Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([C:19](=[O:43])[N:20]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)[CH:21]([C:23]1[NH:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[CH3:22])[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([OH:17])=[CH:12][C:11]=1[CH3:18])([CH3:4])([CH3:3])[CH3:2].[OH:45]O.[OH-].[Na+]>CCO>[C:1]([O:5][C:6](=[O:44])[NH:7][CH:8]([C:19](=[O:43])[N:20]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41](=[O:45])[NH2:42])[CH:36]=1)[CH:21]([C:23]1[NH:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:27]=1)[CH3:22])[CH2:9][C:10]1[C:11]([CH3:18])=[CH:12][C:13]([OH:17])=[CH:14][C:15]=1[CH3:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: OO
Reactant: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(Cc1cccc(C#N)c1)C(C)c1nc(-c2ccccc2)c[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)cc(C)c1CC(NC(=O)OC(C)(C)C)C(=O)N(Cc1cccc(C(N)=O)c1)C(C)c1nc(-c2ccccc2)c[nH]1
Temperature: 7.5 °C
Reaction time: 18 h

Procedure:
A solution of [1-{(3-cyano-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.070 g, 0.12 mmol) in 3 mL of EtOH was treated with 1.0 mL of 30% hydrogen peroxide followed immediately by 0.1 mL of a 6M aqueous solution of NaOH. The reaction mixture was stirred vigorously for 18 h and quenched by pouring into chilled (5-10° C.) water. The aqueous solution was extracted five times with Et2O and the combined extracts were dried over MgSO4, filtered, and concentrated to provide 0.051 g of [1-{(3-carbamoyl-benzyl)-[1-(4-phenyl-1H-imidazol-2-yl)-ethyl]-carbamoyl}-2-(4-hydroxy-2,6-dimethyl-phenyl)-ethyl]-carbamic acid tert-butyl ester as a colorless residue (HPLC: 84% @ 254 nm and 77% @ 214 nm). MS (ES+) (relative intensity): 612.5 (100) (M+1). This sample was of sufficient quality to use in the next reaction without further purification.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([OH:19])=[O:18].Cl>C(O)CC(C)C>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:16][C:17]([O:19][CH2:11][CH2:1][CH:2]([CH3:16])[CH3:3])=[O:18]
Reactant: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Agent: Cl
Solvent: CC(C)CCO
Product: CC(C)CCOC(=O)Cc1ccc2c(c1)CCc1ccccc1S2
Reaction time: 1.5 h

Procedure:
A solution of 250 mg. of 10,11-dihydrodibenzo[b.f]thiepin-2-acetic acid in 30 ml. of isoamyl alcohol is saturated with hydrogen chloride. After 90 minutes, the excess alcohol is distilled off under reduced pressure to yield isoamyl 10,11-dihydrodibenzo[b.f]thiepin-2-acetate, which can be further purified by thin layer chromatography.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[C:9]1=[O:18].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[S:19]1[CH:23]=[CH:22][C:21]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])=[CH:20]1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: OB(O)c1ccsc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(=O)N(c2ccsc2)c2ccccc21
Reaction time: 8 h
Yield: 4.7 %

Procedure:
Triethylamine (56.9 mL, 0.408 mol), was added to a mixture of 1H-indole-2,3-dione (15.0 g, 0.102 mol), copper (II) acetate (46.0 g, 0.255 mol), and 3-thienylboronic acid (19.6 g, 0.153 mol) in CH2Cl2 (500 mL). The reaction mixture was stirred overnight, filtered through Celite, rinsed with EtOAc/hexane (1:1, 300 mL), and concentrated in vacuo. The crude product was purified by column chromatography on silica using Hexane/EtOAc (1:1), giving the desired product (1.1 g, 50%)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: COc1cccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3n2)c1
Yield: 99.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.004 mL (0.058 mMol) 3-methoxybenzoyl chloride, 0.016 gm (98%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])=[CH:10][C:5]=2[CH2:4][O:3]1>C(O)(C(F)(F)F)=O>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([OH:14])=[O:13])=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(c1)COC2=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetate (1.2 g, 4.8 mmol) was dissolved in TFA and stirred at room temperature for one h. The reaction mixture was concentrated and pumped under vacuum overnight to afford the title compound. LC-MS (IE, m/z): 193.2 [M+1]+.
Reaction SMILES: CO[N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[C:7]([OH:14])[CH:6]=1.C(=O)=O.[ClH:18].[H][H]>C(O)C.O1CCCC1.[Pd]>[ClH:18].[ClH:18].[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH2:3])=[CH:6][C:7]=1[OH:14]
Reactant: [H][H]
Reactant: CON=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: NCc1ccc(N)c(O)c1
Yield: 97 %

Procedure:
A solution of 3-hydroxy-4-nitrobenzaldehyde O-methyloxime (5.9 g, 30 mmol) in ethanol (100 mL) and tetrahydrofuran (100 mL) is degassed with solid carbon dioxide, then charged with 10% palladium on carbon (500 mg) and concentrated hydrochloric acid (5.5 mL). The mixture is shaken under 50 psi hydrogen gas until consumption of hydrogen had ceased. The mixture is then filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure to give 2-amino-5-(aminomethyl)phenol dihydrochloride (6.1 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][CH:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (1.0 g, 3.77 mmol) was treated with 4-amino-piperidine-1-carboxylic acid tert-butyl ester following general procedure B to afford 4-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (1.48 g). Thus obtained amino-ester (500 mg, 1.17 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish 4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg). LCMS: m/z 537 [M+1]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.[O:34]1[C:38]2([CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH2:37][NH:36][C:35]1=[O:44].CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:41]3[CH2:40][CH2:39][C:38]4([O:34][C:35](=[O:44])[NH:36][CH2:37]4)[CH2:43][CH2:42]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:20]
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: O=C1NCC2(CCNCC2)O1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(-c3ncc(CN4CCC5(CC4)CNC(=O)O5)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), 1-oxa-3,8-diazaspiro[4.5]decan-2-one (110 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (82 mg, yield 43%) as colorless crystals from a fraction eluted with ethyl acetate. melting point 224° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][N:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=1
Reactant: Cc1sc2nc(-c3cnccn3)nc(Cl)c2c1Cl
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: Cc1sc2nc(-c3cnccn3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyrazin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[Cl:24])[C:6]=2[CH:11]=1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
A mixture of Example 1 (1.17 g) (prepared as described previously described), 1-(bromomethyl)-2,3-dichlorobenzene (1.19 g) and K2CO3 (1.27 g) in DMF (80 mL) was stirred at 80° C. for 3 h. When TLC showed no starting material, the mixture was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (1.59 g, 83%) 1H NMR (300 MHz, CDCl3) δ ppm 2.67 (s, 3H), 5.45 (m, 2H), 6.24 (t, 1H, J=7.8 Hz), 7.10 (t, 1H, J=7.8 Hz), 7.47 (t, 1H, J=7.8 Hz), 7.59 (d, 1H, J=1.8 Hz), 8.24 (d, 1H, J=1.8 Hz); LC-MS: m/e=416 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]2[CH2:6][CH:5]([C:13](O)=[O:14])[CH2:4][C:3]1=2.[CH3:17][Li]>O1CCCC1>[CH3:17][C:13]([CH:5]1[CH2:4][C:3]2[C:2]([CH3:16])([CH3:1])[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7]=2[CH2:6]1)=[O:14]
Reactant: [Li]C
Reactant: CC1(C)CCC(C)(C)C2=C1CC(C(=O)O)C2
Solvent: C1CCOC1
Product: CC(=O)C1CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
7.3 g of 4,5,6,7-tetrahydro-4,4,7,7-tetramethyl-2-indanecarboxylic acid are dissolved in 150 ml of tetrahydrofuran and treated slowly while cooling with ice and stirring vigorously with 47.3 ml of methyl lithium (1.6 molar in ether). After stirring for 3 hours at room temperature, the mixture is poured on to ice, extracted with ether, washed with water, dried over sodium sulphate and evaporated. After distillation of the crude product, there are obtained 5.6 g of 2,2,5,5-tetramethyl-bicyclo[4.3.0]non-1(6)-en-8-yl methyl ketone as a colourless liquid of boiling point 53°-60° C./0.01 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][C:5]=1[CH2:19][NH:20][CH2:21][CH2:22][CH3:23])([O-])=O.S1C=CC=C1.O=[Si]=O>CO.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[CH:6][C:5]=1[CH2:19][NH:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=[Si]=O
Solvent: CO
Solvent: c1ccsc1
Product: CCCNCc1cc(Oc2cccc(C#N)c2)ccc1N

Procedure:
A mixture of 3-(4-nitro-3-propylaminomethyl-phenoxy)-benzonitrile (0.045 mol) in methanol (250 ml) was hydrogenated with 10% Pd/C (2 g) as a catalyst in the presence of thiophene solution (2 ml). After uptake of H2 (3 equiv.), the reaction mixture was filtered over dicalite and the filtrate was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The purest product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:28]([O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:34]=[CH:33][C:32]([O:31][C:28](=[O:30])[CH3:29])=[CH:39][CH:38]=5)[C:20]([C:24]#[N:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Br)ccc21
Reactant: CC(=O)Oc1ccc(CBr)cc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C#N)c4Cc3ccc(OC(C)=O)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-cyano-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-acetoxy-benzyl bromide following a procedure analogous to that described for Intermediate 7.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:14]([CH3:31])=[C:13]([CH3:32])[N:12]=1.O>COCCOCCOC>[CH3:32][C:13]1[C:14]([CH3:31])=[C:15]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:16]([N+:17]([O-:19])=[O:18])=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:12]=1
Reactant: Oc1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCNC(=O)OC(C)(C)C)c1C
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Phenol (1.19 g, 12.6 mmol) was added in portions to a chilled (0° C.) suspension of sodium hydride (0.52 g of 60%, 13.1 mmol) in diglyme (4 mL). The reaction mixture was then stirred for 30 minutes. A warm solution of tert-butyl 2-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]ethylcarbamate (3.0 g, 8.70 mmol) in diglyme (6 mL) was added and the reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled and poured slowly into water (100 mL). The resulting tan solid was isolated by filtration, washed with water, dried and then recrystallized from isopropanol (25 mL) to provide 2.07 g of tert-butyl 2-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]ethylcarbamate as white needles. The reaction was repeated using 66.5 g of starting material to provide 50.4 g of product as white needles, m.p. 158-160° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([OH:14])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1.C([O-])([O-])=O.[K+].[K+].[CH2:27](Br)[CH:28]=[CH2:29]>CC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:14][CH2:29][CH:28]=[CH2:27])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: C=CCBr
Reactant: CCOC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Yield: 90.3 %

Procedure:
A mixture of 6.06 g (0.02 mol) of product of Example 3, 2.8 g (0.02 mol) of K2CO3, 30 g of allyl bromide, and 50 ml of acetone was held at reflux for 4 hours and concentrated. The residue was treated with water and extracted into ether. The ether solution was dried and concentrated. The residue was kugelrohr distilled at 133 Pa (pot temperature 110° C.) to give 6.2 g (90%) of product, nD25 1.4330.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To an ice cold solution of ethyl isonipecotate (60 g, 0.382 mol) and triethylamine (38.65 g, 0.382 mol) in tetrahydrofuran (360 ml) was added dropwise benzoyl chloride (53.7 g, 0.382 mol) over a period of about 2 hours under nitrogen atmosphere. The reaction mixture was stirred for about 2 hours at the same temperature, and was filtered. The filtrate was evaporated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over magnesium sulfate, and evaporated in vacuo. Crystallization from isopropyl alcohol gave the titled compound (90.9 g).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(CCC2C=CC(O)=CC=2)C=1.Cl.ClCCN1CCCCC1.C[O:41][C:42]1[CH:43]=[CH:44][C:45]([CH:65]2[CH2:74][CH2:73][C:72]3[C:67](=[CH:68][CH:69]=[C:70]([O:75]C)[CH:71]=3)[CH2:66]2)=[C:46]([CH2:48][CH2:49][C:50]2[CH:64]=[CH:63][C:53]([O:54][CH2:55][CH2:56][N:57]3[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[CH:52][CH:51]=2)[CH:47]=1>>[OH:41][C:42]1[CH:43]=[CH:44][C:45]([CH:65]2[CH2:74][CH2:73][C:72]3[CH:71]=[C:70]([OH:75])[CH:69]=[CH:68][C:67]=3[CH2:66]2)=[C:46]([CH2:48][CH2:49][C:50]2[CH:64]=[CH:63][C:53]([O:54][CH2:55][CH2:56][N:57]3[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]3)=[CH:52][CH:51]=2)[CH:47]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(OCCN3CCCCC3)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CCc1ccc(O)cc1)C2
Agent: Cl
Agent: ClCCN1CCCCC1
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1CCc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 73.6 %

Procedure:
Synthesized from 4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenol and 1-(2-chloroethyl)piperidine hydrochloride according to an analogous synthetic method to Preparation Example 40, 1-{2-{4-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]ethyl}phenoxy}ethyl}piperidine (167 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (116 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([NH:23][CH:24]2[CH:28]([O:29]CC3C=CC=CC=3)[O:27][C:26](=[O:37])[CH2:25]2)=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CN(C)C=O.CO.[OH-].[OH-].[Pd+2]>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:21]([NH:23][CH:24]([CH:28]=[O:29])[CH2:25][C:26]([OH:37])=[O:27])=[O:22])[CH3:20])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)[C@H](NC(=O)CCc1ccccc1)C(=O)N[C@@H](C)C(=O)NC(C=O)CC(=O)O
Reaction time: 3 h
Yield: 72.4 %

Procedure:
To a solution of 188 mg of N-(3-phenylpropionyl-valinyl-alaninyl)-4-amino-5-benzyloxy-2-oxo-tetrahydrofuran in 2 mL of dimethylformamide and 3 mL of methanol was added ~100 mg of Pd(OH)2 on carbon. After the mixture had been stirred vigorously under hydrogen for 3 hours, the mixture was filtered through a 0.22 μm nylon membrane filter and concentrated. The residue was purified by MPLC on silica-gel (22×300 mm column, eluted with a gradient of dichloromethane to 8% formic acid and 32% methanol in dichloromethane) to afford 112 mg of the title compound as a colorless solid: 1H NMR (400 MHz, CD3OD (1:1 mixture of diastereomeric hemiacetals in this solvent)) δ7.3-7.1 (m, 5H, Ar--H), 4.58 (d, 0.5H, J=4.06 Hz, CH(OH)(OCD3)), 4.56 (d, 0.5H, J=3.96 Hz, CH(OH)(OCD3)), 4.34 (m, 1H, CHN), 4.24 (m, 1H, CHN), 4.02 (d, 1H, J=7.38 Hz, CHN), 2.91 (t, 2H, J=7.61Hz, CH2CON), 2.7-2.4 (m, 4H, CH2Ph, CH2CO2), 2.00 (m, 1H, CH(CH3)2), 1.32 (d, 3H, J=7.10 Hz, CHCH3), 0.88 (d, 3H, J=6.82 Hz, CH(CH3)2), 0.85 (d, 3H, J=6.83 Hz, CH(CH3)2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:14][C:12]([CH3:15])([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Yield: 95.4 %

Procedure:
To a solution of 4-bromobenzoyl chloride (25.08 g, 114 mmol) in THF (120 mL) at ±78° C. was added potassium tert-butoxide (120 mL, 1 M in THF, 120 mmol). The reaction mixture was warmed from −78° C. to room temperature over 2 h, and diluted with diethyl ether. The organic phase was washed with saturated NaHCO3 (2×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% ethyl acetate in hexanes) gave tert-butyl 4-bromobenzoate (27.96 g, 95%) as a colorless oil: 1H NMR (600 MHz, CDCl3) δ 7.84 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 1.59 (s, 9H); ESIMS calcd 257.0 (M++H), found 257.1 (M++H).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:20](=[O:21])[C:16]3([CH2:19][CH2:18][CH2:17]3)[N:15]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=O)=[CH:24][CH:23]=3)[C:14]2=[S:32])=[CH:9][C:8]=1[C:33]([F:36])([F:35])[F:34])#[N:6].[CH3:37][NH2:38]>C1COCC1>[CH3:37][NH:38][C:29](=[O:31])[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([N:15]2[C:14](=[S:32])[N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]#[N:6])=[C:8]([C:33]([F:35])([F:36])[F:34])[CH:9]=3)[C:20](=[O:21])[C:16]32[CH2:19][CH2:18][CH2:17]3)=[CH:27][CH:26]=1
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CN
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CNC(=O)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Thionyl chloride (0.238 g, 2 mmol) was added dropwise to a mixture of {4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetic acid (46c) (0.357 g, 0.777 mmol) in THF (5 ml) cooled to 0° C. The mixture was stirred for 1 hour at room temperature and then methylamine (0.5 ml) was added into the mixture. The mixture was stirred for an additional 2 hours. The medium was filtered and the filtrate was concentrated and chromatographed (dichloromethane:acetone, 80:20) to yield N-methyl-2-{4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diaza-spiro[3.4]oct-5-yl]phenyl}acetamide (46e) [RD149] (0.348 g, 0.738 mmol, 95%), the structure of which is illustrated in Formula 18, as an off-white powder.