Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: Cc1ccc(OCC(=O)O)c(Br)c1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c(Br)c1
Yield: 34.2 %

Procedure:
A solution of (2-bromo-4-methyl-phenoxy)-acetic acid (879 mg, 3.34 mmol) and benzoic acid N′-isopropyl-hydrazide (714 mg, 4.00 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.45 ml, 8.35 mmol) and PyBroP (2.33 g, 5.01 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (463 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]#[N:13])=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:8]1[CH:9]=[C:10]([C:12]#[N:13])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:14])[C:2]=2[Cl:1]
Reactant: BrBr
Reactant: N#Cc1cccc2ccc(O)c(Cl)c12
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a mixture of 8-chloro-7-hydroxy-1-naphthonitrile (0.127 g, 0.63 mmol) and glacial acetic acid (1 mL) in a pressure tube was added a solution of bromine (0.24 g, 1.5 mmol) in glacial acetic acid (2 mL). The tube was sealed and the mixture was stirred at 100° C. overnight. The reaction was cooled, poured into water (50 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with sodium bicarbonate solution, dried over sodium sulfate, filtered, stripped of solvent, and purified on a silica column (20% ethyl acetate—hexanes) to yield 0.10 g (56%) of the title compound as a yellow solid. An analytical sample was prepared by preparative reverse phase HPLC to yield the title compound as a white solid: mp 148-150° C.; 1H NMR (DMSO-d6): δ 7.47 (1H, d, J=8.98 Hz), 7.95 (1H, d, J=9.02 Hz), 8.32 (1H, d, J=2.08 Hz), 8.55 (1H, d, J=2.08 Hz), 11.33 (1H, s); MS (ESI) m/z 280/282/284 (M−H)−.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[CH2:12][CH2:13][CH2:14][OH:15]>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: Oc1cccc(F)c1
Reactant: OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1cccc(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a pre-dried round bottom flask, equipped with a magnetic stirrer, add sodium hydride (60% dispersion in mineral oil, 4.80 g, 0.120 mol) under a nitrogen atmosphere. Wash the sodium hydride with hexanes (3×100 mL) to remove the mineral oil then dimethylformamide (165 mL) is added. The resulting suspension is cooled to 0° C. and a solution of 3-fluorophenol (11.20 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise resulting in gas evolution and a color change from green to blue-green. After stirring the reaction mixture at rt for approximately 30 min the reaction is recooled to 0° C. and a solution of 3-chloro-1-propanol (9.46 g, 0.100 mol) in dimethylformamide (35 mL) is added dropwise. The resulting reaction mixture is heated to 60° C. for 2.5 h. The solution is cooled, the dimethylformamide is removed under reduced pressure and the resulting reaction mixture is diluted with water (250 mL) and extracted with diethyl ether (3×150 mL). The combined organic extracts are washed with water (200 mL), 2 M aqueous sodium hydroxide (200 mL), water (200 mL) and brine (200 mL). The organic layer is dried over magnesium sulfate, filtered and concentrated to afford the slightly impure title compound (13.32 g, 78%) as an amber oil which is used directly in the next reaction without purification: Rf 0.40 (19:1 CH2Cl2/MeOH); 1H NMR (300 MHz; CDCl3), δ 1.68 (t, J=5.1 Hz, 1H), 2.04 (quintuplet, J=6.0 Hz, 2H), 3.83-3.89 (m, 2H), 4.10 (t, J=6.0 Hz, 2H), 6.59-6.70 (m, 3H), 7.17-7.25 (m, 1H); 19FNMR (282 MHz, CDCl3), δ-112.13; APCI MS m/z 153 [C9H11FO2+H—H2O]+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH:9](O)[CH2:8][CH2:7][O:6][P:5]1(=[O:18])[N:11]([CH2:15][CH2:16][Cl:17])[CH2:12][CH2:13][Cl:14].[CH:19]1([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[SH:26][CH2:27][CH2:28][S:29]([O-:32])(=[O:31])=[O:30].ClC(Cl)(Cl)C(O)=O>CN(C)C=O>[CH:19]1([NH3+:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Cl:1][CH2:2][CH2:3][N:4]1[CH:9]([S:26][CH2:27][CH2:28][S:29]([O-:32])(=[O:31])=[O:30])[CH2:8][CH2:7][O:6][P:5]1([N:11]([CH2:15][CH2:16][Cl:17])[CH2:12][CH2:13][Cl:14])=[O:18]
Reactant: O=S(=O)([O-])CCS
Reactant: O=P1(N(CCCl)CCCl)OCCC(O)N1CCCl
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: [NH3+]C1CCCCC1
Solvent: CN(C)C=O
Product: O=P1(N(CCCl)CCCl)OCCC(SCCS(=O)(=O)[O-])N1CCCl
Reaction time: 48 h

Procedure:
340 mg (1 mmol) of 3-(2-chloroethyl)-2-(bis-(2-chloroethyl)-amino)-4-hydroxy-tetrahydro-2H-1,3,2-oxazaphosphorin-2-oxide and 240 mg (1 mmol) cyclohexylammonium-2-mercaptoethanesulphonate in 2 ml of dimethylformamide were mixed with a trace of trichloroacetic acid and were stored for 2 days at -25° C. The reaction mixture was then precipitated with 20 times the quantity of ether. The residue was washed and dried.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.O>CN(C)C=O>[Si:15]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]#[N:10])=[N:7][CH:8]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc(CO)cn1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)nc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
5-(Hydroxymethyl)pyridine-2-carbonitrile (258 mg) was dissolved in dimethylformamide (8 ml), tert-butyl dimethylchlorosilane (347 mg) and imidazole (326 mg) were added, and the mixture was stirred at room temperature for 1% hr. Water (20 ml) was added and the mixture was stirred, extracted with ethyl acetate (once with 50 ml and once with 20 ml), washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (405 mg).
Reaction SMILES: [S:1]([C:5]1[S:13][C:8]2=[CH:9]N=C[CH:12]=[C:7]2[CH:6]=1)(=[O:4])(=[O:3])[NH2:2].S1C2C=C[N:19]=[CH:18]C=2C=C1.S1C2=CN=CC=C2C=C1>>[S:1]([C:5]1[S:13][C:8]2[CH:9]=[CH:18][N:19]=[CH:12][C:7]=2[CH:6]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: c1cc2sccc2cn1
Reactant: NS(=O)(=O)c1cc2ccncc2s1
Agent: c1cc2ccsc2cn1
Product: NS(=O)(=O)c1cc2cnccc2s1

Procedure:
The title compound was prepared according to the procedure described for 2-sulfamoylthieno[2,3-c]pyridine (Example 1) except thieno[3,2-c]pyridine was substituted for thieno[2,3-c]pyridine. This title compound was obtained in 41% yield; m.p. 193°-194° C., after crystallization from ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][CH2:9][CH:10]1[O:15][CH:14]([C:16]2[O:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:13]2=[C:22]3[N:34]([CH3:35])[C:33](=[O:36])[N:32]([CH3:37])[C:31](=[O:38])[C:23]3=[C:24]([C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)[N:12]2[CH2:11]1)=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CN)OC3c2ccc(Cl)o2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc(-c2c3c(=O)n(C)c(=O)n(C)c3c3n2CC(CNC(=O)CCCBr)OC3c2ccc(Cl)o2)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Bromobutyryl chloride (29.4 mg, 0.158 mmol) was added to a solution of 8-(aminomethyl)-10-(5-chlorofuran-2-yl)-1,3-dimethyl-5-(4-methylthiazol-2-yl)-7,8-dihydro-1H-pyrimido[4′,5′:3,4]pyrrolo[2,1-c][1,4]oxazine-2,4(3H,10H)-dione (61 mg, 0.132 mmol) and triethylamine (0.022 mL, 0.158 mmol) in DCM (4 mL). The mixture was stirred at room temperature for 3.5 hours, then diluted with DCM (30 ml) and washed with saturated NaHCO3(aq) (30 ml). The organic phase was passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:28])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Reactant: CC(C)(N)CO
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11 mg, 0.12 mmol) in THF to provide 165. LC/MS (ESI+): m/z 480 (M+H). 1H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.93 (s, 1H), 7.78-7.48 (m, 6H), 7.43-7.26 (m, 2H), 4.85 (t, J=6.1, 1H), 4.47 (d, J=9.0, 4H), 3.49 (d, J=6.0, 2H), 1.29 (s, 6H)
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:12]([N:15]([CH3:17])[CH3:16])[CH2:13][CH3:14])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[K+].[K+].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.O>[CH3:16][N:15]([CH3:17])[CH:12]([CH2:13][CH3:14])[CH:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=3)[S:3][C:4]=2[CH:10]=1)[N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CCC(C(c1ccc2nc(Br)sc2c1)n1ccnc1)N(C)C
Reactant: COC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCC(C(c1ccc2nc(-c3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 80 °C

Procedure:
A mixture of 1-(2-bromobenzo[d]thiazol-6-yl)-1-(1H-imidazol-1-yl)-N,N-dimethylbutan-2-amine (663 mg, 1.75 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (409 mg, 2.275 mmol), tetrakis(triphenylphosphine)palladium (505 mg, 0.437 mmol), potassium carbonate (725 mg, 5.25 mmol), DME (25 mL) and water (5 mL) was degassed, filled with N2, and heated to 80° C. for 3 h. The reaction mixture was evaporated, dissolved in 10% methanol in DCM, loaded onto a PTLC plate and eluted with 6% methanol in DCM to yield methyl 4-(6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)benzoate. MS ESI: m/z 435.19 [M+1+].
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:29])[C:14]([C:26](O)=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:11][C:10]=2[F:30])[CH2:3]1.[CH3:31][C:32]1[CH:39]=[C:38]([O:40][C:41]([F:44])([F:43])[F:42])[CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[C:18]([O:19][CH3:20])=[C:17]3[C:12]([C:13](=[O:29])[C:14]([C:26]([NH:35][CH2:34][C:33]4[CH:36]=[CH:37][C:38]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:39][C:32]=4[CH3:31])=[O:27])=[CH:15][N:16]3[CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:11][C:10]=2[F:30])[CH2:5]1
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12
Reactant: Cc1cc(OC(F)(F)F)ccc1CN
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
212 mg (0.49 mmol) of 7-[(3RS,5SR)-3,5-dimethylpiperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinoline-3-carboxylic acid (salt free compound of Example 50A) and 366 mg (0.98 mmol) of 2-methyl-4-trifluoromethoxybenzylamine (Example 69A) are dissolved together with 357 mg (0.69 mmol) of PyBOP and 30 mg (0.25 mmol) of 4-dimethylaminopyridine in 4 ml of DMF and stirred for 12 h at room temperature. The reaction mixture is then purified by preparative HPLC (Method 7). A solid is obtained. Yield: 170 mg (56% of theory).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7](#[N:9])[CH3:8].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[O:15]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([OH:10])[CH:12]=1)[CH2:8][C:7]#[N:9]
Reactant: O=Cc1cccc(O)c1
Reactant: CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCC(O)c1cccc(O)c1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of KOtBu (68.5 g, 614 mmol) in THF (350 mL), cooled to −50° C., was added acetonitrile (30.3 mL, 540 mmol), dropwise over a period of 5 min. The resulting mixture was stirred at −50° C. for 30 min following which a solution of 3-hydroxybenzaldehyde (30.0 g, 244 mmol) in THF (150 mL) was added slowly, over a period of 10 min. This was then allowed to warm to 0° C. and stirred for another 3 h during which the reaction was found to be complete. The reaction was quenched by slow addition of ice-water followed by extraction with EtOAc. The combined organics were washed with water, brine and dried over Na2SO4. The solution was concentrated under reduced pressure to give 3-hydroxy-3-(3-hydroxyphenyl) propanenitrile (127) as yellow oil which was purified by flash column chromatography (0 to 20% EtOAc-hexanes gradient). Yield (25.0 g, 62%): 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 6.90-6.93 (m, 1H), 6.82 (dd, J=8.0, 2.4 Hz, 1H), 4.91-5.03 (m, 1H), 2.76 (d, J=6.4 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1C
Product: Clc1cncc(NCc2cccnc2)n1
Yield: 93 %

Procedure:
A mixture 2,6-dichloropyrazine (0.671 mmol) and 3-picolylamine (2.014 mmol) in xylene (25 ml) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl3 (3×50 ml). The combined organic extracts were washed with brine (1×100 ml), dried (Na2SO4) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane:ethyl acetate gradient mixture to afford the desired product (93%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][OH:21])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][O:13][C:12]([CH2:19][CH2:20][O:21][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])([CH2:16][CH2:17][CH3:18])[C:5]=1[NH:6]2
Reactant: CCCC1(CCO)OCCc2c1[nH]c1c(F)ccc(Br)c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC1(CCO[Si](C)(C)C(C)(C)C)OCCc2c1[nH]c1c(F)ccc(Br)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of (5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acid ethyl ester (2.0 g, 5.02 mmol) in THF (10 mL) was added LAH (5.27 mL of 1.0 M in THF, 5.27 mmol) slowly at room temperature. The mixture was stirred for 30 minutes at room temperature. The reaction mixture was quenched by the addition of H2O (0.5 mL) and then 10% NaOH (0.5 mL) was added to the mixture. Na2SO4 was added to the mixture and the resulting mixture was filtered. The filtrate was concentrated to give 1.79 g (100%) of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol as yellow oil. A mixture of 2-(5-bromo-8-fluoro-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol (1.79 g, 5.02 mmol), imidazole (0.854 g, 12.55 mmol) and tert-butyldimethylsilyl chloride (0.909 g, 6.03 mmol) in DMF (10 mL) was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL). The organic solution was washed with H2O (5×100 mL) and brine (100 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 7% EtOAc in hexanes) to give 2.29 g (97%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 8.97 (bs, 1H), 6.95 (dd, J=8.37, 4.17 Hz, 1H), 6.57 (d, J=10.41, 8.37 Hz, 1H), 3.98–3.54 (m, 4H), 3.00 (m, 2H), 2.00–0.90 (m, 6H), 0.80 (s, 9H), 0.74 (d, J=7.32 Hz, 3H), 0.06 (s, 3H), 0.03 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7](O)=[N:8][CH:9]=1)(=[O:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.CCN(C1C=CC=CC=1)CC>>[C:1]([C:4]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][C:7]([Cl:18])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc(O)ncc1C(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)c1nc(Cl)ncc1C(C)=O
Temperature: 25 °C

Procedure:
A mixture of ethyl 5-acetyl-2-hydroxy-4-pyrimidinecarboxylate (2.91 g, 13.8 mmol), phosphoryl chloride (11 ml, 118.0 mmol) and diethylaniline (3 ml, 18.0 mmol) is heated to reflux under N2 for 45 min, after which it is cooled to RT and worked up. The residue is distilled, then dissolved in a small amount of methylene chloride and set aside to crystallize. The solid is then filtered, rinsed with methylene chloride and dried to give ethyl 5-acetyl-2-chloro-4-pyrimidinecarboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1.[CH:34](=O)[CH3:35].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:30]([Cl:31])=[CH:29][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:34][CH3:35])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccccc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccccc1

Procedure:
4-Amino-N-((1-(5-benzylaminopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide (1.46 g) as starting compound, acetaldehyde (0.19 ml) and sodium cyanoborohydride (0.43 g) were reacted and treated in the same manner as in Example 136 to give 0.8 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-benzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=1
Reactant: COc1cccc(OC)c1
Reactant: COc1ccc(CC(=O)Cl)cc1
Product: COc1ccc(CC(=O)c2ccc(OC)cc2OC)cc1
Yield: 51.6 %

Procedure:
Synthesized from 1,3-dimethoxybenzene (8.2 g) and 4-methoxyphenylacetyl chloride (10.0 g) according to an analogous synthetic method to Preparation Example 66, the title compound (8.0 g) was obtained.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:15]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CC1C=Cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 98% indene (364 mmoles) in 300 ml of THF was cooled to -78° C. under argon. An equimolar amount of n-butyllithium was added to the solution. The resulting mixture was allowed to warm to room temperature. It was then charged to an equimolar amount of 95% cinnamyl chloride (58.45 g) in 100 ml of THF at -30° C. The mixture was then allowed to warm to room temperature and react for one hour to form cinnamyl indene. The cinnamyl indene was concentrated down to a residue under strong vacuum, and then washed and concentrated twice with 100 ml of hexane. The residue was washed a third time with 100 ml of warm hexane and filtered while hot. The filtrate was again concentrated down to a residue under vacuum. The cinnamyl indene filtrate melted at 55°-69° C. Recovery yield was 62%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=2)[N:7]=1.Cl.[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH2:20])[CH3:16].C(N(CC)CC)C>CN(C)C=O>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][NH:20][C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)=[O:13])[CH3:16]
Reactant: O=C(O)c1cn2nc(Cl)ccc2n1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
0.593 g of 6-chloroimidazo[1,2-b]pyridazine-2-carboxylic acid was suspended in 7.5 ml of N,N-dimethylformamide; 0.535 g of N,N′-carbonyldiimidazole and 0.46 g of glycine ethyl ester hydrochloride were added, followed by stirring at room temperature for 30 minutes. To this mixture, 0.457 ml of triethylamine was added, followed by further stirring for 1 hour. Ice water was added to the reaction mixture; the crystal precipitated was collected by filtration, washed with water and dried to yield 0.749 g of the title compound.
Reaction SMILES: CS(O[CH2:6][C:7]1([F:13])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)(=O)=O.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O.C(OCC)(=O)C>[F:13][C:7]1([CH2:6][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OCC1(F)CCOCC1
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CC1(F)CCOCC1

Procedure:
A mixture of EXAMPLE 138A (1.8 g) and potassium phthalimide (2.356 g) in N,N-dimethylformamide (30 mL) was heated at 150° C. overnight, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, concentrated and chromatographed on silica gel eluting with 30% ethyl acetate in hexanes to give the product.