Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([OH:15])=O)=O)(C)(C)C.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][CH2:26][NH:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl>CN(C=O)C.O1CCOCC1.O>[NH:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13]([N:25]1[CH2:26][CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]1[C:21]1[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:35])[F:34])=[CH:19][CH:20]=1)=[O:15]
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: O=C([C@H]1CCCN1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (R)-1-(tert-butoxy-carbonyl)pyrrolidine-2-carboxylic acid (0.078 g, 0.36 mmol), (R)-1-(4-(trifluoro-methyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.100 g, 0.36 mmol) and DIEA (0.047 g, 0.36 mmol) in DMF (2 mL) was added HATU (0.14 g, 0.36 mmol). The reaction mixture was continued to stir overnight at RT, hydrolyzed with H2O, extracted with DCM (3×), dried over Na2SO4, concentrated and purified by ISCO (20% EtOAc/hexanes) to give the white solid which was dissolved in p-dioxane (2 mL) and added 1 mL of 4M HCl in p-dioxane. The mixture was continued to stir at RT overnight, concentrated, taken up in H2O, and neutralized by saturated aqueous NaHCO3, and filtered the light yellow solid which was dried by air. MS (ESI, positive ion) m/z: 375 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].[NH2:27][C@@H:28]1[C@H:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29]1>>[CH2:34]([C@@H:33]1[CH2:32][CH2:31][N:30]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][C@@H:28]1[NH:27][C:21]([C:14]1[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]2[O:10][C:9]([CH3:25])([CH3:24])[C:8](=[O:26])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:13]=1)=[O:22])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2ccccc2)[C@@H](N)C1
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3Cc3ccccc3)cc21

Procedure:
Using 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (rac.)-(3R,4R)-3-amino-4-benzylpiperidine-1-carboxylate (US 2005/182095), the title compound was obtained in a similar manner to Reference Example 197.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:17])[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>>[CH2:21]([O:23][C:24](=[O:29])[C:25]([CH3:27])([O:17][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[C:2]([CH3:1])[N:3]2[CH2:18][CH2:19][CH3:20])[CH3:26])[CH3:22]
Reactant: CCCn1c(C)c(-c2ccncc2)c2c(O)cccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccncc2)c2c(OC(C)(C)C(=O)OCC)cccc21

Procedure:
The above compound was prepared from 2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-4-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH:9]=1)[CH3:6])C.[Li+].[OH-]>C1COCC1.CO>[CH3:36][C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([CH3:35])[C:15](=[O:34])[CH2:16][C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH:9]=1)([CH3:6])[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(N(C)C(=O)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC(=O)N(C)c1cccc(OC(C)(C)C(=O)O)c1
Reaction time: 6 h

Procedure:
0.50 g (0.97 mmol) of the above prepared 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-phenoxy]-propionic acid ethyl ester was dissolved in 15 ml of THF/MeOH=2:1. To the stirred solution was added 1.16 ml of a LiOH-solution (1 molar in water). After 6 hours, the reaction mixture was poured into crashed ice/HCl and extracted twice with CH2Cl2; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated to give 0.47 g of pure title compound as colorless foam.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37].CCCCCC.C(OCC)(=O)C>O1CCCC1.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:41][C:39]([Si:36]([CH3:37])([CH3:38])[O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:7]1[C:6]2[CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[CH:17]=[CH:16][C:15]=2[S:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH3:40])[CH3:42]
Reactant: CC(=O)c1ccc2c(c1)Nc1ccccc1S2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)N(CCCCCCO[Si](C)(C)C(C)(C)C)c1ccccc1S2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of 500 mg (2.07 mmol) of 2-acetylphenothiazine in 8 mL of tetrahydrofuran is cooled to -78° C. and 4.14 mL (2.07 mmol) of a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene is added. After five minutes, a solution of [(6-bromohexyl)oxy]-(1,1-dimethylethyl)dimethyl silane in 2 mL of tetrahydrofuran is added and the reaction is allowed to warm to room temperature. The mixture is diluted with 25 mL of ethyl acetate and washed with 10% sodium bisulfate solution and saturated sodium chloride solution, then dried over magnesium sulfate and concentrated in vacuo to give a dark colored residue. Flash chromatography (3:1 hexane/ethyl acetate) provides 318 mg (33%) of 1-[10-[6-[[(1,1-dimethylethyl)dimethylsilyl]oxy]hexyl]-10H-phenothiazin-2-yl]ethanone as a dark colored oil. The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1680, 1600, 1560 cm-1 ; MS m/e calculated for C26H37NO2SSi: 455.2314, found 455.2312.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][NH:16][CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26](Cl)=[O:27])[CH2:22][CH2:21]1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:26]([N:23]4[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]4)=[O:27])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Solvent: ClCCl
Product: CN1CCN(C(=O)N2CCC3(CC(C#Cc4cccc(Cl)c4)=NO3)C2)CC1
Reaction time: 20 h
Yield: 40.6 %

Procedure:
To a solution of Compound 27d (150 mg, 0.58 mmol) in dichloromethane (10 mL) was added TEA (0.248 mL, 1.73 mmol) followed by 4-methyl-1-piperazinecarbonyl chloride (122 mg, 0.748 mmol). The reaction mixture was kept under stirring for 20 h. After evaporation the residue was purified by means of automated isocratic RP chromatography (SP01®TM-Biotage; NH4HCO3/AcCN 55:45) affording 91 mg of the title compound as a gummy oil. Yield: 49%.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:13][CH2:12]1>COC(C)(C)C>[CH:1]1([NH:7][C:8]([NH:20][CH2:19][CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]2)=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(CCCN)CC1
Reactant: S=C=NC1CCCCC1
Solvent: COC(C)(C)C
Product: CN1CCN(CCCNC(=S)NC2CCCCC2)CC1
Reaction time: 18 h
Yield: 82.7 %

Procedure:
Cyclohexyl isothiocyanate (1.51 g, 10.7 mmole) in 5 mL t-butyl methyl ether was added to a solution of 1.68 g (10.7 mmole) 3-(4-methyl-1-piperazinyl)propylamine (Lancaster Synthesis, Windham N.H.) in t-butyl methyl ether (10 mL). After 18 hr at room temp., filtration gave 2.64 g (83%) 1-cyclohexyl-3-[(4-methyl-1-piperazinyl)propyl]thiourea, melting pt. 109-111° C. A solution of 2.388 g (8 mmole) of this thiourea in 12 mL ethanol containing 2.1 mL (25.2 mmole) conc. HCl was added to a warm solution of 2.755 g (16 mmole) 2-methyl-1,4-naphthoquinone in 20 mL warm ethanol with stirring. After 3 days, 1.925 g crude solid was filtered out. Of this, 1.0 g was recrystallized from 20 mL 95% methanol+80 mL acetone to give 0.927 g (40%) of the title compound, melting pt. 242-244° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH2:20])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:16]4[N:17]=[C:18]([NH:20][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[N:19]=[C:15]4[CH:14]=[CH:13][N:12]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1nc2ccnc(-c3ccc4c(c3)OCCO4)n2n1)C1CC1
Temperature: 25 °C

Procedure:
To a solution of 5-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-[1,2,4]triazolo[1,5-c]pyrimidin-2-ylamine (0.04 g, 0.148 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.052 mL, 0.371 mmol) followed by cyclopropanecarbonyl chloride (0.034 mL, 0.371 mmol). The reaction mixture was then allowed to warm to ambient temperature, and the solvent removed under reduced pressure. The crude product was purified by preparatory HPLC. 1H NMR (300 MHz, DMSO): 1.84-1.88 (m, 4H), 2.00-2.08 (m, 1H), 4.31-4.36 (m, 4H), 7.06 (d, 1H), 7.64 (d, 1H), 8.21 (dd, 1H), 8.35 (d, 1H), 8.39 (d, 1H), 11.37 (s, 1H). LCMS Method: 2: RT: 3.51 min, MI: 338 [M+1].
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH3:19][C:20]1[O:24][C:23]([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)=[CH:22][CH:21]=1>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:26]=[C:25]([C:23]4[O:24][C:20]([CH3:19])=[CH:21][CH:22]=4)[O:29][N:28]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1ccc(-c2cc(C(=O)O)no2)o1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)Cn3ccc(-c4ccc(C#N)c(Cl)c4)n3)no2)o1
Yield: 41.5 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(5-methylfuran-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (150 mg, 0.575 mmol) and 5-(5-methyl-furan-2-yl)-isoxazole-3-carboxylic acid (111 mg, 0.575 mmol). The product was purified by Flash-chromatography. Yield 41.5%. 1H-NMR (400 MHz; MeOD): δ 1.28 (d, 1H), 2.38 (dd, 3H), 4.27-4.45 (m, 2H), 4.54-4.63 (m, 1H), 6.23-6.26 (m, 1H), 6.66 (s, 1H), 6.77 (d, 1H), 6.91 (td, 1H), 7.71 (d, 1H), 7.75 (dd, 1H), 7.86 (dd, 1H), 8.05 (dd, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>ClCCl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Product: O=C(c1ccc(I)cc1)N1CCCCC1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a suspension of 4-iodo-benzoyl chloride (2.00 g, 7.51 mmol) in dichloromethane (25 mL) was added piperidine (1.85 mL, 18.76 mmol). The reaction mixture was heated at reflux for 1.5 hour and then cooled to room temperature. The organic layer was washed with an aqueous 1M HCl solution, brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (2.37 g, 100%) as a white solid.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[K+].Cl.Cl[CH2:14][C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2.Cl.[K+].[Br-]>CS(C)=O.O>[OH:25][C:22]1[CH:23]=[CH:24][C:15]([CH2:14][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2
Reactant: Oc1ccc(CCl)c2cccnc12
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N[C@@H](CSCc1ccc(O)c2ncccc12)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
L-cysteine hydrochloride hydrate (37 mg, 0.31 mmol) was dissolved in DMSO (3 ml). To the solution powdered KOH (36 mg, 0.34 mmol) was added, and the mixture was stirred for 30 min at room temperature. Then, powdered 5-chloromethyl-8-hydroxyquinoline hydrochloride (A2) (65 mg, 0.34 mmol) was added. The suspension was stirred at room temperature 12 h, 2 N HCl was added and the pH was adjusted to 5. The precipitate was washed with water and acetone. The crude product was further purified by semi-preparative HPLC to yield compound M12: 53 mg (61%). HPLC (tR): 38.1 min (linear gradient: 50% B for the first 4 min, increased linearly to 100% B for 60 min) [α]D20=20.5° (c=1.0, H2O); 1H NMR (250 MHz, D2O) 2.89 (d, J=5.6 Hz, 2H), 3.95 (dd, J=5.1, 5.0 Hz, 1H), 4.18 (s, 2H), 7.25 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.96 (dd, J=8.7, 5.5 Hz, 1H), 8.88 (d, J=5.4 Hz, 1H), 9.22 (d, J=8.7 Hz, 1H); IR (KBr) cm−1: 3438 (broad), 3081, 1685, 1637, 1560; Mass spectrometry: calculated for C12H12N2O3 m/z [M+H]+=279.33. found [M+H]+=279.13.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:32](O)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([NH:30][CH:31]([C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[C:32]([NH:16][C:14]2[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=2)=[O:33])=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccc(F)cc1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)C(NC(=O)Cc2cc(F)cc(F)c2)c2ccc(F)cc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-(4-fluorophenyl)acetic acid to afford the title compound: MS 530 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:4][CH:3]=1.[C:15](O)(=O)[C:16]1[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:18]=[O:19].[BH4-].[Na+]>C(O)C>[O:19]=[C:18]1[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2SC(=O)NC2=O)cc1
Reactant: O=Cc1ccccc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NC(=O)C(c2ccc(N3Cc4ccccc4C3=O)cc2)S1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.4 %

Procedure:
Into 50 ml of ethanol were dissolved 4.90 g of 5-(4-aminophenyl)-thiazolidine-2,4-dione and 3.54 g of phthalaldehydic acid, and the solution was refluxed for 2 hours. After cooling by standing, 1.78 g of sodium borohydride were added and the mixture was stirred for 20 minutes at room temperature. Thereafter, solvent was distilled off under reduced pressure and 10 ml of glacial acetic acid were added to the residue, which was stirred for 10 minutes at 100 ° C. After cooling by standing, 100 ml of water were added and the crystals deposited were collected by filtration, washed with water and dried. These were recrystallized from ethanol to obtain 6.90 g of title compound.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31]CC)=[O:30]>CC(C)=O>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:14]([CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([O:20][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[CH:7][C:6]=43)[C@@H:15]1[CH2:16][CH2:17][C:18]2=[O:19]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccc(OCC(=O)O)cc4CC[C@H]3[C@@H]1CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
The mixture of estrone (540 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol), and acetone (25 ml) was refluxed for 6 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml dioxane and 14 ml 5% sodium hydroxide solution were added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 2, and then extracted three times with ethyl acetate (15 ml each). The organic phases were combined, washed with water and brine, dried over magnesium sulfate, filtered, and then evaporated in vacuo. The residue was recrystallized from ethanol to give 246 mg estra-1,3,5(10)-trien-17-one-3-oxyacetic acid as white crystals, mp 205-208° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1cc(Cl)ccn1
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2cc(Cl)ccn2)nc2cccnc21
Yield: 20.8 %

Procedure:
The cyclization was effected by heating 12.3 g (0.037 mole) of N-[3-[[(4-chloro-2-pyridinyl)carbonyl]amino]-2-pyridinyl]glycine ethyl ester at 200°-210° C. (oil bath) for 15 minutes. The dark residue was dissolved in methylene chloride and filtered. The filtrate was treated with Florisil®, filtered, and evaporated to an oil, which crystallized upon standing. The solid was recrystallized from methanol-water, washed with 50% aqueous methanol, and dried under high vacuum at 50° C. overnight to give 2.44 g (21%) of title compound, mp 99°-101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1.[CH3:15]C1C(C2C=CC=CN=2)=NC(C)=CC=1.CC1C(C2C=CC=CN=2)=NC=C(C)C=1.[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)P(=O)(N(C)C)N(C)C>[CH2:43]([OH:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[CH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:3]=1)=[CH2:15]
Reactant: Cc1ccc(C)c(-c2ccccn2)n1
Reactant: Cc1cc(C)nc(-c2ccccn2)c1
Agent: Cc1cnc(-c2ccccn2)c(C)c1
Solvent: OCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=Cc1cc(C)nc(-c2ccccn2)c1
Reaction time: 0.75 h
Yield: 61 %

Procedure:
500 g (2.75 mols) of a mixture of isomers, consisting of 4,6-dimethyl-2,2'-bipyridine (45% by weight), 3,6-dimethyl-2,2'-bipyridine (45% by weight) and 3,5-dimethyl-2,2'-bipyridine (10% by weight), are reacted in accordance with the procedure of Example 1(a). The crude product formed is heated under 133 to 400 Pa for 2 hours at 120° to 125° C. and then for 45 minutes at 170° C. (bath temperature). 299 g of a distillate are thus obtained which has a boiling range of 65°-107° C. and which is composed of 65% by weight of 3,6-dimethyl-2,2'-bipyridine, 7% by weight of 3,5-dimethyl-2,2'-bipyridine as well as 17% by weight of benzyl alcohol and 10% by weight of hexamethylphosphoric acid triamide. The residue is heated under 0.1 Pa and, in a boiling range of 48° -170° C., a mixture distils off which is subjected to a fractional redistillation after di-tert.-butyl-p-cresol has been added as a polymerisation inhibitor. Thus, 51 g of (4-(2-benxyloxy)-ethyl)-6-methyl-2,2'-bipyridine, 11 g of 3,6- and 3,5-dimethyl-2,2'-bipyridine, 105 g of benzyl alcohol and 147 g of 4-vinyl-6-methyl-2,2'-bipyridine (61% of theory) are obtained.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:11]([O:12]C(=O)C)[CH2:10][O:9][CH:7]([OH:8])[C@@H:6]1[F:16])(=O)C.C[O-].[Na+]>CO>[F:16][C@@H:6]1[C@@H:5]([OH:4])[C@@H:11]([OH:12])[CH2:10][O:9][CH:7]1[OH:8]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)COC(O)[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1OC[C@H](O)[C@H](O)[C@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 17 (5.7 g, 24.1 mmol) in dry methanol (220 mL) was treated with 0.1 N NaOMe in methanol (114 mL, 11.4 mmol) and stirred for 1 hour at room temperature. The solution was then neutralized with DOWEX 50W X8-100, filtered and evaporated to afford 18 (3.7 g, 24 mmol, 100%) as a yellow syrup: 13C-NMR (D2O) δ 94.19 (C-1α, d, JC-1,F=23.0), 92.24 (C-2α, d, JC-2,F=179.6), 90.10 (C-1β, d, JC-1,F=20.3), 88.60 (C-2β, d, JC-2,F=182.3), 70.77 (C-3α, d, JC-3,F=18.2), 69.03 (C-4β, d, JC-4,F=8.0), 68.90 (C-4α, d, JC-4,F=10.2), 66.85 (C-3β, d, JC-3,F=18.2), 66.32 (C-5α), 62.21 (C-5β).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]#[C:14][C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1.CO>O1CCCC1.[Pd]>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[CH2:13][CH2:14][C:15]1[N:16]=[C:17]2[CH:23]=[CH:22][N:21]([S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=1
Reactant: COc1cc(OC)c(F)c(C#Cc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(F)c(CCc2cnc3c(ccn3S(=O)(=O)c3ccccc3)n2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a stirred solution of 2-[(2,6-difluoro-3,5-dimethoxyphenyl)ethynyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (490 mg, 1.08 mmol) in tetrahydrofuran (8 mL)/methanol (10 mL), Pd/C (10% w/w, 365 mg, 0.343 mmol) was added. The resulting mixture was stirred under H2 at ambient temperature. After 24 hr, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (400 mg, 81%). LCMS calculated for C22H19F2N3O4S (M+H)+: m/z=460.1. Found: 460.1.
Reaction SMILES: [Na].[CH:2]([C:4]1[N:5]([CH2:9][C:10]([NH:12][CH:13]2[C:20](=[O:21])[N:19]3[CH:14]2[S:15][CH2:16][C:17]([CH2:25][S:26][C:27]2[N:31]([CH3:32])[N:30]=[N:29][N:28]=2)=[C:18]3[C:22]([OH:24])=[O:23])=[O:11])[CH:6]=[CH:7][CH:8]=1)=[O:3].[C:33]([O:36][CH2:37]Cl)(=[O:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:36][CH2:37][O:23][C:22]([C:18]1[N:19]2[CH:14]([S:15][CH2:16][C:17]=1[CH2:25][S:26][C:27]1[N:31]([CH3:32])[N:30]=[N:29][N:28]=1)[CH:13]([NH:12][C:10](=[O:11])[CH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[CH:2]=[O:3])[C:20]2=[O:21])=[O:24])(=[O:35])[CH3:34]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reactant: CC(=O)OCCl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCOC(=O)C1=C(CSc2nnnn2C)CSC2C(NC(=O)Cn3cccc3C=O)C(=O)N12
Reaction time: 0.5 h

Procedure:
The sodium salt of 7-[[(2-formyl-1-pyrryl]acetyl]-amino]-3-[[(1-methyltetrazol-5-yl)thio]methyl]-8oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 3 grams, is added to about 40 ml of dry dimethylformamide (DMF) and stirred for 30 minutes. The 4.0 ml of chloromethyl acetate in 5 ml of DMF was added. This mixture is stirred for about 4 hours at room temperature. This mixture is diluted with ethyl acetate and thoroughly washed with water. The ethyl acetate portion is dried over sodium sulfate, filtered and evaporated to give the title compound.