Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:3]=1.[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.O>CN1CCCC1=O.C(OCC)(=O)C.CCCCCC>[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:2]2[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:11][CH:10]=3)[CH:3]=2)=[CH:28][CH:27]=1
Reactant: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Cl)ncn2)cc1
Reactant: Nc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: O=C(Nc1ccccc1)Nc1ccc(Oc2cc(Nc3ccc(F)cc3)ncn2)cc1
Yield: 39.5 %

Procedure:
N-(4-(6-Chloropyrimidin-4-yloxy)phenyl)-N′-phenylurea (68.0 mg, 0.200 mmol) and 4-fluoroaniline (111 mg, 1.00 mmol) were heated and stirred in 1-methylpyrrolidone (1 ml) at 130° C. for 3 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with saturated aqueous sodium bicarbonate, water and saturated saline and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (33.0 mg, 0.079 mmol, 40%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][NH2:31])=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([NH:30][NH:31][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][N:17]=[CH:18][C:10]=3[NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NNc1ccnc2cc(Cl)ccc12
Product: O=C(NNc1ccnc2cc(Cl)ccc12)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N′-(7-chloroquinolin-4-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotino-hydrazide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.50 mmol of 7-chloroquinolin-4-yl-hydrazine. LC/MS [7.69 min; 534 (M+1)]
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].C([O-])([O-])=O.[K+].[K+].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.[BH4-].[Na+]>CO.C(OCC)(=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:28][C:24]1[O:23][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccco1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Clc1c(NCCNCc2ccco2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride (73 mg, 0.25 mmol) in 4 mL of MeOH, K2CO3 (104 mg, 0.75 mmol) was added. After 10 min, 21 μL (0.253 mmol) of furan-2-carbaldehyde were added. The resulting solution was stirred for 2 h at room temperature, added with sodium borohydride (10 mg, 0.275 mmol) and the reaction was allowed to stir for further 15 h at rt. The mixture was diluted with 10 mL of ethyl acetate and transferred to a separatory funnel. The organic layer was washed with water and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (CH2Cl2/MeOH 95:5 plus 0.3% NH4OH) to afford N-(1-chloronaphthalen-2-yl)-N′-(furan-2-ylmethyl)ethane-1,2-diamine as a yellow oil (63% yield).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8]([CH3:26])([CH3:25])[CH:9]2[NH:12][C:13]([C:15]2[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][C:20]([Cl:24])=[CH:19][CH:18]=3)=[O:14])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Cl.Cl[CH2:31][CH2:32][N:33]([CH3:35])[CH3:34]>CN(C=O)C.C(Cl)Cl.CCOCC>[Cl:24][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])[C:15]([C:13]([NH:12][C@H:9]1[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:11]=3)[CH2:7][C:8]1([CH3:26])[CH3:25])=[O:14])=[CH:23]2
Reactant: CC1(C)Cc2ccc(C#N)cc2C1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C)CCn1c(C(=O)N[C@H]2c3cc(C#N)ccc3CC2(C)C)cc2cc(Cl)ccc21
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-chloro-1H-indole-2-carboxamide (30 mg, 0.083 mmol) in DMF (0.3 mL) at rt was added NaH (60% dispersion, 17 mg, 0.42 mmol). After stirring for 15 min, 2-chloro-N,N-dimethylethanamine hydrochloride (36 mg, 0.25 mmol) was added and the resulting mixture was heated at 65° C. for 4 h. After cooling to rt, the reaction mixture was subjected to purification by reverse-phase HPLC using MeOH/water mixtures with 0.1% TFA as the diluent. Fractions containing the major product were collected, combined and concentrated in vacuo to remove the MeOH. The resulting aqueous solution containing the product was made neutral by addition of sat. aq. NaHCO3 and the product was extracted with EtOAc (3×10 mL). The combined extracts were washed with brine, dried over anhyd Na2SO4, filtered and concentrated in vacuo to afford an oil. The oil was redissolved in DCM/Et2O (50/50, 2 mL) and reconcentrated to yield an oil which solidified under vacuum to afford the title compound in the form of a white solid (16 mg). HPLC Ret. time: 2.84 min. LCMS MH+ (m/z) 435.30. 1H NMR: (MeOH-d4, 400 MHz): 7.65 (d, 1H), 7.62-7.60 (m, 2H), 7.51 (d, 1H), 7.42 (d, 1H), 7.30 (dd, 1H), 7.12 (s, 1H), 5.45 (s, 1H), 4.80 (t, 2 H), 3.12 (br m, 2H), 2.93 (m, 2H), 2.59 (s, 6H), 1.32 (s, 3H), 1.07 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[S:23][C:24]=1[CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol (example 5 c]) in the presence of triphenylphosphine and di-tert-butyl azodicarboxylate to yield (6-{2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester as light yellow oil.
Reaction SMILES: C(N1C2C(=O)N(CCC3C=CC=CC=3)C([Cl:23])=NC=2N=C1N1CCCC(NC(=O)OC(C)(C)C)C1)C#CC.Cl.[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]2[N:54]([CH2:55][C:56]#[C:57][CH3:58])[C:53]3[C:52](=[O:59])[N:51]([CH2:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:67]#N)[C:50]([C:69]#[N:70])=[N:49][C:48]=3[N:47]=2)[CH2:41]1>>[ClH:23].[NH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]2[N:54]([CH2:55][C:56]#[C:57][CH3:58])[C:53]3[C:52](=[O:59])[N:51]([CH2:60][CH2:61][C:66]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:67]=4)[C:50]([C:69]#[N:70])=[N:49][C:48]=3[N:47]=2)[CH2:41]1
Reactant: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2nc(Cl)n(CCc3ccccc3)c(=O)c21
Reactant: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(Cc3ccccc3C#N)c(=O)c21
Agent: Cl
Product: CC#CCn1c(N2CCCC(N)C2)nc2nc(C#N)n(CCc3ccccc3)c(=O)c21

Procedure:
The title compound was synthesized by using t-butyl [1-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate according to the method described in Example 242 (f) and (g).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:30])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:30])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:18][O:19][CH2:20][CH3:21])[C:7]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOCc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: ClCCl
Product: CCOCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8-Cyclopentyl-6-ethoxymethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (4.60 g, 14.40 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (4.89 g, 18.72 mmol) were dissolved in dichloromethane (30 mL) and stirred at ambient temperature for 12 hours. The crude product was then purified by silica gel chromatography to give 8-cyclopentyl-6-ethoxymethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white waxy solid (2.67 g, 55.3%). 1H NMR δ(400 MHz, CDCl3) 8.94 (s, 1H), 7.81 (t, J=1.7 Hz, 1H), 5.98 (m, 1H), 4.50 (d, J=1.7 Hz, 1H), 3.68 (q, J=7.1 Hz, 2H), 2.96 (s, 3H), 2.22 (m, 2H), 2.12 (m, 2H), 1.94 (m, 2H), 1.69 (m, 2H), 1.31 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([O:60][Si](CC)(CC)CC)([CH2:50][CH2:51][C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:53])[CH:46]([O:68][CH3:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([O:72][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:80])[CH3:2]>CC#N>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:70])=[CH:43][CH:44]2[CH2:49][CH2:48][C:47]([OH:60])([CH2:50][CH2:51][C:52]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[O:53])[CH:46]([O:68][CH3:69])[CH2:45]2)[CH:7]([CH3:71])[CH:6]([OH:72])[CH2:5][C:4]1=[O:80])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(CCC(=O)c4ccccc4)(O[Si](CC)(CC)CC)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)(CCC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC

Procedure:
The product of Step 32A was deprotected (HF, CH3CN) according to standard procedures to give the title compound. MASS:(FAB) 930 (M+ + Li).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[F:30][C:27]([F:28])([F:29])[C:19]1[CH:18]=[C:17]([C:10]2([C:13]([F:14])([F:15])[F:16])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[N:20]=1
Reactant: FC(F)(F)c1cc(C2(C(F)(F)F)CCN(Cc3ccccc3)C2)cc(C(F)(F)F)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: FC(F)(F)c1cc(C2(C(F)(F)F)CCNC2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
The solution of 4-[1-benzyl-3-(trifluoromethyl)pyrrolidin-3-yl]-2,6-bis(trifluoromethyl)pyridine (1.4 g) and 1-chloroethyl chloroformate (0.905 g) in dichloroethane was heated to reflux for 3 hours. The mixture was cooled to room temperature and then concentrated under the reduced pressure. Methanol was added to the resultant residue, which was then heated with stirring at 60° C. for two hours. The mixture was cooled to room temperature, to which was then added water. The solution was washed twice with the mixed solvent of hexane. The solution was neutralized with sodium hydroxide and then extracted with tert-butyl methyl ether three times. The organic layer was combined, which was then washed with brine and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure to yield 2,6-bis(trifluoromethyl)-4-[3-(trifluoromethyl)pyrrolidin-3-yl]pyridine (0.781 g).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11]O.C(N(CC)CC)C.CS([Cl:36])(=O)=O>ClCCl>[Cl:36][CH2:11][C:10]1[O:9][C:8]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:7][C:6]=1[CH2:5][O:4][CH2:3][C:2]([F:24])([F:23])[F:1]
Reactant: OCc1oc(-c2ccc(C(F)(F)F)cc2)nc1COCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)COCc1nc(-c2ccc(C(F)(F)F)cc2)oc1CCl
Temperature: 25 °C

Procedure:
422 mg [4-(2,2,2-Trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol were dissolved in 5 ml dichloromethane and cooled in an ice bath. 247 μl triethylamine were added, followed by the addition of 110 μl methanesulfonylchloride. The ice bath was removed and the resulting mixture stirred at room temperature over night. 50 ml dichloromethane were added and the reaction mixture was then washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to obtain 509 mg 5-chloromethyl-4-(2,2,2-trifluoro-ethoxymethyl)-2-(4-trifluoromethyl-phenyl)-oxazole as an oil which was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([CH3:20])[O:19][CH2:18][CH2:17][O:16]3)[C:10]=2[F:21])[CH2:5][CH2:4]1)[CH3:2].Cl>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3([CH3:20])[O:16][CH2:17][CH2:18][O:19]3)[C:10]=2[F:21])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(C3(C)OCCO3)c2F)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCC(c2cccc(C3(C)OCCO3)c2F)CC1

Procedure:
Preparation according to preparation 18: 1-ethyl-4-[2-fluoro-3-(2-methyl-1,3-dioxolan-2-yl)phenyl]-1,2,3,6-tetrahydropyridine (0.73 g, 2.5 mmol), methanol (20 ml), palladium on carbon (0.32 g) and hydrochloric acid (0.2 ml, cone). Yield: 0.7 g. MS m/z (relative intensity, 70 eV) 293 (M+, 23), 292 (12), 279 (15), 278 (bp) 84 (16).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH2:7][CH3:8])[CH2:4][NH2:5].Br[CH2:10][CH:11]1[O:16][CH2:15][CH2:14][CH2:13][O:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:11]([O:12][CH2:13][CH3:14])[CH2:10][NH:5][CH2:4][CH:3]1[O:2][CH2:1][CH2:8][CH2:7][O:6]1
Reactant: BrCC1OCCCO1
Reactant: CCOC(CN)OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(CNCC1OCCCO1)OC
Temperature: 25 °C

Procedure:
2-Methoxy-2-ethoxyethylamine (0.11 mole), 2-bromomethyl-1,3-dioxane (0.1 mole), triethylamine (20 ml) and toluene (150 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction is heated at reflux for a period of about 12 hours. After this time the reaction mixture is allowed to cool to room temperature and is filtered. The reaction mixture is then stripped of solvent and unreacted starting materials under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)amine.
Reaction SMILES: O1CCCC1.[Si]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:21]2([OH:44])[CH2:26][CH2:25][N:24]([CH2:27][C:28]34[CH2:43][CH:35]([C:36]5[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][C:41]=53)[C:34]3[C:29]4=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][CH2:22]2)[CH:18]=[N:19][CH:20]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]2[CH:35]3[CH2:43][C:28]([CH2:27][N:24]4[CH2:23][CH2:22][C:21]([C:17]5[CH:18]=[N:19][CH:20]=[C:15]([CH2:14][OH:13])[CH:16]=5)([OH:44])[CH2:26][CH2:25]4)([C:29]4[C:34]3=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:41]=2[CH:40]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cncc(C2(O)CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
A tetrahydrofuran solution (15 mL) of 4-(5-(tert-butyldimethylsilyl)oxymethyl-3-pyridyl)-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidin-4-ol (1.70 g, 3.04 mmol) was cooled to 0° C. under nitrogen and treated with tetrabutylammonium fluoride (1.0N in tetrahydrofuran, 3.20 mL, 3.20 mmol, 1.05 eq). The reaction was warmed to room temperature and stirred at that temperature for 3 h. Water (15 mL) was added and the resulting aqueous phase was extracted with ethyl acetate (3×15 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered, and reduced to an oil. This procedure resulted in 1.20 g (89%) of the title compound. TLC analysis (Rf 0.11, 5% methanol in diethyl ether). No additional purification was required. 1H NMR (CDCl3, 250 MHz) 8.62 (s, 1H), 8.42 (s, 1H), 7.84 (s, 1H), 7.21 (m, 4H), 6.94 (m, 3H), 4.69 (s, 2H), 4.27 (s, 1H), 3.44 (s, 2H), 2.90 (m, 2H), 2.74 (m, 2H), 2.62 (d, J=1.3 Hz, 2H), 2.11 (m, 2H), 1.76 (m, 2H) MS (CI, CH4) m/z 447 (M+1,100), 449 (32), 475 (M+29,19), 429 (71), 431 (25). The free base was dissolved in ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (room temperature, 10 pascal, 18 h) to yield a white solid, mp 235°-240° C. (dec).
Reaction SMILES: Cl.[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].Br[C:31]1[CH:36]=[C:35]([C:37](F)(F)F)[CH:34]=[CH:33][C:32]=1Cl>>[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:34]3[CH:33]=[CH:32][CH:31]=[CH:36][C:35]=3[CH3:37])[CH2:25][C:24]2=[O:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: FC(F)(F)c1ccc(Cl)c(Br)c1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2s1
Agent: Cl
Product: Cc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4s3)CCCCC2)C(=O)C1

Procedure:
In accordance with the same procedure as in Example 85, except that 4-[N-[1-[N-(benzothiophen-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride was used instead of 4-[N-[1-[N-(furan-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride and 1-bromo-2-chloro-5-trifluoromethylbenzene was used instead of 1-bromotoluene in Step 1 thereof, 123 mg of the titled compound was prepared.
Reaction SMILES: [OH-].[Na+].CC(O)C.[CH2:7]([S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(OCC)(=O)C>[CH2:7]([S:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(SCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(SCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
10% Sodium hydroxide aqueous solution 1.0 mL was added to a suspension of 2-propanol 4.0 mL of methyl 4-(benzylthio)-2-(4-fluoroanilino)benzoate 0.36 g at room temperature, and it was heated and refluxed for 2 hours. After the reaction mixture was cooled to room temperature, 1.0 mol/L hydrochloric acid and ethyl acetate were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, solid matter was filtrated to give 4-(benzylthio)-2-(4-fluoroanilino)benzoic acid 0.30 g of white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:11][O:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.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>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:13]([O:12][CH3:11])=[O:14])[CH:3]=[C:4]2[CH:10]=[N:9]1
Reactant: Brc1cnc2[nH]ncc2c1
Reactant: COC(=O)c1cccc(B(O)O)c1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cccc(-c2cnc3[nH]ncc3c2)c1
Temperature: 110 °C
Reaction time: 15 h
Yield: 64.5 %

Procedure:
A mixture of 5-bromo-1H-pyrazolo[3,4-b]pyridine (2.00 g, 10.10 mmol), 3-(methoxycarbonyl)phenylboronic acid (2.20 g, 12.12 mmol), sodium bicarbonate (2.2 g, 6.00 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.250 g, 0.202 mmol) in dioxane/water (40 mL/10 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded methyl 3-(1H-pyrazolo[3,4-b]pyridin-5-yl)benzoate (8) (1.65 g, 65% yield) as yellow solids. S: m/z 254.0 (M+H+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[CH:10]([CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)C(=O)C)=[CH:5][C:4]=1[N+:25]([O-:27])=[O:26].Cl>>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[CH2:10][CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)=[CH:5][C:4]=1[N+:25]([O-:27])=[O:26]
Reactant: CC(=O)C(CC1C(=O)C2CCN1CC2)C(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: O=C(CCC1C(=O)C2CCN1CC2)c1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
In a manner similar to Example XXVI react 1-(4-chloro-3-nitrophenyl)-2-[(3-oxo-1-azabicyclo[2.2.2]oct-2-yl)methyl]-1,3-butanedione hydrochloride in refluxing concentrated hydrochloric acid to afford the title compound.