Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[OH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH2:24]>CN(C)C=O>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:24][CH2:23][C:22]([CH3:26])([OH:21])[CH3:25])[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: CC(C)(O)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCC(C)(C)O)c1C
Temperature: 5 °C

Procedure:
Triethylamine (15.20 ml) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (16.080 g) in dimethylformamide (160 ml), and then 2-hydroxy-2-methylpropylamine (7.143 g) was added with stirring. After 1 day the resulting mixture was cooled to about 5° C. After 4 days the solvent was removed under reduced pressure, and the resulting oil was dissolved in ethyl acetate (200 ml). The resulting solution was extracted with water (3×65 ml), and the combined aqueous layers were extracted with ethyl acetate (50 ml). The combined organic layers were dried with magnesium sulfate, and the solvent was removed under reduced pressure. The crystals that formed upon cooling were recrystallized from 1:1 hexane/ethyl acetate and then from ethyl acetate. The resulting purified crystals were used in the next step.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:36]2[O:40][N:39]=[C:38]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][N:48](C)[C:49](=O)OC(C)(C)C)=[CH:43][C:42]=3[F:57])[CH:37]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]3[CH2:35][CH2:34][O:33][CH2:32]3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[CH:20][N:21]=1)=O)(C)(C)C>ClCCl>[F:57][C:42]1[CH:43]=[C:44]([CH2:47][NH:48][CH3:49])[CH:45]=[CH:46][C:41]=1[C:38]1[CH:37]=[C:36]([C:17]2[C:16]([NH2:15])=[N:21][CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH:31]4[CH2:35][CH2:34][O:33][CH2:32]4)(=[O:29])=[O:30])=[CH:24][CH:23]=3)[N:18]=2)[O:40][N:39]=1
Reactant: CN(Cc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)c(F)c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2cc(-c3nc(-c4ccc(S(=O)(=O)C5CCOC5)cc4)cnc3N)on2)c(F)c1
Reaction time: 2 h
Yield: 54 %

Procedure:
TFA (281.6 mg, 190.3 μL, 2.470 mmol) was added to a solution of tert-butyl N-[[4-[5-[3-[bis(tert-butoxycarbonyl)amino]-6-(4-tetrahydrofuran-3-ylsulfonylphenyl)pyrazin-2-yl]isoxazol-3-yl]-3-fluoro-phenyl]methyl]-N-methyl-carbamate (100 mg, 0.1235 mmol) in dichloromethane (2.069 mL) at room temperature and the resulting solution stirred for 2 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected and lypholised to give the product as a yellow solid (34.0 mg, 44% yield); 1H NMR (400.0 MHz, DMSO) d 2.13-2.19 (m, 2H), 2.63 (m, 3H), 3.66 (m, 1H), 3.76 (m, 1H), 3.85 (m, 1H), 4.04 (m, 1H), 4.21-4.28 (m, 3H), 7.27 (m, 2H), 7.52 (m, 1H), 7.60-7.65 (m, 2H), 8.00 (m, 2H), 8.12 (t, 1H), 8.36 (m, 2H) and 8.94 (m, 3H) ppm; MS (ES+) 510.2
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>O1CCCC1.CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)C(=O)OC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
Commercially available 6-nitro-1(3H)-isobenzofuranone (9.9 g, 55 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 ml)-methanol (60 ml), then 5% palladium-charcoal catalyst (1.5 g) was added thereto, and the mixture was stirred at room temperature for 20 hours under an atmosphere of hydrogen gas. The reaction mixture was filtered, and the solid was washed successively with ethyl acetate and methanol. The filtrate and washings were combined, and the resulting solution was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (6.21 g) as a crystalline solid. The washings were concentrated, and the residue was crystallized from a mixed solvent of ethyl acetate-hexane to give an additional amount of the title compound (0.95 g, total yield 87%).
Reaction SMILES: [C:1]([OH:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].CS(O[CH2:21][C:22]1[S:26][N:25]=[N:24][C:23]=1[CH3:27])(=O)=O.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([S:8][CH2:21][C:22]1[S:26][N:25]=[N:24][C:23]=1[CH3:27])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(=S)c1ccccc1
Reactant: Cc1nnsc1COS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nnsc1CSC(=O)c1ccccc1
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, 6.64 ml (56.5 m mol) of thiobenzoic acid was added to a stirred solution of potassium tert-butoxide (6.07 g, 54.1 m mol) in DMF (80 ml) at 0° C. After stirring for 10 minutes, 5-methanesulfonyloxymethyl-4-methyl-1,2,3-thiadiazole (9.8 g, 47.0 m mol) in DMF (30 ml) was added to the mixture slowly at the same temperature. The whole mixture was stirred at 80° C. for 2 hours, poured into a mixture of diluted aqueous sodium hydrogen carbonate and ethyl acetate. Aqueous layer was separated, the organic layer was washed with brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was treated on silica gel (eluent: n-hexane/ethyl acetate=9/1-8/2) to afford 5-benzoylthiomethyl-4-methyl-1,2,3-thiadiazole (7.51 g).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=O)=[C:11]3[CH2:10][S:9]2)[CH:3]=1.[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1.C>O1CCOCC1.C(#N)C.C(N(CC)CC)C>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:16]([C:15]2[CH:14]=[CH:13][N:12]3[C:11]=2[CH2:10][S:9][CH:8]3[C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)=[O:18])[CH:25]=1
Reactant: O=C(O)c1ccn2c1CSC2c1cccnc1
Reactant: Cc1ccnc(N)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccnc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 23.2 %

Procedure:
The hydrochloride of the acid chloride derived from (+)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxylic acid (12 g) is added, at a temperature between 65° and 72° C., to a solution of 2-amino-4-methylpyridine (4.3 g) and triethylamine (8.1 g) in dioxane (300 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 7 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with a saturated aqueous sodium bicarbonate solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (13.3 g) is thereby obtained, which is dissolved in boiling acetonitrile (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 2 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (75 cc in total) add 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. (+)-N-(4-methyl-2-pyridyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.1 g) in the form of cream-coloured crystals, m.p. 174° C., is thereby obtained. ([α]D20 =+82°±0.9°; c=1.09; dimethylformamide).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH:10]=[C:11]2[N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[CH:22]2)[CH2:3]1.CN1CCC(=O)CC1.C1(C)C=CC=CC=1.CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>CCOC(C)=O>[N:21]1([C:11]2[C@:12]3([CH2:14][CH2:15][C@H:16]4[C@@H:7]([CH2:6][CH2:5][C:4]5[C@:17]4([CH3:20])[CH2:18][CH2:19][C:2](=[O:1])[CH:3]=5)[C@@H:8]3[CH2:9][CH:10]=2)[CH3:13])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Agent: CC(C)[O-]
Agent: CN1CCC(=O)CC1
Agent: [Al+3]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(n3cnc4ccccc43)=CC[C@@H]12
Yield: 82.8 %

Procedure:
From a mixture of compound 5 (660 mg, 1.70 mmol), 1-methyl-4-piperidone (2.5 mL), and toluene (40 mL) was distilled off ca. 10 mL. Aluminum isopropoxide (521 mg, 2.55 mmol) was then added, and the mixture was refluxed under Ar for 4 h. After cooling, the mixture was diluted with EtOAc (50 mL), washed successively with 5% aqueous NaHCO3 (x3) and brine (x2), and then dried (Na2SO4). The solvent was evaporated, and the crude product was purified by FCC [CH2Cl2/EtOH (25:1)] to give the title compound 6 (544 mg, 82%): mp 201-204° C.; IR(CHCl3) 2946, 2858, 1622, 1611, 1490, 1453, 1376, 1291, 1270, 1228, 1189, 893, 850, 837, 722, 662, 615, 568, 553, 537, 519 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H 18-CH3), 1.24 (s, 3H, 19-CH3), 5.78 (s, 1H, 4-H), 5.99 (s, 1H, 16-H), 7.31 (m, 2H, aromatic-Hs), 7.48 (m, 1H, aromatic-H), 7.81 (s, 1H, aromatic-H), and 7.95 (s, 1H, 21-H). HRMS calcd 409.2250 (C26H30ON2.Na+). found 409.2250.
Reaction SMILES: [O:1]1[C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=c1[nH]ccc2ccoc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1nccc2ccoc12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
The mixture of furo[2,3-c]pyridin-7(6H)-one (12.0 g, 87.6 mmol) and phosphorous oxychloride (21.3 g, 139 mmol) was placed in an oven-dried two-necked flask, then was heated to reflux for 3-4 h under a nitrogen atmosphere. The reaction mixture was cooled to RT, then poured into ice-cold water (250 mL). After it was basified with 10% aq. NaOH solution, the mixture was extracted with diethyl ether (3×100 mL), dried over anhydrous potassium carbonate, filtered and concentrated to give 10.0 g (75%) of the title compound as brown crystals. 1H NMR (300 MHz, CDCl3): δ 6.87 (d, J=1.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([NH2:9])[CH:5]=[N:6][C:7]=1[CH3:8].[N:11]([O-])=O.[Na+]>C(O)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[C:4]2[NH:9][N:11]=[CH:10][C:3]=12
Reactant: O=N[O-]
Reactant: Cc1ncc(N)c(C)c1Br
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ncc2[nH]ncc2c1Br
Temperature: 60 °C
Yield: 52.5 %

Procedure:
To a solution of 5-bromo-4,6-dimethylpyridin-3-amine (1.00 g, 4.98 mmol) in acetic acid (12 mL) at ambient temperature was added sodium nitrite (364 mg, 5.28 mmol) and the mixture heated to 60° C. for 1.5 hr. The cooled reaction mixture was concentrated in vacuo, the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the biphasic mixture filtered through a celite pad. The separated aqueous phase was extracted with ethyl acetate, and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 10-100% ethyl acetate in heptane) to afford the title compound as a pale brown solid (554 mg, 53%). 1H NMR (300 MHz, DMSO) δ 13.91 (s, 1H), 8.95 (s, 1H), 8.14 (s, 1H), 2.67 (s, 3H). LCMS: M+H+=212 & 214.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.[H-].[Na+].[C:25](OCCBr)(=[O:27])[CH3:26]>CN(C)C=O>[OH:27][CH2:25][CH2:26][N:3]1[C:2](=[O:1])[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4]1
Reactant: CC(=O)OCCBr
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a suspension of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (1.0 g) and sodium hydride (60% 0.15 g) in N,N-dimethylformamide (10 ml) was added acetoxyethyl bromide (0.58 g) at 5° C., and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into ice-water, and extracted twice with ethyl acetate. The extracts were combined, washed successively with 1N sodium hydroxide solution and sodium chloride aqueous solution, dried over magnesium sulfate, and then evaporated in vacuo. The residue was dissolved in 1,4-dioxane (12 ml) and a solution of sodium hydroxide (0.34 g) in water (1.5 ml) was added thereto. The reaction mixture was stirred at 60° C. for 3 hours, and evaporated in vacuo. The residue was treated with water and extracted with chloroform. The extract was washed with sodium chloride aqueous solution, dried over magnesium sulfate, and then evaporated in vacuo. The residue was crystallized from ethyl acetate to afford 3-[ 2-(2-hydroxyethyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.84 g).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:13]=[C:12]3[NH:25][CH3:26])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C2C=C3C(=CC=2)N=C(C2C=NC=CC=2)N=C3N2CCCC2)C=CC=1.N1CCCC1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:26][NH:25][C:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[CH:10]=2)[N:15]=[C:14]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:13]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(OC)c3)cc12
Agent: BrB(Br)Br
Agent: COc1cccc(-c2ccc3nc(-c4cccnc4)nc(N4CCCC4)c3c2)c1
Agent: O=C([O-])O
Solvent: C1CCNC1
Solvent: ClCCl
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3cccc(O)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a suspension of 6-(3-methoxyphenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (prepared in a similar method described for 6-(3-methoxy phenyl)-2-(pyridine-3-yl)-4-(pyrrolidin-1-yl)quinazoline using Scheme 74, substituting N-methylamine for pyrrolidine) (1.00 g, 2.9 mmol) in CH2Cl2 (15 mL) and boron tribromide 1M solution in dichloromethane (8.76 ml, 8.76 mmol) was added at 0° C. The reaction mixture was stirred overnight at room temperature after which it was carefully poured into a vigorously stirring mixture of ice and saturated aqueous solution of NaHCO3. The resultant solid was collected by filtration, dried and then dissolved in a mixture of K2CO3 (2 g) and methanol (50 mL). The solution was then acidified using aqueous NH4Cl solution. (50 mL) and the precipitate which formed was collected by filtration and dried to give 0.95 g of 3-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenol as pale yellow solid (99%). LCMS m/z=329 (M+1) (Method D) (retention time=1.30 min). 1H NMR (300 MHz, DMSO) δ 9.63 (s, 1H), 9.60 (s, 1H), 8.77 (d, J=8.0 Hz, 1H), 8.74-8.59 (m, 2H), 8.54 (s, 1H), 8.05 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.54 (dd, J=7.9, 4.8 Hz, 1H), 7.38-7.12 (m, 3H), 6.82 (d, J=7.8 Hz, 1H), 3.17 (d, J=4.3 Hz, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].N[CH2:7][C@@H:8]1CC[CH2:10][N:9]1CC>>[CH3:1][N:2]([CH2:7][CH2:8][NH:9][CH3:10])[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: CCN1CCC[C@H]1CN
Product: CNCCN(C)CCO

Procedure:
By using 2-(methylamino)ethanol (867.5 mg) as a starting material, the title compound (740 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: B(Cl)(Cl)Cl.C[O:6][C:7]1[CH:8]=[C:9]([N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:10]=[C:11]([O:13]C)[CH:12]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([N:15]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:10]=[C:11]([OH:13])[CH:12]=1
Reactant: CCCCCCCN(c1cc(OC)cc(OC)c1)S(=O)(=O)c1ccc(C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCCCCCCN(c1cc(O)cc(O)c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 286.5 %

Procedure:
Boron trichloride solution (145 mL, 1.0 M in CH2Cl2) was added dropwise to a solution of N-(3,5-Dimethoxy-phenyl)-N-heptyl-4-methyl-benzenesulfonamide (19.0 g, 47 mmol) and tetrabutylammonium iodide (53.5 g, 145 mmol) in 250 mL of anhydrous dichloromethane at −78° C. under argon atmosphere. The reaction mixture was stirred at −78° C. for 20 minutes, and then at 0° C. for 2 h. The reaction was quenched by addition of 100 mL of water slowly. The organic layer was separated and washed with water, 30% aqueous NaHSO3 solution, water and brine, and dried over anhydrous sodium sulfate. Removal of solvent and drying reagent provided 50.83 g of a semi-solid crude product. This material was chromatographed on silica gel column eluted with a mixture of petroleum ether and acetone (2:1) to afford 16.83 g (94.6%) of the title compound as a light yellow solid.
Reaction SMILES: [H][H].C([O:10][CH2:11][C@@H:12]1[C@@H:16]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH2:14][C@H:13]1[OH:21])C1C=CC=CC=1.C(OCC)(=O)C>[C].[Pd].C(O)(=O)C>[CH2:17]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([OH:21])[C@@H:12]1[CH2:11][OH:10])[CH2:18][CH2:19][CH3:20]
Reactant: [H][H]
Reactant: CCCC[C@H]1CC[C@@H](O)[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCC[C@H]1CC[C@@H](O)[C@@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
In an atmosphere of hydrogen, a mixture of 4.29 g of (1R,2S,3S)-2-benzyloxymethyl-3-butylcyclopentan-1-ol (prepared in Reference Example 7), 500 ml of 10% palladium-carbon, 20 ml of ethyl acetate and 10 ml of acetic acid was stirred for 16 hrs at room temperature. After stirring the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:3) as eluent to give 2.59 g of the title compound having the following physical characteristics in a 91.8% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH:13][S:14]([OH:17])(=[O:16])=[O:15].[CH3:18]O>>[S:14](=[O:15])(=[O:13])([OH:17])[OH:16].[CH3:18][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1ccc(N)cc1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 3-(4-amino-phenyl)-propionic acid (1.00 g, 6.05 mmol) in 10 mL of methyl alcohol (MeOH) was added 0.80 mL of conc H2SO4. The resulting mixture was refluxed for 2 h, concentrated down to ca. half volume by distillation and then cooled to 45° C. Methyl tert-butyl ether (MTBE, 15 mL) was added. The mixture was allowed to cool to 0° C. and stirred for 0.5 h. The solid was collected by filtration and washed with 1:4 MeOH/MTBE (2×10 mL), MTBE (3×10 mL) and dried under reduced pressure. The title compound (1.43 g, 85%) was obtained as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 8.40-11.0 (br s, 4H), 7.34 (d, 2H, J=8.2 Hz), 7.23 (d, 2H, J=8.2 Hz), 3.57 (s, 3H), 2.86 (t, 2H, J=7.4 Hz), 2.64 (t, 2H, J=7.4 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([F:37])=[C:21]([NH:25][C:26](=[O:36])[C:27]2[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C1(C)C=CC=CC=1.Cl>O1CCOCC1>[CH3:35][N:33]([CH3:34])[C:30]1[CH:29]=[CH:28][C:27]([C:26]([NH:25][C:21]2[C:20]([F:37])=[C:19]([C:3]3[C:4]4[C:12]5[C:7](=[CH:8][C:9]([N:13]6[CH2:18][CH2:17][O:16][CH2:15][CH2:14]6)=[CH:10][CH:11]=5)[NH:6][C:5]=4[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N:1][CH:2]=3)[CH:24]=[CH:23][CH:22]=2)=[O:36])=[CH:32][CH:31]=1
Reactant: CN(C)c1ccc(C(=O)Nc2cccc(C(CN)c3c[nH]c4cc(N5CCOCC5)ccc34)c2F)cc1
Reactant: CCOC(=O)C=O
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)c3ccc(N(C)C)cc3)c2F)c2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.1 %

Procedure:
To a solution of N-(3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-fluorophenyl)-4-(dimethylamino)benzamide (0.321 g, 0.640 mmol) and ethyl 2-oxoacetate in toluene (50%) (0.279 mL, 1.408 mmol) in 1,4-dioxane (30 mL) at room temperature was added hydrogen chloride (4 N in 1,4-dioxane) (0.480 mL, 1.92 mmol). The mixture turned to heterogeneous and it was stirred room temperature for 16 hr. The volatiles were removed under vacuum. The residue was diluted with water (30 mL), basified with NaHCO3 solution to pH 10, and extracted with ethyl acetate (4×40 mL). The combined extract was washed with brine (30 ml), dried over anhydrous MgSO4, and concentrated to dryness under vacuum. To the residue were added 1,4-dioxane (1 mL) and p-xylem (15 mL) and 10% Pd/C (0.4 g), and the mixture was heated at 140° C. under an ambient atmosphere for 4.5 hr. The solid phase was removed by suction filtration. The filtrate was diluted with ethyl acetate (120 ml), washed with brine (25 ml), and dried over anhydrous MgSO4. Removal of solvent under vacuum, followed by triturating with Et2O (8 mL), provided the desired product (0.144 g, 0.238 mmol, 37.1% yield) as a tan solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[C:3]=1[F:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[C:3]=2[F:17])=[CH:21][CH:20]=1
Reactant: O=C1NCCn2c1cc1cc(F)c(F)c(Br)c12
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCn2c1cc1cc(F)c(F)c(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, white solid (60 mg, 72%), MS (ISP) m/z=333.3 [(M+H)+], mp 332.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-7,8-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 6) (75.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).