Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH:19]=[C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CO.C(Cl)Cl>[C:20]1(=[CH:19][CH2:18][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCC=C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=S(=O)(CC=C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 38.5 gm of sodium phenyl sulfinate and then 3.85 gm of sodium carbonate were introduced into 116 cc of methanol and 44 gm of freshly prepared 1-bromo-2-cyclohexylidene-ethane were added dropwise over 30 minutes and at room temperature. The reaction mixture was then agitated for 1 hour and 30 minutes at room temperature after which the reaction mixture was poured into 400 cc of ice water. The precipitate formed was vacuum filtered, washed with water and dried. The raw product thus obtained was dissolved at high temperature in a mixture consisting of methylene chloride and methanol. The solution obtained was dried over magnesium sulfate, concentrated to a small volume and admixed with isopropyl ether. The precipitate formed was vacuum filtered and dried to obtain 36.4 gm of (2-cyclohexylidene-ethyl)-phenyl sulfone, having a melting point of 70° C. A sample of this product, crystallized from isopropyl ether, had a melting point of 70° C.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.[C:28](Cl)(=[O:30])[CH3:29]>C1COCC1.CCN(C(C)C)C(C)C.CCOC(C)=O>[C:28]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)(=[O:30])[CH3:29]
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.062 g) in THF (2.5 mL) and DIEA (0.030 mL) was added acetyl chloride (0.015 mL). After 30 minutes, the reaction mixture was diluted with EtOAc and the solution washed with NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: CH2Cl2/MeOH: 99/1, Chromatotron) afforded the titled compound (0.046 g,). MS (m/z) 510 (MH+). mp 89.6° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([OH:14])[C:3]=1[C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+].[C:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=O)=[CH:28][CH:27]=1)#[N:25].O>CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]2[C:3]=1[C:15](=[O:17])[CH:16]=[C:30]([C:29]1[CH:33]=[CH:34][C:26]([C:24]#[N:25])=[CH:27][CH:28]=1)[O:14]2
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)c1c(O)cc(N2CCOCC2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(-c2cc(=O)c3c(O)cc(N4CCOCC4)cc3o2)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 1.5 %

Procedure:
To a suspension of 1-(2,6-dihydroxy-4-morpholin-4-yl-phenyl)-ethanone (45 mg, 0.190 mmol) and K2CO3 (130 mg, 0.948 mmol) in acetone (3 mL) was added 4-cyanobenzoyl chloride 33 mg, 0.20 mmol). The reaction vessel was sealed and heated to 60° C. for 14 h. After cooling to room temperature, water (about 2 mL) was added, and the mixture was allowed to stir for about 10 min. The contents were transferred to a separatory funnel and extracted with EtOAc (3×15 mL). The organic layer was dried (MgSO4) and concentrated. The concentrate was suspended in 50% EtOAc/hexanes and filtered to yield 1 mg (1%) of 4-(5-hydroxy-7-morpholin-4-yl-4-oxo-4H-chromen-2-yl)-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)=[O:24])=[C:21]([CH3:28])[N:20]=2)=[CH:15][CH:14]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)O
Product: Cc1nc(-c2ccc(F)cc2)ccc1C(=O)Nc1ccc2cccnc2c1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (26 mg, 0.8 mmol) and 6-(4-fluorophenyl)-2-methylnicotinic acid (D24) (50 mg, 0.22 mmol) as a white solid. MS(ES): MH+ 358, M-H+ 356.
Reaction SMILES: [Cl-].[CH3:2][NH3+].[C:4]1([CH:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[C:12]([NH2:26])[O:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN.Cl>O.CO>[C:4]1([CH:10]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=3)=[C:12]([NH:26][CH3:2])[O:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Reactant: C[NH3+]
Agent: CN
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CO
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Yield: 93.2 %

Procedure:
In this example, 2 g of methylammonium chloride was added at room temperature to a stirred slurry containing 10 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 60 ml of aqueous 40 wt % methyl amine followed by the addition of 50 ml of methanol. The resulting suspension was heated to reflux and refluxed overnight (about 15--18 hours). The mixture was cooled to room temperature and added to a dilute acid solution containing 58 ml of aqueous 12N hydrochloric acid in 300 ml of water. This mixture was extracted twice with methylene chloride. The methylene chloride extracts were combined and successively washed once with water, once with saturated aqueous sodium bicarbonate and once with saturated aqueous sodium chloride. The washed solution was dried over magnesium sulfate and evaporated under vacuum affording 9.2 g of the title compound as a pale yellow foam (yield=88%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:32]([O:34]CC)=[O:33])[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:32]([OH:34])=[O:33])[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:12]=2[N:13]=1
Reactant: CCOC(=O)c1cc(NCc2ccco2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2ccc(Oc3ccccc3)cc2)c2nc(NCc3ccco3)cc(C(=O)O)c12
Yield: 60.5 %

Procedure:
(see, e.g., Neres, J., et al., J Med Chem 2013, 56, 2385-405). A solution of ester 51 (40 mg, 0.08 mmol) and 1N NaOH (3.5 mL, 3.5 mmol) in THF (1.5 mL) was refluxed for 3 h. Reaction mixture was diluted with water (10 mL) and washed with EtOAc (10 mL×2). Aqueous layer was acidified with 1N HCl and extracted with EtOAc (10 mL×2). Combined organic extracts were washed with brine, dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to give the title compound (22 mg, 61%) as an orange solid. 99% pure by HPLC. 1H NMR (500 MHz, DMSO-d6) δ 7.79 (t, J=5.1 Hz, 1H), 7.54 (s, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H), 6.95 (d, J=7.9 Hz, 2H), 6.90 (d, J=8.3 Hz, 2H), 6.86 (s, 1H), 6.33 (s, 1H), 6.25 (s, 1H), 5.35 (s, 2H), 4.57 (d, J=5.2 Hz, 2H), 2.41 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 167.35, 157.85, 157.05, 156.29, 153.26, 152.02, 142.37, 140.38, 135.41, 133.48, 130.46, 130.44, 130.08, 123.85, 118.98, 118.97, 110.81, 107.38, 103.37, 49.09, 37.87, 15.96. ESI MS: m/z 455.0 (M+H)+.
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[CH2:27][CH2:28][OH:29])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=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[CH2:27][CH2:28][O:29][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=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)c4CCO)cc3)cc2)CC1
Reactant: BrCc1ccncc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCOCc4ccncc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 34, Step 4, using 1-{4′-[4-(2-hydroxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 4-bromomethyl-pyridine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([OH:22])[CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH:21]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: Oc1cncc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1cncc(Cl)c1
Yield: 96.7 %

Procedure:
Using the method of Example 21.2, 4-fluoro-3-nitrobenzotrifluoride (7.4 g) and 3-chloro-5-hydroxypyridine (4.59 g) were heated with potassium carbonate (5.4 g) in DMF at 80° C. for 1 h, then 60° overnight. Workup gave the title compound (10.9 g) as a yellow solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:13][N:14]=[C:7]1[CH:6]=[CH:5]2)[CH3:22]
Reactant: Ic1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Reactant: CCCCC(CC)COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(ccc3nnc(-c4ccccn4)n32)c1
Temperature: 90 °C

Procedure:
5k (890 mg, 2.4 mmol) and 3-mercaptopropionic acid 2-ethylhexyl ester (630 mg, 2.9 mmol) were dissolved in 1,4-dioxane (20 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.86 mL, 4.8 mmol), Pd2dba3 (54 mg, 0.06 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (69 mg, 0.12 mmol) were added, and the mixture was degassed with N2 for an additional 10 minutes. The reaction was heated to 90° C. until no starting material was seen by tlc analysis, and then the mixture was concentrated and purified by silica gel chromatography to give the desired product, 5m.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([C:11]1[N:12]=[C:13]([NH:16][C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:14][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1csc(N)n1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.2 %

Procedure:
To a solution of 2-(2-amino-4-thiazolyl)malonic acid diethyl ester in dichloromethane (15 parts) are added trityl chloride (1.05 equivalents) and triethylamine (1.05 equivalents) under nitrogen at 0° C. After stirring at room temperature for 24 hours, the reaction mixture is poured onto diluted hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated in vacuum to give 2-(2-tritylamino-4-thiazolyl)malonic acid diethyl ester. Yield: 98.2%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[CH2:12][NH:11][N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:26][C:27]1[C:31]([N:32]=[C:33]=[O:34])=[C:30]([CH3:35])[O:29][N:28]=1>C(Cl)Cl>[CH3:26][C:27]1[C:31]([NH:32][C:33]([N:11]2[CH2:12][C:13]([C:15]([O:17][CH3:18])=[O:16])([CH3:14])[C:9]([C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=3)=[N:10]2)=[O:34])=[C:30]([CH3:35])[O:29][N:28]=1
Reactant: Cc1noc(C)c1N=C=O
Reactant: COC(=O)C1(C)CNN=C1c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(C)CN(C(=O)Nc2c(C)noc2C)N=C1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole hydrochloride (10 mmole), triethylamine (20 mmole), methylene chloride (30 ml and 3,5-dimethylisoxazole-4-yl isocyanate (Maybridge Chemical Co. Ltd.) (10 mmole) were reacted by stirring at room temperature for 30 minutes. The reaction mixture was then washed twice with water, dried with magnesium sulfate concentrated giving a 95% yield of N-(3,5-dimethylisoxazol-4-yl)-3-(4-chlorophenyl)-4-carbomethoxy-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide mp 214°-216° C. NMR data was consistent with the structure.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:20]C(=O)C)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO>[N:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([NH2:20])[CH:13]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: Nc1cc(CCCN2CCCCC2)cc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
N-[3-(3-Piperidin-1-yl-propyl)-5-trifluoromethyl-phenyl]-acetamide (1.33 g) was dissolved in EtOH (40 ml) and 12 N HCl (40 ml) was added. After stirring overnight at 70° C. and RT, the mixture was concentrated in vacuo, affording 3-(3-piperidin-1-yl-propyl)-5-trifluoromethyl-phenylamine as a brown oil.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)(C)C.[C:21]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:21]1([C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([OH:5])[C:7]=3[CH:8]=2)[CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: O=C1CCCC1
Reactant: CC(C)[Si](Oc1cccc2[nH]ccc12)(C(C)C)C(C)C
Product: Oc1cccc2[nH]c(C3=CCCC3)cc12

Procedure:
2-Cyclopent-1-enyl-1H-indol-4-ol was prepared from 4-triisopropylsilyloxy-1H-indole and cyclopentanone as described for 14c.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:36][C:37]1[C:38](=[O:55])[C:39]([C:49]2[N:53]([CH3:54])[N:52]=[CH:51][CH:50]=2)=[N:40][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:42]=1.[N:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[CH2:66][CH2:67]O>C1(C)C=CC=CC=1>[CH3:54][N:53]1[C:49]([C:39]2[C:38](=[O:55])[C:37]([O:36][CH2:67][CH2:66][C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[N:56]=3)=[CH:42][N:41]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:40]=2)=[CH:50][CH:51]=[N:52]1
Reactant: OCCc1ccc2ccccc2n1
Reactant: Cn1nccc1-c1nn(-c2ccccc2)cc(O)c1=O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1nccc1-c1nn(-c2ccccc2)cc(OCCc2ccc3ccccc3n2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.2 %

Procedure:
Toluene (20 mL) was added to di-tert-butyl diazene-1,2-dicarboxylate (345 mg), triphenylphosphine (459 mg) and the mixture was stirred at room temperature for 10 min. Then, 5-hydroxy-3-(1-methyl-1H-pyrazol-5-yl)-1-phenylpyridazin-4(1H)-one (268 mg), and further, 2-quinolin-2-ylethanol (260 mg) were added, and the mixture was stirred at room temperature for 64 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol). A fraction containing the title compound was again purified by NH silica gel column chromatography (hexane/ethyl acetate) and crystallized from hexane/ethyl acetate to give the title compound (297 mg) as white needles.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH2:9]([OH:11])[CH3:10].Cl>C(OCC)C>[NH2:2][C:1]([O:11][CH2:9][CH3:10])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C=C(N)OCC
Yield: 53.8 %

Procedure:
In an oven-dried flask were placed 113.1 g of redistilled ethyl cyanoacetate, 46 g of ethanol (distilled from calcium hydride), and 500 ml of anhydrous diethyl ether. The solution was cooled to 0°, 36.5 g of hydrogen chloride gas were added and the flask was sealed. The mixture was refrigerated for several days until precipitation of white solid was observed. The white precipitate was collected by filtration and immediately resuspended in approximately 300 ml of diethyl ether. The ether-suspension was mixed with 1000 ml of a 40% aqueous solution of potassium carbonate (previously cooled to 0°). The ether layer was separated and placed over 30 g of anhydrous potassium carbonate. The aqueous phase was washed three times with 150 ml portions of diethyl ether. The washings were added to the ether phase over potassium carbonate. The combined ether phase and washings were decanted onto approximately 80 g of fresh anhydrous potassium carbonate. The potassium carbonate was removed by filtration and the ether was removed by evaporation under reduced pressure. The residue was distilled at 0.25 mm hg. The fraction distilling at 60° was collected to yield 85.5 g of ethyl 3-amino-3-ethoxyacrylate, nD25 = 1.4808. The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[O:5][C:6]1[CH:34]=[CH:33][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23]CC4C=CC=CC=4)=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:31]#[N:32])=[CH:8][CH:7]=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:38]=[CH:37][CH:36]=[CH:35][C:4]=1[O:5][C:6]1[CH:34]=[CH:33][C:9]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]=2[C:31]#[N:32])=[CH:8][CH:7]=1
Reactant: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1OCc1ccccc1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Nc3ccc(Oc4ccccc4OC)cc3)c(C#N)cnc2cc1O

Procedure:
The product from step (1) (7.2 g, 14.3 mmole) trifluoroacetic acid (40 ml) and thioanisole (8.38 ml, 71.5 mmole) was refluxed in a nitrogen atmosphere for 3 hours. After cooling the trifluoroacetic acid was removed by rotary evaporation and the oily residue was stirred with ice and water and basified with aqueous ammonia (S.G. 0.880). The resulting suspension was filtered and the solid was washed successively with water, ethyl acetate and diethyl ether and then dried to give 4-(4-(2-methoxyphenoxy)-anilino)-3-cyano-6-methoxy-7-hydroxyquinoline.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:27]([N:29]1[CH2:33][CH2:32][S:31][CH2:30]1)=[O:28])=O)(C)(C)C>Cl.O1CCOCC1>[CH3:25][O:24][C:22](=[O:23])[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:27]([N:29]3[CH2:33][CH2:32][S:31][CH2:30]3)=[O:28])[NH:8][CH2:12]2)=[O:26])[CH:17]=1
Reactant: COC(=O)c1cccc(C(=O)NC[C@H]2C[C@@H](C(=O)N3CCSC3)N(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1

Procedure:
A solution of Example 18A (100 mg) in 4 M HCl in dioxane (2 mL) was stirred at room temperature for 16 hours, and concentrated under reduced pressure. The residue was taken up and concentrated under reduced pressure under the following solvents, methanol (10 mL), ether (10 mL) and dichloromethane (10 mL) to provide the titled compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:22][CH2:23][N:24]3[C@H:29]4[CH2:30][CH2:31][C@@H:25]3[CH2:26][CH:27]([N:32]3[C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=5[N:34]=[C:33]3[CH3:41])[CH2:28]4)[CH2:13][CH2:12][N:11]([C:14](=[O:21])[C:15]([CH3:20])([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:42][CH2:43][C:44](Cl)=[O:45].CCN(C(C)C)C(C)C>>[Cl:42][CH2:43][C:44]([NH:19][C:15]([C:14]([N:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:22][CH2:23][N:24]2[C@H:29]3[CH2:30][CH2:31][C@@H:25]2[CH2:26][CH:27]([N:32]2[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N:34]=[C:33]2[CH3:41])[CH2:28]3)[CH2:9][CH2:10]1)=[O:21])([CH3:20])[CH:16]([CH3:17])[CH3:18])=[O:45]
Reactant: O=C(Cl)CCl
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(N)C(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)C(C)(NC(=O)CCl)C(C)C)CC1
Yield: 52.4 %

Procedure:
2-chloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide was obtained from treating 1,1-dimethylethyl {1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}carbamate, example 915, (0.623 g, 0.94 mmol) with HCl as outlined in the procedure for Example 890 to form 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.524 g, 99%). 1-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)-2,3-dimethyl-1-oxo-2-butanamine (0.050 g, 0.09 mmol), Chloro-acetyl chloride (0.011 g, 0.09 mmol) and DIEA (0.034 g, 0.534 mmol) were reacted following the procedure outlined in Example 890 to give the title compound, 2-chloro-N-{1-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-1,2-dimethylpropyl}acetamide (0.030 g, 52%) as an oil. ES-LCMS m/z 636 (M+1).
Reaction SMILES: [OH-].[K+].C[Si](C)(C)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].C(OCC)(=O)C.Cl>CO.CCCCCC>[C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])#[CH:5]
Reactant: Cc1ccccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C#Cc1ccccc1C
Temperature: 0 °C
Yield: 73.4 %

Procedure:
Potassium hydroxide (10 g, 1.8 mol) added in 4 portions to a stirred solution of trimethyl-(2-methylphenyl)ethynylsilane (114.0 g, 0.61 mol) in methanol (400 ml) at 0° C. The mixture was stirred at 0° C. until the reaction was complete (by tlc 1:1 ethyl acetate:hexane). The mixture was neutralised by the addition of 10% hydrochloric acid and the product was extracted into dichloromethane (2×150 ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. The residual oil was purified by short path distillation (Kugelrohr) to give 1-ethynyl-2-methylbenzene (52.03 g) as a clear oil. B.pt. 45° C./12 mBar. 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.35 (s, 3H) (ArCH3), 3.2 (s, 1H)(CH), 7.0-7.2 (m, 3H) (3×ArH), 7.4 (m, 1H) (ArH); GC purity 98%, GC retention time 7.94 min.