Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].Br[C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9][C:11]1[O:15][CH:14]=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Cc1ccc(F)cc1S
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1Sc1cc(C(=O)O)co1

Procedure:
In an open flask cuprous oxide (500 mg., 3.5 mmoles) and 2-methyl-5-fluorothiophenol (1.0 g., 7 mmoles) were combined in 35 ml. of dimethylformamide and heated in an oil bath at 135°-140° C. for 2.5 hours. The mixture was cooled slightly, 5-bromofuran-3-carboxylic acid (668 mg., 3.5 mmoles) was added and the mixture refluxed for approximately 16 hours. Crude product was isolated according to Example 16. The resulting oil was crystallized by trituration with water (170 mg.). Recrystallization from methanol/water gave purified 5-(2-methyl-5-fluorophenylthio)furan-3-carboxylic acid (125 mg., m.p. 150°-152° C., m/e 252).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[N:13][NH:14]2.[CH3:22][O:23][NH2:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:22][O:23][NH:24][C:19]([C:18]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2)=[O:21]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of 4-(2-fluoro-4-iodophenylamino)-1H-indazole-5-carboxylic acid (70 mg, 0.176 mmol) and O-methyl-hydroxylamine (19 mg, 0.21 mmol) in DMF (2 mL) was added EDCI (40 mg, 0.21 mmol), HOBt (28 mg, 0.21 mmol) and DIPEA (70 μL, 0.42 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate then water, dried (Na2SO4), filtered and concentrated in vacuo. The resultant solid was triturated with a solution of hot methanol/water/NaHCO3, the solid filtered off, washed with water to give the title compound as a pale pink solid (33 mg, 44%). LCMS (Method A): RT=9.09 min, [M+H]+=427. 1H NMR (DMSO-d6, 400 MHz) 13.20 (1 H, s), 11.62 (1 H, s), 9.99 (1 H, s), 7.66 (1 H, dd, J=10.33, 1.94 Hz), 7.46-7.40 (2 H, m), 7.23 (1 H, s), 7.01 (1 H, d, J=8.78 Hz), 6.92 (1 H, t, J=8.66 Hz), 3.64 (3 H, s).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:8]([Cl:21])=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[Cl:21][C:8]1[C:7]([CH2:6][CH2:5][OH:4])=[CH:16][C:15]2[NH:14][C:13](=[O:17])[CH:12]3[CH2:18][CH2:19][CH2:20][CH:11]3[C:10]=2[CH:9]=1
Reactant: CC(=O)OCCc1cc2c(cc1Cl)C1CCCC1C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(CCO)c(Cl)cc2C2CCCC12
Reaction time: 72 h
Yield: 84.7 %

Procedure:
380 mg (1.2 mmol) of 7-acetoxyethyl-8-chloro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one is dissolved in 30 ml of methanol and mixed with 341 mg (2.5 mmol) of potassium carbonate. After 3 days at room temperature, the batch is diluted with ethyl acetate, washed with water, dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with ethyl acetate-ethanol yields 270 mg of product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1.O[Li].O.Cl>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[F:26])(=[O:18])=[O:17])[CH:3]=1
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (545 mg, 1.24 mmol) in THF (10 ml) was added a solution of LiOH.H2O (104 mg, 2.48 mmol) in H2O (2 ml). The reaction was stirred at room temperature for 1.5 hours, acidified with 1M HCl, and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The crude product was triturated with CH2Cl2, filtered, rinsed with H2O, and dried to yield the title compound as beige solid (500 mg, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:14]([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:14]([CH3:16])[CH3:15])[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of 4-bromo-1H-pyrazole (5 g, 34 mmol) in DMF (70 ml) were added K2CO3 (11.83 g, 85.6 mmol, 2.5 eq.) and 2-bromopropane (6.3 g, 51.36 mmol, 1.5 eq.) and the mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off and the crude residue was purified by column chromatography (60-120 silica gel, 20% ethyl acetate in hexane) to afford the product in 89% yield (5.8 g). 1H NMR (300 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.50 (s, 1H), 4.49-4.43 (m, 1H), 1.38 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:30][CH2:31][C:32](O)=[O:33])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:32](=[O:33])[CH2:31][CH2:30][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)CCN1CCOCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCN1CCOCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-morpholin-4-yl-propionic acid to yield (3aR,4S,7aR)-4-(3-morpholin-4-yl-propionyloxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=4.088 min; LC-MS Method III
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(Oc2ccc(OC)cc2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 61.2 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-methoxy-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.29 g, 0.42 mmol) was reacted with trimethylsilyl acetylene (0.41 g, 4.2 mmol), CuI (5 mg), triethylamine (1.76 mL, 12.7 mmol), and dichlorobis(triphenylphosphine) palladium (0) (23.4 mg, 0.034 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(4-methoxy-phenoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 61%)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.Cl.[CH3:14][O:15][C:16]([CH2:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1)=[O:17].[Br:29]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]([CH2:18][C:16]([O:15][CH3:14])=[O:17])[CH2:28][CH2:27]2
Reactant: COC(=O)CC1CCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC1CCc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a mixture of aqueous solution of potassium carbonate (30 g) and ethyl acetate was dispersed 2-methoxycarbonylmethyltetrahydroquinoline hydrochloride (24.8 g, 0.1 mol). The organic layer was separated, dried over magnesium sulfate, and concentrated. The residue was dissolved in DMF (400 mL) and a solution of N-bromosuccinimide (21.36 g, 0.12 mol)in DMF (400 mL) was added dropwise at 0° C. The mixture was stirred for 5 h at room temperature, poured into water (250 mL), and extracted with ether (250 mL). The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 36 g of the crude title compound (quant) which was used for the next step without purification. The specimen for characterization was obtained by silica gel column chromatography of the crude compound with 1:1 dichloromethane/hexane to 100% dichloromethane: 1H NMR (270 MHz, CDCl3) δ7.02~7.06 (m, 2H), 6.38 (dd, 1H, J=1.7, 7.3 Hz), 4.53 (br, 1H), 3.75 (s, 3H), 3.72~3.75 (m, 4H), 2.70~2.85 (m, 2H), 2.49~2.53 (m, 1H), 1.89~1.99 (m, 1H), 1.61~1.75 (m, 1H),
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[C:13](Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]>ClCCl.CN(C1C=CN=CC=1)C>[CH3:15][C:14]([CH3:17])([CH3:16])[C:13]([O:1][C@@H:2]1[C@H:3]([O:4][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@@H:5]([O:6][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([O:8][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@@H:9]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[O:10]1)=[O:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
D-glucose (25.0 g, 0.139 mol) was suspended in anhydrous dichloromethane (416 mL) under nitrogen and the resulting mixture was stirred for 5 minutes at room temperature, then cooled to 0° C. and stirred for 10 minutes. To the resulting mixture was then added TEA (154.7 mL), dropwise over about 10-15 min, with stirring; then DMAP (1.25 g, 0.0102 mol) in one portion. To the resulting mixture was added pivaloyl chloride (136 mL) diluted with dichloromethane (83 mL) at 0° C., over 30 min. The ice bath was removed and the resulting mixture stirred at room temperature for 20 hours. The resulting mixture was then poured into dichloromethane (500 mL) and hydrochloric acid (1.5M, 375 mL) and the resulting phases separated. The organic layer was washed with sodium bicarbonate solution (550 g in 500 mL DI water, 1N) and then evaporated to a small volume. To the resulting residue was added ethanol (95%, 240 mL) and the mixture heated to reflux temperature to yield a homogeneous mixture. The resulting mixture was cooled to 0° C., resulting in the formation of white crystals, which were filtered and dried in vacuo at room temperature, overnight, to yield the title compound.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].Br[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:9][N:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)COc1ccc(CBr)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCc1ccc(OCC(F)(F)F)cn1
Temperature: 0 °C
Yield: 54.6 %

Procedure:
Dissolve sodium azide (270 mg, 4.0 mmol) in DMF (30 mL). Cool the solution to 0° C., then add 2-bromomethyl-5-(2,2,2-trifluoroethoxy)-pyridine (440 mg, 1.6 mmol) at 0° C. Slowly heat the mixture from 0° C. to 80° C. over 30 min. Cool the reaction, dilute with EtOAc (100 mL) and wash with 10% aqueous NaCl (3×25 mL). Collect the organic layer and concentrate in vacuo to a volume of 50 mL. Transfer the solution to a pressure vessel. Add 10% Pd/C (Degussa type E101, 50% water by wt, 500 mg) and pressurize the vessel under hydrogen (10 psi) for 1 h with stirring. Filter the mixture through Celite® and wash filter cake with warm methanol followed by DCM. Concentrate in vacuo, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (180 mg, 54%). MS (ES+) m/z: 207 (M+H)+.
Reaction SMILES: [C:1]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[N:14]=2)[N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[O:33]1[CH2:38][CH2:37][N:36]([C:39](=[O:43])[CH2:40][C:41]#[N:42])[CH2:35][CH2:34]1.C(O)(=O)C.N1CCCCC1>C(O)C>[N:36]1([C:39]([C:40](=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([NH:16][C:13]3[N:14]=[C:15]4[C:7]([C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5])=[CH:8][N:9]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:31])([CH3:30])[CH3:32])[C:10]4=[N:11][CH:12]=3)=[CH:18][CH:19]=2)[C:41]#[N:42])=[O:43])[CH2:37][CH2:38][O:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: N#CCC(=O)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCOCC4)cc3)nc12
Yield: 55.6 %

Procedure:
To a 50 ml three necked round bottom flask 4-(7-pivaloyl-5-((2-(trimethylsilyl)-ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)benzaldehyde (0.25 g, 0.00055 mole) and 3-morpholino-3-oxopropanenitrile (0.34 g, 0.0022 mole) was taken in ethanol (20 ml). To this reaction mixture, piperidine acetate (1.0 ml) was added drop wise at RT. After completion of the addition, reaction mixture was refluxed for 4 hr. After completion of the reaction, ethanol was distilled out under vacuum and water was added to the residue. The aq. layer was extracted with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product. The crude compound was purified using column purification by eluting the compound with 40-50% ethyl acetate in hexanes to yield 0.18 g of 2-(morpholine-4-carbonyl)-3-(4-(7-pivaloyl-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)phenyl)acrylonitrile which was converted to the title compound using the procedure described in Example 1, Step 2 above.
Reaction SMILES: [ClH:1].C[C:3]1C=C2[C:6]([NH:7]C=C2CCN)=[C:5](Br)[CH:4]=1.Cl.[CH3:17][C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[C:22]([CH3:24])[CH:23]=1>>[ClH:1].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]2[C:19]=1[C:4]([CH2:5][CH2:6][NH2:7])=[CH:3][NH:25]2
Reactant: Cc1cc(Br)c2[nH]cc(CCN)c2c1
Reactant: Cc1cc(C)cc(NN)c1
Agent: Cl
Product: Cc1cc(C)c2c(CCN)c[nH]c2c1

Procedure:
4,6-Dimethyltryptamine hydrochloride was prepared (1.06 g) as described for 5-methyl-7-bromotryptamine hydrochloride in Example 4, except using 3,5-dimethylphenylhydrazine hydrochloride (7.65 g) as starting material. ##STR53##
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([CH2:14][NH:15]C(=O)C[Cl:18])[C:5]=1[OH:20])(=[O:3])[CH3:2].Cl>C(O)C>[ClH:18].[C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])[CH:7]=[C:6]([CH2:14][NH2:15])[C:5]=1[OH:20])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Agent: Cl
Solvent: CCO
Product: CC(=O)c1cc(C(C)(C)C)cc(CN)c1O
Yield: 92.3 %

Procedure:
To 1.49 g of 2-acetyl-4-tert-butyl-6-(N-chloroacetylaminomethyl)phenol (prepared in Example 1) dissolved in 10 ml of ethanol were added 4.0 ml of conc. hydrochloric acid and heated at reflux for 20 hous. The reaction mixture was concentrated at reduced pressure and the residue was recrystallized from a mixed solvent of methanol and diethyl ether to give 1.19 g of the title compound having the following physical properties as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[C:32]1([N:38]2[C:42]3([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:41](=[O:48])[NH:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:45]3[CH2:44][CH2:43][C:42]4([N:38]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH2:39][NH:40][C:41]4=[O:48])[CH2:47][CH2:46]3)=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one as in General Procedure 10 to give the title compound. LCMS: m/z=661.00 (M+H+); retention time=0.87 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(O)=O>C1COCC1.O>[O:30]=[C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.8 %

Procedure:
To a cooled solution (−78° C.) of ethyl 2-(pyridin-3-yl)acetate (1.842 mL, 12.11 mmol) in THF (12.2 mL) was added LiHMDS (12.11 mL, 12.11 mmol) and the mixture was stirred 15 min. A solution of benzoyl chloride (1.474 mL, 12.71 mmol) in THF (24.4 mL) was added slowly and the mixture was warmed to room temperature and stirred for 12 h. The reaction was quenched with AcOH (1.386 mL, 24.21 mmol), diluted with H2O (50 mL), and extracted with EtOAc (3×75 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a clear oil (1.82 g). LCMS m/z=270.2 [M+H]+.
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][C:21]=1[F:32]>CO>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:18][C@H:2]([OH:1])[CH2:3][O:4][C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=3[CH:7]=[C:8]3[CH2:13][CH2:12][O:11][C:9]3=[O:10])[CH2:30][CH2:31]2)=[CH:22][C:21]=1[F:32]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Reactant: Fc1cc(C2CCNCC2)ccc1Cl
Solvent: CO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2ccc(Cl)c(F)c2)CC1
Yield: 33.7 %

Procedure:
By the reaction in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (1.0 g) and 4-(4-chloro-3-fluorophenyl)piperidine (0.8 g) in methanol (50 ml), the title compound (0.58 g), melting point 114–115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([SH:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.S(OC)(O[CH3:29])(=O)=O.[OH-].[Na+].C(O)C>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([S:22][CH3:29])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Sc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.1 g (3.0 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-thiol, 1.0 ml (10 mmole) of dimethyl sulfate, 20 ml of 1N sodium hydroxide and 10 ml of ethanol was stirred at room temperature for 15 min. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give an oil. Crystallization from ether gave colorless prisms, mp 187°-188° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][C:25]#[N:26]>CN(C=O)C>[C:25]([CH2:24][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1])#[N:26]
Reactant: N#CCBr
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC#N
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
To a solution of 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.5 g, 2.23 mmol) in DMF (5 mL) was added Cs2CO3 (1.45 g, 4.46 mmol) and bromoacetonitrile (0.54 g, 4.46 mmol). The mixture was heated at 70° C. for 10 min. Additional bromoacetonitrile (0.35 g, 2.9 mmol) was added, and heating was continued for another 10 min. Upon cooling, the mixture was partitioned between Et2O and 0.1N HCl. The organic phase was washed with sat'd brine. The combined aqueous phases were washed with Et2O, and this organic phase was washed with sat'd brine. The combined organic phases were dried (Na2SO4), filtered and concentrated to dryness, to yield a brown solid (0.59 g), which was used in the next step without further purification: LC/MS (ES) shows 87% title compound (m/z 264 (M+1)) and 13% starting material.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)#[N:31]>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]([S:38]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1)#[N:31]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1

Procedure:
2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and 4-cyanobenzenesulfonyl chloride (121 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (157 mg, 71% yld). MS(ES+) 440.1(M+H)+.