Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2.C(Cl)(Cl)Cl.[CH3:30][N:31](C=O)C>[C-]#N.[Zn+2].[C-]#N>[C:30]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]([CH2:15][CH2:16][CH:17]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH3:18])[CH2:5]2)#[N:31]
Reactant: CCCN(CCC)C(C)CCC1Cc2cc(Br)ccc2C1OCOC
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)C(C)CCC1Cc2cc(C#N)ccc2C1OCOC
Temperature: 80 °C
Reaction time: 48 h

Procedure:
The compound (552 mg) obtained in Example 11-8 was dissolved in DMF (1.67 ml) and added with zinc cyanide (94.3 mg) and tetrakistriphenyl phosphine palladium (61.8 mg), followed by stirring at 80° C. for 48 hours. The reaction solution was added with chloroform and washed with a 7% aqueous ammonium solution and a saturated saline solution. The resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (436.8 mg) as a yellow oily substance.
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:26][C:27]1[CH:57]=[CH:56][CH:55]=[C:54]([F:58])[C:28]=1[CH2:29][CH2:30][C@H:31]1[O:36][CH2:35][C@@H:34]([CH2:37][O:38][C:39](=[O:46])[NH:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:33](C(OC(C)(C)C)=O)[CH2:32]1>>[F:44][C:42]([F:43])([F:45])[CH2:41][NH:40][C:39](=[O:46])[O:38][CH2:37][C@@H:34]1[CH2:35][O:36][C@H:31]([CH2:30][CH2:29][C:28]2[C:54]([F:58])=[CH:55][CH:56]=[CH:57][C:27]=2[NH:26][C:5](=[O:6])[C@H:4]([C@H:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[NH2:1])[CH2:32][NH:33]1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccnc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccnc2ccccc12

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 of Example 99 using the procedures given in steps 2-4 of Example 93. MS (ES) m/z=688 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].C(C1CCOC1=O)=C>CO>[O:2]1[CH2:3][CH2:4][CH:5]([C:6]([O:7][CH3:8])=[O:10])[CH2:9][CH2:1]1
Reactant: COCCC1CCOC1=O
Agent: C=CC1CCOC1=O
Solvent: CO
Product: COC(=O)C1CCOCC1
Yield: 26 %

Procedure:
The patent examples demonstrate that when operating in the gas phase in the presence of fluidized Al2O3 catalysts at a temperature of from 240° to 270° C. yields of tetrahydropyrancarboxylate of only 36 to 42% are achieved (based on 3-(2'-hydroethyl)-dihydro-2(3H)furanone used)(Examples 1 and 2). The by-products formed under these conditions comprise from 18 to 20 % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and from 16 to 27% of 3-vinyldihydro-2(3H)furanone. Example 1b demonstrates that the by-product 3-(2'-methoxyethyl)-dihydro-2(3H)furanone can be reacted with methanol to form methyl tetrahydropyran-4-carboxylate to give a yield of 26%. On the other hand, the reaction of the by-product 3-vinyldihydro-2(3H)furanone with methanol as described in Example 1c provides a yield of only 10%.
Reaction SMILES: CS(OC[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:35][O:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][N:42]([CH2:45]CN)[CH2:41][CH2:40]1>C(N(CC)CC)C>[CH3:35][O:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][N:42]([CH2:45][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[N:16]=[CH:17][C:22]4[CH2:21][CH:20]([C:19]5[CH:18]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:23]=4[N:24]=3)=[CH:12][CH:13]=2)[CH2:43][CH2:44]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2)C3)cc1
Reactant: COCCN1CCN(CCN)CC1
Solvent: CCN(CC)CC
Product: COCCN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-phenyl-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, 2-(4-(2-methoxyethyl)piperazin-1-yl)ethanamine and triethylamine as described in general procedure 2 to afford the desired product. Yellow solid (34%). M.p.=52-54° C. 1H NMR 400 MHz (CDCl3) δ 8.40 (d, J=7.6 Hz, 1H), 8.17 (s, 1H), 7.63 (d, J=8.4 Hz, 2H), 7.43 (t, J=6.4 Hz, 1H), 7.38 (t, J=6.4 Hz, 1H), 7.29-7.21 (m, 6H), 7.14 (d, J=2.0 Hz, 2H), 7.01 (d, J=7.6 Hz, 1H), 4.30 (t, J=7.2 Hz, 1H), 3.52 (t, J=6.0 Hz, 2H), 3.36 (s, 3H), 3.22-3.06 (m, 2H), 2.81 (t, J=8.0 Hz, 2H), 2.64-2.50 (m, 12H). LCMS m/e 520 (M+H).
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[F:7][C:8]1[CH:9]=[C:10]([S:15](Cl)(=[O:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].[OH-].[Na+].OS(O)(=O)=O>O.O1CCOCC1>[F:7][C:8]1[CH:9]=[C:10]([S:15]([OH:17])=[O:16])[CH:11]=[CH:12][C:13]=1[F:14]
Reactant: O=S(=O)(Cl)c1ccc(F)c(F)c1
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(O)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.6 %

Procedure:
To sodium sulfite (22.2 g, 176 mmol) in 80 ml water at RT was added dropwise over 20 min a solution of 3,4-difluoro-benzenesulfonyl chloride (5.00 g, 23.5 mmol) in 40 ml dioxane. 1 M aq NaOH (40 ml) was then added dropwise until the reaction mixture was pH 14 and the mixture was then allowed to stir at RT for a further 16 h. The mixture was then cooled to 0° C. and concentrated H2SO4 added until the reaction mixture was pH 1. The mixture was extracted three times with ethyl acetate and the combined organic phases washed with saturated aq NaCl solution and then dried with Na2SO4. Evaporation in vacuo yielded the title compound (4.21 g, 97%) as a white crystalline solid. MS (ISN): 177.1 M−H−
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]1)C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC1CCNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl (1-benzylpyrrolidin-3-yl)methylcarbamate (3.0 g, 10.33 mmole) in EtOAc (100 ml) was added Pd(OH)2 on carbon (0.3 g). The mixture was stirred under H2 balloon at room temperature for 3 h and filtered through Celite. The filtrate was concentrated to give colorless oil (1.87 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22].Br[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]4)=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc(N)c(F)c3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(N)c(F)c4)c3cc2C#N)CC1
Yield: 50.7 %

Procedure:
4-(4-Amino-3-fluorophenoxy)-7-hydroxy-6-quinolinecarbonitrile (500 mg), tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate (550 mg), potassium carbonate (700 mg) and dimethylformamide (5 ml) were stirred together at 60° C. for 2 hours. Water and ethyl acetate were added for extraction, and the extract was dried over magnesium sulfate. The drying agent was filtered out, and silica gel was added to the filtrate which was then distilled off under reduced pressure for adsorption. The reaction solution-adsorbed silica gel was subjected to column chromatography (hexane:ethyl acetate=1:1, followed by 1:2, 1:3, ethyl acetate) in a dry column packed with silica gel, to obtain 423 mg of a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:19][C:4]1[N:3]=[C:2]([C:23]2[CH:24]=[N:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 90 °C

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (6.8 g, 22.8 mmol), 5-chloropyridine-3-boronic acid (3.95 g, 25.1 mmol), cesium carbonate (22.3 g, 68.4 mmol), and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.67 g, 2.28 mmol) were combined in a vial that had been oven-dried and flushed with nitrogen. Dioxane (73 mL) and water (18 mL) were added, and the vial was sealed and heated to 90° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 6-chloro-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C19H20Cl2N4 [M+H]+ 375. found 375.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: NCc1ccccn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(=O)(=O)NCc2ccccn2)cc1
Reaction time: 0.08 h
Yield: 52.7 %

Procedure:
Ex-53A: A solution of 4-acetyl-benzenesulfonyl chloride (1.94 g, 8.89 mmol) and triethylamine (1.85 mL, 13.3 mmol) in anhydrous THF (15 mL) was treated with 2-(aminomethyl)pyridine (1.01 g, 9.34 mmol) at room temperature under nitrogen. The reaction mixture was stirred for 5 minutes and a precipitate formed. The reaction mixture was diluted with water (10 mL) and suction filtration gave 4-acetyl-N-pyridin-2-ylmethylbenzenesulfonamide as a yellow solid (1.36 g, 65%). 1H-NMR (300 MHz, DMSO-d6) 8.38 (m, 3H), 8.06 (d, 2H, J=9.0 Hz), 7.87 (d, 2H, J=7.8 Hz), 7.58 (d, 1H, J=8.7 Hz), 7.25 (dd, 1H, J=5.4, 4.5 Hz), 4.04 (d, 2H, J=3.9 Hz), 2.60 (s, 3H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]1C=C2C(C=CC(COC3C=C(C=CCC4C=CC=CC=4C(OC)=O)C=CC=3)=N2)=C[CH:7]=1.[SH:37][CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>>[SH:37][CH2:38][CH:39]([CH3:43])[C:40]([O:42][CH2:6][CH3:7])=[O:41]
Reactant: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reactant: CC(CS)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(C)CS

Procedure:
At -10° C., AlCl3 (2.437 g, 18.3 mmol) was added to a solution of the styrene of Step 7 (1.013 g, 2.28 mmol) and 3-mercapto-2-methylpropanoic acid (356 mg, 2.96 mmol, obtained from the hydrolysis of ethyl 3-mercapto-2-methylpropanoate (Example 1, Method B, Step 6) as in Example 7, Step 4, or alternatively from the NaOH hydrolysis of ethyl 3-(acetylthio)-2-methylpropanoate) in 25 mL of CH2Cl2 and the mixture was stirred at 0° C. in the dark for 2 h. Cold aq NH4OAc, EtOAc and THF were then added and the mixture was stirred until complete dissolution of the oil. The product was extracted with EtOAc:THF 1:1, dried over Na2SO4 and concentrated. The sodium salt of the acid was formed in EtOH with 500 μl of 10N NaOH. It was purified on an Amberlite ion exchange resin XAD-8: elution with water separate the sodium 3-mercapto-2-methyl-propanoate and elution with methanol afforded the title acid as an impure sodium salt. The compound was dissolved in saturated aq NH4Cl, extracted with EtOAc:THF 1:1, dried over Na2SO4 and purified by flash chromatography on silica using acetone:toluene:acetic acid 5:95:1 to yield 766 mg (60%) of the title acid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[O:7][CH:8]=[C:9]([C:11]([NH:13][C@@H:14]([CH3:30])[CH2:15][N:16]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[CH:22]=3)=[N:17]2)=[O:12])[N:10]=1)(=[O:5])[CH3:4]>C(O)C>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:11]([C:9]3[N:10]=[C:6]([CH:3]([OH:5])[CH3:4])[O:7][CH:8]=3)=[O:12])[CH3:30])[N:17]=2)[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)co1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Sodium borohydride (0.019 g, 0.498 mmol) was added into a flask and the atmosphere was replaced with nitrogen. Dry ethanol was added and the reaction mixture was cooled to 0° C. (S)-2-acetyl-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)oxazole-4-carboxamide (0.099 g, 0 0.249 mmol) was added and the reaction mixture was warmed slowly to RT while stirring overnight. The crude product was cooled to 0° C., the pH was adjusted to 6 and the mixture was evaporated. 5% of DCM/MeOH was added and the crude product was washed with 1M NaHCO3, water and dried. Yield 89%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 1.63 (d, 3H), 2.51 (s, 1H), 4.25-4.31 (m, 1H), 4.41 (dd, 1H), 4.54-4.63 (m, 1H), 5.00 (q, 1H), 6.61 (d, 1H), 7.49 (d, 1H), 7.68 (d, 1H), 7.70 (d, 1H), 7.86-7.89 (m, 1H), 7.95-7.96 (m, 1H), 8.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([CH3:27])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:18]C)=[C:9]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br>>[CH:15]1([CH2:14][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([CH3:1])=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][C:20]=3[CH3:27])[CH:6]=[CH:7][C:8]=2[OH:18])(=[O:13])=[O:12])[CH2:17][CH2:16]1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1S(=O)(=O)CC1CC1
Agent: BrB(Br)Br
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Cyclopropylmethanesulfonyl-4-(2,6-dimethyl-4-nitro-phenoxy)-phenol was prepared from 5-(2,6-dimethyl-4-nitro-phenoxy)-2-methoxy-cyclopropylmethanesulfonylbenzene according to a procedure analogous to that described in EXAMPLE 2, Step B. Boron tribromide (1M in dichloromethane, 2.0 equiv) was used. After 30 minutes, ice water (50 ml) was added to quench the reaction, and the mixture was extracted with dichloromethane (3×25 ml). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was dissolved in ethyl acetate/methanol and stirred with activated carbon, then filtered through Celite® and concentrated. The title product of Step C was used in the next step without further purification. MS (APCI−) Calc.: 377.4, Found: 376.1 (M−1).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][O:11]1)=[O:10]>CCOCC>[OH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=1[C:9]([NH:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: NNc1ccccc1
Reactant: O=C1OCc2ccccc21
Solvent: CCOCC
Product: O=C(NNc1ccccc1)c1ccccc1CO
Temperature: 20 °C

Procedure:
The method adopted is disclosed in Wislicenus (Berichte 20 401). Phenyl hydrazine (27 ml) and phthalide (33 g ) were heated together at 70° to 80° C. for 3 hours. After cooling to 20° C. the solid product was stirred with ether (100 ml) and the product collected by filtration, washed with ether and recrystallised from 2-propanol. Yield 9.6 g (16%) melting point 170°-172° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[CH3:35])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: Cn1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21
Temperature: 23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50.0 mg, 0.108 mmol), triphenylphosphine (85 mg, 0.325 mmol), methanol (13 ml, 0.791 mmol) and methylene chloride (5 mL) was added diethyl azodicarboxylate (51 ml, 0.325 mmol) at 0° C. The reaction was allowed to warm to 23° C. After 2.5 h, an additional 2 equivalents of methanol, triphenylphosphine, and diethyl azodicarboxylate were added. After 16 h, the reaction was concentrated in vacuo and the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole (30) which was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-methyl-7-aza-indole (158) as described in example 6: Mass Spectrum (CI) 376 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[Cl-].[S:19]1[C:23]([C@:24]23[CH2:32][NH2+:31][CH2:30][C@H:29]2[CH2:28][S:27][C:26]([NH:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:25]3)=[CH:22][CH:21]=[N:20]1.O>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[N:4][C:5]([N:31]2[CH2:30][C@@H:29]3[C@@:24]([C:23]4[S:19][N:20]=[CH:21][CH:22]=4)([N:25]=[C:26]([NH:33][C:34](=[O:41])[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[S:27][CH2:28]3)[CH2:32]2)=[N:6][CH:7]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: O=C(NC1=N[C@@]2(c3ccns3)C[NH2+]C[C@H]2CS1)c1ccccc1
Agent: [Cl-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1=N[C@@]2(c3ccns3)CN(c3ncc(F)cn3)C[C@H]2CS1)c1ccccc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
5-Fluoro-2-chloropyrimidine (58 mL, 608.3 mol), and diisopropylethylamine (227 mL 1.30 mol, 227.3 mL) is added to N-[(4aR,7aR)-7a-isothiazol-5-yl-4a,5,6,7-tetrahydro-4H-pyrrolo[3,4-d][1,3]thiazin-6-ium-2-yl]benzamide chloride (174.2 g, 434.5 mol), in N-methylpyrrolidone (1.4 L) at 22° C. and stirred. The reaction is heated at 100° C. for 4 hours and then cooled to room temperature. The crude mixture is added to water (14 L) and then stirred 1 hour. A white solid is collected by filtration and dried under vacuum to constant weight. The crude product is purified by silica gel chromatography, eluting with ethyl acetate: methylene chloride (3/1) to give the title compound (139 g, 72%). ES/MS (m/e): 441.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[BH4-].[Na+].Cl>CO>[NH2:11][CH2:10][C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([Br:1])[C:3]=1[CH3:12]
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1[nH]c(=O)c(CN)c(C)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To a stirred solution of 5-bromo-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1 g, 4.44 mmol) and NiCl2.6H2O (0.21 g, 0.89 mmol) in methanol at 0 oC, NaBH4 (0.68 g, 17.78 mmol) was added portion wise. Reaction mixture was then stirred at rt for overnight period. On completion, it was acidified using 3N HCl and stirred at rt for 3 h. Solvent was removed under reduced pressure. Residue was washed with diethyl ether and basified with aq. NH4OH. Compound was extracted in 10% MeOH in DCM and dried over anhydrous Na2SO4 to give the title compound (0.96 g, 94%) which was used as such for coupling reaction.
Reaction SMILES: C(OC(=O)C(OCC)CC1C=CC(O)=CC=1C)C.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:28][CH:29]=[C:30]([CH2:32]CO)[N:31]=2)=[CH:23][CH:22]=1.COC1C=CC(C(N)=S)=CC=1.[Cl:46]CC(CCl)=O>>[Cl:46][CH2:32][C:30]1[N:31]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[S:28][CH:29]=1
Reactant: O=C(CCl)CCl
Reactant: COc1ccc(-c2nc(CCO)cs2)cc1
Agent: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: COc1ccc(C(N)=S)cc1
Product: COc1ccc(-c2nc(CCl)cs2)cc1

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with 2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethanol (prepared from 4-methoxy-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a] to yield 4-chloromethyl-2-(4-methoxy-phenyl)-thiazole, followed by side chain elongation in analogy to the sequence described in example 13 a] to 13 d]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield [rac]-2-ethoxy-3-(4-{2-[2-(4-methoxy-phenyl)-thiazol-4-yl]-ethoxy}-2-methyl-phenyl)-propionic acid ethyl ester as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][N:16]2[CH:24]=1.CC1ON=C(C2C=CC=CC=2)C=1C1N=[C:39]2[CH:44]=[C:43](C(O)=O)[CH:42]=[CH:41][N:40]2C=1>>[CH:41]1([NH:40][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=3)[CH:17]=2)=[O:23])[CH2:42][CH2:43][CH2:44][CH2:39]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)O)ccc2n1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(C(=O)NC3CCCC3)ccc2n1
Yield: 85 %

Procedure:
As described for Example 15, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-6-carboxylic acid (96 mg, 0.3 mmol), instead of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid, was converted to the title compound (98 mg, 85%) which was obtained as a light yellow foam. MS: m/e=387.3 [M+H]+.