Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([OH:26])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([N:8]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]([O:26][CH3:27])[C:14]([CH2:23][CH:24]=[CH2:25])=[CH:15][C:16]=2[O:20][CH2:21][CH3:22])[S:9]1(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCc1cc(OCC)c2c(c1O)S(=O)(=O)N(Cc1ccccc1)C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C=CCc1cc(OCC)c2c(c1OC)S(=O)(=O)N(Cc1ccccc1)C2=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 2-benzyl-4-ethoxy-6-allyl-7-hydroxysaccharin (2.45 g), potassium carbonate (2.76 g) and methyl iodide (1.84 g) in acetone was heated at 50° C. with stirring for two hours, then poured with stirring into ice-water (500 mL). The resulting gooey precipitate crystallized overnight affording 2-benzyl-4-ethoxy-6-allyl-7-methoxysaccharin, 2.35 g, 92% yield, mp 92°-94° C.
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:21])=[C:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5]1.[OH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[OH:35][C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[OH:22])[CH2:30][CH2:31][N:32]([CH2:6][CH2:7][C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([N:3]([CH3:2])[CH3:21])=[O:5])[CH2:33][CH2:34]1
Reactant: C[N+](C)=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1C1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(CCN1CCC(O)(c2ccccc2O)CC1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
In 20 mL of anhydrous dimethylformamide were dissolved 3.5 g (10 mmol) of dimethyl(tetrahydro-3,3-diphenyl-2-furylidene)ammonium bromide and 1.93 g (10 mmol) of 4-(2-hydroxyphenyl)-4-piperidinol. To the resulting solution was added 3.2 g (30 mmol) of sodium carbonate, followed by stirring at 80° C. for 1.5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent and the residue thus obtained was dissolved in ethyl acetate. The resulting solution was washed with water and dried. The residue obtained by concentrating the solvent under reduced pressure was purified by chromatography on a silica gel column, whereby 3.6 g (yield: 78.6%) of 4-(4-hydroxy-4-(2-hydroxyphenyl)piperidino)-N,N-dimethyl-2,2-diphenylbutaneamide (Compound No. 1) was obtained.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1>C1COCC1.Cl>[N:11]1([CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1ncn(C2CCC3(CC2)OCCO3)n1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(n2cncn2)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
1-(1,4-Dioxa-spiro[4.5]dec-8-yl)-1H-[1,2,4]triazole (379 mg, 1.81 mmol) is dissolved in a 1:1 mixture of THF and 3N HCl aqueous solution (9 mL). The resulting mixture is stirred at 40° C. for 5 h. Most of the THF is removed under vacuum then the remaining mixture is neutralized using a 3N NaOH aqueous solution until a basic pH is reached. It is extracted with 3 portions of 10 mL of dichloromethane. The organic portions are combined, dried over anhydrous Na2SO4 and concentrated to afford 4-[1,2,4]triazol-1-yl-cyclohexanone as a white waxy solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([N:20]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[C:11]=1[CH3:19])=O)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C@H:5]1[CH2:6][CH2:7][C@@H:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[C:11]=2[CH3:19])[NH:20]1)=[O:34])[CH3:2]
Reactant: CCOC(=O)C(CCC(=O)c1ccc(OC)c(C)c1C)N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@@H](c2ccc(OC)c(C)c2C)N1
Reaction time: 18 h

Procedure:
A solution of 2-(benzhydrylideneamino)-5-(4-methoxy-2,3-dimethylphenyl)-5-oxopentanoic acid ethyl ester (16.56 mmol) in EtOH (80 mL) containing 10% Pd/C (760 mg) is stirred under an atmosphere of H2 (double-stuffed balloon) for 18 h. The reaction mixture is then filtered through of pad of Celite using MeOH for the rinse. The filtrated is concentrated in vacuo to a nearly colorless syrup, which is used in the next reaction without further purification. 1H NMR (CDCl3, 400 MHz): 7.46 (d, J=8.6 Hz, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.40 (dd, J=8.8, 6.6 Hz, 1H), 4.23 (q, J=8.8 Hz, 2H), 3.90 (dd, J=8.6, 5.4 Hz, 1H), 3.82 (s, 3H), 2.29 (s, 3H), 2.19 (s, 3H), 2.25-2.05 (m, 4H), 1.72-1.65 (m, 1H), 1.31 (t, J=8.8 Hz, 3H). Electrospray MS: m/z 278 [M+1].
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:14]2[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(Oc2cccc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 40.7 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 3-nitrophenol (1.67 g) and potassium carbonate (1.80 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 24 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 3-(4-methylpyridin-2-yloxy)-nitrobenzene (935 mg).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([F:25])=[C:11]([C:16]3[C:17]([C:23]#[N:24])=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:12]([F:15])=[CH:13][CH:14]=2)O1.Br[C:28]1[N:32]2[N:33]=[CH:34][C:35]([C:37]([F:40])([CH3:39])[CH3:38])=[N:36][C:31]2=[N:30][CH:29]=1>>[F:40][C:37]([C:35]1[CH:34]=[N:33][N:32]2[C:28]([C:9]3[C:10]([F:25])=[C:11]([C:16]4[C:17]([C:23]#[N:24])=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[C:12]([F:15])=[CH:13][CH:14]=3)=[CH:29][N:30]=[C:31]2[N:36]=1)([CH3:39])[CH3:38]
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2F)OC1(C)C
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2n1
Yield: 38 %

Procedure:
3′-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,2′,6′-trifluorobiphenyl-2-carbonitrile was reacted with 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine by a similar procedure to that described in Example 2, step e, to give the title compound in 38% yield as a yellow solid: mp 166-169° C. (EtOAc-isohexane); 1H NMR (360 MHz, CDCl3) δ 1.85 (6H, d, J 22.1); 7.25 (1H, td, J 8.6, 1.4), 7.46 (1H, td, J 8.6, 2.7), 7.54–7.59 (2H, m), 8.30 (1H, dt, J 8.3, 6.2), 8.35 (1H, d, J 3.0), 8.80 (1H, d, J 1.2); MS (ES+) m/z 412 [M+H]+. Anal. Found: C, 61.34; H, 3.29; N, 16.72%. Required for C21H13F4N5.0.05C4H8O2: C, 61.24; H, 3.25; N, 16.84%.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=O>COCCOC.C(OCC)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:23][CH3:24])=[C:19]([CH:22]=1)[CH:20]=[C:5]1[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]1=[O:7]
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: CCc1ccc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: CCc1ccc(Br)cc1C=C1C(=O)C(C)(C)OC1(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethyl-3(2H)-furanone (13.4 g, 94.34 mmol) in anhydrous 1,2-dimethoxyethane (32 ml) is added sodium methoxide (5.6 g, 103.8 mmol) in one portion, and the reaction mixture is stirred at this temperature for 5 minutes. To the resulting slurry is then added a solution of 5-bromo-2-ethyl-benzaldehyde (20 g, 94.34 mmol) in 1,2-dimethoxyethane (32 ml) dropwise over 10 minutes. The solution is next stirred at 0° C. for 1 hour, then diluted with diethyl ether and washed with 2M hydrochloric acid (×2). Organic fractions are combined, dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to afford 4-(5-bromo-2-ethylbenzylidene)-2,2,5,5-tetramethyldihydrofuran-3-one (30.2 g) as a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH2:11]([N:13](CC)[CH2:14]C)C.CNC.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:13]([CH3:14])[CH3:11])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccnc1Br
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C)C(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
In DMF (20 mL) was dissolved 2-bromonicotinic acid (2.00 g, 9.90 mmol). To this were added triethylamine (4.14 mL, 29.7 mmol), dimethylamine (2 mol/L solution in THF, 9.90 mL, 19.8 mmol), 1-hydroxybenzotriazole monohydrate (2.27 g, 14.85 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.85 g, 14.85 mmol), and the mixture was stirred at room temperature for 12 hours. A saturated aqueous ammonium chloride solution was added to the mixture and extraction with ethyl acetate was performed. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated from the filtrate under-reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give compound DA1 (1.40 g, 60% yield).
Reaction SMILES: [CH:1]1([N:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:13]([O:15]C(C2C=CC([N+]([O-])=O)=CC=2)C)=O)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:45][NH:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64]>CN(C)C=O>[CH:1]1([N:12]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:13]([N:46]([CH3:45])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[O:15])[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: CCCCCCCCCCCCN(C(=O)OC(C)c1ccc([N+](=O)[O-])cc1)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CCCCCCCCCCCCCCCCCCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(C)C(=O)N(CCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 50 °C

Procedure:
3.1 g of the compound of Example 47 are dissolved in 50 ml of dimethylformamide and treated with 5.0 g of potassium carbonate. 1.8 g of N-methyloctadecylamine are added and the mixture is heated to 50° C. After the reaction has ended, the mixture is cooled to room temperature and filtered, the filtrate is evaporated in vacuo and the residue is purified by column chromatography (eluent toluene/isopropanol 10:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][N:16]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH:10]([CH2:15][NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)C(CN)C1

Procedure:
To a stirred solution of 3-azidomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.624 mmol, 0.16 g) in ethyl acetate (5 mL) was added 10% palladium on carbon (0.1 g, wet). The resultant reaction mixture was subjected to hydrogenation using a balloon full of hydrogen for 4 h. The catalyst was filtered through a pad of celite and the filtrate was concentrated to provide 3-aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.C[C:37]([CH3:39])=[O:38]>>[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:21][CH:20]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH3:39][C:37]([OH:17])=[O:38]
Reactant: CC(C)=O
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Product: CC(=O)O
Temperature: 47.5 °C

Procedure:
Bazedoxifene free base (2 g) and acetone (20 mL) are mixed and heated to 45-50° C. to produce a clear solution, which is filtered. The filtrate is cooled to 25-35° C. and seed crystals (20 mg) are added, followed by drop-wise addition of acetic acid (0.26 g). n-Heptane (50 mL) is added drop-wise over 30 minutes. The formed solid is collected by filtration, sequentially washed with n-heptane (10 mL), and then suction dried for 5 minutes. The wet solid is dried under vacuum at 70° C. for about 4-5 hours to afford 1.5 g of crystalline bazedoxifene acetate Form D.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12].[OH-].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O>CC(C)=O.C1(C(SC(C2C=CC=CC=2)C=C(C)C)C=C(C)C)C=CC=CC=1.C1C=CC=CC=1>[CH3:12][C:11]1([CH3:13])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[S:7][CH2:9][CH2:10]1
Reactant: Sc1ccccc1
Reactant: CC(C)=CCBr
Agent: CC(C)=CC(SC(C=C(C)C)c1ccccc1)c1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CC1(C)CCSc2ccccc21

Procedure:
Thiophenol (1) and 1-bromo-3-methyl-2-butene (2) are heated at reflux with sodium hydroxide in acetone resulting in phenyl-3-methylbut-2-enylsulfide (3). The phenyl-3-methylbut-2-enyl sulfide (3) is cyclized by refluxing with phosphorus pentoxide and phosphoric acid in benzene to yield 4,4-dimethylthiochroman (4). The 4,4-dimethylthiochroman (4) is reacted with acetyl chloride catalyzed by tin (IV) chloride (SnCl4) in benzene resulting in 4,4-dimethyl-6-acetylthiochroman (5). The 4,4-dimethyl-6-acetylthiochroman (5) is dehydrated with lithium diisopropylamide (LDA) and diethyl chlorophosphate in tetrahydrofuran (THF) results in the initial 6-ethenyl phosphonate intermediate (6). This intermediate undergoes further reaction with two equivalents of LDA to give 4,4-dimethyl-6-ethynylthiochroman (II).
Reaction SMILES: [Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
1,1-Dimethylethyl 4-(5-bromo-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidinecarboxylate (D36) (1.32 mmol, 541 mg) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (5 mL) added and the mixture stirred under argon at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, Na2CO3 (10% aqueous solution) added and the product extracted with ethyl acetate (×3). The organic layers were combined, dried (MgSO4) and the solvent removed under reduced pressure to afford the product as a yellow solid (1.16 mmol, 359 mg, 88%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][CH2:21]O)[N:19]=2)=[CH:11][CH:10]=1.Cl.[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>>[CH3:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:21][CH2:20][C:18]1[N:19]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][CH:13]=2)[O:16][CH:17]=1
Reactant: C[C@@H]1CCCN1
Reactant: OCCc1coc(-c2ccc(OCc3ccccn3)cc2)n1
Agent: Cl
Product: C[C@@H]1CCCN1CCc1coc(-c2ccc(OCc3ccccn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Example 53 from 2-{2-[4-(Pyridin-2-ylmethoxy)-phenyl]-oxazol-4-yl}-ethanol (See Intermediate 66) and (R)-2-methylpyrrolidine hydrochloride [CAS 41720-98-3]. MS (m/e): 364.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[N:12]O)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H][H]>O1CCCC1.CO.[Ni]>[CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH2:12])[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1cccc2c1C(=NO)CO2
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c1C(N)CO2
Yield: 96.5 %

Procedure:
A mixture of the above described 4-methoxy-benzofuran-3-one oxime (27.7 g, 155 mmol; HPLC 1.448 min) and Raney-Nickel (13.85 g) in tetrahydrofuran (700 mL) and methanol (700 mL) was hydrogenated at 100 bar hydrogen-pressure at 100° C. for 22 h. Filtered the catalyst off, washed with methanol and tetrahydrofuran, all volatiles very removed in vacuum to give the title compound as a brown oil (24.7 g, 98%, HPLC 0.4 min), MS (ISP) m/e=166.2 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[S:20][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2].N1(O)[C:25]2C=CC=C[C:24]=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.C(=O)(O)[O-].[NH4+]>CN(C)C=O.C(#N)C.O>[CH2:1]([C:3]1[S:20][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:24][CH3:25])=[O:18])[CH2:13][CH2:12]3)[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(N3CCC(C(=O)O)CC3)ncnc2s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C1CCN(c2ncnc3sc(CC)cc23)CC1
Temperature: 30 °C
Reaction time: 12 h
Yield: 16.1 %

Procedure:
A mixture of 1-[6-ethylthieno[2,3-d]pyrimidin-4-yl]piperidine-4-carboxylic acid (950 mg, 3.26 mmol, 1.00 equiv), 1H-1,2,3-benzotriazol-1-ol (586 mg, 4.34 mmol, 1.33 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (834 mg, 4.34 mmol, 1.33 equiv), amine hydrochloride (307 mg, 5.74 mmol, 1.76 equiv) and triethylamine (876 mg, 8.66 mmol, 2.66 equiv) in N,N-dimethylformamide (15 mL) was stirred for 12 h at 30° C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1×50 mL of brine. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (211-Waters 2767-2(HPLC-08)) under the following conditions: column: Xbridge Prep C,8, 5 um, 19*150 mm; mobile phase: water with 50 mmol ammonium bicarbonate and acetonitrile (10.0% acetonitrile up to 22.0% in 2 min, up to 32.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); detector: UV 220 nm. Purification afforded 167.4 mg (18%) of Compound I-177 as a white solid. 1H NMR: (400 MHz, CDCl3) δ 8.45 (1H, s), 6.95 (1H, s), 5.48-5.53 (1H, d), 4.54-4.57 (2H, d), 3.18-3.24 (2H, t), 2.89-2.92 (2H, q), 2.49-2.55 (1H, m), 2.03-2.05 (2H, m), 1.84-1.94 (2H, m), 1.35-1.38 (3H, t). MS: m/z 291 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][C:28]=4[F:36])[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:6])=[O:5])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([C:27]4[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=4[F:36])[NH:19][C:20]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:37])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4ccc([N+](=O)[O-])cc4F)[nH]c3-c3ccccc3)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(-c4ccc(N)cc4F)[nH]c3-c3ccccc3)cc21
Yield: 73.7 %

Procedure:
Reflux a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(2-fluoro-4-nitrophenyl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.59 g), ammonium formate (0.29 g) and Pd/C (10%, 0.12 g) in ethanol (20 mL) at 95° C. for 6 hours. Filter over Celite® and concentrate filtrate under reduced pressure to provide the title compound (0.41 g, 75%). MS(ES+): m/z=491.2 (M+H)+
Reaction SMILES: CO[C:3](=[O:36])[CH:4]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19]C2C=CC=CC=2)=[N:8][C:9]([NH:12]C2C=CC=CC=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O.[C:42](O)(=O)[CH3:43]>C(OCC)(=O)C>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([CH:4]2[C:3](=[O:36])[N:19]([C:43]3[CH:42]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:7]3[N:8]=[C:9]([NH:12][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=1
Reactant: CC(=O)O
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(OC)cc(OC)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COc1cc(OC)cc(C2Cc3cnc(Nc4ccccc4)nc3N(c3ccccc3)C2=O)c1
Temperature: 120 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-dimethoxy-phenyl)-propionic acid methyl ester (0.11 mg, 0.23 mmol) (from Example 3c supra) in glacial acetic acid (2 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 120° C. overnight. The reaction mixture was then diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6-(3,5-dimethoxy-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as light brown solid. (Yield 73.3 mg, 71.4%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14]2[NH:18][N:17]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27]4)=[C:22]([O:32][CH3:33])[CH:21]=3)[N:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[CH:4][CH:3]=1.[I-].[Na+].C(N(C(C)C)CC)(C)C>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][N:18]3[N:17]=[C:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[C:29]([Cl:31])[N:28]=[CH:27]5)=[C:22]([O:32][CH3:33])[CH:21]=4)[N:15]=[C:14]23)=[CH:4][CH:3]=1
Reactant: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(Br)cc3)n2)ccc1-n1cnc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Product: COc1cc(Nc2nc3n(n2)CCCCC3c2ccc(Br)cc2)ccc1-n1cnc(Cl)c1
Yield: 20.4 %

Procedure:
A solution of 5-(1-(4-bromophenyl)-5-chloropentyl)-N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-1H-1,2,4-triazol-3-amine (2.5 g, 4.54 mmol), sodium iodide (3.40 g, 22.7 mmol), and diisopropylethylamine (0.793 mL, 4.54 mmol) in acetone (10 mL) was heated in a sealed vessel at 100° C. for 12 h. The reaction was concentrated in vacuo. The crude product was purified using silica gel column chromatography (50% EtOAc/chloroform) to afford 475 mg (19% yield) of the titled compound as an off-white solid. LC-MS (M+H)+ 515.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.45-7.47 (m, 3 H), 7.40 (d, J=2.1 Hz, 1 H), 7.04-7.10 (m, 3 H), 7.00 (d, J=1.5 Hz, 1 H), 6.79 (dd, J=8.5, 2.4 Hz, 1 H), 6.64 (s, 1 H), 4.15-4.27 (m, 3 H), 3.76 (s, 3 H), 2.14-2.21 (m, 1 H), 1.91-2.10 (m, 3 H), 1.80-1.91 (m, 2 H).