Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:26])=[C:6]([NH:8][C:9]2[S:10][C:11](=[CH:15][C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[CH:21][CH:20]=[CH:19]4)[C:12](=[O:14])[N:13]=2)[CH:7]=1.Cl.[C:28](=[NH:31])(S)[CH3:29].CO>CN(C=O)C>[ClH:26].[Cl:26][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[NH:31])[CH3:29])=[CH:7][C:6]=1[NH:8][C:9]1[S:10][C:11](=[CH:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][CH:20]=[CH:19]3)[C:12](=[O:14])[N:13]=1
Reactant: Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Reactant: CC(=N)S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=N)Nc1ccc(Cl)c(NC2=NC(=O)C(=Cc3ccc4ncccc4c3)S2)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled (0 deg.) solution of 2-(5-amino-2-chloro-phenylamino)-5-quinolin-6-ylmethylene-thiazol-4-one (39.7 mg, 0.1 mmol) in DMF (1 ml) was added thioacetimidate hydrochloride 9 (28 mg, 0.11 mmol). The mixture was warmed to room temperature and stirred for over night. DMF was removed by nitrogen gas blowing and resulting oil was dissolved with methanol. Insoluble solid was collected by filtration and washed with methanol, followed by desiccation in vacuo to afford the title (14 mg, 0.031 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]>CCO.C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][CH:24]=1)[CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)#[N:2]
Reactant: N#Cc1cccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Solvent: CCO
Solvent: C1CCOC1
Product: N#Cc1cccc(CN2CCN(c3ccc(N)cc3)CC2)c1
Temperature: 55 °C
Yield: 85.9 %

Procedure:
To a stirred solution of 1-(3-cyano-benzyl)-4-(4-nitro-phenyl)-piperazine (52 g) in EtOH (1.2 L) and THF (300 mL) was added portionwise SnC2.2H2O (145.6 g) at room temperature and the mixture was heated at 55° C. for 16 hours. After evaporation of the solvents, the residue was taken in water, basified with NaOH at pH 14 and extracted with CH2Cl2. The organic layer was then washed with water, dried over Na2SO4, and evaporated. The residue was cristallized from disopropyl ether to give the title compound (40.5 g) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[CH:4][C:5]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>ClCCl>[Br:1][C:2]1[C:3]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:5]2[N:9]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:26]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: FC(F)(F)c1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(Br)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (203 mg, 0.41 mmol, Example 89g) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (148 mg, 1.15 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (94 mg,; 0.57 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to afford the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH2:10]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:6][O:5][C:3]([CH2:2][CH2:7][CH2:8][CH2:9][N:20]1[CH2:21][CH2:22][CH:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:18][CH2:19]1)=[O:4]
Reactant: CCCC(Br)C(=O)OC
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Yield: 77.7 %

Procedure:
A mixture of methyl bromovalerate (1.56 g, 8.0 mmol), 4-benzylpiperidine (1.49 g, 8.5 mmol) and potassium carbonate (2.93 g, 21.25 mmol) in 30 mL of acetonitrile was refluxed under N2 for 12 hr. The inorganic salt was removed through a short column of silica gel and washed with ethyl acetate (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography, giving 1.8 g (78%) of the product as a pale yellow oil. 1H NMR (CHCl3), 1.312 (m, 2 H), 1.505-1.593 (m, 7 H), 1.831 (m, 2 H), 2.292 (m, 4 H), 2.505 (d, J=6.9 Hz, 2H), 2.860 (d, J=11.4 Hz, 2 H), 3.647 (s, 3 H), 7.136 (m, 5 H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:29][CH2:30]Cl)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Ca+2]>C1(C)C=CC=CC=1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:28][CH2:29][CH2:30][N:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][CH:2]([OH:1])[CH2:11][O:12][C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:5][CH2:6]2)=[CH:25][CH:26]=1
Reactant: OC(COc1ccc(F)cc1)CN1CCCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1
Product: OC(COc1ccc(F)cc1)CN1CCCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reaction time: 2.5 h

Procedure:
5.9 g (0.022 mol) of 1-[2-hydroxy-3-(4-fluorophenoxy)propyl]homopiperazine and 6.2 g (0.022 mol) of 4,4-bis(4-fluorophenyl)butyl chloride were dissolved with 3.2 g of calcium carbonate in 100 ml of toluene and heated to boiling under reflux with stirring for 2.5 h. After cooling, filtration with suction was carried out, the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography. (Silica gel, eluent methylene chloride with 4% methanol). Yield 4.0 g, oxalate, C30H35F3N2O2.2 C2H2O4, melting point 160°-165° C.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:33][CH3:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].Cl>C(#N)C.O.[Li+].[OH-]>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([N:21]([CH2:33][CH3:34])[CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=2)=[O:20])=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCC(=O)N(CC)Cc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of ethyl(2S)-2-ethoxy-3-[4-(2-{ethyl[4-(trifluoromethyl)benzyl]amino}-2-oxoethoxy)phenyl]propanoate ((0.308 g, 0.64 mmol) in acetonitrile (32 mL) was added aqueous 0.10 M LiOH (16 mL) and the solution was stirred at room temperature overnight. After neutralisation with 5% HCl, the solvent volume was reduced in vacuo and the remaining aqueous phase was diluted with water and aqueous 0.10 M LiOH (to a total volume of 100 mL, pH˜10) and washed with diethyl ether (2×100 mL). The aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with 5% HCl (100 mL) and brine (100 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.279 g (96%) of a colourless oil.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])(O)O.Br[C:16]1[C:21](=[O:22])[N:20]([CH3:23])[C:19]2[N:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])[N:25]=[CH:26][C:18]=2[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOCC>O1CCOCC1.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>[F:33][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([F:34])[C:27]=1[N:24]1[C:19]2[N:20]([CH3:23])[C:21](=[O:22])[C:16]([C:4]3[CH:5]=[C:6]([CH:10]=[C:11]([F:14])[C:12]=3[CH3:13])[C:7]([OH:9])=[O:8])=[CH:17][C:18]=2[CH:26]=[N:25]1
Reactant: Cc1c(F)cc(C(=O)O)cc1B(O)O
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
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: C1COCCO1
Solvent: CCOCC
Product: Cc1c(F)cc(C(=O)O)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 78.1 %

Procedure:
In a 25 mL sealed glass tube, a mixture of tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 μmol), 3-borono-5-fluoro-4-methylbenzoic acid (218 mg, 1101 μmol), and 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (312 mg, 917 μmol) in 4.6 mL of dioxane and 1.0 M solution of sodium carbonate (2.3 mL, 2.3 mmol) was heated in a microwave at 130° C. for 30 min. The reaction mixture was treated with 15 mL of ether and washed with 5 mL of 2 N NaOH, The ether layer was discarded. The aqueous extracts were acidified to pH 4 with 5 N HCl and extracted with 3×25 mL EtOAc. The combined EtOAc layers were dried over MgSO4, filtered and concentrated in vacuo (rotovap) affording the title compound (296 mg) as a viscous oil which solidified to an off-white amorphous solid under vacuum overnight. MS (ESI, pos.ion) m/z: 414.0 (M+1).
Reaction SMILES: [C:1]([O-])(O)=[O:2].[Na+].Cl.[NH2:7][C@@H:8]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:9]([O:11][CH3:12])=[O:10].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:13]1([C@H:8]([N:7]=[C:1]=[O:2])[C:9]([O:11][CH3:12])=[O:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C([O-])O
Reactant: COC(=O)[C@@H](N)C1CCCCC1
Agent: Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N=C=O)C1CCCCC1
Reaction time: 1 h

Procedure:
A 500 mL round-bottom flask was charged with saturated NaHCO3 (80 mL) and DCM (80 ml) and cooled in an ice bath with vigorous stirring. Methyl (2S)-amino(cyclohexyl)acetate hydrochloride (4.0 g, 19.26 mmol) was added followed by triphosgene (1.886 g, 6.36 mmol). The contents of the reaction flask were stirred for 1 hr with cooling, then poured into a reparatory funnel. The layers were separated, and the aqueous layers were extracted with 20 mL DCM. The combined organic portions were dried with anhydrous MgSO4, filtered and evaporated to give the title compound as a colorless oil. 1H NMR (CDCl3): δ 3.90 (d, J 4, 1H), 3.81 (s, 3H), 1.88-1.83 (m, 1H), 1.79-1.76 (m, 2H), 1.69-1.62 (m, 2H), 1.54-1.48 (m, 1H), 1.29-1.11 (m, 5H) ppm.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:32]=[CH:31][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:21][CH:20]=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>ClCCCl>[CH2:33]([N:16]([CH3:15])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[CH:31][CH:32]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=Cc1ccccc1
Reactant: CNCCc1ccc(Oc2ccc(O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCc1ccc(Oc2ccc(O)cc2)cc1)Cc1ccccc1
Yield: 58 %

Procedure:
Sodium triacetoxyborohydride (131 mg, 0.62 mmol) was added to a solution of 4-[4-(2-Methylamino-ethyl)-phenoxy]-phenol (75 mg, 0.31 mmol), benzaldehyde (34 mg, 0.32 mmol), acetic acid (19 mg, 0.32 mmol), and 1,2-dichloroethane (5 mL). Stirred the reaction at room temperature overnight, quenched with a pH=10 buffer, then extracted with dichloromethane (3×25 mL). The combined dichloromethane extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (100 mg). The crude product is purified by flash column chromatography on silica gel eluting with ethanol in dichloromethane to yield 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol, (60 mg): m/z=334.01 (M+1); HPLC=97% (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM. 1H NMR (CDCl3, 300.00 MHz): 7.42-7.28 (m, 7H), 7.11-7.05 (m, 2H), 6.97-6.79 (m, 4H), 3.63 (s, 2H), 2.86-2.78 (m, 2H), 2.71-2.63 (m, 2H), 2.33 (s, 3H),
Reaction SMILES: [CH3:1][Mg]Br.[CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].O>C1COCC1>[OH:5][CH:4]([C:6]1[N:11]=[CH:10][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)[CH3:1]
Reactant: C[Mg]Br
Reactant: COC(=O)c1ccc(C=O)nc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of methyl magnesium bromide (1M in THF) (3.03 mL, 3.03 mmol) was added drop wise to a solution of methyl 6-formylpyridine-3-carboxylate (Intermediate 195, 0.50 g, 3.03 mmol) in THF (20 mL) at −78 C. The reaction mixture was stirred at −78 C for 1 h and water (20 mL) was added. The mixture was warmed to room temperature and extracted with EtOAc (3×20 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound as an off-white solid (0.407 g, 74%). Method B HPLC-MS: MH+ requires m/z=182 Found: m/z=182, Rt=1.11 min (98%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl.COP([CH2:24][C:25]([O:27][CH3:28])=[O:26])(OC)=O>O1CCCC1.C(OCC)(=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C:13](=[CH:24][C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In tetrahydrofuran (40 ml), methyl dimethylphosphonoacetate (1.8 ml) was dissolved. To the resulting solution, 60% oily sodium hydride (450 mg) was added under ice cooling, followed by stirring under the same condition. After the addition of a solution of 1-(tert-butoxycarbonyl)-4-piperidone (2.0 g) in tetrahydrofuran (tetrahydrofuran: 10 ml) and stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate. To the diluted solution, 2N hydrochloric acid was added. The organic layer was separated, washed with a saturated aqueous solution of sodium bicarbonate and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (hexane:ethyl acetate=6:1), whereby the title compound (2.35 g, 92%) was obtained.
Reaction SMILES: CN1CCN(C)[C:4]2[CH:9]=NC=[CH:12][C:3]1=2.[C:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=[O:15])[CH3:14]>CO>[C:13]([N:16]1[CH:21]2[CH:20]([CH2:12][CH2:3][CH2:4][CH2:9]2)[N:19]([C:22](=[O:24])[CH3:23])[C:18]2[CH:25]=[CH:26][N:27]=[CH:28][C:17]1=2)(=[O:15])[CH3:14]
Reactant: CN1CCN(C)c2cnccc21
Reactant: CC(=O)N1CCN(C(C)=O)c2cnccc21
Solvent: CO
Product: CC(=O)N1c2ccncc2N(C(C)=O)C2CCCCC21

Procedure:
27 (1.20 g, 6.34 mmol), 40 ml of pyridine, 30 ml (32.36 g, 317 mmol, ρ=1.082 g/ml) of acetic anhydride and 0.234 g (25 mol %) of PPY were introduced into a 250 ml round-bottomed flask while cooling in ice. The reaction mixture was heated to an oil bath temperature of 100° C. and maintained at this temperature for 48 hours. The reaction was followed by TLC on basic aluminum oxide (EtOAC/MeOH, 10:1). After cooling to room temperature, the solvent was distilled off under reduced pressure and the crude product obtained was purified by flash chromatography on basic aluminum oxide (EtOAc/MeOH, 10:1). This gave a dark yellow solid (1.17 g, 4.31 mmol, 68%). Rf=0.45 (EtOAC/MeOH, 10:1). 1H NMR: (400 MHz, CDCl3): δ=1.34 (m, 4H), 1.60 (d, 4H), 2.23 (s, 3H, H3C—CO—N), 2.27 (s, 3H, H3C—CO—N), 4.74 (m, 1H), 4.85 (m, 1H), 7.25 (d, 3J=5.6 Hz, 1H, H-4), 8.41 (d, 3J=5.6 Hz, H-3), 8.49 (s, 1H, H-1) ppm. 13C NMR (75 Hz, CDCl3): δ=21.7, 21.9 (C-7,8), 23.1, 23.6 (H3C—CO—N), 28.4, 28.5 (C-6,9), 55.2, 56.0 (CH, C-5a,9a), 119.6 (C-4), 130.8 (Cq, C-10a), 141.6 (Cq, C-4a), 147.1, 147.2 (C-1, C-3) 169.1, 169.2 (C═O) ppm. GC-MS (EI): RT 10.45 min, m/e (%) 274 (13), 273 (M+, 58), 232 (15), 231 (100), 230 (42), 216 (5), 214 (5), 213 (5), 203 (3), 202 (4), 190 (13), 189 (84), 188 (45), 173 (5), 172 (6), 160 (7), 159 (5), 158 (5), 147 (8), 146 (40) 134 (6), 133 (13), 132 (15), 120 (7), 43 (9); IR (neat): ν=2940 (m), 1660 (vs), 1587 (m), 1559 (w), 1498 (s), 1448 (w), 1427 (w), 1388 (m), 1353 (w), 1337 (m), 1289 (s); 1270 (s), 1248 (s), 1248 (m), 1220 (w), 1183 (w), 1102 (w), 1036 (m), 978 (m), 857 (w), 839 (w) 777 (w) cm−1. HRMS (EI): calculated for C11H15N3 273.1477 [M+], found: 273.1482.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:13][CH2:12]1
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C#N)cc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 4-fluorobenzonitrile (2.0 g) and 1-methylpiperazine (2.5 g) in dimethylsulfoxide (30 ml) was added potassium carbonate (4.6 g), and the solution was stirred for 1 hour at 120° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide 4-(4-methylpiperazin-1-yl)benzonitrile (2.34 g). This compound (1.1 g) was used according to an analogous synthetic method to Preparation Example 16 to provide the title compound (1.1 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH2:23])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[N:35]=[C:34]([NH:39][C@@H:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42][C@@H:41]2[O:49][CH3:50])[N:33]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]1[CH:14]([O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:18])[CH3:17])[CH2:13][C@H:12]([NH:23][C:36]2[N:35]=[C:34]([NH:39][C@@H:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][C@@H:41]3[O:49][CH3:50])[N:33]=[C:32]([Cl:31])[N:37]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](N)C[C@H]1COCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1nc(Cl)nc(N[C@H]2CC(O[Si](C)(C)C(C)(C)C)[C@H](COCc3ccccc3)C2)n1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
To a solution of (1R,3S,4S)-3-[(benzyloxy)methyl]-4-{[tert-butyl(dimethyl)-silyl]oxy}cyclopentanamine (486.5 mg, 0.001450 mol) and triethylamine (0.55 mL, 0.0040 mol) in THF (2.1 mL) was added 4,6-dichloro-N-[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1,3,5-triazin-2-amine (410 mg, 0.0013 mol) and the mixture was stirred for 2 hours. The reaction was concentrated and the residue was purified by flash chromatography (0 to 25% EtOAc/hexanes) to obtain 250 mg (31%) of the title compound. LC/MS: Rt=2.96 min, ES+ 610 (FA standard).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[CH3:23][C:24]1[N:25]=[CH:26][S:27][CH:28]=1.CC(O[K])=O>CN(C=O)C.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>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:28]2[S:27][CH:26]=[N:25][C:24]=2[CH3:23])[CH:14]=1)=[O:8])[CH3:5]
Reactant: Cc1cscn1
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)O[K]
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2scnc2C)c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 7.9 %

Procedure:
To a stirred solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (0.41 g, 1 mmol) and 4-methylthiazole (5 mmol) in 4 ml of DMF was added Pd(PPh3)4 (0.03 mmol) and CH3COOK (0.198 g, 2 mmol). The reaction mixture were heated to 100° C. and stirred for 14 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with n-hexanes/ethyl acetate (1:6) to give 4′-Methyl-5-(4-methyl-thiazol-5-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (30 mg, 80%) as a light yellow solid, MS (M+H)=381.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH2:20]([O:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.8 %

Procedure:
To 3-hydroxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (1.76 g, 10.0 mmol) dissolved in DMF (10 ml) were added potassium carbonate (2.76 g, 20.2 mmol) and benzyl bromide (1.308 ml, 11.0 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, and the residue was mixed with water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 35 g, ethyl acetate/hexane=1/9). The objective fractions were concentrated under reduced pressure to obtain 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene (2.79 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[Br:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[C:1]([N:15]1[CH2:16][CH2:17][CH:12]([Br:11])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC1CCNCC1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)N1CCC(Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
Benzoyl chloride (1.41 g) was added to a solution of 4-bromopiperidine hydrobromide (2.45 g) in THF (30 ml) at 0° C., followed by triethylamine (2.2 g, 2.2 eq). The solution was stirred at room temperature for 1 h, and evaporated and. The residue was dissolved in dichloromethane (100 ml), washed with water, 1M HCl and saturated sodium bicarbonate, dried and evaporated to give the title compound as colourless oil (2.76 g, 100%).