Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[C:6]([OH:8])[CH:7]=1.[CH2:11]1[O:13][C@H:12]1[CH2:14]Cl.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[C:6]([CH:7]=1)[O:8][CH2:14][C@H:12]1[O:13][CH2:11]1
Reactant: N#Cc1ccc(Cl)cc1O
Reactant: ClC[C@H]1CO1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(Cl)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.2 %

Procedure:
A mixed solution of 5.0 g of 5-chloro-2-cyanophenol and 6.0 g of R-(-)-epichlorohydrin was heated at 120° C. for 2 hours under a nitrogen stream. Toluene (50 ml), 0.1 g of benzyl triethylammonium chloride and 20 ml of a 30% sodium hydroxide were added, and the mixture was stirred at room temperature for 2 hours. The organic layer was separated and dried over magnesium sulfate. The solvent was then evaporated. Ethanol was added to the residue to crystallize it. The crystals were then recrystrallized from ethyl acetate to give 2.4 g (2S)-(+)-(5-chloro-2-cyanophenoxy)-2,3-epoxypropane.
Reaction SMILES: [N:1]1[O:2][C:3]([C:10]([OH:12])=O)=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH2:32])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[N:13]1([CH2:19][C:20]2[CH:34]=[CH:33][C:23]3[NH:24][C:25]([C:27]4[C:31]([NH:32][C:10]([C:3]5[O:2][N:1]=[C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=56)=[O:12])=[CH:30][NH:29][N:28]=4)=[N:26][C:22]=3[CH:21]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1onc2ccccc12
Reactant: Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1c[nH]nc1-c1nc2cc(CN3CCOCC3)ccc2[nH]1)c1onc2ccccc12
Yield: 32.2 %

Procedure:
A mixture of benzo[c]isoxazole-3-carboxylic acid (46 mg, 0.28 mmol), 3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.33 mmol), EDC (64 mg, 0.33 mmol) and HOBt (45 mg, 0.33 mmol) was stirred at room temperature in DMF (2.5 ml) for 20 h. The mixture was reduced in vacuo and the residue partitioned between EtOAc (5 ml) and water (2 ml), the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and reduced in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-MeOH (100:0-90:10)] to give benzo[c]isoxazole-3-carboxylic acid[3-(5-morpholin-4-ylmethyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-amide as a white solid (40 mg, 32%). (LC/MS: Rt 2.13, [M+H]+ 444).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(OCCO)cc1
Yield: 35.4 %

Procedure:
A mixture of 148.8 g (1.20 mole) of p-methoxyphenol, 170.0 g (2.11 mole) of 2-chloroethanol and 47.2 g (1.18 mole) of sodium hydroxide in 1.5 liter of absolute ethanol was heated at reflux for 22 hr. The solution was filtered, and the solvent was removed from the filtrate in vacuo. The residue was crystallized from methylene chloride-hexane to give 71.4 g (35%) of title compound as a white crystalline solid, mp 69°-71° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([CH:9]=[CH:10][CH:11]=O)=[CH:7][CH:6]=1.[CH3:15][O:16]/[C:17](/[CH3:23])=[CH:18]\[C:19]([O:21]C)=[O:20]>O1CCCC1>[CH3:15][O:16][C:17]([CH:23]=[CH:11][CH:10]=[CH:9][C:8]1[CH:13]=[CH:14][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)=[CH:18][C:19]([OH:21])=[O:20]
Reactant: COc1ccc(C=CC=O)cc1
Reactant: COC(=O)/C=C(/C)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C=CC=Cc1ccc(OC)cc1)=CC(=O)O
Temperature: 0 °C
Yield: 63.8 %

Procedure:
16.5 g of an 80% by weight suspension of sodium hydride in white oil (corresponding to 0.55 mol of NaH) were mixed with 500 ml of anhydrous tetrahydrofuran and, while stirring efficiently at 50° to 60° C., a mixture of 81 g (corresponding to 0.5 mol) of p-methoxycinnamaldehyde and 65 g (corresponding to 0.5 mol) of methyl β-methoxycrotonate was added dropwise. The rate of this dropwise addition was chosen so that the mixture continued to boil gently. It was then stirred at 65° C. for 3 hours and subsequently at room temperature overnight. To work up the reaction mixture was cooled and mixed with 0.5 l of ice-water and then extracted with methyl tertbutyl ether. The remaining alkaline aqueous phase was acidified with dilute hydrochloric acid while cooling in ice, and the precipitate was filtered off and thoroughly washed with water. Drying resulted in 83 g of the title compound of melting point 187° C. (after recrystallization from ethyl acetate), corresponding to a yield of 64%.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:7]([CH3:20])=[C:8]([C:13]([S:16][CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].[I-:21].[K+]>O.Cl>[I:21][C:6]1[C:7]([CH3:20])=[C:8]([C:13]([S:16][CH:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [I-]
Reactant: COC(=O)c1c(SC(C)C)ccc(N)c1C
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1c(SC(C)C)ccc(I)c1C
Temperature: 80 °C
Yield: 77.8 %

Procedure:
A solution of sodium nitrite (6.7 g) in water was added to a stirred, cooled mixture of methyl 3-amino-2-methyl-6-(1-methylethylsulphenyl)-benzoate (18 g) in concentrated hydrochloric acid while maintaining the temperature below 0° C. The resultant mixture was added to a solution of potassium iodide (16 g) in water while maintaining the temperature at about 80° C. The resultant mixture was stirred at 80° C. for 15 mins then cooled to room temperature. It was diluted with water and extracted with dichloromethane. The organic layer was washed with sodium bicarbonate solution, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 3-iodo-2-methyl-6-(1-methylethylsulphenyl)benzoate (20.5 g) as a red oil. NMR (CDCl3) 1.25 (d,6H) 2.35(s,3H) 3.2(m,1H) 3.9(s,3H) 6.9(d,1H) 7.6(d, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:2]1.[O:19]1[C:21]2([CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:20]1>CO>[OH:19][C:21]1([CH2:20][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:3][CH2:2]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(NCC1CCNCC1)OCc1ccccc1
Reactant: C1CC2(CCO1)CO2
Solvent: CO
Product: O=C(NCC1CCN(CC2(O)CCOCC2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.4 %

Procedure:
A mixture of benzyl (piperidin-4-ylmethyl)carbamate (7.77 g, 31.3 mmol, prepared according to Bose, D. Subhas et al., Tetrahedron Lett., 1990, 31, 6903) and 1,6-dioxaspiro[2.5]octane (4.29 g, 37.6 mmol, prepared according to Satyamurthy, Nagichettiar et al., Phosphorus Sulfur, 1984, 19, 113) in methanol (93 mL) was stirred at room temperature for 20 h. Then, the mixture was refluxed for 8 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (v/v=20/1) to give 5.60 g (49%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH:21]=[CH:20]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:20]4)=[C:10]([CH2:33][CH2:34][CH3:35])[CH:9]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(ccn2CC(=O)O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.5 %

Procedure:
To a solution of methyl (5-{3-[4-(4-ethyl-1,3-thiazol-2-yl)-2-propylphenoxy]propoxy}-1H-indol-1-yl)acetate (Example 53, 89 mg, 0.18 mmol) in 3.0 mL THF, was added LiOH.H2O (30 mg, 0.72 mmol) in water (1.0 mL). The mixture was stirred for 12 h at rt. The solvents were evaporated and the residue was suspended in a small volume of water. The pH of the mixture was adjusted to 3 with 1 N HCl. The aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated to give 65 mg (75%) of the product as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 1H), 7.35 (dd, 1H), 7.10-7.05 (m, 2H), 7.08 (d, 1H), 6.90 (dd, 1H), 6.78 (s, 1H), 6.45 (d, 1H), 6.35 (d, 1H), 4.85 (s, 2H), 4.34 (t, 2H), 4.26 (t, 2H), 2.92 (q, 2H), 2.55-2.45 (m, 2H), 2.25-2.15 (m, 2H), 1.62-1.50 (m, 2H), 1.35 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:12][N:11](C(OCC[Si](C)(C)C)=O)[C:8]2=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:13]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]3)[CH2:12][NH:11][C:8]2=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)OCC[Si](C)(C)C)c1ccc(S(C)(=O)=O)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(S(C)(=O)=O)cc32)C1
Reaction time: 1 h
Yield: 107.2 %

Procedure:
1-(2-(Trimethylsilyl)ethyl) 1′-tert-butyl 5-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine]-1,1′-dicarboxylate (133 mg, 0.27 mmol) was dissolved in tetrahydrofuran (3 mL). Thereafter, tetra-n-butylammonium fluoride (1 M tetrahydrofuran solution, 0.5 mL) was added to the above obtained solution at room temperature, and the thus obtained mixture was then stirred for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to obtain tert-butyl 5-(methylsulfonyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (102 mg, quant.) in the form of a white amorphous product.
Reaction SMILES: NC(N)=S.[CH3:5][N:6]([CH3:19])[S:7]([C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=1[OH:18])(=[O:9])=[O:8].[Cl:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[S:30]>>[Cl:16][C:15]1[CH:14]=[CH:13][C:12]([NH:17][C:29]([NH:28][C:22]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=2[Cl:20])=[S:30])=[C:11]([OH:18])[C:10]=1[S:7]([N:6]([CH3:19])[CH3:5])(=[O:9])=[O:8]
Reactant: Fc1ccc(N=C=S)c(Cl)c1
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=S
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2ccc(F)cc2Cl)c1O
Yield: 54.9 %

Procedure:
Following the general procedure for thiourea formation outlined in example 12, N,N-dimethyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (526 mg, 2.10 mmol) and 2-chloro-4-fluorophenylisothiocyanate (586 mg, 3.1 mmol) were coupled to form the desired thiourea (505 mg, 55%). EI-MS m/z 437.75 (M−).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][Si:10]([CH3:60])([CH3:59])[CH2:11][CH2:12][O:13][CH2:14][N:15]([CH2:51][O:52][CH2:53][CH2:54][Si:55]([CH3:58])([CH3:57])[CH3:56])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[CH:17]=1>CC#N>[CH3:58][Si:55]([CH3:57])([CH3:56])[CH2:54][CH2:53][O:52][CH2:51][N:15]([CH2:14][O:13][CH2:12][CH2:11][Si:10]([CH3:9])([CH3:59])[CH3:60])[C:16]1[N:21]2[N:22]=[CH:23][C:24]([C:25]3[CH:26]=[N:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:29][CH:30]=3)=[C:20]2[N:19]=[C:18]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]2)[C:17]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccc5)nc4)c3n2)CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(Oc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NBS (246 mg, 1.38 mmoL) was added to a solution of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate (1022 mg, 1.38 mmoL) in CH3CN (15 mL). After stirring at room temperature for 30 min, the mixture was concentrated in vacuo. Purification by column chromatography afforded tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-bromo-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yloxy)piperidine-1-carboxylate: LCMS tR=3.59 Min (5 min run, UV254nm). Mass calculated for, M+ 824.3, observed LC/MS m/z 825.1 (M+H).
Reaction SMILES: CCCCCC.[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][CH:23]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10]>COC(C)(C)C>[CH3:7][O:8][C:9]([NH:11][C@@H:12]([CH:33]([CH3:35])[CH3:34])[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20]([NH:22][C@H:23]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH:24]([CH3:26])[CH3:25])=[O:21])=[O:14])=[O:10]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)NC(C(=O)C(F)(F)F)C(C)C)C(C)C
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)C(F)(F)F)C(C)C)C(C)C
Yield: 30 %

Procedure:
Hexane (13 ml) was added to a solution of (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[2-methyl-1-(2,2,2-trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (0.85 g; SSS:SSR 53:47; hydrate:ketone 1:1) in tert-butyl methyl ether (8.5 ml) until cloudiness persisted. The solution was then warmed to give a clear solution, seeded with substantially pure crystalline SSS diastereoisomer and allowed to stand. A white solid crystallised which was collected by filtration to give (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(2,2,2-trifluoroacetyl)propyl]-pyrrolidine-2-carboxamide as a crystalline solid in 30% yield, SSS:SSR 95:5; hydrate:ketone 80:20; NMR similar to that of the product of Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][O:19][CH2:20][CH3:21].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][O:19][CH2:20][CH3:21])=[C:4]([F:9])[CH:3]=1
Reactant: CCOCCBr
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCOc1ccc(Br)cc1F
Reaction time: 18 h

Procedure:
To a mixture of 4-bromo-2-fluorophenol (10.07 g) and potassium carbonate (9.5 g) in DMF (100 ml) was added at room temperature 2-bromoethylethyl ether (6.0 ml), and the mixture was stirred for 18 hours. To the mixture was added 2-bromoethylethyl ether (1.2 ml), and the mixture was stirred at 55° C. for 5 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water (thrice) and saturated brine (once), and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give pale yellow oil of 4-bromo-1-(2-ethoxyethoxy)-2-fluorobenzene (13.79 g).
Reaction SMILES: [F-].[Cs+].C(OC([N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)[N:18]=2)[CH2:13][CH2:12][CH2:11]1)=O)(C)(C)C.[C:32]1([C:38]#[C:39][C:40]([O:42]CC)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.O.C(OCC)(=O)C>[C:32]1([CH:38]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][CH2:21][CH2:20][C:17]4[CH:16]=[CH:15][C:14]5[CH2:13][CH2:12][CH2:11][NH:10][C:19]=5[N:18]=4)=[CH:31][CH:30]=3)[CH:26]=[CH:27]2)[CH2:39][C:40]([OH:42])=[O:41])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CC(c1ccccc1)n1ccc2cc(OCCc3ccc4c(n3)NCCC4)ccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 113.7 %

Procedure:
CsF (15.2 g, 100 mmol) was added to a solution of 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (20.0 g, 50.8 mmol) in anhydrous DMF (50 mL). Ethyl phenylpropiolate (16.5 mL, 100 mmol) was added to the mixture at room temperature and the solution was allowed to stir under a nitrogen atmosphere at 60° C. for 4 h. The mixture was diluted with water (1 L), the crude mixture was dissolved in ethyl acetate (500 mL), washed with water, then brine, dried and concentrated under vacuum to give a yellow gum as crude product. Purification of the crude mixture on silica gel (1:1 pet-ether/ether) gave the title compound as a bright yellow solid (25.5 g, 88% yield), a mixture of E/Z isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:21]([O:27][CH:28](CC)[CH3:29])(=[O:26])[CH2:22][C:23](C)=O.[OH-].[K+].S(=O)(=O)(O)O>O.C(O)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]2[C:3]=1[NH:4][C:22]([C:21]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23]2
Reactant: COc1ccc(N)c(Cl)c1
Reactant: CCC(C)OC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc2cc(OC)cc(Cl)c2[nH]1
Temperature: -5 °C
Reaction time: 4 h
Yield: 3.5 %

Procedure:
2-Chloro-4-methoxyaniline (2.719 g, 14 mmol) was added to 8.0M aqueous hydrochloric acid (15 ml) and the suspension cooled to −5° C. Sodium nitrite (1.063 g, 15.4 mmol) was added as a solution in water (3 ml). After addition the pH was brought to pH 4–5 by addition of sodium acetate. In a separate flask, ethyl-α-ethyl acetoacetate (2.18 ml, 15.4 mmol) in ethanol (15 ml) at −5° C. was treated with potassium hydroxide (864 mg, 15.4 mmol) in water (3 ml) followed by ice (4 g). The diazonium salt prepared initially was then added rapidly to the second solution and stirred at −5° C. for 4 hours then allowed to warm to ambient temperature overnight. The mixture was extracted with ethyl acetate (3×100 ml) and the organic solutions dried (MgSO4), filtered and solvent removed in vacuo to give an orange oil. This oil was dissolved in ethanol (35 ml) and the flask fitted with a reflux condenser. Concentrated sulphuric acid (35 ml) was then added dropwise, this caused the reaction to reflux with no external heating. The solution was stirred for 1 hour then the solvent removed by evaporation. The residue was taken up in water then extracted with ethyl acetate (3×100 ml). The organic solution was washed with brine, dried (MgSO4), filtered and evaporated to give a brown oil. The crude oil was purified by silica column chromatography, eluting with dichloromethane to give ethyl 7-chloro-5-methoxyindole-2-carboxylate (125 mg, 4%).
Reaction SMILES: [CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21]S(C)(=O)=O)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].[CH2:34]([N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[C:46]([CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])[CH:35]=[CH2:36]>>[CH3:1][N:2]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=1)[CH2:20][CH2:21][N:51]1[CH2:52][CH2:53][CH:48]([C:46]([C:38]2[N:37]([CH2:34][CH:35]=[CH2:36])[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[N:39]=2)=[O:47])[CH2:49][CH2:50]1)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N(C)CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1
Reactant: C=CCn1c(C(=O)C2CCNCC2)nc2ccccc21
Product: C=CCn1c(C(=O)C2CCN(CCC(CN(C)C(=O)c3cc(-n4cnnn4)ccc3OC)c3ccc(Cl)c(Cl)c3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide and 4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([NH2:31])[CH:28]=2)[CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:31][C:27]4[CH:28]=[C:29]5[C:24](=[CH:25][CH:26]=4)[CH2:23][N:22]([CH3:21])[CH2:30]5)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1Cc2ccc(N)cc2C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)cc2C1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(2-methyl-2,3-dihydro-1H-isoindol-5-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (75.0 mg, 0.244 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (40.0 mg, 0.270 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.049 g, 48%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.7 Hz, 1H), 8.23 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.3 Hz, 2H), 7.65 (d, J=7.3 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.02 (t, J=7.0 Hz, 1H), 6.98 (s, 1H), 3.94 (s, 2H), 3.88 (s, 2H), 3.09 (s, 3H), 2.61 (s, 3H). MS=420 (MH)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.B(OC)(OC)[O:26]C.C(O)(=O)C.OO.S(=O)(O)[O-].[Na+]>C1COCC1>[N:8]1([C:5]2[N:4]=[CH:3][C:2]([OH:26])=[CH:7][N:6]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COB(OC)OC
Reactant: Brc1cnc(N2CCCCC2)nc1
Agent: O=S([O-])O
Agent: OO
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Oc1cnc(N2CCCCC2)nc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 97.9 %

Procedure:
A solution of 5-bromo-2-piperidin-1-ylpyrimidine (1.00 g, 4.15 mmol) in freshly distilled THF (5.2 mL), was purged with argon and cooled to −78° C. To the cooled reaction mixture was added drop-wise a solution of n-butyllithium in hexane (2.5 M, 1.99 mL, 4.98 mmol). The reaction mixture was stirred at −78° C. for 10 minutes and then added dropwise over 10 minutes to a solution of trimethyl borate (0.559 mL, 4.98 mmol) in THF (5.2 mL), which had been purged with argon and cooled to 0° C. The resulting reaction mixture was stirred at 0° C. for a further 20 minutes, followed by addition of acetic acid (0.356 mL, 6.22 mmol). After a further 5 minutes of stirring, a 30% aqueous solution of hydrogen peroxide (0.517 mL, 4.57 mmol) was added dropwise and stirring continued at 0° C. for 5 minutes. A saturated aqueous solution of sodium bisulfite (50 mL) was added and the mixture extracted with EtOAc. The organic extract was washed with a saturated aqueous brine solution, dried over anhydrous sodium sulfate, filtered over Celite™ and concentrated in vacuo. The crude material was purified using silica gel chromatography eluting with 25% EtOAC in hexane to afford the title compound (728 mg, 98%):
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[Br:12][CH2:13][CH2:14]Br>>[Br:12][CH2:13][CH2:14][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9]
Reactant: BrCCBr
Reactant: COC(=O)c1ccccc1O
Product: COC(=O)c1ccccc1OCCBr

Procedure:
The subtitle compound was prepared from methyl salicylate (5 g) and 1,2-dibromoethane (30.67 g) by the method of example 21 step (ii). Purified by chromatography eluting with 10% ethyl acetate in isohexane. Yield 4.9 g.