Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:20][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: C#Cc1ccc(F)c(F)c1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cccnc3)no2)cc1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 1A (78 mg, 0.5 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.60-7.75 (m, 2H), 7.76-7.85 (m, 2H), 8.05 (ddd, J=11.4, 7.6, 2.4 Hz, 1H), 8.37 (dt, J=7.9, 2.0 Hz, 1H), 8.78 (dd, J=5.1, 1.7 Hz, 1H), 9.14 (d, J=1.7 Hz, 1H) ppm; MS (DCI/NH3) m/z 259 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[NH:15][C:14](=[O:16])[O:13][N:12]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[NH:15][C:14](=[O:16])[O:13][N:12]=1
Reactant: COc1ccc(F)c(-c2noc(=O)[nH]2)c1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]c(-c2c(F)ccc(O)c2F)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
A solution of 3-(2,6-difluoro-3-methoxyphenyl)-4H-[1,2,4]oxadiazol-5-one (0.09 g, 0.39 mmol) in DCM (3 ml) was cooled to −78° C. followed by addition of BBr3 (0.10 ml, 1.18 mmol). The reaction mixture was stirred at 25° C. for 2 h. After the completion of the reaction mixture (TLC monitoring), solution of NaHCO3 (20 ml) was added at 0° C. and extracted with ethyl acetate (3×50 ml). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.08 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:19]=[C:18]2[CH2:28][O:29][CH3:30])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13]C)[C:6]([O:15]C)=[N:5]2.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([N:17]2[C:21]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[N:20][N:19]=[C:18]2[CH2:28][O:29][CH3:30])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:15])[NH:5]2
Reactant: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: Cl
Solvent: C1COCCO1
Product: COCc1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 71.2 %

Procedure:
A mixture of (±)-6,7-dichloro-2,3-dimethoxy-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (3.0 g, 6.7 mmol), 2M aqueous hydrochloric acid solution (10 mL) and 1,4-dioxane (50 mL) was heated under reflux for 9 hours, cooled, and concentrated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution and acidified to pH 4.5 with concentrated hydrochloric acid to afford a thick white precipitate. This was collected by filtration and washed with water to give (±)-6,7-dichloro-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]-2,3(1H,4H)-quinoxalinedione (2.0 g, 68%) as an off-white solid, mp 230-232° C.
Reaction SMILES: [I:1][C:2]1[NH:6][C:5]([CH:7]([CH3:9])[CH3:8])=[N:4][C:3]=1[CH3:10].[O:11]1[CH2:16]CC(C=O)C[CH2:12]1>>[I:1][C:2]1[NH:6][C:5]([CH:7]2[CH2:9][CH2:16][O:11][CH2:12][CH2:8]2)=[N:4][C:3]=1[CH3:10]
Reactant: O=CC1CCOCC1
Reactant: Cc1nc(C(C)C)[nH]c1I
Product: Cc1nc(C2CCOCC2)[nH]c1I

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 159.2, except tetrahydro-2H-pyran-4-carbaldehyde was used in place of isobutyraldehyde.
Reaction SMILES: Cl.[Si]([O:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:18](=[N:19][C:20]=1[CH:21](OC)[O:22]C)[N:17]([C:26]([NH:28][C:29]1[CH:34]=[C:33]([O:35][CH:36]3[CH:41]4[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]4)[CH2:37]3)[C:32]([C:44]#[N:45])=[CH:31][N:30]=1)=[O:27])[CH2:16][CH2:15][CH2:14]2)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[C:44]([C:32]1[C:33]([O:35][CH:36]2[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[CH:34][C:29]([NH:28][C:26]([N:17]2[C:18]3[C:13](=[CH:12][C:11]([CH2:10][OH:9])=[C:20]([CH:21]=[O:22])[N:19]=3)[CH2:14][CH2:15][CH2:16]2)=[O:27])=[N:30][CH:31]=1)#[N:45]
Reactant: COC(OC)c1nc2c(cc1CO[Si](C)(C)C(C)(C)C)CCCN2C(=O)Nc1cc(OC2CN3CCC2CC3)c(C#N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1cnc(NC(=O)N2CCCc3cc(CO)c(C=O)nc32)cc1OC1CN2CCC1CC2

Procedure:
Aqueous hydrochloric acid (3 M, 1 ml) was added to a solution of racemic 6-(((tert-butyldimethylsilyl)oxy)methyl)-N-(5-cyano-4-(quinuclidin-3-yloxy)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 78, 120 mg, 0.193 mmol) in THF (1.6 ml) at room temperature. After stirring for 100 min saturated aqueous NaHCO3 was added, the mixture extracted with DCM (3×), the organic layers dried over Na2SO4 and evaporated. The residue was sonicated with EtOAc (2 ml) and hexanes (2 ml) and then filtered to give the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: NC1CC1
Product: Fc1ccc(CCNC2CC2)cc1

Procedure:
Synthesized according to typical procedures C and D from (4-fluorophenyl)acetic acid and cyclopropylamine.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH:16]([CH:26]3[CH2:28][CH2:27]3)[O:15][C:14]2=[O:29])=[O:12])=CC=1)([O-])=O.Cl.Cl.FC1C=CC=CC=1[C@H]1CC[C@H](N2CCC(N)C2)CC1>>[CH:26]1([CH:16]2[O:15][C:14](=[O:29])[N:13]([C:11]([OH:12])=[O:10])[CH:17]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:27][CH2:28]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Agent: Cl
Agent: NC1CCN([C@H]2CC[C@H](c3ccccc3F)CC2)C1
Product: O=C(O)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1

Procedure:
The title compound was prepared from the reaction of the product of Step C above and trans-1-[4-(2-fluoro-phenyl)-cyclohexyl]-pyrrolidin-3-ylamine dihydrochloride ##STR86##
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([SH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.II>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH:16]([S:18][S:18][CH:16]([C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:19])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)[CH3:17])[CH3:17]
Reactant: CC(S)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: II
Solvent: ClCCl
Product: CC(SSC(C)C(O)(Cn1cncn1)c1ccc(F)cc1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
To dichloromethane (20 ml) was added (2RS,3RS)-2(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (0.3 g). To the mixture was added dropwise at room temperature a dichloromethane solution (10 ml) of iodine (0.17 g). The mixture was stirred for 30 minutes at room temperature, washed with a 5% aqueous solution of sodium hydrogensulfite and dried (Na2SO4). The solvent was then distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×30 cm), eluting with ethyl acetate - hexane (4:1). The objective fraction was concentrated. Addition of diethyl ether-hexane (2:1) to the concentrate gave bis[3-(2,4- difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2butyl] disulfide (Compound 15, 0.15 g) as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([CH2:6][C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16]([S:19]([C:22]5[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=5)(=[O:21])=[O:20])[C:13]=4[N:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:2]1.Cl[C:30]1[CH:35]=[N:34][C:33]([C:36]#[N:37])=[CH:32][N:31]=1.CCN(C(C)C)C(C)C.C(Cl)Cl>C(O)CC>[S:19]([N:16]1[C:13]2[N:14]=[CH:15][C:10]3[N:11]([C:7]([CH2:6][C@@H:3]4[CH2:4][CH2:5][N:1]([C:30]5[N:31]=[CH:32][C:33]([C:36]#[N:37])=[N:34][CH:35]=5)[CH2:2]4)=[N:8][N:9]=3)[C:12]=2[CH:18]=[CH:17]1)([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C[C@@H]4CCNC4)n23)cc1
Reactant: N#Cc1cnc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C[C@@H]4CCN(c5cnc(C#N)cn5)C4)n23)cc1
Temperature: 150 °C
Yield: 27.7 %

Procedure:
A mixture of (S)-1-(pyrrolidin-3-ylmethyl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.160 g, 0.404 mmol, prepared using B from Preparation #A.1 and E with HCl), 2-chloro-5-cyanopyrazine (0.084 g, 0.60 mmol, ArkPharm) and DIEA (0.28 mL, 1.6 mmol) in n-PrOH (2.0 mL) was heated in a CEM microwave at about 150° C. for about 30 min (250 psi maximum pressure, 10 min maximum ramp, 200 maximum watts). The reaction mixture was cooled to ambient temperature and DCM (20 mL) was added. The solution was washed with water (20 mL) and brine (20 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was taken up in DCM (10 mL), adsorbed onto silica gel (1 g), and purified by silica gel chromatography eluting with 100% EtOAc to give a pink solid. The material was triturated with a mixture of EtOAc (10 mL) and 10% MeOH in DCM (10 mL). The insoluble material was collected by filtration to give (S)-5-(3-((6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)methyl)pyrrolidin-1-yl)pyrazine-2-carbonitrile as an off-white solid (0.056 g, 27%): LC/MS (Table 1, Method c) Rt=1.34 min; MS m/z: 500 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].CC1C=C(C)N=C(C)C=1.CC1C([IH+:40])=C(C)N=C(C)C=1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([I:40])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4]
Reactant: Cc1cc(C)c([IH+])c(C)n1
Reactant: COC(=O)c1ncc2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: COC(=O)c1nc(I)c2ccn(Cc3ccccc3)c(=O)c2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of 6-benzyl-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (130 mg, 0.42 mmol) and bis(2,4,6-trimethylpyridine)iodine(I) hexafluorophosphate (1.08 g, 2.10 mmol) in 5 mL of CH2Cl2 was stirred at r.t. for 16 h. The mixture was diluted with CH2Cl2 (50 mL) and washed with dilute sodium bisulfite and 1 M HCl. The organic layer was dried over MgSO4 and concentrated to give 180 mg of the title compound as a pale yellow solid. 1H NMR (CDCl3, 200 MHz): δ=13.56 (s, 1H), 7.20-7.50 (m, 6H), 6.77 (d, 1H, J=7.4 Hz), 5.30 (s, 2H), 3.99 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH2:7]2)=[CH:4][CH:3]=[N:2]1.Cl.C(Cl)Cl.CO>O1CCOCC1>[NH:1]1[C:5]([CH:6]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:4][CH:3]=[N:2]1
Reactant: O=C(OCc1ccccc1)N1CCCC(c2ccn[nH]2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: c1cc(C2CCCNC2)[nH]n1
Yield: 56.8 %

Procedure:
A 250-mL round-bottom flask was charged with a solution of benzyl 3-(1H-pyrazol-5-yl)piperidine-1-carboxylate (14 g, 46.61 mmol, 1.00 equiv, 95%) in dioxane (100 mL). To the mixture was added conc.HCl (60 mL, 36%). The resulting mixture was refluxed for 2 hours. The progress was monitored by TLC (DCM:MeOH=10:1). Upon completion, the resulting mixture was concentrated on a rotary evaporator. Then, pH was adjusted to 9 with saturated aqueous Na2CO3. The resulting mixture was then extracted with THF (8×200 mL). Combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration on a rotary evaporator, the residue was purified by a silica gel column chromatography eluted with EtOAc/MeOH (10:1) affording 3-(1H-pyrazol-5-yl)piperidine as pale yellow oil (4 g, 54%). LCMS: [M+H]+: 152.1; 1H NMR (CDCl3) δ 7.47 (s, 1H), 6.05 (s, 1H), 3.16 (m, 1H), 3.11 (m, 2H), 2.99 (m, 1H), 2.76 (m, 1H), 2.57 (m, 2H), 1.95 (m, 1H), 1.56 (m, 1H), 1.46 (m, 2H).
Reaction SMILES: O[CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.O=S(Cl)[Cl:19].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:19][CH2:2][CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: OCC(CN1CCOCC1)c1ccccc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCC(CN1CCOCC1)c1ccccc1
Yield: 76.6 %

Procedure:
To a solution of 1-hydroxy-3-morpholino-2-phenylpropane (650 mg, 2.94 mmol) prepared in the above (3) dissolved solved in dichloromethane (10 ml), SOCl2 (420 mg, 3.53 mmol) in dichloromethane (5 ml) was added while chilling with ice. After the resulting solution was stirred to cause reaction at room temperature for 23 hours, saturated aqueous sodium bicarbonate was added while chilling with ice. The prepared solution was extracted with dichloromethane, and the extract was washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation under reduced pressure to obtain a crude product. The product was purified by silica gel column chromatography using acetone/hexane=1/5 to obtain 540 mg of the titled compound as a colorless oil (yield: 76.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15]C(=O)C)[N:8]([CH3:19])[CH:7]=[C:6]2[C:20]1[N:28](S(C2C=CC(C)=CC=2)(=O)=O)[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][OH:15])[N:8]([CH3:19])[CH:7]=[C:6]2[C:20]1[NH:28][C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH:21]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCOC(C)=O
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(C)c2cc1OCCO
Yield: 32.6 %

Procedure:
2-[5-Methoxy-6-(2-hydroxyethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure as described in example 89a, but using 0.5 g of 2-[5-methoxy-6-(2-acetyloxyethoxy)-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 8.43 ml of a 5N aqueous potassium hydroxide solution. After purification by flash-pack chromatography (silica, 95/05 by volume dichloromethane/methanol as eluents, argon), 0.103 g of 2-[5-methoxy-6-(2-hydroxyethoxy)-1-methyl-1H-indol-3-yl]-1H-pyrrolo[2,3-b]pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][CH:14]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)[CH2:18][CH2:17][N:16]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:15]3)=[O:12])[CH:9]=2)[N:4]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:3]=1.[N:53]1[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=1>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:26][C:22]1[CH:21]=[C:20]([CH:19]2[CH2:18][CH2:17][N:16]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[CH2:15][CH:14]2[NH:13][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:3]=[C:2]3[C:56]2[CH:57]=[CH:58][N:53]=[CH:54][CH:55]=2)=[O:12])[CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(Br)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(F)c2)C(NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C

Procedure:
tert-butyl 3-(3-bromo-1-trityl-1H-indazole-5-carboxamido)-4-(3-fluorophenyl)-piperidine-1-carboxylate (80 mg, 0.105 mmol) was added to a vial containing pyridin-4-ylboronic acid (13 mg, 0.105 mmol) and tetrakis(triphenylphosphine)palladium (13 mg, 0.0105 mmol). After purging the vial with nitrogen gas, dioxane (0.5 mL) and 2M sodium carbonate (0.5 mL) was added to the vial respectively. The reaction mixture was stirred and was heated to 80° C. for overnight. Upon completion, the mixture was concentrated under vacuo. Water (3 mL) was added and was extracted using dichloromethane (3×5 mL). The extracts were combined and dried using anhydrous sodium sulfate. The resulting suspension was filtered and concentrated. The crude product was progressed to the next step without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:20][OH:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Na+].[CH3:24]OS(=O)(=O)OC.[Cl-].[NH4+].FC(F)(F)C(O)=O.[OH-].[Na+]>O1CCCC1.C(Cl)Cl>[CH3:24][O:21][CH2:20][C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCC1(c2ccccc2)CCNCC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
4-(Hydroxymethyl)-4-phenyl-1-piperidinecarboxylic acid tert-butyl ester (953 mg) was dissolved in tetrahydrofuran (10 ml), and the mixture was cooled to 0° C. Sodium hydride (157 mg) was added and the mixture was stirred for 20 min. Dimethylsulfuric acid (0.5 ml) was added, and the mixture was stirred for 5 hr. After completion of the reaction, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a colorless oil. Methylene chloride (6 ml) and trifluoroacetic acid (0.5 ml) were added to the oil, and the mixture was stirred at room temperature for 7 hr. After completion of the reaction, 1N sodium hydroxide was added, and the mixture was extracted three times with chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-(methoxymethyl)-4-phenylpiperidine (237 mg, yield 35%).
Reaction SMILES: [Cl:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[N:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1c(C)ccnc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccnc(Cl)c1C(=O)O
Yield: 79.1 %

Procedure:
A mixture of 21.8 g (0.109 mole) of ethyl 2-chloro-4-methyl-nicotinate (6) and 55 mL of a 2N-sodium hydroxide solution in 20 mL of ethanol, was refluxed for 8 hours. The solution was acidified with 2N hydrochloric acid and extracted with ether. The organic phase was dried over magnesium sulfate, filtered and concentrated to give 14.8 g (79%) of 2-chloro-4-methylnicotinic acid (7)- as a white solid, mp: 152-154° C., MS (MH)+ 172, NMR (DMSO) ppm: 2.34 (s,3H); 7.39 (d,1H); 8.33 (d,1H); 14.0 (bs COOH).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[CH2:23]([C:27]1[CH:34]=[CH:33][C:30]([C:31]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:32]=2)=[C:29]([Cl:35])[CH:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CN(N=C(Cl)c1c(F)cccc1Cl)S(=O)(=O)c1ccccc1
Reactant: CCCCc1ccc(C#N)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)c(Cl)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
N-methyl-N-(phenylsulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.10 g), 4-butyl-2-chlorobenzonitrile (0.60 g) and anhydrous aluminum chloride (0.50 g) are added to o-dichlorobenzene (10 ml) and stirred at 120° C. for 1 hour. On completion of the reaction, chloroform (100 ml) is added and washed with dilute hydrochloric acid. After washing with water, the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solution of hexane-ethyl acetate as eluent to give 0.70 g of compound (refractive index: 1.5667).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:16]C=O)[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[NH2:16])=[CH:4][CH:3]=1
Reactant: O=CNC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixed solution of bis(4-fluorophenyl)methylformamide (13.9 g, 56.2 mmol), concentrated hydrochloric acid (80 ml) and methanol (160 ml) was stirred at 90° C. for 1.5 hours and cooled to room temperature, then a 6 N aqueous sodium hydroxide solution (170 ml) was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the objective product as a solid material. Yield (amount) 11.5 g, yield (rate) 93.5%
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:10]([O:24][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: C(OCC1CO1)C1CO1
Product: CCCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of tetradecanol.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)OC1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.O>C1(C)C=CC=CC=1.Cl.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:19][CH2:20][N:21]([CH:4]2[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]2)[CH2:22][CH2:23]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: O=C1CCC(N2CCN(c3ccccn3)CC2)CC1
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A solution of 1,4-cyclohexanedione monoethyleneketal (50.0 g), 1-(2-pyridyl)piperazine (52.16 g), and p-toluenesulfonic acid (0.5 g) in 500 ml of toluene is refluxed with a Dean-Stark trap until the theoretical amount of water is collected (about four hours). The solvent is evaporated in vacuo and the residue is dissolved in 750 ml of methanol. This solution is cooled in an ice bath and sodium cyanoborohydride (30.1 g) is added in small portions over a two-minute period. The resulting suspension is stirred mechanically and over the next 30 minutes enough concentrated hydrochloric acid solution is added dropwise to the reaction mixture to maintain a pH of about 4. The solvent is removed in vacuo to leave a semisolid residue which is dissolved in 300 ml of a 10% solution of hydrochloric acid in a well ventilated fume hood. This solution is diluted with an equal volume of acetone and refluxed for two hours. The volatile components of the mixture are removed in vacuo and the residue is cooled in an ice bath and made basic with concentrated ammonium hydroxide. The white solid which forms is recrystallized from ethyl acetate-heptane to give 52.4 g of the title compound; mp 142°-144° C.