Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[O:26][C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC(=O)O2
Reaction time: 48 h
Yield: 90.9 %

Procedure:
5-Methyl-3-(S)-phenyl-indan-1-one (400 mg, 1.8 mmol) and mCPBA (98%, 485 mg, 2.8 mmol) were suspended in dry CH2Cl2 (6 ml) at 0° C. followed by TsOH:H2O (20 mg). The reaction was kept at 4° C. for 48 h. The mixture was diluted with 10 ml of CH2Cl2 and washed with 2×10 ml of saturated Na2SO3, saturated NaHCO3 and brine. Flash chromatography eluting with ethyl acetate:pentane 10:90 gave 390 mg (90%) of the title compound. Rf 0.83 (ethyl acetate:pentane 20:80) (ChiralCel OD-H) 0.5 mL/min of hexane/isopropanol 95/5 (S)-isomer 15.18 min, (R)-isomer 17.42 min, 89% ee. IR (neat cm−1): 2900, 2360, 1769, 1495, 1208, 1145. 1H NMR δ: 2.28 (s, 3H), 3.05 (m, 1H), 4.32 (t, J=6.8 Hz, 1H), 6.98 (s, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.11 (dd, J=2.0, 8.4 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.19 (s, 1H), 7.33 (m, 3H) 13C NMR δ: 20.7, 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8. MS (EI 70 eV) m/z (rel. intensity): 238 (55) [M+], 220 (57), 195 (100), 181(10), 165 (12), 152 (9).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][C:7]#[N:8].[C:12](OCC)(=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>C(O)C>[CH3:2][C:3]1[CH:4]=[C:5]([CH:6]([C:12](=[O:17])[CH2:13][CH:14]([CH3:16])[CH3:15])[C:7]#[N:8])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(CC#N)c1
Reactant: CCOC(=O)CC(C)C
Agent: [Na]
Solvent: CCO
Product: Cc1cccc(C(C#N)C(=O)CC(C)C)c1
Temperature: 112 °C
Yield: 95.8 %

Procedure:
To a solution of 2.99 g (0.13 g. atm) of sodium in 50 ml of absolute ethanol, heated to 60° C., was added 11.81 g (0.09 m) of 3-methyl-benzyl cyanide followed by the slow addition, over a period of 20 minutes of 31.27 g (0.24 m) of ethyl isovalerate. The reaction mixture was heated under reflux overnight (18 hrs.). During this period the color of the solution turned from yellow to dark orange. After approximately 70 ml of solvent and excess of ethyl valerate was removed by distillation, 75 ml of toluene was added and additional 30 ml of the solvent was removed by heating the mixture to 112° C. The reaction mixture was cooled, diluted with 100 ml of toluene and was washed twice with water. The aqueous extracts were combined and acidified with 6N hydrochloric acid. The product was extracted in 300 ml of methylene chloride. The organic extract was washed with water, dried over magnesium sulfate and was concentrated under vacuum to afford 18.56 g of orange colored oil. Crystallization from ethyl acetate hexane solution afforded 14.0 g. of a white solid. m.p. 46.5°-50° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[N:7]=1.[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].CN1CCCC1=O>C(OCC)(=O)C>[Br:8][C:6]1[N:7]=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([F:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: Cn1cc(Br)nc(Br)c1=O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cn1cc(Br)nc(Nc2ccc(F)c([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Yield: 69.2 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-2(1H)pyrazinone (10 g; 37.5 mmol), 4-fluoro-3-nitroaniline (5.9 g; 37.5 mmol), and 1-methyl-2-pyrollidinone (30 mL) was heated at 140 degrees for 1 hr. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and filtered to give 5-bromo-3-(4-fluoro-3-nitro-phenylamino)-1-methyl-1H-pyrazin-2-one (1) as a yellow solid (8.9 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:17][CH2:18]Br>CS(C)=O.CN(C)C=O>[F:17][CH2:18][O:7][N:8]=[C:9]([C:15]#[N:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C#N)=NO
Reactant: FCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCOC(=O)C(C#N)=NOCF
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
Potassium carbonate (110.6 g, 0.8 ml) was added to ethyl 2-hydroxyimino-cyanoacetate (56.8 g, 0.4 mol) in dimethylsulfoxide (200 ml) under ice-cooling, and the mixture was stirred for 10 mins, and then Fluoromethyl bromide (48.8 g, 0.4 mol) in N,N-dimethylformamide (40 ml) was added dropwise to the mixture under ice-cooling. The mixture was stirred at an internal temperature of 20° to 30° C. for 2.5 hrs. The reaction solution was dispersed in ice water (1 L), and it was extracted with ethyl acetate (800 ml, 500 ml, and 500 ml). The combined extracts were washed twice with saturated brine (300 ml) and dried over sodium sulfate, and then concentrated to give a concentrate (66.4 g) which was purified by column chromatography using silica gel (60 g) to give ethyl 2-fluoromethoxyimino-cyanoacetate (46.6 g, yield: 66.9%) as an oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1.C(N(CC)CC)C.I.[NH2:31][C:32]1[C:33]([C:40]([NH:42][C:43](=[NH:46])SC)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1>C(O)C>[NH2:31][C:32]1[C:33]([C:40]([N:42]=[C:43]([NH2:46])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:22]=[CH:21][C:9]([O:10][CH2:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:13])=[CH:8][CH:7]=2)=[O:41])=[N:34][C:35]([Cl:39])=[C:36]([NH2:38])[N:37]=1
Reactant: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NC(=O)c1nc(Cl)c(N)nc1N)NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
A solution of 2-[4-(4-aminobutyl)phenoxy]-N-phenylacetamide 19 (100 mg, 0.35 mmol) and triethylamine (0.14 mL, 1.00 mmol) in absolute ethanol (2 mL) was stirred at 60° C. for 30 min, after which 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methyl-isothiourea hydriodide (140 mg, 0.37 mmol) was added in one portion. The reaction mixture was stirred at that temperature for 4 h, cooled to room temperature, and concentrated by rotary evaporation. The crude residue was triturated with water and filtered. The filter cake was purified by flash silica gel column chromatography eluting with dichloromethane/methanol/concentrated ammonium hydroxide (500:10:0, 500:10:1, 200:10:1, v/v) to give 2-(4-{4-[N′-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)guanidino]butyl}phenoxy)-N-phenylacetamide (20, PSA 17482) as a yellow solid (120 mg, 67% yield). mp 168-170° C. 1H NMR (300 MHz, DMSO-d6) δ 6 1.55 (m, 4H), 2.55 (m, 2H), 3.16 (m, 2H), 4.65 (s, 2H), 6.60 (br s, 2H), 6.90 (d, 2H), 7.08 (m, 2H), 7.15 (d, 2H), 7.30 (m, 5H), 7.60 (d, 2H), 9.00 (br s, 1H), 10.00 (br s, 1H). m/z (ESI): 511 [C24H27ClN8O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:10].C(=O)([O-])[O-].[K+].[K+].[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C)C=O>[C:22]([O:28][CH2:29][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C@@H:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[CH3:10])(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cc1cccc(C(C)c2ncc[nH]2)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc([C@@H](C)c2nccn2COC(=O)C(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To a suspension of the compound of Example 1 (120 mg, 0.6 mmol) and potassium carbonate (246 mg, 1.8 mmol) in dimethylformamide (4 ml) was added chloromethyl pivalate (215 μl, 1.5 mmol) and the reaction mixture stirred at room temperature overnight. Water (10 ml) was added and the mixture then extracted with ethyl acetate (2×10 ml). The organic layers were combined, washed with water (10 ml) and brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (2 ml) and purified by automated preparative liquid chromatography (Gilson system, 150 mm×21.2 mm LUNA C18(2) 5 μm column) using an acetonitrile:water gradient [50:50 to 95:5]. The appropriate fractions were concentrated in vacuo to give the title compound (136 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].F[C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1.O>CN1C(=O)CCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Fc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 75.8 %

Procedure:
Sodium hydride (0.9 g, 60% dispersion in mineral oil) was added to a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (4 g) in NMP (40 ml) and the solution stirred for 1 h, then a solution of 3-fluorobenzotrifluoride (3.5 g) in NMP (10 ml) was added and the mixture was stirred for 2 h at 80 ° C. The mixture was added to water (200 ml) and extracted with diethyl ether (2×100 ml), the solvent washed with water, 1 M sodium hydroxide and brine, dried and evaporated to give the title compound as yellow oil (5.2 g) which was carried through to the next step without purification.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C@H:20]1[CH2:24][NH:23][C@H:22]([C:25]([NH2:27])=[O:26])[CH2:21]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:23]3[CH2:24][C@H:20]([F:19])[CH2:21][C@H:22]3[C:25]([NH2:27])=[O:26])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H]1C[C@@H](F)CN1
Agent: Cl
Product: NC(=O)[C@@H]1C[C@@H](F)CN1C(=O)c1ccc(C2CC2)c(OCC2CC2)n1
Yield: 72.6 %

Procedure:
In analogy to the procedure described in Example 47 b), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 50 mg, 214 μmol) was reacted with (2S,4R)-4-fluoropyrrolidine-2-carboxamide hydrochloride (CAN 796884-06-5, 39.8 mg, 236 μmol) to obtain the title compound (54 mg, 73%) as white solid; LC-MS (UV peak area, ESI) 100%, 348.1727 [MH+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)#[N:19]>>[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1)#[N:19]
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: N#Cc1ccccc1B(O)O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccccc2C#N)cc1
Yield: 60 %

Procedure:
Prepared in a similar manner to Example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 2-cyanophenylboronic acid. Yield: 60%. 1H NMR (400 MHz, CDCl3): δ 0.8 (d, 6H), 1.65 (s, 6H), 1.67-1.70 (m,1H), 3 (t, 2H), 7.4-7.55. (m, 3H), 7.6 (d, 2H), 7.65 (td, 2H), 7.8 (d, 1H). MS (M+H, 321).
Reaction SMILES: C([O:8]P(=O)(O)OCC1C=CC=CC=1)C1C=CC=CC=1.[CH:20]1([N:26]=[C:27]=[N:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.O>C1COCC1>[C:27]([NH:26][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)([NH:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:8]
Reactant: O=P(O)(OCc1ccccc1)OCc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
A flask fitted with a nitrogen inlet, overhead stirrer, teflon-coated thermocouple probe, and pressure-equalizing addition funnel was charged with 350 milliliters of dry (water content ≤50 μg/mL), peroxide-free tetrahydrofuran, followed by 50.0 grams (174 millimoles) of dibenzylphosphoric acid (DBP), and the resulting mixture was stirred until the solid dissolved (about 10-15 minutes). A solution of 18.9 grams (91.6 millimoles) of dicyclohexylcarbodiimide (DCC) in 215 milliliters of THF was added from the addition funnel to a stirred, cooled (water-bath) solution of DBP at a rate to maintain the temperature at about 20°-25° C. The reaction is slightly exothermic and the addition took about 30 minutes. Within minutes, a precipitate of dicyclohexylurea formed in the mixture. Stirring was continued for about 2 hours at 20°-25° C. The reaction was monitored by HPLC assay using VYDAC C-18 (300A, 4.6×250 mm) column with water (0.02M KH2PO4) acetonitrile as eluent. The reaction was complete in about 1 hour (assay showing <2 percent unreacted DBP). The mixture was then filtered while excluding moisture to remove dicyclohexylurea. The filter cake was washed with two 25 milliliter portions of THF. The solution when assayed by HPLC showed 45.9 grams (98 percent) yield of tetrabenzyl pyrophosphate (TBPP) in 620 milliliters of THF (0.137M). The filtrate was then stored at 0° C. with exclusion of moisture until the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.N1CCCCC1.[CH3:42][C:43]([N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)([CH3:46])[CH:44]=O>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:42][C:43]([CH3:46])([N:47]3[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)[CH3:44])[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCOCC1
Temperature: 105 °C
Yield: 21 %

Procedure:
To a sealed tube was added 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (900 mg, 1.91 mmol), ethanol (12 mL), piperidine (0.23 mL, 2.29 mmol) and 2-methyl-2-morpholino-propanal (0.49 mL, 2.86 mmol). The tube was sealed and heated to 105° C. for 24 hrs. The mixture was then cooled, concentrated and then dissolved in ethyl acetate (100 mL) and washed with 5% citric acid (100 ml) and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (column size 100 g. Solvent system 4%-8% MeOH/EtOAc) to obtain 245 mg (21% yield) of the title compound. MS (pos. ion) m/z: 611 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:15][CH:14]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19]3)=[O:17])[CH2:13][S:12]2)[CH:6]=[N:7][C:8]=1[O:9]C.Cl>C(OCC)(=O)C.O1CCOCC1>[CH3:1][O:2][CH:3]1[C:8](=[O:9])[N:7]=[CH:6][C:5]([CH:11]2[NH:15][CH:14]([C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:22][CH2:23]3)=[O:17])[CH2:13][S:12]2)=[CH:4]1
Reactant: COc1cc(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)cnc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC1C=C(C2NC(C(=O)N3CCN(CCCc4ccccc4)CC3)CS2)C=NC1=O
Yield: 29.7 %

Procedure:
1-[2-(5,6-Dimethoxy-3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine (730 mg) was dissolved in 25 ml of ethyl acetate. To the solution was added with stirring at room temperature 2N hydrogen chloride solution in dioxane. The resultant powder was collected by filtration and dissolved in saturated sodium carbonate solution. Ethyl acetate was added, the organic layer was separated and washed with water, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 25 ml; 10% methanol-ethyl acetate) to give 210 mg of 1-[2-(5-methoxy-6 oxo 5,6-dihydro-3-pyridyl)thiazolidin-4-ylcarbonyl]-4-(3-phenylpropyl)piperazine.
Reaction SMILES: [C:1](=[S:3])=S.[NH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>CC(C)=O>[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][N:16]([CH3:17])[CH3:18])[CH:12]=[CH:13][CH:14]=1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: CN(C)Cc1cccc(OCCCN)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN(C)Cc1cccc(OCCCN=C=S)c1

Procedure:
A solution of carbon disulphide (8.36 g) in acetone (16 ml) was added dropwise to a stirred solution of 3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (20.8 g) in acetone (60 ml) at -10° to 0° during 15 minutes. A solution of mercuric chloride (27.2 g) in acetone (40 ml) was added slowly at -15° and after the addition the suspension was warmed to 0° and triethylamine (23 g) added dropwise. The suspension was refluxed for 45 minutes then filtered and evaporated to give an oil which was chromatographed (alumina, grade 3/ether). The appropriate eluate was evaporated to a yellow oil consisting of the title compound (8.7 g).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3N=CC=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:35]1[N:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3[C:35]4[N:36]([CH:38]=[CH:39][N:40]=4)[CH:37]=[CH:23][N:22]=3)[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc2cc(-c3ncccn3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Brc1ncccn1
Product: Cc1cc2cc(-c3nccn4ccnc34)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(1-(4-chlorophenyl)-6-(imidazo[1,2-a]pyrazin-8-yl)-3-methylnaphthalen-2-yl)acetic acid (61) was prepared in a similar fashion to compound 59 with the substitution of 8-chloroimidazo[1,2-a]pyrazine hydrobromide (See Guzi, T. J, Paruch, K., et. al. US 20070105864, p. 121) for 2-bromopyrimidine in step 2. The title compound (0.017 g) was isolated as an amorphous pale yellow powder. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H27ClN3O3: 500.7; found: 500.0. 1H-NMR: 400 MHz, (CD3CN) δ: 9.00 (d, J=1.2 Hz, 1H); 8.39 (d, J=4.4 Hz, 1H); 8.20 (dd, J=8.8, 1.2 Hz, 1H); 8.11 (d, J=4.4 Hz, 1H); 8.06 (d, J=1.2 Hz, 1H); 7.99 (s, 1H); 7.62-7.56 (m, 3H); 7.38 (d, J=8.8 Hz, 1H); 7.36 (br d, J=8.8 Hz, 1H); 5.25 (s, 1H); 2.58 (s, 3H); 0.99 (s, 9H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COC(=O)NNC(=O)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
36.0 g. (0.4 moles) of methyl carbazate and 70.0 g. (0.4 moles) of p-chloro-benzoyl chloride are reacted in an analogous manner to Example 2. Thus 74.5 g. of the desired compound are obtained, yield 81.5%, m.p.: 160° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([OH:35])=O)=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[Cl:25][C:26]1[N:31]=[C:30]([CH3:32])[C:29]([C:33]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:35])=[CH:28][CH:27]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (460 mg, 1.21 mmol) was added to a solution of 6-chloro-2-methyl-3-pyridinecarboxylic acid (commercially available, e.g. from Anichem, or may be prepared according to known methods) (173 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.440 ml, 2.52 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (371 mg, 1.20 mmol) was then added and stirring was continued for one hour. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave a dark brown gum. Purification by silica chromatography (Biotage SP4, 25S cartridge), eluting with 12-100% ethyl acetate in isohexane, gave the title compound (456 mg) as a pale yellow gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[SH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[O-].[Na+]>[Cu].CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: Nc1ccc(I)cn1
Agent: [Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1ccc(Sc2ccccn2)cn1

Procedure:
11.0 G. (0.05 moles) of 2-amino-5-iodo pyridine, 6.1 g. (0.055 moles) of 2-mercapto pyridine, 2.97 g. (0.055 moles) of sodium methoxide and 1.0 g. of copper powder are combined in 200 ml. of methanol and heated at 150° C for 12 hours in a glass lined bomb. The reaction mixture is filtered and the filtrate evaporated to dryness in vacuo. The residue is dissolved in 300 ml. of methylenechloride and washed 5 times with 2.5 N sodium hydroxide and 3 times with saturated sodium chloride solution. The methylene chloride is dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in boiling methanol, treated with decolorizing carbon, filtered and evaporated to dryness affording 2-amino-5-(2-pyridylthio) pyridine, m.p. 121° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:18]/[C:19]2[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=2[O:27][CH3:28])/[C:9]1=[O:29])=O)(C)(C)C.[F:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:46])=[C:35]([CH:37]=[N:38][C:39]([O:41][Si](C)(C)C)=[CH2:40])[CH:36]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:29])[C:10]3([CH:18]([C:19]4[CH:24]=[C:23]([Cl:25])[C:22]([F:26])=[CH:21][C:20]=4[O:27][CH3:28])[CH2:40][C:39](=[O:41])[NH:38][CH:37]3[C:35]3[CH:36]=[C:31]([F:30])[CH:32]=[CH:33][C:34]=3[CH3:46])[C:11]2=[CH:12][CH:13]=1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: COc1cc(F)c(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Product: COc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 1.7 %

Procedure:
A mixture of E/Z-6-chloro-3-(5-chloro-4-fluoro-2-methoxy-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3 g, 6.8 mmol) and 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (30 mmol) prepared in Example 4 in toluene (30 mL) was heated at 60° C. for 3 h, and concentrated in vacuo. To the residue was added DCM (30 mL) and TFA (5 mL), and the resultant solution was stirred at room temperature for 3 h, then concentrated. The residue was partitioned between ethyl acetate and aqueous diluted NaOH solution. The organic layer was washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was purified by flash chromatography to give the title compound as white solid (60 mg).