Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15]C)=[O:14].[OH-].[K+].CO.Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCO
Product: COc1ccc2ccccc2c1C(=O)O
Temperature: 0 °C
Yield: 67.8 %

Procedure:
A solution of 21.6 g of the compound of Step A above in 48 ml of Claisen's alkali solution (solution of 21 g of KOH in 15 ml of water, made up to 60 ml with methanol) is heated at reflux for 4 hours. The reaction mixture is then diluted with 50 ml of water and poured into 75 ml of 15.5% hydrochloric acid solution cooled to 0° C. with stirring. The white precipitate formed is then filtered off over a Buchner funnel and then washed with water and dried under a phosphoric vacuum. The dry residue obtained is dissolved in a solution of ethanol and water (80:20, v/v) at boiling. After cooling to 0° C., 13.7 g of the expected product are obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([O:15][CH3:16])[C:9]=3[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:33])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:33][C:13]1[C:14]2[N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:7]=[C:8]([C:17]3[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[S:20][CH:21]=3)[C:9]=2[C:10]([O:15][CH3:16])=[N:11][CH:12]=1
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3ccnc(OC)c23)cs1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2nn(C3CCCC3)c3c(Br)cnc(OC)c23)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (103 mg) obtained in Step D of Example 12 in DMF (5 mL) was added NBS (56.4 mg) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (117 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].[NH2-:9].[Na+]>>[NH2:9][C:4]1[C:3]([OH:8])=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=1
Reactant: Cc1ccncc1O
Reactant: [NH2-]
Agent: [Na+]
Product: Cc1ccnc(N)c1O

Procedure:
A mixture of 218.0 g of 4-methyl-3-pyridinol and 78.0 g of sodium amide are placed in a pressure vessel and heated at 150° for 6 hours. The vessel is allowed to cool, the solid mass is removed and added portionwise to 1 l. of cold 2-propanol. Subsequently, 20% aqueous acetic acid is added until the pH is 5.5 and the whole concentrated to dryness in vacuo. The residue is extracted thoroughly with chloroform and the chloroform extracts washed with saturated aqueous sodium chloride, dried and concentrated. The residue is fractionally crystallized from ethyl acetate to give 2-amino-4-methyl-3-pyridinol.
Reaction SMILES: [O:1]=[S:2]1(=[O:57])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:50])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH2:39][CH2:38][C@@H:37]([C:40]([O:42]CC4C=CC=CC=4)=[O:41])[CH2:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1.[OH-].[Li+]>C1COCC1.CO>[O:57]=[S:2]1(=[O:1])[CH2:7][C@@H:6]2[CH2:8][C@H:3]1[CH2:4][N:5]2[CH2:9][CH2:10][NH:11][C@:12]12[CH2:53][CH2:52][C@@H:51]([C:54]([CH3:56])=[CH2:55])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:50])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:32])([CH3:33])[C:21]([C:34]2[CH2:39][CH2:38][C@@H:37]([C:40]([OH:42])=[O:41])[CH2:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)OCc7ccccc7)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3C[C@@H]4C[C@H]3CS4(=O)=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC[C@H](C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
To a solution of (R)-benzyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (65.2 mg, 0.082 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 3N lithium hydroxide (0.136 mL, 0.409 mmol). The reaction mixture was stirred at 75° C. for 3 h and then cooled to rt. The reaction content was subjected to reverse phase HPLC purification using prep-HPLC method 6 and dried under vacuum to give (R)-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-((1S,4S)-2,2-dioxido-2-thia-5-azabicyclo[2.2.1]heptan-5-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylic acid (48.2 mg, 0.049 mmol, 59.9% yield) as a white solid. LC/MS: m/e 707.5 (M+H)+, 4.07 min (method 8). 1H NMR (400 MHz, 1:1 CDCl3:METHANOL-d4) δ 5.33 (br. s., 1H), 5.21-5.13 (m, 1H), 4.77 (s, 1H), 4.70 (s, 1H), 3.98 (br. s., 1H), 3.64 (br. s., 1H), 3.40-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.16 (dd, J=11.4, 3.8 Hz, 2H), 3.11-3.05 (m, 2H), 3.05-2.94 (m, 2H), 2.83-2.70 (m, 1H), 2.58 (d, J=12.2 Hz, 1H), 2.48 (ddt, J=17.4, 6.1, 2.9 Hz, 1H), 2.44-2.36 (m, 1H), 2.32-2.22 (m, 2H), 2.21-2.12 (m, 2H), 2.11-2.04 (m, 2H), 2.03-1.91 (m, 5H), 1.87-1.72 (m, 3H), 1.71 (s, 3H), 1.68-1.53 (m, 5H), 1.52-1.37 (m, 7H), 1.34 (s, 1H), 1.32-1.23 (m, 1H), 1.09 (s, 3H), 1.05 (s, 3H), 0.95 (s, 3H), 0.93 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(C)(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
A heterogeneous mixture of 4-nitrophenol (5 g), methyl 2-bromoisobutyrate (5.6 mL) and K2CO3 (7.5 g) in acetone (60 mL) was refluxed overnight. The reaction mixture was then diluted with water (150 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were evaporated to give methyl 2-(4-nitrophenoxy)isobutyrate (49).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[CH:31][CH:32]=[C:33]([C:35]#[N:36])[N:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: N#Cc1cccc(Br)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(C#N)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 6-bromo-pyridine-2-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][C:12]1[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[CH:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]2[N:16]([C:17]3[C:18]([Cl:24])=[CH:19][CH:20]=[CH:21][C:22]=3[Cl:23])[N:15]=[CH:14][C:13]=2[CH:25]([CH3:27])[CH3:26])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Temperature: 80 °C
Yield: 94.2 %

Procedure:
A solution of 4-bromo-3-methyl-phenol (135 mg, 0.723 mmol) and 5-bromomethyl-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (210 mg, 0.603 mmol) in dimethylformamide (1.0 mL) is treated with potassium carbonate (84 mg, 0.603 mmol). The reaction mixture is heated at 80° C. for 60 minutes and cooled to room temperature. The mixture is loaded directly onto a silica gel column and purified with 25% EtOAc/Hexanes to provide 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (0.258 g, 94%). ES/MS m/e (M+1) 454.8.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([OH:17])[CH:11]=1)[CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:31])[C:29]#[CH:30])[CH3:26]>CC(C)=O>[CH3:1][CH2:2][CH2:3][CH:4]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:31])[O:17][C:12]=2[CH:11]=1)=[O:18])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(O)c1
Reactant: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(CCC)NC(=O)c1ccc2c(c1)OC(CC(=O)OCC)O2
Yield: 71 %

Procedure:
N-(heptan-4-yl)-3,4-dihydroxybenzamide (example 18a) (0.29 mmol, 75 mg) was dissolved in dry acetone with 6 eq excess (242 mg) of potassium carbonate then 1.2 eq excess (36 μl) of propynoic acid ethyl ester was added and a mixture was refluxed for 24 h. The solvent was evaporated and a solid was dissolved in dichloromethane and extracted with 10% NaHCO3 and water. The crude product was purified by chromatography on silica gel to give 72 mg of desired product (71%). 1H NMR (500 MHz, CDCl3): δ 0.91-0.94 (t, 6H), L23-1.30 (m, 4H), 1.37-1.41 (4H), 2.97-2.98 (d, 2H), 3.70-3.74 (dd, 2H), 4.12-4.17 (m, 1H), 4.2-4.24 (m, 3H), 5.61-5.64 (d, 1H), 6.58-6.60 (t, 1H), 6.79-6.81 (d, 1H), 7.23 (s, 1H), 7.60-7.85 (b, 1H). MS (M+H, 350.1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Reactant: COc1cccc(B(O)O)c1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cccc(OC)c2)cc1

Procedure:
The colourless oil (E)-ethyl 3-(3′-methoxy-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (example 50a) and 3-methoxyphenyl boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[C:8]1([CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:7](=[O:24])[C:6]([C:25]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:26])=[C:5]2[OH:33].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:21](=[CH:22][CH:23]=1)[C:8]1([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:7](=[O:24])[C:6]([C:25]([NH:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[O:26])=[C:5]2[OH:33]
Reactant: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCNCC2)C1=O
Temperature: 23 °C
Reaction time: 20 h
Yield: 87.7 %

Procedure:
A solution of methyl N-((6-chloro-4-hydroxy-2-oxo-1′-(tert-butoxycarbonyl)-spiro[naphthalene-1,4′-piperidin]-3-yl)carbonyl)glycinate (333 mg, 695 μmol) in dioxane (10 mL) was treated with HCl (4.0M in 1,4-dioxane (1738 μL, 6953 μmol)). The reaction was stirred at 23° C. After 20 hours, the reaction was concentrated in vacuo affording 231 mg of the title compound as the hydrochloride salt. MS m/e=379.2 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[C:7]([OH:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:12]=1)O.[C:16]([O:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[CH:23]=[CH2:24])(=[O:18])[CH3:17]>C(Cl)Cl.[N+](C)([O-])=O>[C:16]([O:19][CH2:20][CH2:21][C:22]1([CH3:25])[CH2:23][CH2:24][C:12]2[C:10](=[C:9]([CH3:13])[C:8]([CH3:14])=[C:7]([OH:15])[C:6]=2[CH3:5])[O:26]1)(=[O:18])[CH3:17]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=CC(C)(O)CCOC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: CC(=O)OCCC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice-cooled mixture of 3.37 g. of aluminum chloride and 40 ml. of methylene chloride was added, dropwise, 3.37 ml. of nitromethane. The resulting solution was stirred 5 minutes, and then 5.114 g. of trimethylhydroquinone was added in one portion. The green mixture was cooled to -20° and a solution of 5.35 g. of 3-hydroxy-3-methyl-4-pentenyl acetate in 20 ml. of methylene chloride was added over 1.0 hour. The mixture was allowed to warm to room temperature, kept there for 2 hours and poured into ice-H2O. The mixture was extracted with methylene chloride and the organic solutions were washed with saturated sodium bicarbonate solution and brine and dried over sodium sulfate. Solvent removal gave crude (±)-2-(2-acetoxyethyl)-6-hydroxy-2,5,7,8-tetramethylchroman as a red oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:4][CH:3]=1.C([O-])(C)(C)C.[K+].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][CH2:32][OH:33].C(OCC)(=O)C>O1CCCC1>[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH2:31][CH2:32][O:33][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][CH2:11][C:10]3([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1CCCN1CCCO
Reactant: Clc1ccc(C2=NC3(CCCCC3)CO2)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1CCCN1CCCOc1ccc(C2=NC3(CCCCC3)CO2)cn1
Temperature: 60 °C
Reaction time: 0.35 h
Yield: 55 %

Procedure:
2-(6-chloropyridin-3-yl)-3-oxa-1-azaspiro[4.5]dec-1-ene ax49 (0.109 g, 0.76 mmol, 1 eq) and potassium tert-butanolate (0.102 g, 0.91 mmol, 1.2 eq) are added to a cold (0° C.) solution of 3-(2-methylpyrrolidin-1-yl)propan-1-ol (0.2 g, 0.8 mmol, 1.05 eq) in tetrahydrofuran (4 ml). The mixture is stirred under microwave irradiation (150 W) at 60° C. for 21 min. Ethyl acetate is then added. The organic layer is washed with a saturated solution of sodium hydrogenocarbonate, dried over magnesium sulfate and the solvent is removed under vacuum to give 0.227 g of yellow oil. The oil is purified over silica (eluent: dichloromethane/methanol/ammonia 97:2.7:0.3) to give 0.149 g of 2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-3-oxa-1-azaspiro[4.5]dec-1-ene 16 as a yellow oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH3:6].[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.Cl>ClCCCl>[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([S:13][CH3:14])=[C:11]([CH:12]=1)[C:20]([C:19]1[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=1)=[O:21])[CH3:6]
Reactant: CCc1ccc(SC)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(SC)c(C(=O)c2ccc(C)cc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (10.8g) was added in portions to an ice-cooled, stirred solution of 4-(ethyl)thioanisole (12.3g) and 4-methylbenzoyl chloride (12.5g) in 1,2-dichloroethane (60 ml). The mixture was allowed to come to ambient temperature and was stirred overnight. It was then poured into a mixture of concentrated hydrochloric acid (about 100 ml) and ice (200 gm), which mixture was extracted with chloroform (3 × 100 ml), and the combined organic fractions were washed with 10% w/v aqueous sodium carbonate solution (2 × 100 ml) and water (100 ml), dried over magnesium sulphate and evaporated to leave the crude product as an oil. This oil was distilled twice to give the title compound as a clear oil (bp 152°-154° C./0.01 mm). The structure was confirmed by NMR.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:49])([F:48])[C:9]([NH:11][C:12]1([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:31][C:30]4[C:29]5=[N:39][N:40]=[C:41]([C:42]6[N:47]=[CH:46][CH:45]=[CH:44][N:43]=6)[N:28]5[CH:27]=[CH:26][C:25]=4[N:24]=3)=[CH:19][CH:18]=2)[CH2:15][C:14](=O)[CH2:13]1)=[O:10].[NH4+].[Cl-]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:49][C:8]([F:48])([F:7])[C:9]([NH:11][C:12]1([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:31][C:30]4[C:29]5=[N:39][N:40]=[C:41]([C:42]6[N:43]=[CH:44][CH:45]=[CH:46][N:47]=6)[N:28]5[CH:27]=[CH:26][C:25]=4[N:24]=3)=[CH:21][CH:22]=2)[CH2:13][C:14](=[CH2:1])[CH2:15]1)=[O:10]
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: C=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl(triphenyl)phosphonium bromide (111 mg, 0.311 mmol) and potassium tert-butoxide (35 mg, 0.311 mmol) in 1,4-dioxane (2 mL) was stirred at 30° C. for 30 minutes. 2,2,2-trifluoro-N-(3-oxo-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (60 mg, 0.104 mmol) in 1,4-dioxane (2 mL) was added, and the mixture was stirred at room temperature for 15 hours. To the mixture was added NH4Cl, extracted with EtOAc, washed with water and brine, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography eluting with 0-10% methanol in CHCl3 to give 2,2,2-trifluoro-N-(3-methylene-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-11) as a white solid.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH2:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)[CH3:20].Cl>C(O)(C)C>[CH2:19]([N:21]1[CH2:26][CH2:25][C:24]2[NH:2][C:4]3[C:18]([C:23]=2[CH2:22]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)[CH3:20]
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Reactant: CCN1CCC(=O)CC1
Agent: Cl
Solvent: CC(C)O
Product: CCN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
13.8 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 6.7 g of 1-ethyl-4-piperidone are stirred in 60 ml of absolute isopropanol for 1 hour, the same amount of isopropanol containing hydrogen chloride is then added and the mixture is boiled under reflux for 4 hours. After evaporating off the solvent, the residue is treated with N NaOH and the base is extracted with methylene chloride. The substance, recrystallised from toluene, melts at 233° C., with decomposition.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=3)[C:13]=2[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccc(F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of {(S)-1-[6-fluoro-1-(5-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (33 mg, 0.09 mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[6-fluoro-1-(5-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethylamine as a yellow oil (19 mg, 79%). LCMS (Method C): RT 0.27 and 1.84 min [M+H]+ 275.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:14])[CH:8]=2)[N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[Cl:14][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])[C:11]([O:12][CH3:13])=[N:10]2
Reactant: COc1nc2cc(Cl)ccc2nc1N
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 96 %

Procedure:
2-Amino-6-chloro-3-methoxyquinoxaline (629 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 811 mg of the titled compound (yield, 96%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:15]=[C:16]([NH2:28])[C:17]3[N:18]([N:20]=[C:21]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]=[C:16]([NH2:28])[C:17]3[N:18]([N:20]=[C:21]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn3nc(-c4ccco4)nc3c(N)n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cn3nc(-c4ccco4)nc3c(N)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of 4-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (50 mg, 0.13 mmol; see Example 28 above) in MeOH (1 mL) was added palladium (10 wt.% on activated carbon, 10 mg). The reaction mixture was stirred at room temperature under hydrogen atmosphere (1 atm) for overnight. The reaction mixture was filtered through Celite and the filtrate was concentrated to yield title compound (2.5 mg, 5%) as yellow solid. 1H NMR (300 MHz, DMSO) δ 8.01 (br s, 1H), 7.89 (s, 1H), 7.47 (s, 2H), 7.09 (br s, 1 H), 6.69 (br s, 1H), 4.06 (d, J=11.7 Hz, 2H), 2.80-2.63 (m, 3H), 1.84-1.80 (m, 2H), 1.69-1.64 (m, 2H), 1.41 (s, 9 H). MS m/z=385 amu (M++H).