Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].Cl.[CH3:15]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:15])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C

Procedure:
In a 1 liter round-bottomed flask were placed 25 g (0.14 mole) 3-hydroxy-4-nitrobenzoic acid, 37% hydrochloric acid (37 ml) and methanol (300 ml). The resulting mixture was refluxed for 10 hours. The reaction mixture was cooled to room temperature and the solvent eliminated in a rotary evaporator. The resulting residue was dissolved in ethyl acetate and washed sequentially with water (1×100 ml), aqueous sodium bicarbonate (1×100 ml), water (1×100 ml) and brine (1×100 ml). The organic layer was dried over anhydrous magnesium sulfate and solvent was removed in the rotary evaporator, yielding 22.5 g of the expected methyl 3-hydroxy-4-nitrobenzoate as a yellow solid which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](S(C3C=CC=CC=3)(=O)=O)[CH:9]=2)[N:5]=[C:4]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]2)[N:3]=1.[CH:34]1([S:37](Cl)(=[O:39])=[O:38])[CH2:36][CH2:35]1.C(N(CC)CC)C.[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>C1COCC1>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[N:5]=[C:4]([NH:26][C@H:27]2[CH2:32][CH2:31][C@H:30]([NH:33][S:37]([CH:34]3[CH2:36][CH2:35]3)(=[O:39])=[O:38])[CH2:29][CH2:28]2)[N:3]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)CC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: O=S(=O)(N[C@H]1CC[C@H](Nc2nc(Cl)cc(-c3c[nH]c4ncccc34)n2)CC1)C1CC1
Temperature: 85 °C

Procedure:
A mixture of Example 275a (350 mg, crude, 0.414 mmol), cyclopropanesulfonyl chloride (116 mg, 0.828 mmol), and triethylamine (0.058 mL, 0.414 mmol) in THF (5 mL) was stirred at room temperature for 1 day and concentrated in vacuo. To the residue was added dioxane (5 mL) and NaOH (20%, 1 mL) and the mixture was heated at 85° C. for 1 hour. The reaction mixture was concentrated and purified by reverse-phase HPLC performed on a Phenomenex Luna C8 AXIA column (30×75 mm, 100 Å) using a gradient of 10% to 95% acetonitrile: 0.1% aqueous trifluoroacetic acid over 12 minutes at a flow rate of 50 mL/minutes to give the title compound (17 mg, 9.2% yield) as trifluoroacetic acid salts. MS (ESI) m/e 447 (M+H)+; 1H NMR (400 MHz, DMSO-d6) ppm 0.94 (d, J=6.41 Hz, 4H) 1.35-1.53 (m, 4H) 1.99-2.11 (m, 4H) 2.50-2.57 (m, 1H) 3.15-3.25 (m, 1H) 3.71-3.82 (m, 1H) 6.66-6.79 (m, 1H) 7.08 (s, 1H) 7.18 (dd, J=7.93, 4.58 Hz, 1H) 8.29 (dd, J=4.73, 1.68 Hz, 1H) 8.35 (s, 1H) 8.79 (d, J=7.02 Hz, 1H) 12.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (2 g, 13.02 mmol) was dissolved in 20 mL dimethylformamide. N-Bromosuccinimide (2.55 g, 14.33 mmol) was added under argon atmosphere. The reaction was stirred at room temperature overnight. The crude was poured into water and the precipitate formed was filtered and washed with water. The yellow solid obtained was dried in the vacuum oven to give 2.77 g (91.5% yield) of the title compound. Purity 99%.
Reaction SMILES: Br[CH:2]([CH:8](Br)[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[Cl:15])[C:3]([O:5]CC)=[O:4].[OH-].[K+]>>[Cl:15][CH:10]1[CH:9]([C:8]#[C:2][C:3]([OH:5])=[O:4])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(Br)C(Br)C1CCCCC1Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)C#CC1CCCCC1Cl

Procedure:
Powdered ethyl α,β-dibromo-β-(3-chloro-4-cyclohexyl)propionate (33.0 g.) is added portion-wise to 20% ethanolic potassium hydroxide (135 ml) at room temperature. The mixture is refluxed on a steam bath for 6 hours. The alcohol is evaporated and the residue is dissolved in water and covered with ether and is acidified with cold, dilute hydrochloric acid. The ether layer is washed with water, saline, and dried over sodium sulfate. The ether is removed to give a residue which is triturated with carbon tetrachloride. Recrystallization is carried out from acetic acid-water. This material is digested and triturated with boiling carbon tetrachloride to give 3-chloro-4-cyclohexylpropiolic acid.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.[CH3:27][CH:28]1[O:33][CH:32]([CH3:34])[CH2:31][NH:30][CH2:29]1>ClCCl>[Cl:17][C:15]1[CH:14]=[C:13]2[C:9]([CH:10]=[N:11][N:12]2[S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[C:8]([C:6]2[O:7][C:3]([CH2:2][N:30]3[CH2:29][C@@H:28]([CH3:27])[O:33][C@H:32]([CH3:34])[CH2:31]3)=[CH:4][N:5]=2)[CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3ncc(CBr)o3)cc(Cl)cc21
Reactant: CC1CNCC(C)O1
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H](C)O1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[5-(bromomethyl)-1,3-oxazol-2-yl]-6-chloro-1-(phenylsulfonyl)-1H-indazole (750 mg, 1.657 mmol) in dichloromethane (50 mL) stirred in air at room temp, was added neat 2,6-dimethylmorpholine (191 mg, 1.657 mmol, available from Aldrich as a mixture of isomers). The reaction mixture was stirred at 20° C. for 20 hr. Volatiles were removed using a rotary evaporator then the crude material was pre-absorbed onto Fluorosil™ and purified by column chromatography on silica (100 g) using a 0-100% ethyl acetate-cyclohexane gradient over 60 mins. Two diastereoisomers were isolated. Appropriate fractions were combined and evaporated in vacuo to give the title compound as a yellow oil (226 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[C:11](I)=[CH:12][N:13]=[C:7]2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Na+:19].[Na+].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Na+:19].[Cl:21][C:22]1[CH:27]=[C:26]([C:11]2[N:8]3[CH:9]=[CH:10][C:5]([C:3]([O-:2])=[O:4])=[CH:6][C:7]3=[N:13][CH:12]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COC(=O)c1ccn2c(I)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C([O-])c1ccn2c(-c3cccc(Cl)c3)cnc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.7 %

Procedure:
A mixture of 3-iodo-imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (230 mg, 0.76 mmol), Pd(PPh3)4 (44 mg, 0.038 mmol), Na2CO3 (161 mg, 1.52 mmol) and 3-chlorophenylboronic acid (131 mg, 0.84 mmol) was heated at reflux for 1 hour. The mixture was then allowed to cool and concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and water (25 mL) and 50% NaOH (5 mL) was added. The mixture was allowed to stir at room temperature for 15 hours then concentrated in vacuo. The mixture was triturated with ethyl acetate (20 mL) and the resulting solid was filtered to afford 3-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid sodium salt (100 mg, 58%) The mixture was dissolved in DMF (2 mL) and EDC (100 mg, 0.52 mmol) and HOBt (70 mg, 0.52 mmol) were added. The mixture was allowed to stir for 10 minutes and 4-aminomethyltetrahydropyran (0.075 mL, 0.52 mmol) was added. The mixture was stirred for 2 hours then poured into water (15 mL) and the product extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-(3-chlorophenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide. 1H NMR (DMSO-d6) δ 8.75 (1H), 8.65 (1H), 8.25 (1H), 8.00 (1H), 7.80 (1H), 7.70 (1H), 7.60 (1H), 7.52 (1H), 7.41 (1H), 3.85 (2H), 3.32 (2H), 3.20 (2H), 1.83 (1H), 1.60 (2H), 1.22 (2H); m/z (M+H)=370.05.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:34]1[S:35][C:36]([CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:37][N:38]=1>>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[S:35][C:36]([CH2:39][N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]3)=[CH:37][N:38]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Clc1ncc(CN2CCCCC2)s1
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)s2)cc1
Yield: 110 %

Procedure:
Using an analogous procedure to that described in Method 44, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 1-[(2-chloro-1,3-thiazol-5-yl)methyl]piperidine (108 mg, 0.5 mmol) to give the title compound (271 mg, >100%) which was carried through the next step; Mass Spectrum: M+H+ 493.
Reaction SMILES: [F:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])(=[O:4])=[O:3].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[CH:14]1([NH:20][C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([F:1])(=[O:4])=[O:3])=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C=Nc1ccccc1S(=O)(=O)F
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Reaction time: 8 h

Procedure:
To a stirred solution of 2-fluorosulphonyl phenyl isocyanate (804 g, 4 moles) in benzene (4 l), cyclohexylamine (457 ml, 4 moles) was added dropwise, whilst the temperature was kept at 60°. The mixture was left standing overnight at room temperature, whereupon the product was collected, washed with benzene (4 l) and dried. Yield : 1070-1090 g (89-90 %), melting point: 177° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].[C:23]([O:27][C:28]([N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1B(O)O)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:21][C:19]([C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([C:31]3[N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH:34]=[CH:33][CH:32]=3)[CH:3]=1)[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(-c2cccn2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (23 g, 62.47 mmol) in DME (300 mL) and water (30 mL) were added 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (14.50 g, 68.72 mmol), Na2CO3 (19.87 g, 187.41 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.877 g, 1.25 mmol). The mixture was degassed with argon and heated to 80° C. for 7 h. Reaction was cooled down and concentrated, the residue was dissolved in 300 mL of DCM and 300 mL of water. The organic phase was decanted, washed with brine then dried over MgSO4, filtered and concentrated to afford a crude compound which was purified on silica, eluting with 80% AcOEt in DCM. The solvents were evaporated to afford tert-butyl 2-(6-(methoxycarbonyl)-2-morpholino-4-oxo-4H-chromen-8-yl)-1H-pyrrole-1-carboxylate (20 g, 70%) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[CH:11][CH:10]=1)([OH:8])[CH3:7])C.[OH-].[K+]>C(O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([C:6]([OH:8])([CH3:7])[CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
10 g. of 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester are dissolved in 50 ml. of ethanol and the solution is heated under reflux with 2 g. of KOH for 3 hours, evaporated and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 121°-123°.
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54][O:55][CH3:56])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([O:15][CH3:16])=[O:14])([CH3:7])[CH3:6].[C:57](=[O:59])=[O:58]>O.O1CCOCC1>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:54][O:55][CH3:56])[N:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[N:34]([C:35]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:12]=1[C:13]([O:15][CH2:16][O:58][C:57](=[O:59])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:14])([CH3:6])[CH3:7]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COCc1nc(C(C)(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 41.9 mg of lithium hydroxide monohydrate in 15 ml of water was added, whilst ice-cooling, to a solution of 0.75 g of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 82(a)] in 15 ml of dioxane, and the mixture was stirred at room temperature overnight. At the end of this time, a small quantity of dry ice was added to the reaction solution, and the dioxane was removed by distillation under reduced pressure. The residue was then dissolved in a small quantity of an aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dried in vacuo at 50° C. for 1 hour. 0.25 g of potassium carbonate were then added to a solution of the resulting residue in 10 ml of N,N-dimethylacetamide, and the mixture was cooled with ice-water. A solution of 0.31 ml of pivaloyloxymethyl chloride in 3 ml of N,N-dimethylacetamide was then added dropwise to the mixture, which was then stirred at 70° C. for 1.5 hours. At the end of this time, water and ethyl acetate were added to the reaction solution. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.79 g of the title compound as a foam-like solid.
Reaction SMILES: Br[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([S:16]([C:19]2[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:11]=[C:10]3[C:26]2[CH:31]=[N:30][CH:29]=[C:28]([CH:32]3[CH2:34][CH2:33]3)[N:27]=2)=[N:5][N:6]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CN1C(=O)CCC1.C(Cl)Cl>[CH:32]1([C:28]2[N:27]=[C:26]([C:10]3[C:9]4[C:13](=[CH:14][CH:15]=[C:7]([C:4]5[O:3][C:2]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[N:6][N:5]=5)[CH:8]=4)[N:12]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:11]=3)[CH:31]=[N:30][CH:29]=2)[CH2:34][CH2:33]1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(Br)o4)ccc32)cc1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(C4CC4)n3)c3cc(-c4nnc(N5CCCC5)o4)ccc32)cc1
Yield: 66.2 %

Procedure:
A brown-orange solution of 2-bromo-5-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazole (35.0 mg, 0.065 mmol) and pyrrolidine (16.2 μL, 0.195 mmol) in NMP (1.0 mL) was heated in a sealed microwave process vial under argon at 120° C. for 18 h. The mixture was then diluted with DCM (5 mL), concentrated onto silica gel, and chromatographically purified (silica gel, 0-10% MeOH/DCM) to provide 2-(3-(6-cyclopropylpyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-5-(pyrrolidin-1-yl)-1,3,4-oxadiazole (22.7 mg, 0.043 mmol, 66%) as a yellow oil: MS (ESI, pos. ion) m/z: 527.2 (M+1).
Reaction SMILES: [CH3:1][C:2](=[CH2:5])[CH:3]=O.Cl[CH:7]([C:13]([CH3:15])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(=O)C.[Na+]>C(O)(=O)C>[OH:14][C:13]1[CH:15]=[CH:3][C:2]([CH3:5])=[CH:1][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: C=C(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)ccc1O
Temperature: 25 °C
Yield: 70.6 %

Procedure:
A stirred mixture of 2-methylacrolein (22.8 g, 92%, 0.30 mol), ethyl 2-chloroacetoacetate (41.1 g, 95%, 0.25 mol) and anhydrous sodium acetate (24.6 g, 0.30 mol) in acetic acid is heated at reflux temperature under N2 for 16 hr., cooled to room temperature and concentrated in vacuo to give a residue. The residue is partitioned between ethyl acetate and water. The organic phase is concentrated in vacuo to give the title product as an oil, 44.2 g, 71.9% purity (70.6% yield), characterized by NMR analysis).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:3]1.Cl.O[N:32]=[C:33]([NH2:36])[CH2:34][CH3:35]>>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:27][N:36]=[C:33]([CH2:34][CH3:35])[N:32]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CCC(N)=NO
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Agent: Cl
Product: CCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 208A) and 56.2 mg (0.451 mmol) of N′-hydroxypropanimidamide hydrochloride were reacted according to the General Method 1. Yield: 80.6 mg (42% of theory).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)([O-])O.[Na+]>C1COCC1>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][N:17]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:23][CH2:22]2)=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)N(CCCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(NC(=O)N(CCCN2CCC(Cc3ccccc3)CC2)c2ccccc2)CC1
Yield: 60 %

Procedure:
The compound obtained in Example 13 (435 mg, 1.00 mmol) and triethylamine (0.335 ml) were dissolved in THF (10 ml). To the solution was added methanesulfonyl chloride (0.155 ml) under ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 ml) under ice cooling, and the mixture was extracted with ethyl acetate (15 ml×3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1 to 4/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were filtered off. The filtrate was concentrated under reduced pressure. To the concentrate was added diethyl ether and resulting precipitates were collected by filtration The precipitates were washed with diethyl ether, and dried under reduced pressure to give the titled compound (310 mg, 0.60 mmol, Yield 60%) as white solid.
Reaction SMILES: [CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[C:34]([F:36])[F:35])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pd]>[CH:1]1([CH:6]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH:34]([F:35])[F:36])=[CH:29][CH:28]=2)[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:24]=[CH:25][CH:26]=2)[CH2:13][C:14]2([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:16][CH2:15]2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(C=C(F)F)cc3)C3CCCC3)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(Cc2cccc(NC(=O)C(c3ccc(CC(F)F)cc3)C3CCCC3)c2)CC1
Reaction time: 8 h

Procedure:
100 mg of Pd/C (10%) were added to a solution of 200.0 mg (0.404 mmol) of (+/−)-tert-butyl 1-[3-({cyclopentyl[4-(2,2-difluorovinyl)phenyl]acetyl}amino)benzyl]cyclopropanecarboxylate in 5 ml of ethanol. Under atmospheric pressure, the mixture was stirred vigorously under an atmosphere of hydrogen overnight. The reaction was then filtered off through Celite and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 151.1 mg (75.2% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=O)[O:6][C:5]2=[CH:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.O.[NH2:20][NH2:21].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:6])[NH:21][N:20]=[C:5]2[CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=Cc2cccnc2)c2cc(Cl)ccc21
Reactant: NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(Cc2cccnc2)c2cc(Cl)ccc12

Procedure:
5-Chloro-3-(pyrid-3-yl)methylenephthalide (2.68 g) was dissolved in 100 ml of ethanol, followed by the addition of 2.0 ml of hydrazine monohydrate. The obtained mixture was heated under reflux for 4 hours, followed by the addition of 200 ml of water. The resulting mixture was neutralized with dilute hydrochloric acid to precipitate crystals, which were recovered by filtration to give 1.87 g of the title compound as a yellow powder.