Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])=[C:4]([C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1C#CCN1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1C=CCN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 2.0 g of (5 mmole) of 1-[4-chloro-2-benzoylphenyl]-3-phthalimidopropyne and 0.1 g of prehydrogenated 10% palladium on barium sulfate in 50 ml of tetrahydrofuran was hydrogenated at room temperature and atmospheric pressure until 85 ml of hydrogen was absorbed. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from ether to give a white solid, mp 70°-72° C. Recrystallization from ether gave colorless prisms, mp 70°-72° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:10][CH3:11])([C:7]([O-:9])=[O:8])[C:4]([O-:6])=[O:5])[CH3:2].[H-].[Na+].[CH2:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C1COCC1>[CH2:10]([C:3]([CH2:1][CH3:2])([C:7]([O:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:8])[C:4]([O:6][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:5])[CH3:11]
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCOC(=O)C(CC)(CC)C(=O)OCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.7 %

Procedure:
To a stirring solution of diethylmalonate (16.0 g, 100 mmol) in THF (200 mL, 0.5 M) was added sodium hydride (2.4 g, 100 mmol). The solution began bubbling and an exothermic reaction occurred. The reaction eventually turned clear and then octyl bromide (17.3 mL, 100 mmol) was added. The reaction was refluxed for 20 hours and then cooled to room temperature. Another equivalent of NaH (2.4 g, 100 mmol) was added to the cloudy white mixture which was then stirred for 4 hours at room temperature. Another equivalent of octyl bromide (17.3 mL, 100 mmol) was added and the reaction was refluxed for 20 hours. The reaction was cooled to room temperature and filtered (NaBr). The mother liquor was collected and concentrated in vacuo to a yellow oil. The crude product was then distilled under vacuum (250° C.) to afford 23.4 g (64%) of pure product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24]([C:26]1[N:27]=[C:28]([N:31]2[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]2)[S:29][CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[N:27]=[C:28]([N:31]5[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]5)[S:29][CH:30]=4)[CH2:23][C:22](=[O:37])[NH:21][C:9]=3[CH:10]=2)=[CH:15][CH:16]=1
Reactant: Cc1cn(-c2nc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)cs2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cn(-c2nc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)cs2)cn1

Procedure:
Prepared from (4′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K76) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (101 mg).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29]C)[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH:1]([N:14]1[CH2:17][C:16](=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C(=C1CN(C(c2ccccc2)c2ccccc2)C1)S(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CS(=O)(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1O
Yield: 51.7 %

Procedure:
On carrying out the operation according to the procedure of Example 32 starting with 1.4 g of 1-benzhydryl-3-[(2-methoxyphenyl)(methylsulfonyl)methylene]azetidine, 10 cm3 of a 1 M solution of boron tribromide and 100 cm3 of dichloromethane, the residue obtained is purified by chromatography on a silica gel column (particle size 0.04-0.06 mm, diameter 4 cm, height 30 cm) at a nitrogen pressure of 0.5 bar with dichloromethane as eluent and collecting 40 cm3 fractions. Fractions 15 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from 40 cm3 of ethyl ether. 0.7 g of 1-benzhydryl-3-[(2-hydroxyphenyl)(methylsulfonyl)methylene]azetidine is obtained melting at 196° C. [NMR spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 3.00 (3H, s, SCH3), 3.60 (2H, s, NCH2), 4.20 (2H, s, NCH2), 4.75 (1H, s, NCH), 6.85 (1H, t, J=7 Hz, CH arom.), 6.90 (1H, d, J=7 Hz, CH arom.), 7.20 (4H, m, 4CH arom.), 7.30 (4H, t, J=7 Hz, 4CH arom.), 7.48 (4H, d, J=7 Hz, 4CH arom.), 9.90 (1H, s, OH)].
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:19][C:20]([NH2:32])([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH3:21]>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:32][C:20]([CH3:21])([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)[CH3:19])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(C)(N)c1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Product: CCCCCCCCC#Cc1ccc(CNC(C)(C)c2ccc(C(F)(F)F)cc2)cc1
Yield: 79 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-dec-1-ynylbenzaldehyde and 1-methyl-1-[4-(trifluoromethyl)phenyl]ethylamine gave the title compound as a colorless oil (79%). 1H NMR (CDCl3, 300 MHz) δ 7.74-7.57 (m, 4H), 7.36 (d, J=8.1 Hz, 2H), 7.24 (d, J=8.3 Hz, 2H), 3.48 (s, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.73-1.22 (m, 18H), 0.91 (t, J=7.0 Hz, 3H). M+(LC/MS(ESI)): 430.4. HPLC (Condition A), Rt: 4.69 min (HPLC purity: 99.8%).
Reaction SMILES: [Li].N.[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>O>[CH2:3]([OH:6])[C:4]#[C:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCBr
Reactant: C#CCO
Agent: N
Agent: [Li]
Solvent: O
Product: CCCCCC#CCO
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a piece of lithium was added to a liquid ammonia (250 ml) in a three neck distillation flask. After the reaction mixture had became dark blue, a catalytic amount of ferric nitrate nonahydrate was added thereto under argon atmosphere. A piece of lithium (2.75 g, 396 mmol) was successively added over 30 min. and the mixture was stirred for one hour. Propargyl alcohol (8.16 g, 146 mmol) was then added and the mixture was stirred for 30 min. Further, n-pentyl bromide (20 g, 132 mmol) was added and the mixture was stirred for 10 min. and allowed to stand overnight at room temperature. To the resulting mixture were added hydrated ether (50 ml) and water (200 ml), and the mixture was then extracted with ether (200 ml, 100 ml, 50 ml×3). The combined ether layers were washed with water (400 ml) and with brine (400 ml), dried over anhydrous sodium sulfate (50 g), and concentrated. Distillation of the residue gave a colorless oily product of 2-octyne-1-ol (9.5758 g, 52%, B.p.: 58°-61° C./0.3 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([C:5]1[N:9]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([C:14]([O:16][CH3:17])=[O:15])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Product: CCCCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 34.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 0.50 g of dimethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 4) and 1.17 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide, 0.51 g of the title compound was obtained as an amorphous solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:15])=[C:7]2[NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:29][CH:28]=1.Cl[C:39](OCC)=[O:40].O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:11]2[N:10]=[CH:9][C:8]3[C:14](=[O:15])[N:16]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)[C:39](=[O:40])[N:26]([C:27]4[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[CH:31][CH:32]=4)[C:7]=3[C:6]=2[N:5]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2ccc(C(C)(C)C#N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3ccc(C(C)(C)C#N)cc3)c2=O)cc1
Temperature: 60 °C
Yield: 46.9 %

Procedure:
Sodium hydride (1.0 g, 25 mmol) was suspended in 25 mL DMF. To the resulting mixture was slowly added dropwise a solution of 6-chloro-4-((4-(2-cyanoprop-2-yl)phenyl)amino)-N-(4-methoxybenzyl)-1,5-naphthyridine-3-carboxamide (2.43 g, 5 mmol) in DMF (25 mL) at room temperature. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 1 hr. To the reaction mixture was slowly added dropwise ethyl chloroformate (1.36 g, 12.5 mmol) under an ice bath. After the completion of the dropwise addition, the resulting mixture was warmed up to 60° C. and reacted for 16 hrs. The reaction was cooled to room temperature, then slowly poured into water, and extracted with ethyl acetate (3×150 mL). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was separated by silicagel column chromatography (EtOAc/PE=0-1/5) to produce a pale yellow solid (1.2 g).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]#[N:19])C1C=CC=CC=1>C(OCC)(=O)C.O1CCCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]#[N:19]
Reactant: N#C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#C[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 6 h
Yield: 99.8 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonitrile (XIII) (1 gm, 0.00389 mol) in a mixture of ethyl acetate and tetrahydrofuran (THF) (4:6, 4 ml:6 ml) containing 10% palladium over carbon (0.300 gm, 50% wet) was hydrogenated at 50-55 psi, for 6 hours at 25° C. The resulting mixture was filtered through a celite pad and residue was washed with mixture of ethyl acetate and tetrahydrofuran (4:6, 4 ml:6 ml). The solvent from the combined filtrate was evaporated under reduced pressure to obtain 0.649 gm of the titled compound of Formula (XIIIa) as oil, which was used as such for the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:33]>>[CH2:1]([O:8][CH2:9][CH:10]([O:23][CH2:24][P:25]([O:30][CH2:31][CH3:32])([O:27][CH2:28][CH3:29])=[O:26])[CH2:11][O:12][N:13]1[CH:21]=[N:20][C:19]2[C:14]1=[N:15][CH:16]=[N:17][C:18]=2[NH2:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(=O)(COC(COCc1ccccc1)COn1cnc2c(Cl)ncnc21)OCC
Reactant: N
Product: CCOP(=O)(COC(COCc1ccccc1)COn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Yield: 64 %

Procedure:
A solution of 9-[3-benzyloxy-2-(diethoxyphosphorylmethoxy)propoxy]-6-chloropurine (570 mg, 1.18 mmol) in ethanolic ammonia (10 ml) was heated in a sealed vessel at 110° C. for 2 hours. After cooling to ambient temperature, the solvent was evaporated and the residue obtained chromatographed on silica (dichloromethane/methanol 95:5 as eluant) to give the title compound (350 mg, 64%). IR: νmax (film) 3320, 3200, 2980, 2900, 640, 1595, 1470, 1450, 1410, 1390, 1370, 1330, 1290, 1240, 1160, 1090, 1050, 1020, 970, 820, 790, 730, 700, cm-1. 1H NMR: δH [(CD3)2SO] 1.22 (6H, t, J=7 Hz, OCH2CH3)2), 3.6-3.75 (2H, m, CH2OCH2Ph), 3.95-4.2 (7H, m, (OCH2CH3)2 +CH2CHCH2 +OCH2P), 4.4-4.65 (2H, m, N-OCH2), 4.52 (2H, s, OCH2Ph), 7.25-7.4 (5H, m, aromatic), 7.39 (2H, br.s, D2O exchangeable NH2), 8.15(1H, s), 8.41 (1H, s). Found: C, 49.81; H, 5.75; N, 14.07%; C20H28N5O6P. H2O requires: C, 49.68; H, 6.25; N, 14.48%, m/z: C20H28N5O5P requires 465.1777; observed: 467.1757.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]=O.[BH4-].[Na+]>COCCOC.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: C=O
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCC(c2ccccc2)CC1
Temperature: 60 °C

Procedure:
4-Phenylpiperidine (12.4 mmol), paraformaldehyde (24.8 mmol) and tetraisopropoxy-titanium (12.4 mmol) are suspended in 1,2-dimethoxyethane (20 ml) and warmed to 60° C. for 30 minutes and stirred at rt for one additional hour. Sodium borohydride (12.4 mmol) is added in portions and the mixture is stirred at rt for 2 hours and at 60° C. for additional 3 hours. After cooling the solvent is evaporated and the residue is dissolved in a mixture of aqueous ammonia (60 ml) and ethyl acetate and filtered carefully. The mixture is extracted three times with ethyl acetate and the combined organic phases are dried over sodium sulfate and evaporated. A pale brown oil is obtained.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[Cl-].[C:20]1([PH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCCCCC.CCOCC>[C:27]1([P:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(CN2CCCCC2)cc1
Reactant: c1ccc(Pc2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc(P(c2ccccc2)c2ccccc2CN2CCCCC2)cc1
Reaction time: 1 h

Procedure:
An 8.77 g portion of 1-(phenylmethyl)piperidine was mixed with 200 ml of ether under argon. A 27 ml portion of 2.6N butyl lithium in hexane was added, this mixture was allowed to stand one hour, then a solution of 12.6 ml of diphenylphosphine chloride in 50 ml of ether was added dropwise. This mixture was stirred 48 hours, then the ether layer was separated, washed with water, then extracted twice with 100 ml of water containing 8 ml of hydrochloric acid followed by water. The aqueous extracts were combined, basified with 12 ml of 10N sodium hydroxide and extracted twice with ether. The ether extracts were combined and concentrated, giving 15.5 g of diphenyl[2-(1-piperidinylmethyl)phenyl]phosphine as an oil.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:5])[CH3:4].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>[Zn]>[OH:5][C:3]([CH3:4])([C:2]([CH3:1])=[CH:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CC(=O)C(C)=CC=Cc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C(C)=CC=Cc1ccccc1

Procedure:
Using 8.60 g of 3-methyl-6-phenyl-3,5-hexadien-2-one, 8.0 ml of ethyl bromoacetate and 4.60 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 12.20 g of ethyl 3-hydroxy-3,4-dimethyl-7-phenyl-4,6-heptadienoate.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[Li+:21].[OH-].Cl>C1COCC1.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:12]([CH2:13][C:14]([O-:16])=[O:15])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:20])#[N:2].[Li+:21]
Reactant: COC(=O)Cc1cncn1Cc1ccc(C#N)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CC(=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of methyl 1-(4-cyano-3-fluoro-benzyl)imidazol-5-ylacetate from Step C (260 mg, 0.95 mmol) in THF (5 mL) and water (1 mL) was added LiOH (40 mg, 0.95 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then the solution was adjusted to pH 7 with 1 N aq. HCl and concentrated to dryness in vacuo to provide the titled product as a white solid which was sufficiently pure for use in the next step.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:3][CH:2]=1.C1CC=CCC=1>[OH-].[OH-].[Pd+2].CCOC(C)=O.CCO>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23][CH3:24])=[O:22])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:5][CH:6]=1
Reactant: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1=CCC=CC1
Product: COC(=O)C1CCCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1

Procedure:
A suspension of methyl 3-{[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.080 g, 0.127 mmol) and Pearlman's Catalyst (0.016 g, 0.023 mmol) in EtOAc (1.5 ml) and EtOH (0.75 ml) was treated with 1,4-cyclohexadiene (0.24 ml, 2.56 mmol). The resulting reaction mixture was microwaved at 120° C. for 90 minutes and then cooled. The cooled reaction mixture was filtered through a Celite™ pad and the filtrate was removed in vacuo. Purification of the resulting residue by reverse phase HPLC eluting with 50-100% MeCN/H2O afforded the title compound as a white solid. LC-MS: calculated for C27H24F2N2O3 462.18, observed m/e: 463.01.01 (M+H)+ (Rt 2.31/4 min).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=2)[CH:21]=1
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Product: O=C(O)c1cccc(COc2ccc(-c3cccnc3)cc2)c1

Procedure:
3-(4-Pyridin-3-yl-phenoxymethyl)-benzoic acid was prepared using the procedure described above for the synthesis of Example 3 from 3-(4-iodo -phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1) and pyridine-3-boronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=306.
Reaction SMILES: [CH2:1]([N:8]1[CH2:24][CH2:23][C:11]2([O:13][C:12]2([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:14]C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CCOCC>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11]([C:12]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])([OH:13])[CH2:23][CH2:24]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC1(c2ccc(F)cc2)OC12CCN(Cc1ccccc1)CC2
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccc(F)cc1)C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
6-Benzyl-2-(4-fluoro-phenyl)-2-methoxy-1-oxa-6-aza-spiro[2.5]octane (0.600 g, 1.83 mmol) was solved in ether (6 mL), 0.6 mL of aqueous HCl was added (37%) and the reaction mixture was stirred at room temperature. After 0.5 h the reaction was finished and water was added and the product precipitate. The mixture was filtrated and the solid was recrystallized ethanol/ether to yield the title compound as a white solid (0.550 g, 1.76 mmol, 96%). MS (m/e): 314.0 (M+H+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:49])([F:48])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:47]=[CH:46][C:28]([O:29][CH2:30][CH2:31][CH2:32][N:33]5[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:33]1([CH2:32][CH2:31][CH2:30][O:29][C:28]2[CH:27]=[CH:26][C:25]([CH:22]3[CH2:21][CH2:20][N:19]([C:16]4[CH2:17][CH2:18][C:13]5[N:14]([C:10]([C:9]([F:49])([F:48])[F:8])=[N:11][N:12]=5)[N:15]=4)[CH2:24][CH2:23]3)=[CH:47][CH:46]=2)[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCCN4CCNCC4)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
TFA (10 mL) was added to tert-butyl 4-[3-[4-(1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]propyl]piperazine-1-carboxylate (2.09 g, 3.53 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia in methanol and the solvents were evaporated to dryness to afford 6-[4-[4-[3-(piperazin-1-yl)propoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (1.700 g, 98%) as a solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:19](=O)[C:18]3[C:17]([C:29]([O:31]CC)=O)=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12]2)=[CH:7][CH:6]=1)[CH3:2].O.[NH2:38][NH2:39]>CO>[CH2:1]([O:3][CH:4]([O:34][CH2:35][CH3:36])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[NH:12][C:13]3[C:18]4[C:19](=[N:38][NH:39][C:29](=[O:31])[C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH:20]2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1ccc(C(OCC)OCC)cc1)N2
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
The crude compound ethyl 2-(4-(diethoxymethyl)phenyl)-3-(4-fluorophenyl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (4.2 g, 8.54 mmol) and hydrazine monohydrate (5 mL) were added in methanol (60 mL) and the mixture was stirred at room temperature for 16 hr. The resulting mixture was concentrated under reduced pressure to a volume of 40 mL and then filtered to obtain the crude title compound (3.0 g, yield 76%). LC-MS (ESI) m/z: 460 (M+1)+.