Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].CCN=C=NCCCN(C)C.Cl.[NH2:34][C:35]1[CH:59]=[CH:58][C:57]([N:60]2[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]2)=[CH:56][C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[N:42][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=2)=[N:44][CH:45]=1)=[O:38]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][N:2]([CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[C:3](=[O:4])[C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([NH:34][C:35]2[CH:59]=[CH:58][C:57]([N:60]3[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]3)=[CH:56][C:36]=2[C:37](=[O:38])[NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=3)=[N:42][CH:41]=2)=[O:10])[CH:6]=1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2C(=O)Nc2cnc(-c3cccc(C(F)(F)F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid (186 mg, 0.64 mmol, 2.00 equiv) in dichloromethane (10 mL), EDC.HCl (92 mg, 0.48 mmol, 1.50 equiv), 4-dimethylaminopyridine (59 mg, 0.48 mmol, 1.50 equiv), and 2-amino-5-(piperidin-1-yl)-N-(2-(3-(trifluoromethyl)phenyl)pyrimidin-5-yl)benzamide (140 mg, 0.32 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 191 mg (71%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 10.97 (m, 2H), 9.66 (s, 1H), 9.25 (s, 2H), 8.63 (m, 2H), 7.99 (m, 4H), 7.79 (m, 1H), 7.63 (m, 2H), 7.42 (s, 1H), 7.26 (m, 1H), 3.99 (m, 2H), 3.83 (m, 2H), 3.61 (m, 4H), 3.43 (m, 2H), 3.24 (m, 6H), 2.95 (s, 3H), 1.59 (m, 6H). MS (ES, m/z): 716 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:4][C:3]=1[CH3:10]
Reactant: C1=COCCC1
Reactant: Cc1cc(O)cc(C)c1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(C)c1Br
Yield: 77.3 %

Procedure:
A solution of 4-bromo-3,5-dimethylphenol (10.5 g, 52.2 mmol), 3,4-dihydro-2H-pyran (8.83 g, 105 mmol) and pyridinium p-toluenesulfonate (2.64 g, 10.5 mmol) in dichloromethane (160 mL) was stirred at room temperature for 80 hrs. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-20% ethyl acetate/hexane) to give the title compound (11.5 g, yield 77%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[C:34]([C:36]([O:38][CH3:39])=[O:37])[CH:33]=[CH:32][C:31]=1B(O)O>>[CH3:39][O:38][C:36]([C:34]1[CH:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)=[C:30]([F:29])[CH:35]=1)=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)c(F)c1
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)c(F)c1

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 2-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as a colorless solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: [Cl-].[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH3+:14])[CH3:13])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].C([O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)=[O:21])(C)(C)C>>[CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:44]([C:40]2[CH:39]=[C:38]3[C:43](=[CH:42][CH:41]=2)[N:35]([CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]4[C:22]([C:20]([OH:21])=[O:19])=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:33][CH:32]=2)[C:36]([CH3:48])=[C:37]3[CH3:47])=[O:45])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1ccc([C@H](C)[NH3+])cc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccc(OC(C)C)cc3)cc12

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(4-isopropoxyphenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 560 [M+1]+.
Reaction SMILES: [OH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10]O>OS(O)(=O)=O>[OH:1][C:2]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(O)C1(O)CCCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1(O)CCCC1
Temperature: 65 °C
Yield: 92 %

Procedure:
A solution of 1-hydroxycyclopentanecarboxylic acid (1.4 g, 10.76 mmol) in MeOH (10 mL) was treated with conc. H2SO4 (1 drop), heated at 65° C. for 2 h, cooled to RT and concentrated to dryness. The residue was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford methyl 1-hydroxycyclopentanecarboxylate (1.45 g, 92%). 1H NMR (400 MHz, CDCl3): δ 3.79 (s, 3H), 2.92 (br s, 1H), 2.11-2.00 (m, 2H), 1.91-1.83 (m, 2H), 1.82-1.72 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11]O>>[C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CO
Product: COC(=O)Cc1ccccc1

Procedure:
Dissolved 13 g (0.1 mol) of phenylacetic acid in 500 ml of anhydrous methanol. Introduced HC1 gas, while refluxing for 3 hours. The solvent was then removed by evaporation. Dissolved the ester in benzene, which was successively washed with water and 10% NaOH. The organic layer was dehydrated with anhydrous magnesium sulfate. The solvent was again removed by evaporation. Methyl phenylacetate was finally purified by column chromatography employing silica gel chloroform system. The solvent was removed by evaporation to yield yellowish liquid. Yield, 6 g (40% ).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Cl:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(Cl)sc21
Product: CC1c2sc(Cl)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-chloro-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]1([CH:17]([N:19]2[CH2:30][CH:22]3[C:23]4[CH:24]=[CH:25][S:26][C:27]=4[C:28](=O)[CH:21]3[CH2:20]2)[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.ClCCl>[CH2:1]=[C:28]1[C:27]2[S:26][CH:25]=[CH:24][C:23]=2[CH:22]2[CH2:30][N:19]([CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:18])[CH2:20][CH:21]12
Reactant: CC(c1ccccc1)N1CC2C(=O)c3sccc3C2C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=C1c2sccc2C2CN(C(C)c3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Potassium bis(trimethylsilyl)amide (308 mg, 1.55 mmol) was added to a solution of methyl triphenylphosphonium bromide (575 mg, 1.61 mmol) in 7 mL of THF at 0° C. After 30 minutes of stirring at 0° C., the product from step e) (303 mg, 1.07 mmol) dissolved in 2 mL of THF was added to the reaction mixture and was allowed to come to room temperature over 1 hour. The reaction mixture was diluted with dichloromethane (30 mL) and was washed with brine, dried (MgSO4) and concentrated to an oil. The crude was purified by column chromatography (SiO2) using 5-55% ethylacetate-hexane gradient to afford the subtitle compound (226 mg, yield: 74.8%). MS calculated for C18H19NS +H: 282, observed: 282.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[F:21][C:22]([F:28])([F:27])[C:23]1([NH2:26])[CH2:25][CH2:24]1>>[F:21][C:22]([F:28])([F:27])[C:23]1([NH:26][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: NC1(C(F)(F)F)CC1
Product: O=C(NC1(C(F)(F)F)CC1)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 1-(trifluoromethyl)cyclopropanamine (CAN 112738-68-8) as starting materials. MS (EI): m/e=392.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([Cl:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:13]([Cu])#[N:14].CN(C=O)C>C(Cl)Cl>[Cl:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([C:13]#[N:14])[CH:11]=2
Reactant: N#C[Cu]
Reactant: Clc1cnc2cc(Br)ccc2c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2cc(Cl)cnc2c1
Temperature: 150 °C

Procedure:
To a flask containing a stir bar was added 7-Bromo-3-chloroquinoline (1.0 g, 4.1 mmol), CuCN (0.55 g, 6.2 mmol), and DMF (25 mL). The mixture was then refluxed at 150° C. overnight. When the reaction was complete, as evidenced by LC analysis, the reaction flask was taken out of the oil bath and cooled to room temperature. To the reaction mixture was then poured DCM (20 mL) and a precipitate formed immediately, which was filtered off. The crude product was adsorbed onto silica gel and purified by silica gel column chromatography (Hexanes:DCM→1:1) to provide the title product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)([CH2:23][CH3:24])[CH2:19][OH:20])=[CH:30][CH:29]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (5 g, 11.3 mmol), as described in Example 3 Step A, in tetrahydrofuran (50 mL) was added lithium aluminium hydride (644 mg, 16.95 mmol) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. Water (10 mL) was carefully added to the reaction mixture, then extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (30/1 to 10/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=359.9 [M-tBu+H]+.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([CH2:25][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[S:1][CH:2]=[CH:3][C:4]2=3)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 10.71 g of 5,6,7,8-tetra-hydro-4H-thieno[3,2-b]azepine and 19.4 ml of triethylamine in 150 ml of dichloromethane under argon is added in small portions 4-nitrobenzoyl chloride (exothermic). The mixture is stirred for 3 hours at 25° C. and then washed with water, sodium bicarbonate solution, brine and dried (Na2SO4). The solvent is removed, the residue dried under vacuum and recrystallized by dissolving in hot ethyl acetate and diluting with hexane. Chilling overnight and filtering gives 16 g of light brown crystals, m.p. 141°-142° C.
Reaction SMILES: [C:1]1([C:7]([Mg]Br)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([C:15]1[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)[O:21][C:19]=2[N:20]=1)(=O)=O.[Cl-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:1]1([C:7]([C:15]2[N:16]=[C:17]([O:31][CH2:32][CH2:33][CH3:34])[C:18]3[N:23]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)[O:21][C:19]=3[N:20]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOc1nc(S(C)(=O)=O)nc2oc(-c3cccc(C)c3)nc12
Reactant: C=C([Mg]Br)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1nc(OCCC)c2nc(-c3cccc(C)c3)oc2n1
Reaction time: 1 h

Procedure:
298 mg of 1-phenyl-vinylmagnesium bromide were added to a solution of 500 mg of 5-methanesulfonyl-7-propoxy-2-(3-methyl-phenyl)-oxazolo[5,4-d]pyrimidine (example 5, step (f)) and 61 mg of lithium chloride in 20 ml of tetrahydrofuran. The reaction mixture was stirred for 1 h. Then 100 ml of ethyl acetate were added. The solution was extracted with 1 N hydrochloric acid, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude title compound.
Reaction SMILES: [CH:1]([CH:3]([C:14]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=1)[C:4](=O)[C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].Cl>C(O)C>[SH:24][C:23]1[N:25]=[C:4]([C:5]2[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=2)[C:3]([C:14]2[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[CH:16][CH:15]=2)=[CH:1][N:22]=1
Reactant: COc1ccc(C(=O)C(C=O)c2ccc(OC)cc2)cc1
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cnc(S)nc2-c2ccc(OC)cc2)cc1
Yield: 47.7 %

Procedure:
A solution of α-formyl desoxyanisoin (21.3 g, 75 mmole) and thiourea (9.75 g, 1.7 equiv) in 375 ml ethanol was treated with 3 N HCl (7.5 ml) and heated at reflux for 3.5 hours. The reaction mixture was concentrated on the rotary evaporator and the residue recrystallized from ethanol to give the title compound (11.6 g), m.p. 188°-191°. Infrared and H-NMR spectra were consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O=C1[N:44](P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.C(=O)([O-])[O-].[NH4+].[NH4+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](=[O:23])[NH2:44])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(N)=O)c2C1)Cc1cc(F)c(F)cc1F
Yield: 109.2 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.206 g, 1.08 mmol) and triethylamine (0.25 mL, 1.62 mmol) were dissolved in 10 mL of tetrahydrofuran under stirring. After stirring for 10 minutes, ammonium carbonate (78 mg, 0.81 mmol) was added. The reaction mixture was reacted at room temperature over-night and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-(1-carbamoyl-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 24a (0.162 g) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)C(C)C)(C)C.[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20]Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:15][O:16][CH2:17][CH2:18][O:19][CH2:20][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COCCOCCl
Reactant: c1cn[nH]c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCn1cccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 1H-pyrazole (13.6 g, 200 mmol) and N,N-diisopropylethylamine (68 mL, 400 mmol) in dichloromethane (150 mL), 2-methoxyethoxymethyl chloride (24.9 mL, 220 mmol) was added with cooling on ice. The reaction solution was stirred at room temperature for 2 hours, and an aqueous sodium hydrogencarbonate solution (500 mL) was then added to the reaction solution, followed by extraction three times with dichloromethane (500 mL). The organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:1) to yield the title compound (29.9 g, 96%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].O.C(=O)(O)[O-].[Na+].[F:25][C:26]([F:34])([F:33])[C:27]([F:32])([F:31])[C:28](O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=[CH:6][C:5]2[NH:17][C:28]([C:27]([F:32])([F:31])[C:26]([F:34])([F:33])[F:25])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(F)cc2F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Fc1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(F)c1
Yield: 16 %

Procedure:
A solution of 4-chloro-5-(2,4-difluorophenoxy)benzene-1,2-diamine (100 mg, 0.37 mmol) in pentafluoropropanoic acid (2 ml) was stirred overnight at 80° C. Then the mixture was poured into water (100 ml), adjusted pH to 7 with aqueous sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 5% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,4-difluorophenoxy)-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a white solid (24 mg, 16%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[P:17]([O-:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[CH2:19]([O:18][P:17]([O:21][CH2:22][CH3:23])([C:2]([OH:1])([CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[CH3:20]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)C(=O)CCNc1cccnc1
Product: CCOC(=O)C(O)(CCNc1cccnc1)P(=O)(OCC)OCC
Reaction time: 96 h

Procedure:
A mixture of 3.36 g (0.01 mole) of ethyl 2-oxo-4-(3-pyridylamino)butanoate in 6.9 g (0.05 mole) of diethyl phosphite is stirred at 20°-30° for 4 days. The excess diethyl phosphite is removed under vacuum on a rotary evaporator, and the crude product is purified by flash chromatography on silica gel using chloroform/ethanol as eluant.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Li][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])O.[Na+]>C(OCC)C>[CH3:9][C:7]1[S:8][C:4]([C:1]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)([OH:3])[CH3:2])=[C:5]([CH3:10])[N:6]=1
Reactant: CC(=O)c1sc(C)nc1C
Reactant: [Li]c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Cc1nc(C)c(C(C)(O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Acetyl-2,4-dimethylthiazole (2.5 g) in dry diethylether (10 ml) was added dropwise to a stirred solution of 3-lithiopyridine (from 3.5 g 3-bromopyridine) in diethylether at -70° C. After 3 hours the mixture was allowed to warm to room temperature. After a further 1 hour, aqueous sodium hydrogen carbonate was added and the organic layer was separated. The aqueous layer was extracted with diethylether. The material obtained from the combined organic layers was purified by flash chromatography to give the title compound, m.p. 107.5°-109° C.
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=2[CH:5]=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24]>>[F:16][C:17]1[CH:18]=[C:19]([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][C@@H:7]([NH:12][C:13](=[O:15])[CH3:14])[C:6]=3[CH:5]=[N:4][CH:3]=2)[CH:20]=[CH:21][C:22]=1[C:23]([F:24])([F:25])[F:26]
Reactant: CC(=O)N[C@@H]1CCCc2c(Br)cncc21
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Product: CC(=O)N[C@@H]1CCCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 83 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (+)-(R)—N-(4-bromo-5,6,7,8-tetrahydroisoquinolin-8-yl)acetamide (intermediate A-12) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as light grey solid in 83% yield. MS: 353.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])N=N[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH:28](N1CCCC1)=[CH2:29]>C(Cl)(Cl)Cl>[C:15]1([C:14]2[CH:28]=[CH:29][C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10][C:9]=2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1nnc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1
Reactant: C=CN1CCCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following General Procedure D, ethyl 5-(4-trifluoromethylphenyl)-6-phenyl-1,2,4-triazine-3-carboxylate (Compound 19, 1 g, 2.68 mmol) and crude 1-vinylpyrrolidine (Compound 38, 1.4 g) in CHCl3 (20 ml) were reacted to produce the title compound as a yellow oil.