CH2:11]([C@H:18]1[CH2:22][NH:21][C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][N:21]([C:8](=[O:10])[CH2:7][O:6][CH2:5][CH2:4][O:3][CH3:2])[C@H:20]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:28][CH:27]=2)=[O:24])[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COCCOCC(=O)O
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Agent: Cl
Product: COCCOCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 26.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(2-methoxyethoxy)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 88, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(2-methoxyethoxy)acetyl)pyrrolidine-2-carboxamide (8.1 mg, 26.6%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): a 9.95 (s, 1H), 7.54 (m, 2H), 7.27 (m, 2H), 7.21-7.15 (m, 7H), 6.93 (m, 2H), 4.47 (m, 1H), 4.08 (m, 2H), 3.62-3.42 (m, 6H), 3.21 (s, 3H), 2.63 (m, 3H), 1.88 (m, 2H). MS (EI) for C29H31FN2O5. found 507.6 (MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([OH:25])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:6]([C@@H:19]1[O:24][CH2:23][C@@H:22]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@H]1CC[C@H](C(c2ccccc2)c2ccccc2)OC1
Yield: 78.7 %

Procedure:
Methanesulfonyl chloride (0.33 g, 2.87 mmol) was reacted with trans-2-diphenylmethyl-tetrahydropyran-5-ol 11 (0.38 g, 1.43 mmol) in the presence of triethylamine (0.22 g, 2.15 mmol) in methylene chloride (10 ml) to give trains-2-diphenylmethyl-tetrahydropyran-5-yl methanesulfonate 13 (0.39 g, 77.8%) as an oil (Procedure A).
Reaction SMILES: C([C@@:9]1([OH:34])[C@@H:13]([CH:14](C(=O)C2C=CC=CC=2)[OH:15])[O:12][C@@H:11]([N:24]2[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]2=[O:26])[C@@:10]1([F:33])[CH3:32])(=O)C1C=CC=CC=1.N>CO>[F:33][C@:10]1([CH3:32])[C@H:9]([OH:34])[C@@H:13]([CH2:14][OH:15])[O:12][C@H:11]1[N:24]1[CH:31]=[CH:30][C:28](=[O:29])[NH:27][C:25]1=[O:26]
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@H](C(O)C(=O)c2ccccc2)[C@]1(O)C(=O)c1ccccc1
Agent: N
Solvent: CO
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of 3′,5′-dibenzoyl-2′-Deoxy-2′-fluoro-2′-C-methyluridine (1.5 g, 1 eq) in MeOH (10 mL) was added a solution of saturated ammonia in MeOH (20 mL). The reaction mixture was stirred at 0° C. for 30 min, and then warmed to room temperature slowly. After the reaction mixture was stirred for another 18 hours, the reaction mixture was evaporated under reduced pressure to give the residue, which was purified by column chromatography to afford pure compound 2′-deoxy-2′-fluoro-2′-C-methyluridine (500 mg, Yield: 60 %).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To a solution of (2R,3S)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.514 mmol) in CH2Cl2 (5 mL) were added successively 3-chloro-2-fluorobenzylamine (0.065 mL, 0.514 mmol), HBTU (293 mg, 0.772 mmol) and DIPEA (0.18 mL, 1.03 mmol), and stirring was continued at RT for 20 h. The reaction mixture was then diluted with CH2Cl2, and the organics were washed with 0.1N aqueous HCl (2×), aqueous NaHCO3 (2×) and brine (1×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:1)=0.62; MS (LC/MS): 397 [M+Na]+, 319 [MH−tBu]+, 275 [MH−Boc]+; tR (HPLC conditions b): 4.72 min.