Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH2:27])[C:18]2=[O:28])[CH2:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1.C(O)C>CCOCC>[CH:29]1([C:32]([NH:27][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:24]=2[C:25](=[O:26])[N:17]([CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12][S:13]([CH3:16])(=[O:14])=[O:15])[C:18]3=[O:28])=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(C(CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)cc1OC
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A stirred mixture of 2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (0.68 g, 1.7 mmol) and cyclopropane carbonyl chloride (1.3 mL) was heated to reflux for 25 min. To the mixture was added ethanol (10 mL) at 0° C. and kept for 30 min. The solvent was removed in vacuo to give a oil. The oil was stirred in ether (20 mL) for 30 min to give a suspension. The suspension was filtered and the solid washed with ether to give a white solid. The solid was purified by column chromatography (Silica Gel, 10% ethyl acetate in methylene chloride) to give cyclopropyl-N-{2-[1-(3,4-dimethoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (330 mg, 42% yield); mp, 130-132° C.; 1H NMR (CDCl3) δ0.92-0.98 (m, 2H, 2CHH), 1.09-1.14 (m, 2H, 2CHH), 1.61-1.64 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.73 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 3.90 (s, 3H, CH3), 4.58 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.90 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84 (d, J=8 Hz, 1H, Ar), 7.09-7.14 (m, 2H, Ar), 7.47 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.6 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 9.68 (s, 1H, NH); 13C NMR (CDCl3) δ6.75, 16.13, 41.54, 48.43, 54.36, 55.81, 55.94, 110.98, 111.11, 114.78, 117.88, 120.27, 124.93, 129.30, 130.94, 136.00, 137.68, 149.19, 149.35, 167.45, 169.48, 172.79; Anal Calcd for C23H24N2O7S: C, 58.46; H, 5.12; N, 5.93. Found: C, 58.10; H, 5.16; N, 5.78.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:18]([CH3:17])[CH:19]=2)[N:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Cc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1

Procedure:
2-Chloro-6-[(3-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C([SiH](CC)CC)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:24][CH:23](O)[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([OH:26])[CH:21]=3)[O:16]2)=[CH:11][CH:10]=1
Reactant: Oc1ccc2c(c1)C(O)CC(c1ccc(F)cc1)O2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCC(c1ccc(F)cc1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylsilane (14 ml) was added slowly into a solution of 2-(4-fluorophenyl)chroman-4,6-diol (2.9 g) in dichloromethane (58 ml). Trifluoroacetic acid (27 ml) was then added dropwise into a reaction mixture and it was stirred at room temperature for 1 hour. The reaction mixture was poured on ice-water and extracted with dichloromethane. The residue was evaporated under reduced pressure with toluene to obtain 2-(4-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6, 2.9 Hz) 6.57 (d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2, 2.4 Hz), 2.95 (ddd, 1H, J −16.8, 11.4, 6.2 Hz), 2.74 (ddd, 1H, J −16.8, 5.3, 3.1 Hz), 2.15 (m, 1H), 2.05 (m, 1H).
Reaction SMILES: C([C@H:3]([S:7]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)(=[N:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([C:18]#[C:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27]([C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)=[O:28])[CH:21]=2)[CH:17]=1)=[O:11])=[O:8])[C:4]([O-])=[O:5])C.[OH:42][CH2:43][CH2:44][NH2:45]>>[CH3:34][N:33]1[C:29]([C:27]([NH:26][C:22]2[CH:21]=[C:20]([C:19]#[C:18][C:16]3[CH:15]=[N:14][CH:13]=[C:12]([CH:17]=3)[C:10]([N:9]=[S@@:7]([CH2:3][C:4]([NH:45][CH2:44][CH2:43][OH:42])=[O:5])(=[O:8])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:11])[CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:30][C:31]([CH3:35])=[N:32]1
Reactant: NCCO
Reactant: CC[C@@H](C(=O)[O-])S(=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=[S@](=O)(CC(=O)NCCO)c4ccccc4)c3)c2)n(C)n1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl[N-({5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]pyridin-3-yl}carbonyl)-S-phenylsulfonimidoyl]acetate and 2-hydroxyethylamine were reacted to give the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CC(=O)OC
Reactant: C=CCOC(=O)C(C)(C)Br
Agent: [Cu]Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,21-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. HCl and once with NaCl solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 79.6 %

Procedure:
A mixture of 1-(4-chlorobenzyl)piperazine (6.32 g; 0.03 mole), 1-bromo-3-chloropropane (4.75 g; 0.03 mole), anhydrous potassium carbonate (6.25 g; 0.045 mole) and butanone (75 ml) was stirred at reflux for 3 hr, cooled and filtered. The filtrate was evaporated in vacuo, and the residue dissolved in ether and washed with water (3x). The solvent solution dried over magnesium sulphate, filtered and evaporated to yield 6.86 g (80%) of the title compound. G.L.C. (5% Dexsil 300, 100°-350° at 15°/min) showed the sample to be 99% pure. A sample was distilled b.p.0.5 150°, and the distillate had the following spectral and analytical characteristics: νmax (film) 2900, 2760, 1480, 1450, 1435 cm-1. δ (CDCl3), 1.95 (2H,m); 2.43 (10H,m); 3.42 (2H,s); 3.56 (2H,t,J 7 Hz); 7.25 (4 H,s) (Found; C, 58.32; H, 7.07; Cl, 24.37; N, 9.79; C14H20Cl2N2 requires; C, 58.34; H, 7.02; Cl, 24.69; N, 9.75%).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH:7]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[BH4-].[Na+]>C(O)C.ClCCl>[OH:1][CH:2]1[CH2:3][CH:4]2[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reaction time: 3 h
Yield: 93.6 %

Procedure:
3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester (8 g, 35.5 mmol) was dissolved in 100 mL of ethanol. Sodium borohydride (2 g, 53.5 mmol) was added to the solution portionwise at room temperature. After stirring for 3 hours, the reaction was evaporated in vacuo to give clear viscous oil. The oil was dissolved in dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and evaporated to afford 7.55 g of 3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid, tert-butyl ester as a white crystalline solid; 1H NMR (300 MHz, DMSO-d6): 4.23 (dd, J=2.7, 4.6 Hz, 1 H), 4.18-4.06 (m, 2 H), 2.17-2.06 (m, 1 H), 1.99-1.91 (m, 3 H), 1.72-1.50 (m, 5H), 1.47 (s, 9H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[Cl:21][C:16]1[CH:15]=[C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)c(Cl)c3)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3ccc(F)c(Cl)c3)c2O1
Yield: 38 %

Procedure:
Treatment of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.68 g, 1.57 mmol) with sodium azide (0.25 g, 3.92 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.035 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.186 g (38%) of (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C.; Anal. calcd. for C15H13ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.38; H, 4.32; N, 4.55.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C-:17]#[N:18].[Na+]>CS(C)=O>[OH:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:17]#[N:18])=[CH:11][CH:12]=1
Reactant: Oc1ccc(NCCCCCCCBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCCCCCCNc1ccc(O)cc1
Yield: 80 %

Procedure:
8-[(4-Hydroxyphenyl)amino]octanenitrile was prepared in 80% yield from 33.2 g [0.11 mol] of 4-[(7-bromoheptyl)amino]phenol and 26.5 g (0.52 mol) of sodium cyanide by the first procedure of Example 2, part d, except that DMSO was used in place of DMF as the solvent.
Reaction SMILES: [OH:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]4=[N:29][N:28]=2)[CH:23]=[CH:22]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:40]>CN(C)C=O>[CH3:40][O:1][C:2]1([CH2:15][O:16][C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:26]=2[N:25]=[C:24]([C:27]2[N:31]4[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]4=[N:29][N:28]=2)[CH:23]=[CH:22]3)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CI
Reactant: Cc1ccn2c(-c3ccc4cccc(OCC5(O)CCN(C(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(COc2cccc3ccc(-c4nnc5cc(C)ccn45)nc23)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
A mixture of tert-butyl 4-hydroxy-4-((2-(7-methyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)methyl)piperidine-1-carboxylate (50 mg, 0.10 mmol) and sodium hydride (18 mg, 0.82 mmol) in dimethylformamide (1 mL) was stirred at ambient temperature for 15 minutes. Iodomethane (0.051 mL, 0.82 mmol) was added and the solution was stirred at ambient temperature overnight. The reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane and washed twice with saturated aqueous ammonium carbonate. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with hexanes and further purified by preparative thin layer chromatography with 1:9 methanol/dichloromethane to provide 25 mg (46%) of desired product.
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].Cl>O1CCCC1>[C:2]([CH:3]([CH2:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)(C)C(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.8 %

Procedure:
A 6.214 g portion of sodium hydride (55% dispersion in oil) was washed with hexane, 150 ml of tetrahydrofuran was added thereto and, under ice-cooling, a solution prepared by dissolving 18.534 g of ethyl 3-oxobutanoate in 75 ml of tetrahydrofuran was added dropwise thereto. After stirring at room temperature for 30 minutes, this solution was added dropwise, under ice-cooling, to a solution prepared by dissolving 25.500 g of 1-bromo-3,3-dimethyl-2-butanone in 150 ml of tetrahydrofuran, followed by stirring overnight at room temperature. After adding 171 ml of 1 M hydrochloric acid to the reaction liquid, tetrahydrofuran was evaporated under a reduced pressure. The residue was extracted with diethyl ether, and the organic layer was washed with water (twice) and saturated brine and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, 30.51 g of ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate was obtained as yellow oil. A 15.00 g portion of this product was dissolved in 250 ml of acetic acid, and 9.48 ml of 4-fluorophenethylamine was added thereto, followed by stirring at 100° C. for 4 hours. The solvent was evaporated under a reduced pressure. The residue was dissolved in ethyl acetate and washed with water, a 1 M sodium hydroxide aqueous solution (twice) and saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:15-1:10) to obtain 15.91 g of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a colorless solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[C:17]2[C:12](=[C:13]([C:19](=[O:21])[NH2:20])[CH:14]=[CH:15][C:16]=2[Br:18])[NH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:22]=O>CO.Cl>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([C:19](=[O:21])[NH2:20])=[C:12]2[C:17]=1[C:9]1[CH2:8][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[NH:1][CH2:22][C:10]=1[NH:11]2
Reactant: C=O
Reactant: CCOC(=O)C(N)Cc1c[nH]c2c(C(N)=O)ccc(Br)c12
Agent: Cl
Solvent: CO
Product: CCOC(=O)C1Cc2c([nH]c3c(C(N)=O)ccc(Br)c23)CN1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 88.6 %

Procedure:
To a solution of ethyl 2-amino-3-(4-bromo-7-carbamoyl-1H-indol-3-yl)propanoate (3.45 g, 9.74 mmol) in methanol (68.8 mL) and 1 M aqueous HCl (52.9 mL) was added 37% aqueous formaldehyde (0.790 mL, 9.74 mmol) and the resulting mixture was heated at 80° C. After 1.5 h, additional formaldehyde (0.79 mL) was added and heating was continued. After 3.5 h, additional formaldehyde (0.79 mL) was again added and heating was continued. After 6 h, the mixture was cooled to room temperature, concentrated, and partitioned between a solvent mixture of CHCl3 and iPrOH (3:1) and 1 M NaOH and NaHCO3 (aq). The organic phase was washed with brine, dried and concentrated to afford the crude product as a light brown solid (3.16 g, 89% yield). LCMS (M+H)+ m/z 365.8, 367.8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[O:22]>>[CH:21]([C:20]1[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=1)[O:17][CH2:16][CH2:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1)=[O:22]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=Cc1cccc(OCCBr)c1
Product: COC(=O)c1ccc2ccn(CCOc3cccc(C=O)c3)c2c1

Procedure:
Methyl 1H-indole-6-carboxylate was alkylated with 3-(2-bromoethoxy)benzaldehyde as described in Example 5, Step 1 to provide methyl 1-(2-(3-formylphenoxy)ethyl)-1H-indole-6-carboxylate.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[C:5]1(=[O:15])[NH:9][C:8](=[O:10])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[K]>CN(C)C=O>[Br:1][CH2:2][CH2:3][N:9]1[C:5](=[O:15])[C:6]2[C:7](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]1=[O:10]
Reactant: BrCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCBr
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 1,2-dibromoethane (30 g, 159.57 mmol, 2.95 equiv) in N,N-dimethylformamide (200 mL). This was followed by the addition of potassium phthalimide (10 g, 54.05 mmol, 1.00 equiv) in several batches. The resulting solution was stirred for 24 h at 60° C. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted with 2×200 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 8 g (57%) of 2-(2-bromoethyl)isoindoline-1,3-dione as a white solid.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=S)[NH:4][CH2:3][CH2:2]1.Br[CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[K+]>C(Cl)Cl>[S:1]1[C:7]2[C:8](=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:9][S:10][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: S=C1NCCSc2ccsc21
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)OCC)=C1CSC2=C1SCCNC2
Reaction time: 2.5 h

Procedure:
(ca) 8.05 g of 3,4-dihydro-thieno[2,3-f][1,4]thiazepine-5(2H)-thione were suspended in 40 ml of methylene chloride and treated under argon with a solution of 7.1 ml of diethyl bromomalonate in 40 ml of methylene chloride. After stirring for 2.5 hours, 50 ml of 10 percent potassium hydrogen carbonate solution were added thereto and the mixture was stirred for 30 minutes. The organic phase was separated and the aqueous phase was extracted twice with methylene chloride. After drying with sodium sulfate, the extract was chromatographed on silica gel, whereby diethyl [3,4-dihydrothieno[2,3-f][1,4]thiazepine-8-(5H)-ylidene]malonate was obtained in the form of slightly yellowish crystals of m.p. 87°-89° (cyclohexane).
Reaction SMILES: C1([O:7][C:8](=S)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])[CH2:34][CH2:33]2)=[O:7])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Yield: 70 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=2)[N:8]=1)(=O)=O.[C:30]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]1([C:7]2[C:15]3[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:25])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[N:8]=2)[CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: COc1nccc2c(OS(=O)(=O)C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c(C3=CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Yield: 45.6 %

Procedure:
A solution of 7-methoxy-1-(4-sulfamoylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate (59 mg), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.3 mg), tetrakis(triphenylphosphine)palladium(0) (7.5 mg) and 2M aqueous sodium carbonate solution (0.33 mL) in DME (5 mL) was stirred under argon atmosphere at 100° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:15][C:14]=3[O:25][CH2:26][CH3:27])[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH2:26]([O:25][C:14]1[CH:15]=[C:16]([C:19]2[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=2)[CH:17]=[CH:18][C:13]=1[NH:12][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:7]=2[N:8]=1)[CH3:27]
Reactant: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(Cl)c2n1
Reactant: NC1CCOCC1
Product: CCOc1cc(-c2cnn(C)c2)ccc1Nc1ncc2ccnc(NC3CCOCC3)c2n1
Yield: 9 %

Procedure:
The title compound was prepared according to the method described for Example 99 using 8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 114) and 4-aminotetrahydropyran. The residue was further purified by passage through a SCX-2 cartridge eluting with 100% MeOH—1M NH3 in MeOH to give the title compound (3 mg, 9%).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O>>[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccccc1Cl
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccccc4Cl)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 2-chlorobenzaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.