Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.O[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:11][O:10][C:8]([C@@H:5]1[CH2:4][CH2:3][C@H:2]([O:1][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=2)[CH2:7][CH2:6]1)=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(O)cc1
Reactant: COC(=O)[C@H]1CC[C@H](O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Reaction time: 18 h

Procedure:
1.1 g of methyl trans-4-hydroxycyclohexanecarboxylate (6.95 mmol, 1.35 eq.), 1 g of tert-butyl 4-hydroxybenzoate (5.15 mmol, 1 eq.) and 2.03 g of triphenylphosphine (7.72 mmol, 1.5 eq.) are placed in 10 mL of tetrahydrofuran at room temperature. 1.5 mL of diisopropyl azodicarboxylate (7.72 mmol, 1.5 eq.) are added dropwise to the reaction medium with stirring. After 18 hours at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered off. The organic phase is washed with sodium hydroxide solution, dried over sodium sulfate, filtered and evaporated to give a residue. This residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 0% to 50%. 1.23 g of tert-butyl cis-4-(4-methoxycarbonylcyclohexyloxy)-benzoate are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC(CO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
1,1,1-Triacetoxy-1,1-dihydro-1,2-benzoiodoxol-3(1H)-one (1.92 g, 4.53 mmol) was added to a solution of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine (1.00 g, 4.01 mmol) in methylene chloride (20 mL) and the mixture was stirred at rt for 45 min. Ether (75 mL) and 1.3 N aq. NaOH (25 mL) were added and stirring was continued for 15 min. The mixture was transferred to a separatory funnel with additional ether (30 mL) and 1.3 N aq. NaOH (20 mL). The organic layer was separated, washed with saturated aq. brine (20 mL), dried (sodium sulfate), decanted, and evaporated to give 846 mg of 1-(benzyloxycarbonyl)-4-piperidine carboxaldehyde as a colorless syrup.
Reaction SMILES: Br[CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4].CN(C=[O:26])C>O>[OH:26][CH:2]([CH2:20][CH3:21])[C:3]([C:5]1[CH:19]=[CH:18][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: CCC(Br)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Solvent: O
Product: CCC(O)C(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
200 mg (581 μmol) 2-bromo-1-(2-phenyl-benzoxazol-6-yl)-butan-1-one are combined with 1.2 ml DMF and 0.8 ml of water. The mixture is stirred for 3 h at 100° C. and then separated by RP-HPLC.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22]([C:24](O)=[O:25])=[CH:21][C:20]=2[CH:27]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:24]([C:22]2[O:23][C:19]3[CH:18]=[CH:17][C:16]([Cl:15])=[CH:27][C:20]=3[CH:21]=2)=[O:25])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc2cc(Cl)ccc2o1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3cc(Cl)ccc3o2)C1

Procedure:
67.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 5-chloro-benzofuran-2-carboxylic acid to give (R)-3-{[(5-chloro-benzofuran-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS377.3 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:18])[CH:14]=2)[C:9]1=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][OH:21]>>[CH3:20][O:21][C:16](=[O:17])[C:15]1[CH:14]=[C:13]([F:18])[CH:12]=[CH:11][C:10]=1[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C(=O)c2ccc(F)cc2C1=O
Reactant: CO
Product: COC(=O)c1cc(F)ccc1C(=O)NC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 5-fluoro-1,3-dioxo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (4.0 g, 15.08 mmol) in MeOH (20 mL) is refluxed for 1 hour. The reaction mixture is allowed to cool to room temperature and then concentrated under reduced pressure to afford 2-tert-butoxycarbonylaminocarbonyl-5-fluoro-benzoic acid methyl ester plus regioisomer (4.5 g, 100%) as a white solid.
Reaction SMILES: [CH3:1][C:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)=O.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].C(Br)C=C.[I-].[I-].[Sm+2]>>[C-:9]1([C:5]([CH3:6])=[CH:4][CH:2]=[CH2:1])[CH:13]=[CH:12][CH:11]=[CH:10]1.[CH-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[Fe+2:14]
Reactant: CC(=O)[c-]1cccc1
Agent: [Fe+2]
Agent: [I-]
Agent: [Sm+2]
Solvent: C=CCBr
Product: C=CC=C(C)[c-]1cccc1
Yield: 99 %

Procedure:
According to the step flow described in Example 1, about 274 mg (1.20 mmole) of ferrocenyl methyl ketone react with 242 mg (2.0 mmole) of allyl bromide and 1.77 mmole of samarium diiodide in a temperature range of about 0° C. to room temperature to produce an oil-type 1-Ferrocenyl-1-methyl-1,3-butadiene (3b) with a weight of about 302 mg (1.19 mmole) and a yield of about 99%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][CH2:33][CH:34]1[CH2:39][NH:38][CH2:37][CH2:36][NH:35]1>>[OH:32][CH2:33][CH:34]1[NH:35][CH2:36][CH2:37][N:38]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:30]=[CH:31][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:29])[CH2:39]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: OCC1CNCCN1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCNC(CO)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 56.6 %

Procedure:
Following a procedure similar to that described in Preparation 8, but using 10.0 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 4.4 g of N,N'-carbonyldiimidazole and 4.0 g of 2-hydroxymethylpiperazine, 6.9 g of the title compound were obtained, as a powder.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)=[O:16])[NH:4][C:3]1([CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.[C:39]1([N:45]2[C:49](Cl)=[N:48][N:47]=[N:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:1]=[C:2]1[N:6]([CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:49]3[N:45]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:46]=[N:47][N:48]=3)[CH2:10][CH2:9]2)[C:5](=[CH:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=2)=[O:16])[NH:4][C:3]1([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1
Reactant: Clc1nnnn1-c1ccccc1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2CC2CCN(c3nnnn3-c3ccccc3)CC2)cc1
Yield: 4 %

Procedure:
To a solution of the title compound of 40B (100 mg, 0.20 mmol) and (1-phenyl-1H-tetrazol-5-yl chloride (50 mg, 0.30 mmol) in CH3CN (1 ml) was added K2CO3 (0.08 9, 0.06 mmol). The mixture was stirred overnight. After removal of CH3CN, the reaction mixture was partitioned between CH2Cl2 and H2O. After separation, the organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude product was chromatographed on silica gel with MeOH—CHCl3—NH4OH (1:99:0.1) as eluents to afford the title compound as a white solid, 5 mg (0.077 mmol, 4% yield).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13](=[O:18])[NH:12][CH:11]=[CH:10]2.N>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[C:13](=[O:18])[NH:12][CH:11]=[CH:10]2
Reactant: COc1cc2cc[nH]c(=O)c2cc1C
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Product: Cc1cc2c(=O)[nH]ccc2cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.9 %

Procedure:
A 1 M solution of boron tribromide (2.9 ml, 2.91 mmol) was added dropwise to a stirred suspension of 6-methoxy-7-methyl-2H-isoquinolin-1-one (100 mg, 0.53 mmol) in 1 ml of dichloromethane at 0-4° C. (ice bath). After stirring for 1 day at ambient temperature the reaction mixture was poured into ice and the pH was adjusted to 9 by adding concentrated aqueous ammonia. The precipitated material was collected by filtration, washed with water, and dried in vacuo to give 6-Hydroxy-7-methyl-2H-isoquinolin-1-one (51 mg, 55%), El-MS: 176.6 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O>C(O)C.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N)cnc1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h

Procedure:
To a solution of the 3-methyl-5-nitro-2-(4-trifluoromethyl-phenyl)-pyridine (3.5 g, 10.56 mmol) in ethanol (50 mL) is added palladium (10%) on carbon (0.700 g, 20% by wt.). The reaction is charged to 15 psi under a hydrogen atmosphere and allowed to stir for 4 hours. The reaction is diluted with ethyl acetate and Celite is added, followed by water. This mixture is then filtered through a pad of celite. The solution is concentrated, diluted with ethyl acetate, poured into a separatory funnel and the organic layer is washed with water and brine. The organic layer is dried over anhydrous sodium sulfate and concentrated. The product is used directly in the next step (2.74 g, 10.87 mmol).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.O[N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>>[N:22]1([O:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:9]=2)[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: On1cccn1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(CCOn2cccn2)cc1)c1ccccc1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 1-hydroxypyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]#[N:21])=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][NH:21][C:29](=[O:31])[CH3:30])=[CH:16][CH:17]=1)[CH2:6][CH2:5]2
Reactant: N#CCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)NCCCc1ccc(OC2CCc3cc(Cl)ccc32)cc1
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a solution of 4-[(5-chloro-2,3-dihydro-1H-inden-1-yl)oxy]benzenepropanenitrile (0.50 g, 1.7 mmol) in tetrahydrofuran (25 mL) was added lithium aluminum hydride (77 mg, 2.0 mmol) under ice-cooling, and the mixture was stirred in an ice bath for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The obtained oil was dissolved in pyridine (20 mL), acetic anhydride (0.18 mL, 0.95 mmol) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (0.11 g, yield 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[C:13](Cl)(=O)C>CO>[CH3:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C=CC(=O)O)cc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(C)cc1

Procedure:
A solution of 6.0 g (37.0 mmol) of 4-methylcinnamic acid in 120 ml of anhydrous MeOH was treated with 6 ml of acetyl chloride and stirred at reflux for 18 hours. Evaporation of the MeOH gave the title ester as a white solid, mp 53.5°-57.5° C.
Reaction SMILES: [OH-].[Na+].[NH:3]([CH2:5][C:6]([OH:8])=[O:7])[CH3:4].[CH:9]([N:12]=[C:13]=[O:14])([CH3:11])[CH3:10]>O>[CH:9]([NH:12][C:13](=[O:14])[N:3]([CH2:5][C:6]([OH:8])=[O:7])[CH3:4])([CH3:11])[CH3:10]
Reactant: CC(C)N=C=O
Reactant: CNCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(=O)N(C)CC(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4 g of sodium hydroxide in 75 ml of water was added 10 g of sarcosine portionwise. The solution was cooled and treated with 11.5 ml of isopropyl isocyanate. After 2 h, the reaction mixture was washed with diethyl ether and the aqueous phase acidified with concentrated HCl to <pH 2. The product was extracted twice with ethyl acetate to give 10.45 g of a white solid which was taken on to the next step.
Reaction SMILES: O[C:2]1([CH3:13])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:13][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCCc2ccccc21
Yield: 80.2 %

Procedure:
Following the procedure of Example 1, step 2, 26.65 g (0.151 mol) of 5-hydroxy-5-methyl-6,7,8,9-tetrahydro-5H-benzocycloheptene in 300 ml of toluene was reacted with 0.30 g of p-toluenesulphonic acid monohydrate. Vacuum distillation yielded 19.17 g (80%) of the title product as a colourless oil, b.p. 62°-65° C./1.0 mm of Hg. NMR δ(CDCl3) 1.81 (2H, q, J=7.1 Hz), 2.07 (2H, m), 2.09 (3H, s), 2.56 (2H, t, J=6.9 Hz), 6.97 (1H, m), 7.14-7.26 (4H, m).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O.[OH-].[Na+]>ClCCl>[Cl:3][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: ClCCCCCc1ccccn1
Temperature: -5 °C
Reaction time: 17 h

Procedure:
A solution of 4.1 mL of thionyl chloride in 30 mL of dichloromethane was added over 10 minutes to a stirred solution of 6.65 g of 2-pyridinepentanol in 60 mL of dichloromethane maintained at -5° C. After the addition was complete, the mixture was stirred at room temperature for 17 hours, then was rechilled to 5° C. as 150 ml of 1N NaOH was added dropwise over 10 minutes. The layers were separated and the aqueous layer was extracted with 75 mL of dichloromethane. The organic layers were washed with brine, then were combined, dried (K2CO3) and evaporated to yield 7.4 g of 2-(5-chloropentyl)pyridine as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O>[C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1)#[N:2]
Reactant: Brc1ccccn1
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: N#Cc1ccc(Nc2ccccn2)c([N+](=O)[O-])c1
Temperature: 200 °C
Yield: 45.9 %

Procedure:
A mixture of 4-Cyano-2-nitroaniline (10.8 g, 66 mmol), 2-bromopyridine (12.6 g, 80 mmol), anhydrous potassium carbonate (9.12 g, 66 mmol) and copper-bronze (1.0 g, 15.7 mmol) in nitrobenzene (100 ml) was heated overnight at 200° C. The reaction mixture was cooled and filtered through a pad of celite. The filter cake was washed with dichloromethane (500 ml) and the filtrate was evaporated. The resultant residue was purified by column chromatography (silica gel, 500 g; n-hexane/ethyl acetate/dichloromethane (4/1/1)) to afford 7.28 g (46%) of 4-Cyano-2-nitro-N-(2-pyridyl)aniline as orange solids. 1H-NMR (CDCl3) δ: 10.53 (1H, br.s), 9.08 (1H, d, J=8.8 Hz), 8.58 (1H, d, J=8.8 Hz), 8.41 (1H, ddd, J=5.8, 1.8, 0.7 Hz), 7.78-7.69 (2H, m), 7.12-7.06 (1H, m), 7.02 (1H, d, J=8.8 Hz).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:16](OC)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[SH:19].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:24]=[C:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[S:19][C:1]([C:3]2[N:8]=[C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)c1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 72.1 %

Procedure:
A mixture of tert-butyl 6-cyano-2-pyridinecarboxylate (1.1 g, 5.3 mmol), methyl thiosalicylate (1.8 g, 10.7 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 12 hrs. After cooling, the precipitated crystals were collected by filtration, recrystallized from tetrahydrofuran-hexane to give the titled compound (1.3 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=C([N+]([O-])=O)C=C[C:3]=1N.C(NC1C=CC=CC=1)=O.[NH2:21][C:22]1([C:28]([OH:30])=O)[CH2:27][CH2:26][CH2:25][O:24][CH2:23]1.NC1(C(OC)=O)CCCOC1.NC1(CO)CCCOC1.OCCN.C(=O)C(C)C>>[CH:2]([CH:8]1[O:30][CH2:28][C:22]2([CH2:27][CH2:26][CH2:25][O:24][CH2:23]2)[NH:21]1)([CH3:3])[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: NC1(C(=O)O)CCCOC1
Agent: CC(C)C=O
Agent: COC(=O)C1(N)CCCOC1
Agent: NC1(CO)CCCOC1
Solvent: NCCO
Product: CC(C)C1NC2(CCCOC2)CO1

Procedure:
2-Methyl-4-nitroaniline was converted to the 2-methyl-4-nitroformanilide according to Method A3a, Step 1. The formanilide was converted to 2-methyl-4-nitrophenyl isocyanide dichloride according to Method A3a, Step 2. 3-Aminotetrahydro-2H-pyran-3-carboxylic acid was converted to the methyl ester according to Method B1b, Step 1. Methyl 3-aminotetrahydro-2H-pyran-3-carboxylate was reduced to 3-amino-3-(hydroxymethyl)tetrahydro-2H-pyran according to Method B1b, Step 2. The 2-hydroxyethylamine was reacted with isobutyraldehyde according to Method B4c, Step 1 to afford 2-isopropyl-1-aza-3,7-dioxaspiro[4.5]decane. The oxazolidine was reduced to 3-isobutylamino-3-(hydroxymethyl)tetrahydro-2H-pyran. The substituted 2-hydroxyethylamine was converted to 3-isobutylamino-3-(acetylthiomethyl)tetrahydro-2H-pyran according to Method C6c, Step 1. The thioacetate was saponified according to Method C6c, Step 2 to give 3-isobutylamino-3-(thiomethyl)tetrahydro-2H-pyran. The 2-thioethylamine was reacted with 2-methyl-4-nitrophenyl isocyanide dichloride to afford 2-(2-methyl-4-nitrophenylimino-1-isobutyl-1-aza-7-oxa-3-thiaspiro[4.5]decane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][OH:29]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:28][OH:29])=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: OC[C@@H]1CCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)N1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To 2-chlorobenzoic acid (10 g; 63.9 mmol) in dimethylformamide (100 ml) under nitrogen was added carbonyldiimidazole (10.9 g; 67.1 mmol) and the solution stirred for 1 h at room temperature. (S)-(+)-2-pyrrolidinemethanol (7.56 ml, 76.6 mmol) was added and the mixture stirred at 40° C. for 18 h. The solvent was removed under reduced pressure and the crude product purified by chromatography on silica (eluting with 50% to 75% ethyl acetate in heptane) to afford (S)-1-(2-chlorobenzoyl)-2-pyrrolidinemethanol (10.2 g), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC(c1cccnc1)N1CCOCC1
Product: Cc1cccc(C(=O)NCC(c2cccnc2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-3-ylethyl)amine.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[CH2:21]([N:23]([CH2:39][CH3:40])[C:24](=[O:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][N:32]1[C:36]([I:37])=[CH:35][N:34]=[CH:33]1)[CH3:22].[CH3:41][C:42]([CH3:44])=[O:43]>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)C>[CH2:39]([N:23]([CH2:21][CH3:22])[C:24](=[O:38])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]([N:32]1[C:36]([I:37])=[CH:35][N:34]=[CH:33]1)[C:42]([OH:43])([CH3:44])[CH3:41])[CH3:40]
Reactant: CC(C)=O
Reactant: CCN(CC)C(=O)c1ccccc1Cn1cncc1I
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccccc1C(n1cncc1I)C(C)(C)O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (0.97 g, 6.39 mmol) in THF (50 mL) at −78° C. under nitrogen is added n-BuLi (2.5M in hexanes, 3.8 mL, 9.6 mmol) and the mixture is warmed to 0° C. After 15 min, the LDA solution is cooled to −78° C. and a solution of N,N-diethyl-2-(5-iodo-imidazol-1-ylmethyl)-benzamide (2.45 g, 6.39 mmol) (example 1b) in THF (5 mL) is added over 15 min. 30 min after the end of addition, acetone (1.86 g, 31.97 mmol) in THF (5 mL) is added to the brown solution and the mixture is stirred for 1 h, whereupon 10% acetic acid in water is added. The mixture is poured in ethyl acetate and the two phases are separated. The organic phase is washed with saturated aqueous sodium bicarbonate. The combined aqueous phase is extracted twice with ethyl acetate. The combined organic phase is dried over MgSO4, filtered through a cotton plug and concentrated in vacuo. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 49:1 to 97:3 to 24:1) to afford U-4478-116 (1.65 g) as a yellow solid; MS (ESI) m/z 442.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9]Cl)=[CH:4][N:3]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18][C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[CH2:9]1)(=[O:13])[CH3:12]
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: ClCc1cnc(Cl)nc1Cl
Product: CC(=O)N1Cc2cnc(Cl)nc2C=Cc2ccccc21
Yield: 46 %

Procedure:
Compound 64B (66.1 mg, 46%) was prepared from 64A (0.10 g, 0.5 mmol) and bb (82 mg, 0.5 mmol) in two steps by a route analogous to that used for the preparation of 1D. HPLC Rt=2.286 min; LCMS Found: (M+H)+=286.