Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[NH2:19][NH2:20]>CCO>[N+:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[CH2:4][C:3]1[C:14]([C:15]#[N:16])=[C:17]([NH2:18])[NH:20][N:19]=1)([O-:13])=[O:12]
Reactant: NN
Reactant: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Solvent: CCO
Product: N#Cc1c(Cc2cccc([N+](=O)[O-])c2)n[nH]c1N

Procedure:
Reagent 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile (0.97 g; 4.0 mmol) was combined with hydrazine (0.3 mL; 6.0 mmol; Sigma-Aldrich) in 10 mL EtOH for 90 minutes at room temperature. Afterwards the reaction was concentrated in vacuo, suspended in brine and extracted with chloroform (3×50 mL). The organic layer was dried over MgSO4, then filtered, and concentrated in vacuo to afford 3-(3-nitrobenzyl)-5-amino-1H-pyrazole-4-carbonitrile (ESI-MS m/z [M+H]+ found 244.5, calculated 244.1). The product was combined with formamide (1.5 mL) and heated to 160° C. overnight. H20 was added to the cooled reaction and the precipitate was filtered and dried to afford 3-(3-nitrobenzyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 271.4, calculated 271.1). This recovered solid (50 mg, 0.19 mmol) was then added to a solution containing benzyl bromide (0.1 mL, 0.28 mmol), K2CO3 (0.125 g), DMF (1.0 mL). The reaction mixture was purged with Argon and stirred overnight at 80° C. The reaction was filtered to remove solid K2CO3, and the filtrate was combined with brine and the organic product was extracted in CH2Cl2 (3×50 mL) to afford 3-(3-nitrobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 361.4, calculated 361.1). This precipitated intermediate was then mixed with excess Zinc dust, 5 mL THF, 0.4 mL HOAc for 12 hours under Argon at room temperature. Afterwards the reaction was filtered through Celite®, extracted with EtOAc and concentrated in vacuo to afford 3-(3-aminobenzyl)-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (ESI-MS m/z [M+H]+ found 331.5, calculated 331.2). To this reduced precursor, molar equivalents of 3-(trifluoromethyl) benzoyl chloride (Sigma-Aldrich) were added drop wise in ice-cold CH2Cl2. The reaction proceeded until completion as judged by TLC, was concentrated in vacuo, resuspended in 50:50 H20-CH3CN, and purified on a C18 column in CH3CN/H20/0.1% TFA (1-100% gradient) to yield final Cmpd BB5 N-(3-((4-amino-1-benzyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)methyl)phenyl)-3-(trifluoromethyl)benzamide (ESI-MS m/z [M+H]+ found 503.4, calculated 503.2).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:15]([O:17]C)=[O:16])[S:10][C:11]=2[CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=[N:3]1.[Br:19]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:15]([OH:17])=[O:16])[S:10][C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
A solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylate (714 mg, 2.70 mmol)[prepared in Example 112] and N-bromosuccinimide (481 mg, 2.70 mmol) in tetrahydrofuran (12 ml) was stirred in a sealed tube for 1 h at 70° C. The reaction mixture was divided and half of the solution was treated with 6N sodium hydroxide (2.251 ml, 13.51 mmol). The reaction mixture stirred at 70° C. in a sealed tube for 12 h and was partitioned between H2O-DCM. The pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and used directly affording 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-propyl-2-thiophenecarboxylic acid (445 mg, 1.35 mmol, 50% yield): LCMS (ES) m/e 329, 331 (M, M+2)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:6]=[C:5]([CH3:15])[CH:4]=1.[C:16]([N:19]1[CH2:23][C:22](=O)[N:21]=[CH:20]1)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:6]=[C:5]([CH3:15])[CH:4]=1)(=[O:18])[CH3:17]
Reactant: Cc1cc(N)n(-c2ccccc2C)n1
Reactant: CC(=O)N1C=NC(=O)C1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1C

Procedure:
5-Amino-3-methyl-1-(2-methylphenyl)pyrazole HCl (Farmaco, 19, 638, 1964) (26.5 g.) and 1-acetyl-2-imidazolinone (18.2 g.) were reacted as described in Example I to give 12.6 g. product, mp 160°-161°.
Reaction SMILES: C[N:2]([CH3:16])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[CH:8]=1)=O.Cl.NC1[N:20]=[CH:21][NH:22][C:23]=1[C:24]([NH2:26])=[O:25]>C(O)(=O)C>[N+:13]([C:9]1[CH:8]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([C:24]([NH2:26])=[O:25])=[C:16]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)([O-:15])=[O:14]
Reactant: CN(C)C=CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: NC(=O)c1[nH]cnc1N
Agent: Cl
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccc([N+](=O)[O-])c3)ccnc12
Yield: 73 %

Procedure:
A stirred mixture of 18.0 g of 3-dimethylamino-3'-nitroacrylophenone (prepared as described in Example 10) and 10.30 g of 4-amino-5-imidazolecarboxamide hydrochloride in 450 ml of glacial acetic acid was heated at reflux for 24 hours. Upon standing at room temperature a crystalline precipitate was formed. The precipitate was collected, washed with saturated sodium bicarbonate solution and then with water to give 13.1 g of product. The material was recrystallized from methanol-chloroform by the addition of hexane and by scratching to give 8.7 g of the product of the example as yellow crystals, mp 282°-284° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:5]=[C:4]([CH3:17])[C:3]=1[NH:18][C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=S.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>C(#N)C>[CH3:17][C:4]1[CH:5]=[C:6]([O:8][C:9]2[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=2)[CH:7]=[C:2]([CH3:1])[C:3]=1[N:18]=[C:19]=[N:21][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1NC(=S)NC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)cc(C)c1N=C=NC(C)(C)C

Procedure:
A reaction vessel is charged with 16.6 g of N-[2,6-dimethyl-4-(3,5-dichloro-2-pyridyloxy)phenyl]-N'-tert-butylthiourea and 12.8 g of 2-chloro-1-methylpyridinium iodide in 150 ml of acetonitrile. With stirring, a solution of 8.4 g of triethylamine in 80 ml of acetonitrile is added dropwise at room temperature. The reaction mixture is subsequently stirred for 2 hours at 80° C. and then concetrated by rotary evaporation at 50° C. 150 ml of hexane are added to the residue and the resultant solution is filtered. The hexane phase is washed with three 30 ml portions of cold water, dried over sodium sulfate and filtered. The filtrate is concentrated by evaporation, affording the title compound of the formula ##STR5## as a clear pale yellow oil which crystallises on standing and has a melting point of 69°-71° C. (compound 1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[O:11])=[O:7].[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].[BH3-]C#N.[Na+].CO>C(O)(=O)C>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:15]2[CH2:16][CH2:17][C@@H:13]([NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)[CH2:14]2)=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: CCCCc1ccc(C=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCCc1ccc(CN2CC[C@@H](NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a mixture of (R)-3-[N-{3-(trifluoromethyl)benzoyl}glycyl]aminopyrrolidine (0.050 mmol), 4-butylbenzaldehyde (0.18 mmol), NaBH3CN (0.23 mmol), and methanol (1.85 mL) was added acetic acid (0.060 mL). The reaction mixture was stirred at 60° C. for 12 h. The mixture was cooled to room temperature, loaded onto Varian™ SCX column, and washed with CH3OH (15 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford (R)-1-(4-butylbenzyl)-3-[{N-(3-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (Compound No. 1648) (20.6 mg, 89%): The purity was determined by RPLC/MS (91%); ESI/MS m/e 462.2 (M++H, C25H30F3N3O2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:18][CH3:19])[C:12]2([C:15](O)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:31][C:32]([F:49])([F:48])[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[C:44]([CH2:46][NH2:47])[CH:43]=[CH:42][N:41]=2)=[CH:36][CH:35]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:18][CH3:19])[C:12]2([C:15]([NH:47][CH2:46][C:44]3[CH:43]=[CH:42][N:41]=[C:40]([C:37]4[CH:36]=[CH:35][C:34]([O:33][C:32]([F:49])([F:31])[F:48])=[CH:39][CH:38]=4)[CH:45]=3)=[O:16])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(OC(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
Acid 15B (303 mg, 1 mmol) was dissolved in 5 ml of THF and at rt DEPC (1.1 equiv, 0.17 ml) and [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (1.1 equiv., 295 mg) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (3:7 EtOAc:Petroleum ether) afforded 100 mg of a white solid. Yield=18% 1HNMR (DMSO, 200 MHz) δ 1.12 (2H, bs), 1.22 (3H, t, J=7.2 Hz), 1.40 (2H, bs), 3.40 (2H, q, J=4.8 Hz), 4.41 (2H, d, J=5.4 Hz), 7.26 (1H, dd, J=3.8 Hz), 7.49 (2H, d, J=8 Hz), 7.65 (2H, dd, J=8.6 Hz), 7.84 (2H, dd, J=6.8 Hz, J′=1.6 Hz), 7.90 (1H, bs), 8.20 (2H, dd, J=6.8 Hz, J′=1.8 Hz), 8.28 (1H, t), 8.59 (1H, d, J=5.2 Hz) [M+1] 553.9 (C25H23ClF3N3O4S requires 553.98).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14]O.N1C(C)=CC(C)=CC=1C.[Cl-].[Li+].CS([Cl:31])(=O)=O.[Cl-].[NH4+]>CN(C=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][CH2:14][Cl:31]
Reactant: OCC=Cc1ccc2ccccc2c1Br
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: ClCC=Cc1ccc2ccccc2c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.4 %

Procedure:
A solution of Example 3C (0.85 g, 3.24 mmol), collidine (0.94 mL, 7.13 mmol) and lithium chloride (0.21 g, 4.97 mmol) in DMF (10 mL) at 0° C. was treated with methanesulfonyl chloride (0.38 mL, 4.87 mmol), stirred 16 hours at room temperature, poured into aqueous ammonium chloride, and extracted with ethyl acetate. The ethyl acetate was washed with water, brine, dried (MgSO4), filtered, concentrated, and purified on silica gel with 3% ethyl acetate/hexanes to provide 0.35 g (38%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:16])([CH3:15])[C:8](=[O:17])[CH2:7][CH2:6]2)#[CH:2].C1COCC1>C(O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:16])([CH3:15])[C:8](=[O:17])[CH2:7][CH2:6]2)[CH3:2]
Reactant: C#Cc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cc2c(cc1OC)C(C)(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
6-Ethynyl-7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (346 mg) was dissolved in ethanol:THF (=2:1 mixture solvent, 20 ml), added with 10% Pd/C (170 mg), and then the mixture was stirred at room temperature for 1 hr under hydrogen atmosphere. The catalyst was removed by filtration and the organic layer was concentrated under reduced pressure to obtain the title compound (322 mg, yield 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[CH:10][CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C(=CC=O)c1ccccc1OC
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(c1ccccc1OC)c1ccccc1OC
Yield: 75.7 %

Procedure:
In the manner described in Example 99, 3,3-bis(2-methoxyphenyl)-2-propenal (7.1 g) was reacted with (carbomethoxymethylene) triphenylphosphorane (9.7 g) in carbon tetrachloride (60 ml) and dichloromethane (20 mL) for 3 days at room temperature and then overnight at reflux. The crude ester isolated in the normal manner was crystallized from 2-propanol-hexane to yield 6.5 g of (E)-5,5-bis(2-methoxyphenyl)-2,4-pentadienoic acid methyl ester, mp 100°-102° C. A portion was recrystallized from the same solvents to furnish the analytical sample, mp 101°-102° C. Anal. Calcd for C20H20O4 : C, 74.06: H, 6.21. Found: C, 73.83; H, 6.23.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O[CH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH:27]=[CH:28][O:29][C:23]=2[CH:22]=1>C(Cl)Cl>[CH3:1][N:3]([CH2:20][C:21]1[N:26]=[CH:25][C:24]2[CH:27]=[CH:28][O:29][C:23]=2[CH:22]=1)[CH3:4]
Reactant: CCN(CC)CC
Reactant: OCc1cc2occc2cn1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CN(C)Cc1cc2occc2cn1
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of triethylamine (3.45 mL, 24.7 mmol) in methylene chloride (16 mL) under a nitrogen atmosphere and cooled below 5° C. was added p-toluenesulfonyl chloride (4.65 g, 24.4 mmol) in one portion. After stirring the mixture for 15 minutes, a solution of 6-hydroxymethylfuro[3,2-c]pyridine (2.68 g, 18 mmol) in methylene chloride (18 mL) was added dropwise. By tlc the reaction was complete in 6-8 hours. Dimethylamine gas was bubbled over the reaction surface until product formation was complete. The reaction solution was washed with water and the product extracted into dilute hydrochloric acid. The acidic aqueous extract was made basic with sodium hydroxide solution and the product extracted into diethyl ether. The ethereal solution was dried over anhydrous sodium sulfate, filtered through a pad of charcoal and evaporated to give an oil (1.76 g). The oil was distilled under vacuum to give 1.56 g (49% yield) of pure product, bp: 93°-94° C./1.6 mm Hg. Upon standing the product crystallized, mp: 42°-44° C.
Reaction SMILES: [OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[NH:15][CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:13])=[CH:7][C:6]=1[O:28][CH3:29].Br[CH2:33][CH2:34]Br.[OH-].[Na+]>ClC(Cl)C.CCOC(C)=O>[OH:1][C:2]([CH3:31])([CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:34][CH2:33][N:15]3[CH:16]=[C:17]([S:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[C:14]3[C:12]2=[O:13])=[CH:7][C:6]=1[O:28][CH3:29]
Reactant: BrCCBr
Reactant: COc1cc(NC(=O)c2cc(SCCc3ccccc3)c[nH]2)ccc1OCC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCn3cc(SCCc4ccccc4)cc3C2=O)ccc1OCC(C)(C)O
Temperature: 50 °C
Reaction time: 4 h
Yield: 54.8 %

Procedure:
A mixture of N-(4-(2-hydroxy-2-methylpropoxy)-3-methoxyphenyl)-4-(phenethylthio)-1H-pyrrole-2-carboxamide (20.0 mg, 0.0450 mmol), 1,2-dibromoethane (20.0 μL, 0.227 mmol), NBu4Br (43.5 mg, 0.135 mmol) and 1N NaOH (0.227 mL, 0.227 mmol) in dichloroethane (0.227 mL) was allowed to stir at 50° C. for 4 h. The reaction mixture was cooled to rt, diluted with EtOAc (20 mL), washed with water (×2, 15 mL), brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC: PHENOMENEX® Luna AXIA 5μ C18 21.2×100 mm, 15 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 5 min hold; 20 mL/min, UV detection at 220 nm, 8.949 min retention time to afford 11.5 mg of the title compound as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6 H), 2.86-2.91 (m, 2 H), 2.92-2.98 (m, 2 H), 3.83 (s, 2 H), 3.85 (s, 3 H), 4.05-4.11 (m, 2 H), 4.24-4.28 (m, 2 H), 6.78-6.84 (m, 2 H), 6.93 (d, J=8.2 Hz, 1 H), 6.96 (d, J=2.2 Hz, 1 H), 7.07 (s, 1 H), 7.18 (d, 7=8.2 Hz, 2 H), 7.21 (d, 7.1 Hz, 1 H), 7.26-7.32 (m, 2 H); HPLC a) column: PHENOMENEX® Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.470 min retention time, (>95%); HPLC b) column: PHENOMENEX® Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.461 min retention time; MS (ESI) 467 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:34][CH2:35][O:36][CH:37]2[CH2:39][CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:34][CH2:35][O:36][CH:37]3[CH2:39][CH2:38]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(Br)cc1Cc1ccc(OCCOC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of 4-(5-bromo-2-chlorobenzyl)phenol (56.7 g, 210 mmol) and Cs2CO3 (135 g, 420 mmol) in DMF (350 mL) was stirred at room temperature for 30 min, and then 2-cyclopropoxyethyl 4-methylbenzenesulfonate (crude intermediate BP from the second preceeding step above) (53.3 g, 210 mmol) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with water (3 L) and extracted with EtOAc. The organic layer was washed with water, then with brine, and dried over Na2SO4. The residue was concentrated and then purified by flash column chromatography on silica gel (eluent PE:EA=10:1) to give intermediate DK as a liquid (51 g, yield 64%). 1H NMR (CDCl3, 400 MHz): δ 7.22˜7.29 (m, 3H), 7.08 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.86 (t, J=4.8 Hz, 2H), 3.38-3.32 (m, 1H), 0.62-0.66 (m, 2H), 0.49-0.52(m, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[CH3:11][CH:12]([CH3:28])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1)=[O:14]>>[OH:4][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([C:18]2[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH:12]([CH3:11])[CH3:28])[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: O[C@H](CCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using (1S)-2-chloro-1-phenylethanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 367.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]([F:27])([F:26])[CH2:22][C:23](O)=[O:24]>>[F:20][C:21]([F:27])([F:26])[CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1)=[O:24]
Reactant: O=C(O)CC(F)(F)F
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)CC(F)(F)F)ccc2F)NC(=S)CO1
Yield: 54.8 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A′7A) (94 mg, 0.33 mmol) and commercially available 3,3,3-trifluoropropionic acid [CAS-no 2516-99-6] (50 mg, 0.39 mmol). The compound was obtained as light yellow foam (71 mg, 46%). MS (ISP): m/z=393.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.[NH2:11][CH2:12][C:13]1[CH:14]=[C:15]([Br:19])[CH:16]=[N:17][CH:18]=1.CO>C(COC)OC>[Br:19][C:15]1[CH:14]=[C:13]([CH2:12][NH:11][C:7]2[NH:6][C:5]([CH3:9])=[N:4][C:3](=[O:10])[C:2]=2[Cl:1])[CH:18]=[N:17][CH:16]=1
Reactant: NCc1cncc(Br)c1
Reactant: Cc1nc(O)c(Cl)c(Cl)n1
Solvent: COCCOC
Solvent: CO
Product: Cc1nc(=O)c(Cl)c(NCc2cncc(Br)c2)[nH]1

Procedure:
A stirred mixture of 5,6-dichloro-2-methyl-4-pyrimidinol (1.20 g, 6.70 mmol) and 5-aminomethyl-3-bromopyridine (3.65 g, 19.5 mmol) in dimethoxyethane (25 mL) was heated at reflux for 14 hours. The mixture was then concentrated in vacuo and diluted with water. The precipitate was isolated by filtration with aqueous rinse, recrystallized twice from ethyl acetate, and then recrystallized a third time, but from methanol, to provide the title compound as a pure product (1.07 g, 3.25 mmol, 48%): mp 274°-275° C.; Rf 0.59 (20% MeOH in EtOAc); 1H NMR (DMSO-D6, 400 MHz)δ11.9 (br s, 1H), 8.57 (d, J=2 Hz, 1H), 8.49 (s, 1H), 7.93 (s, 1H), 7.46 (t, J=6 Hz, 1H), 4.56 (d, J=6.1 Hz, 2H), 2.18 (s, 3H); IR (KBr) 3300 (NH), 2790-3000 (CH), 1660, 1615, 2590 (C=C, C=N); mass spectrum m/e 329.8 (M+, 70%), 292.9 (M+ -Cl, 32%).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37]C3C=CC(C(OCC)=O)=CC=3)=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1>>[CH3:25][C:26]1([CH3:50])[C:35]2[CH:34]=[CH:33][C:32]([C:36]#[C:37][C:16]3[CH:15]=[CH:14][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])=[CH:31][C:30]=2[C:29](=[O:49])[CH2:28][CH2:27]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CC1(C)CCC(=O)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CCC(=O)c2cc(C#Cc3ccccc3C(=O)O)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4- [(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl ) ethynyl]benzoic acid (Compound 7 ) , 500 mg (1.45 mmol) of ethyl 4-[(5,6,7,8 -tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl) ethynyl]benzoate (Compound 2 ) was converted into the title compound using 4 ml (4 mmol) of LiOH (1N aqueous solution).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][N:40]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:22]=[C:17]([C:7]4[CH:6]=[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)[N:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=5)[CH:8]=4)[CH:18]=[N:19][CH:20]=3)=[CH:30][CH:29]=2)[CH2:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=Cc1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(6′-cyclopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-benzaldehyde (Example 2.64)(1 eq, 0.204 mmol, 80 mg) in DCM (3 ml) is treated with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.2 eq, 0.448 mmol, 83.2 mg) followed by AcOH (1.2 eq, 0.245 mmol, 0.14 ml) and sodium triacetoxyborohydride (3.1 eq, 0.632 mmol, 134 mg). The reaction mixture is stirred at room temperature overnight and then extracted with DCM. The organic portion is washed with water, dried (MgSO4) and concentrated in vacuo to afford the title compound which is used in the next step without further purification; [M+H]+ 563.