Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([OH:15])[C:12]([F:16])=[CH:11][C:3]=1[C:4]([NH:6][S:7]([CH3:10])(=[O:9])=[O:8])=[O:5].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[Cl:25])[CH2:18][O:15][C:13]1[C:12]([F:16])=[CH:11][C:3]([C:4]([NH:6][S:7]([CH3:10])(=[O:8])=[O:9])=[O:5])=[C:2]([F:1])[CH:14]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CS(=O)(=O)NC(=O)c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CS(=O)(=O)NC(=O)c1cc(F)c(OCc2ccc(Cl)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 2,5-Difluoro-4-hydroxy-N-(methylsulfonyl)benzamide (Preparation 18 10.6 g, 42.2 mmol) in DMSO (53 mL) was added 4-(bromomethyl)-1,2-dichlorobenzene (10.63 g, 44.3 mmol) and potassium carbonate (11.66 g, 84.4 mmol) and the reaction stirred at ambient temperature for 18 hours. The reaction was quenched with aqueous hydrogen chloride solution (1 M, 100 mL) and water (100 mL). The resulting off-white precipitate was stirred at room temperature for 1 hour, filtered and washed with water (3×100 mL). The resulting pale yellow solid was suspended in acetone (106 mL) and heated at reflux for 1 hour. The suspension was then cooled to room temperature and filtered to yield the first crop of the crude title compound as a white solid (11.6 g, 67%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH3:30])[CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].C(O)C.[BH4-].[Na+]>C1COCC1.O>[Si:23]([O:22][CH:13]([C:14]([CH3:20])([CH3:21])[CH2:15][OH:16])[CH:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:30])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)C(O[Si](C)(C)C(C)(C)C)C(C)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)C(O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Temperature: 25 °C
Reaction time: 13 h
Yield: 28.2 %

Procedure:
To a mixed solution of ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-dimethyl-3-(tert-butyldimethylsilyloxy)pentanoate (5.42 g) and calcium chloride (2.06 g) in THF (50 mL)-ethanol (25 mL) was added sodium borohydride (1.56 g) and the mixture was stirred at room temperature for 13 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/1) to give the title compound as a colorless solid (yield: 1.38 g, yield: 28%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.C([O-])=O.[NH4+].Cl.CCOCC>CO.[OH-].[Pd+2].[OH-]>[N:10]1([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: CCOCC
Product: Nc1ccc(N2CCCC2)nc1

Procedure:
Combine 5-nitro-2-pyrrolidin-1-yl-pyridine (5.6 g, 29 mmol), palladium hydroxide (1.96 g, 35 wt. %), ammonium formate (9.1 g, 145 mmol), 1N HCl/Et2O (41 ml), in methanol (289 ml) and stir. Heat reaction mixture to reflux for 1 hour. Cool reaction mixture and add carbon to decolorize. Filter the solution through celite, add 50 ml of saturated NaHCO3, and evaporate in vacuo to remove the methanol and ether. Extract the residue 3 times into CH2Cl2 from saturated NaHCO3, dry over Na2SO4, and evaporate in vacuo to obtain 6-pyrrolidin-1-yl-pyridin-3-ylamine. Mass spec.: M+1=164 (AP+).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Fc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(F)ccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-5-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([N+:15]([O-])=O)[CH:7]=1.[OH:18][CH2:19][CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([NH:30][C:31]([C:33]3[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=3)=[O:32])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]2[N:12]=[C:37]([C:36]3[CH:35]=[CH:34][C:33]([C:31]([NH:30][C:26]4[CH:25]=[C:24]5[C:29](=[CH:28][CH:27]=4)[N:21]([CH2:20][CH2:19][OH:18])[CH:22]=[CH:23]5)=[O:32])=[CH:40][CH:39]=3)[NH:15][C:8]=2[CH:7]=1
Reactant: COCCOc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: O=Cc1ccc(C(=O)Nc2ccc3c(ccn3CCO)c2)cc1
Product: COCCOc1ccc2nc(-c3ccc(C(=O)Nc4ccc5c(ccn5CCO)c4)cc3)[nH]c2c1

Procedure:
Compound 674 was prepared according to the procedure similar to that described in Scheme III from 1-(2-methoxyethoxy-3,4-dinitrobenzene and 4-(1-(2-hydroxyethyl)-5-indolylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C27H26N4O4: 471.20; found: 471.05.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].CCN(CC)CC.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of crude 1-(bromomethyl)-2-chloro-4-nitro-benzene (29.1 mmol; 50% pure) in 30 mL of DCM was added Et3N (4.2 mL, 30 mmol) and 1-methylpiperazine (3.4 mL, 30 mmol). After stirring for 3 h at ambient temperature, aq. NaHCO3 was added and the mixture was extracted with DCM. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide 6.80 g of product as a dark yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[H][H]>C(O)C.[Pt]=O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: c1cncc(-c2ncc[nH]2)c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: c1c[nH]c(C2CCCNC2)n1
Yield: 108 %

Procedure:
3-(1H-imidazol-2-yl)pyridine (4.0 g, 0.0275M) and platinum oxide (0.5 g) in ethyl alcohol (50 ml) and 1NHCl (50 ml) was reduced at 45 psig of hydrogen for 4 hrs. The reaction mixture was filtered and the filtrate was stripped to dryness and crystallized from MeOH-EtOH to give 3-(1H-imidazol-2-yl)piperidine (4.5 g, 74% yield, mp 295° dec.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:17][C:18]1([CH3:42])[CH2:27][CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)[C:20]=2[CH2:19]1>>[NH2:1][C:2]1[C:7]([S:8]([CH2:10][CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])=[O:9])=[CH:6][C:5]([C:36]2[CH:37]=[CH:38][C:32]3[O:31][CH2:30][CH2:29][N:28]([C:21]4[C:20]5[CH2:19][C:18]([CH3:17])([CH3:42])[CH2:27][CH2:26][C:25]=5[N:24]=[CH:23][N:22]=4)[CH2:34][C:33]=3[CH:35]=2)=[CH:4][N:3]=1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: CC(C)(O)CCS(=O)c1cc(Br)cnc1N
Product: CC(C)(O)CCS(=O)c1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N

Procedure:
Prepared according to the method of example 5 by using 4-[(2-amino-5-bromopyridin-3-yl)sulfinyl]-2-methylbutan-2-ol (reagent preparation 41) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, Methanol-d4): 8.40 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H), 7.51 (s, 1H), 7.42 (d, 1H), 7.05 (d, 1H), 4.68 (s, 2H), 4.33 (m, 2H), 3.94 (m, 2H), 3.20 (m, 2H), 2.79 (t, 2H), 2.47 (s, 2H), 1.80 (m, 2H), 1.67 (t, 2H), 1.21 (s, 6H), 0.88 (s, 6H); MS (EI) for C29H37N5O3S: 536 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[S:10][C:9]=2[CH:21]=O)=[CH:4][CH:3]=1.Cl.[O:24]([NH2:26])[CH3:25]>>[CH3:25][O:24][N:26]=[CH:21][C:9]1[S:10][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:12]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: CON
Reactant: Cc1c(-c2ccc(O)cc2)sc(C=O)c1-c1ccc(O)cc1
Agent: Cl
Product: CON=Cc1sc(-c2ccc(O)cc2)c(C)c1-c1ccc(O)cc1
Yield: 62.1 %

Procedure:
Starting from 3,5-bis(4-hydroxyphenyl)-4-methylthiophene-2-carbaldehyde (0.86 g, 2.8 mmol) in place of 3-(3-methoxyphenyl)-5-(4-methoxyphenyl)-4-methylthiophene-2-carbaldehyde and methoxylamine hydrochloride (0.25 g, 3.0 mmol) in place of hydroxylamine hydrochloride, the title compound (0.59 g, 62%, m.p. 219-25° C.) was synthesized in essentially the same manner as described in Example 16, Step 1. Contains 6% E form as determined by NOE.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:27]([O-])([N+]([O-])=O)=[O:28]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:27]=[O:28])[C:5]([N:7]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:8]1[O:16][CH2:15][C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 67.9 %

Procedure:
3.1 g of 1-(2-chloroethyl)-3-isobutyl-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.3 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-L-arabinopyranosylurea are thereby obtained as pale yellow caramel.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=O)[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2].[C:26](#[N:30])[CH2:27][C:28]#[N:29]>CCO.N1CCCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH:9]=[C:27]([C:26]#[N:30])[C:28]#[N:29])[CH:6]=[CH:5][C:4]=1[N:11]=[C:12]1[S:16][CH2:15][C:14]2([CH2:20][CH2:19][CH2:18][CH2:17]2)[N:13]1[CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH3:2]
Reactant: CCc1cc(C=O)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: CCc1cc(C=C(C#N)C#N)ccc1N=C1SCC2(CCCC2)N1C1CCCC1
Reaction time: 2 h
Yield: 28.5 %

Procedure:
To a solution of 2-(2-ethyl-4-formylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane (Method D11a; 0.037 g, 0.104 mmol) in EtOH (10 mL) was added malononitrile (0.007 g, 0.104 mmol) and piperidine (4 drops). The reaction mixture was stirred at room temp. for 2 h, then concentrated under reduced pressure. The residue was purified by preparative TLC (20% EtOAc/hex) to give 2-(2-ethyl-4-(2,2-dicyanovinyl)phenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane as a yellow solid (0.012 g, 28%): mp 135-136° C.
Reaction SMILES: ClCCO[C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].N1(C2CCNCC2)CCCCC1.[I-].[Na+]>COCCOC>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:5]=1)[N:12]=[CH:11][C:10]([C:15]#[N:16])=[C:9]2[NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnc2cc1OCCCl
Agent: C1CCN(C2CCNCC2)CC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c2c1
Temperature: 137.5 °C

Procedure:
A mixture of 222.5 mg (0.5 mmol) of 7-(2-chloroethoxy)-6-methoxy-4-(4-phenoxyphenylamino)quinolin-3-carbonitrile, 841.4 mg (5.0 mmol) of 4-piperidinopiperidine and 49.5 mg (0.33 mmol) of sodium iodide in 6.0 mL of ethylene glycol dimethyl ether are heated in a sealed tube at 135-140° C. for 17 hours to yield the crude product. Solvents are removed in vacuo. Purification of the oily residue is carried out by preparative thin layer chromatography (eluting with 85:15 dichloromethane/methanol) to provide 137.7 mg of 742-[1,4′]bipiperidinyl-1′-yl-ethoxy)-6-methoxy-4-(4-phenoxy-phenylamino)-quinoline-3-carbonitrile as a light yellow solid, mp 141° C. (decompose).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21]([C:25](O)(O)[C:26]([F:29])([F:28])[F:27])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[F:1][C@H:2]1[CH2:4][C@H:3]1[C:5]([NH:7][C:8]1[N:9]=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1[CH:19]=[N:20][C:21](/[C:25](=[N:39]/[CH2:38][C:37]3[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=3)/[C:26]([F:27])([F:29])[F:28])=[CH:22][C:23]=1[CH3:24])[CH:12]=2)=[O:6]
Reactant: Cc1cc(C(O)(O)C(F)(F)F)ncc1-c1ccc2cc(NC(=O)[C@@H]3C[C@@H]3F)ncc2c1
Reactant: COc1ccc(CN)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(C/N=C(/c2cc(C)c(-c3ccc4cc(NC(=O)[C@@H]5C[C@@H]5F)ncc4c3)cn2)C(F)(F)F)cc1
Temperature: 100 °C

Procedure:
To a mixture of (1S,2S)-2-fluoro-N-(7-(4-methyl-6-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyridin-3-yl)isoquinolin-3-yl)cyclopropanecarboxamide (113.8 mg; 0.2614 mmol) and toluene (2 mL) was added a scoop of oven-dried 4 angstrom molecular sieves and a premixed solution of 4-methoxybenzylamine (54 μL; 0.393 mmol) and acetic acid (23 μL; 0.401 mmol) in toluene (1 mL). The reaction mixture was then heated at 100° C. for 3 days. The reaction mixture was cooled to room temperature and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-10% methanol in dichloromethane) to yield 99.7 mg of a 1:1 mixture of the title compound and unreacted starting material. LCMS (ESI): M+H=419.2.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@:19]1([CH3:51])[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(#N)C.CCOC(C)=O>[C:21]([O:20][C@:19]1([CH3:51])[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Compound 57 may be prepared according to Scheme 7, above. To a solution of uracil (4 g) in acetonitrile (120 ml) was added BSA (18 ml) and the mixture was stirred at 100° C. for 30 minutes. After cooling to room temperature, 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (10 g) in acetonitrile (120 ml) and 5 nCl4 (7 ml) were added. The reaction mixture was stirred at 100° C. for 4 hours. The mixture was diluted with EtOAc and a saturated solution of NaHCO3 was added at 0° C. followed by filtration on celite. The filtrate was extracted with EtOAc and the organic layer was washed with a saturated solution of NaHCO3. After drying over Na2SO4 and filtration, the organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0→20% EtOAc in dichloromethane to yield 2′,3′,5′-tri-O-benzoyl-2′-C-methyluridine (80%). 2′,3′,5′-tri-O-benzoyl-2′-C-methyluridine was characterized by the following spectroscopic data: MS (ESI, EI+) m/z=571.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18](=[O:25])[NH:17]1>>[S:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([O:25][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=3)[O:11][C:2]([CH3:1])([CH3:15])[CH:3]2[OH:14])=[N:17]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1[nH]sc2ccccc12
Product: CC1(C)Oc2ccc(C#N)cc2C(Oc2nsc3ccccc23)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and benzo[d]isothiazol-3-one as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1S(C)(=O)=O)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([NH2:36])[CH3:35].O1CCCC1>C(OCC)C.CN(C)C=O>[CH2:1]([N:4]1[C:18](=[O:19])[C:17]2[C:11]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][C:9]3[CH:20]=[CH:21][CH:22]=[CH:23][C:8]=3[C:7]=2[N:6]=[C:5]1[NH:36][CH2:34][CH3:35])[CH:2]=[CH2:3]
Reactant: CCN
Reactant: C=CCn1c(S(C)(=O)=O)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1c(NCC)nc2c(c1=O)C1(CCCCC1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
3-Allyl-2-(methylsulfonyl)-3H-spiro[benzo[h]quinazoline-5,1′-cyclohexan]-4(6H)-one (6, 306 mg, 0.796 mmol) and potassium carbonate (165 mg, 1.19 mmol) were added to 1 mL of dry dimethylformamide stirring under nitrogen atmosphere. A 2.0M solution of ethylamine in tetrahydrofuran (1 mL, 2 mmol) was then added, and the reaction was tightly capped and allowed to stir at room temperature for 5 hours. Another 1 mL portion of ethylamine solution was added at 5 hours, and the reaction allowed to stir for another 12 hours. At this point, the reaction mixture was diluted with diethyl ether and washed twice with water and once with brine. The organic layer was dried over MgSO4, vacuum filtered, and concentrated in vacuo. The residue was then loaded onto a silica flash column (50 g column, 10% to 33% ethyl acetate:hexanes), which isolated title compound in 85% yield (237 mg, 0.678 mmol) as a white crystalline solid. 1H NMR (500 MHz, CDCl3) δ ppm: 8.15, 7.33, 7.22, 5.94, 5.35, 5.31, 3.60, 3.04, 2.61, 1.72, 1.58, 1.39, 1.30.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:4].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:9]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])=[O:4]
Reactant: COC(=O)C1C(=O)CCC1CSc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CC1(C(=O)OC)C(=O)CCC1CSc1ccccc1
Yield: 64.2 %

Procedure:
In accordance with the process of Example 22, 2-oxo-5-phenylthiomethylcyclopentanoic acid methyl ester (792 mg; 3 m mol), ethyl bromoacetate (501 mg; 3 m mol) and potassium carbonate (415 mg; 3 m mol) were used to obtain 674 mg of 1-ethoxycarbonylmethyl-2-oxo-5-phenylthiomethyl-cyclopentanecarboxylic acid methyl ester as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:64])[NH:4][CH:5]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:57])[CH:45]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:46]6[CH2:51][CH2:50]O[CH2:48][CH2:47]6)=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=[O:7].C(C(CC)C(NC(OC)=O)C(O)=O)C>>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:20]=[CH:19][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][N:8]6[C:6](=[O:7])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:64])[C:58]6[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=6)=[N:17][CH:16]=5)=[CH:23][CH:22]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:57])[CH:46]([CH2:51][CH3:50])[CH2:47][CH3:48]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C6CCOCC6)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1
Agent: CCC(CC)C(NC(=O)OC)C(=O)O
Product: CCC(CC)C(NC(=O)OC)C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1
Yield: 21 %

Procedure:
This compound was prepared according to the procedure used to prepare {2-[2-(5-{4-[6-(2-{1-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidin-1-yl]-2-oxo-1-phenyl-ethyl}-carbamic acid methyl ester (Example ES) using 3-Ethyl-2-methoxycarbonylamino-pentanoic acid (0.032 g, 0.156 mmol) to give the title compound (0.023, 21% yield) as a white solid. LCMS-ESI+: calc'd for C49H54N8O6: 850.42 (M+); Found: 851.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:10][C:9]2=[O:23])=[CH:4][C:3]=1[NH:24][CH3:25].[CH:26]12[CH2:31][CH:30]1[C:29](=O)[O:28][C:27]2=[O:33].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C1COCC1.CC(O)=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]4[N:1]=[C:29]([CH:30]5[CH2:31][CH:26]5[C:27]([OH:28])=[O:33])[N:24]([CH3:25])[C:3]=4[CH:4]=3)[C:9](=[O:23])[CH:10]=2)=[CH:21][CH:20]=1
Reactant: O=C1OC(=O)C2CC12
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 1-(4-amino-3-(methylamino)phenyl)-4-((4-chlorobenzyl)oxy)pyridin-2(1H)-one (2.0 g), 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.662 g) and triethylamine (1.175 ml) in THF (80 ml) was stirred at room temperature overnight. After concentration of the mixture in vacuo, AcOH (80 ml) was added to the residue. The mixture was stirred at 80° C. for 1 h. After concentration of the mixture in vacuo, the mixture was neutralized with saturated NaHCO3 solution at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with IPE and dried to give the title compound (1.67 g) as a brown solid.