Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25](Cl)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:31][O:32][CH2:33][CH2:34][S:35]([CH2:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42])(=[O:37])=[O:36]>C(O)CCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C:23]1[C:28]([F:29])=[CH:27][N:26]=[C:25]([NH:42][C:41]2[CH:43]=[CH:44][CH:45]=[C:39]([CH2:38][S:35]([CH2:34][CH2:33][O:32][CH3:31])(=[O:37])=[O:36])[CH:40]=2)[N:24]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Fc1ccc(-c2nc(Cl)ncc2F)c(OCc2ccccc2)c1
Reactant: COCCS(=O)(=O)Cc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCO
Solvent: C1COCCO1
Product: COCCS(=O)(=O)Cc1cccc(Nc2ncc(F)c(-c3ccc(F)cc3OCc3ccccc3)n2)c1
Temperature: 140 °C
Reaction time: 60 h
Yield: 8.9 %

Procedure:
4N solution of hydrogen chloride in dioxane (0.11 mL; 0.45 mmol) was added to a stirred solution of 4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (150 mg; 0.45 mmol) and 3-{[(2-methoxyethyl)sulfonyl]methyl}aniline (155 mg; 0.68 mmol; UkrOrgSynthesis Ltd.) in 1-butanol (1.0 mL). The batch was stirred at 140° C. for 60 hours. After cooling the batch was diluted with ethyl acetate and sodium bicarbonate solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by preparative HPLC to give the desired product (19 mg; 0.04 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[CH:26]=O)=[CH:4][N:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:42]([NH:44][CH2:45][CH3:46])[CH3:43]>C(O)(=O)C.ClCCCl>[CH2:42]([N:44]([CH2:45][CH3:46])[CH2:26]/[CH:25]=[CH:24]/[C:5]1[C:6]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=1)[CH3:43]
Reactant: Nc1ncc(/C=C/C=O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCN(CC)C/C=C/c1cnc(N)c2c(-c3ccc(Oc4ccccc4)cc3)csc12

Procedure:
A mixture of Example 360B (30 mg, 0.080 mmol), sodium triacetoxyborohydride (35 mg, 0.16 mmol), 1 drop of acetic acid, and diethylamine (12 mg, 0166 mmol) in 1,2-dichloroethane (2 mL) was stirred for 2 hours at ambient temperature. The mixture was concentrated and the residue was purified by reverse phase chromatography followed by lyophilization to provide the desired product as the acetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 7.94 (s, 1H), 7.55 (s, 1H), 7.44 (m, 4H), 7.20 (t, 1H), 7.11 (m, 4H), 6.67 (d, 1H), 6.22 (m, 1H), 5.55 (br s, 2H), 3.28 (d, 2H), 2.52 (q, 4H), 1.87 (s, 3H), 1.00 (t, 6H); MS m/e 430.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[C:4]([F:14])[C:3]=1[C:15]1[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1.O[C@H]1CCOC1>>[F:14][C:4]1[CH:5]=[C:6]([O:8][C@H:9]2[CH2:13][CH2:12][O:11][CH2:10]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:15]1[S:16][CH:17]=[C:18]([C:20]([OH:22])=[O:21])[N:19]=1
Reactant: O=C(O)c1csc(-c2c(F)cc(O[C@@H]3CCOC3)cc2F)n1
Agent: O[C@H]1CCOC1
Product: O=C(O)c1csc(-c2c(F)cc(O[C@H]3CCOC3)cc2F)n1

Procedure:
Following the procedure for Intermediate 147, replacing (R)-3-hydroxytetrahydrofuran with (S)-3-hydroxytetrahydrofuran provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([NH2:21])=[O:20].B(F)(F)F>>[Cl:1][C:2]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:3]=1[CH:4]([CH:18]([C:17]([NH2:23])=[O:22])[C:19]([NH2:21])=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OC(c1ccccc1)c1ccc(Cl)cc1Cl
Reactant: NC(=O)CC(N)=O
Agent: FB(F)F
Product: NC(=O)C(C(N)=O)C(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
Another method of preparation is accomplished by the reaction of 2,4-dichlorobenzhydrol with malonamide in the presence of acid and BF3 to yield 2,4-dichlorobenzhydrylmalonamide which in turn is allowed to react with formamide in the presence of dimethyl sulfoxide and base to yield 4,6-dihydroxy-5-(2,4-dichlorobenzhydryl)pyrimidine. This dihydroxy compound is allowed to react with excess phosphorus oxychloride to yield the 4,6-dichloro-5-(2,4-dichlorobenzhydryl)pyrimidine.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](=[N:24][CH3:25])([N:21]([CH3:23])[CH3:22])=[O:20])=[CH:15][CH:14]=1.C(#N)C.O1CCCC1.NCCN>C(O)C>[NH2:3][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([S:19](=[N:24][CH3:25])([N:21]([CH3:22])[CH3:23])=[O:20])=[CH:17][CH:18]=1
Reactant: CN=S(=O)(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)N(C)C
Solvent: CCO
Solvent: CC#N
Solvent: C1CCOC1
Product: CN=S(=O)(c1ccc(CN)cc1)N(C)C
Temperature: 60 °C

Procedure:
A solution of 4-((1,3-dioxoisoindolin-2-yl)methyl)-N,N,N′-trimethyl-benzene-sulfonimidamide (preparation 60c, 280 mg, 0.78 mmol) in a 2:1:1 mixture of acetonitrile, tetrahydrofuran and ethanol (8 mL) is treated with 1,2-diaminoethane (116 μL, 1.74 mmol). The mixture is heated at 60° C. for 5 h, and another portion of 1,2-diaminoethane (26 μL, 0.39 mmol) is added. After 1.5 h all volatiles are removed under reduced pressure. The residue is treated with dichloromethane, and the mixture is filtered. The filtrate is concentrated under reduced pressure. Yield: 172 mg (97% of theory). ESI mass spectrum: [M+H]+=228; r.t. HPLC: 0.66 min (V011_S01).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([C:19]#N)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=[N:13]2)=[C:4]([F:25])[CH:3]=1.C(OCC)C.C[Mg]I.Cl>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:10])[CH3:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([CH3:19])=[C:15]([C:21]([F:23])([F:22])[F:24])[CH:14]=[N:13]2)=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2ncc(C(F)(F)F)c(C#N)c2=O)c(F)cc1Cl
Agent: C[Mg]I
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(OC(C)C)c(Cl)cc2F)c1=O
Reaction time: 0.33 h
Yield: 46.5 %

Procedure:
After 1.035 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-cyano-5-trifluoromethylpyridazin-3-one (The present compound 1-5) was dissolved in 6.0 mL of tetrahydrofuran, 3.1 mL of a diethyl ether solution of methylmagnesium iodide (0.98M diethyl ether solution) was added to the tetrahydrofuran solution at 0° C. and stirred for 20 min under a nitrogen stream. Afterwards, the reaction solution was poured into 3N-hydrochloric acid and extracted with ethyl acetate. After the organic solvent was washed with aqueous saturated sodium bicarbonate and concentrated, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate/hexane=1/9) to afford 0.467 g of 2-(4-chloro-2-fluoro-5-isopropoxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 2-5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH:18]([CH3:20])[CH3:19])[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)CC)C>>[CH:18]([CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][Cl:22])=[CH:7][CH:6]=2)[NH:9][C:10]1=[O:21])([CH3:19])[CH3:20]
Reactant: O=C(Cl)CCl
Reactant: CC(C)C1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: CC(C)C1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
10.0 g. (0.0357 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-isopropyl-3(2H)-isoquinolinone are reacted, in 150 ml. of glacial acid, with 5.07 g. (0.045 moles) of chloroacetyl chloride in the presence of 4.55 g. (0.045 moles) of triethylamine. The reaction conditions are the same as given in Example 1. The crude product is recrystallized from butanol to yield 9.95 g. of the title compound; m.p.: 269°-270°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]1=2>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][C:16]1[S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH:15]=1
Reactant: c1ccc2sccc2c1
Reactant: COc1ccc(C=O)cc1Br
Product: COc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
Preparation was performed in a similar manner as in Preparation Example 4 using 3-bromo-4-methoxybenzaldehyde and benzo[b]thiophene.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]1[CH2:17][NH:16][C@@H:15]([CH3:18])[CH2:14][NH:13]1.C(=O)(O)[O-].[Na+]>C(O)CCCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][C@H:15]([CH3:18])[NH:16][CH2:17][C@@H:12]2[CH3:11])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C[C@H]1CN[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCO
Product: C[C@H]1CN(c2ccc([N+](=O)[O-])cc2)[C@@H](C)CN1

Procedure:
A mixture of 4-fluoronitrobenzene (30.34 g, 0.22 mole), cis-2,5-dimethylpiperazine (25 g, 0.22 mole) and sodium bicarbonate (24 g, 0.28 mole) in n-pentanol (150 ml) was heated under nitrogen at 90°-100° for 18 hours. After filtration, the n-pentanol was removed under reduced pressure and the residue was partitioned between methylene chloride and water. The organic phase was separated, washed again with water, dried over magnesium sulphate, and concentrated under reduced pressure. The residue was triturated with ice water to yield a yellow solid. The solid was filtered off and dried to yield the title compound, m.p. 93°-4° (37 g, 71%).
Reaction SMILES: C([NH:8][C@H:9]([C:13](O)=[O:14])[CH:10]([CH3:12])[CH3:11])(OC(C)(C)C)=O.[ClH:16].[NH2:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=2[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]1=2>>[ClH:16].[NH2:8][C@H:9]([C:13]([NH:17][N:18]1[C:24](=[O:25])[CH:23]([CH3:26])[C:22]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:21]=2[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]1=2)=[O:14])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1C(=O)N(N)c2ccccc2-c2ccc(F)cc21
Agent: Cl
Product: CC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccc(F)cc21

Procedure:
Following General Procedure D and using N-Boc-L-valine (Aldrich) and 5-amino-9-fluoro-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin6-one (Example 12), the title compound was prepared.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:21]=[CH:20][C:19]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=3)[CH:12](O)[CH2:11][C:10]=2[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCN(S(F)(F)[F:36])CC>ClCCl>[F:36][CH:12]1[CH2:11][C:10]2[CH:9]=[C:8]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:21]=[CH:20][C:19]=2[C:18]2[C:13]1=[CH:14][C:15]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:16][CH:17]=2
Reactant: CCCCCCOc1ccc2c(c1)CC(O)c1cc(OCCCCCC)ccc1-2
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCCCCCOc1ccc2c(c1)CC(F)c1cc(OCCCCCC)ccc1-2

Procedure:
From 2,7-dihexyloxy-9,10-dihydrophenanthren-9-ol by reaction with DAST in abs. dichloromethane.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][N:5]1[C:9]2[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1.O.FC(F)(F)C(O)=O>ClCCCl>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[N:5]([CH2:4][CH:3]=[O:2])[C:9]3[C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1cccc2nc(-c3ccc(F)cc3)n(CC(OC)OC)c12
Solvent: ClCCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2nc(-c3ccc(F)cc3)n(CC=O)c12
Yield: 84.7 %

Procedure:
The solution of methyl 1-(2,2-dimethoxyethyl)-2-(4-fluorophenyl)-1H-benzo[d]imidazole-7-carboxylate (1.1 g, 3.1 mmol) from Step A above in 1,2-dichloroethane (5 mL) with water (3 mL) and trifluoroacetic acid (3 mL) was stirred at reflux for 2.5 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with methylene chloride, neutralized with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered, and concentrated under reduced pressure to afford methyl 2-(4-fluorophenyl)-1-(2-oxoethyl)-1H-benzo[d]imidazole-7-carboxylate (820 mg, 84%) as a clear oil: 1H NMR (500 MHz, CDCl3) δ 9.80 (s, 1H), 8.05 (d, J=8.0, Hz, 1H), 7.98 (d, J=7.5, Hz, 1H), 7.62 (dd, J=7.5, 5.0 Hz, 2H), 7.36 (t, J=8.0 Hz, 1H), 7.21 (t, J=7.5 Hz, 2H), 5.25 (s, 2H), 3.92 (s, 3H); MS (ESI+) m/z 313 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[NH3:12].CO>>[NH2:12][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: N
Solvent: CO
Product: Nc1nc(Cl)nc2nc[nH]c12

Procedure:
A solution of 2,6-dichloropurine 0.5 g (2.7 mmol) in 30% ammonia-methanol solution was heated at 100° C. in autoclave for 12 hours. The solution was condensed to give the subject compound. The compound may be used in next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[S:20][CH:21]=[CH:22][C:15]=12>CN(C)C=O>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[S:20][CH:21]=[CH:22][C:15]=23)[CH2:5][CH2:4]1
Reactant: CN(C)C1CCC(O)CC1
Reactant: Clc1ccnc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Oc2ccnc3sccc23)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(dimethylamino)cyclohexan-1-ol (127 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL). This was followed by the addition of sodium hydride (71 mg, 1.77 mmol, 3.00 equiv, 60%). The resulting solution was stirred for 30 minutes at 80° C. in an oil bath. 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 3 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of ethanol. The resulting mixture was concentrated under vacuum. The residue was purified on a silica gel column with dichloromethane/methanol (10:1). The resulting product (50 mg) was further purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% NH4HCO3 (3.0% water with 0.05% NH4HCO3 up to 3.0% in 1 min, up to 4.7.0% in 13 min, up to 100.0% in 2 min); Detector, uv 254/220 nm. This resulted in 9.6 mg (6%) of N,N-dimethyl-4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexan-1-amine as a white solid. MS: (ES, m/z): 277.10 [M+H]+ 1 NMR (300 MHz, CD3OD, ppm): δ 1.49-1.69 (m, 4H), 2.06 (d, J=12.3 Hz, 2H), 2.34 (m, 9H), 4.60 (m, 1H), 7.01 (d, J=5.8 Hz, 1H), 7.38 (d, J=6.0 Hz, 1H), 7.52 (d, J=6.3 Hz, 1H), 8.36 (d, J=5.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)P(N(C)C)(N(C)C)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].I[CH2:46][CH3:47]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH2:46][CH3:47])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCOC(=O)C1CCc2ccc(OCc3ccccc3)cc2O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(CC)CCc2ccc(OCc3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a 320 ml anhydrous THF solution of ethyl 7-benzyloxychromane-2-carboxyate 14.6 g (46.6 mmol) was added hexamethylphosphoramide (10.5 ml, 60.4 mmol). Upon cooling in a dry ice-acetone bath, sodium bis(trimethylsilyl)amide (1.0M/THF) (60.5 ml, 60.5 mmol) was added via syringe over 15 min period. The resulting orange solution was stirred at that temperature for 30 min before iodoethane (18.6 ml, 233 mmol) was added via syringe. The reaction was slowly warmed to rt and stirred overnight. The solvent was removed under reduced pressure, and the residue was diluted with AcOEt and aqueous NH4Cl (NH4Cl 7.2 g/200 ml water). The organic layer was separated, and the aqueous layer was extracted twice with AcOEt. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and chromatographed on silica gel eluting with 7.5% AcOEt/hexanes to give the title compound 15.2 g (96%).
Reaction SMILES: Br[C:2]1[C:3]([CH:16]2[CH2:18][CH2:17]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[N:24][CH:25]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH:16]1([C:3]2[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[C:20]([F:19])[CH:21]=3)=[CH:11][CH:10]=[C:9]3[C:4]=2[CH2:5][CH2:6][C:7]2[N:8]3[C:12]([CH3:15])=[N:13][N:14]=2)[CH2:18][CH2:17]1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nnc2n1-c1ccc(Br)c(C3CC3)c1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cncc(F)c3)c(C3CC3)c1CC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-6-cyclopropyl-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (147-8; 0.250 g, 0.00082 mol) and (5-fluoropyridin-3-yl)boronic acid (0.126 g, 0.009 mol) in the mixture of 1,4-dioxane (10 mL) and water (10 mL) was added sodium carbonate (0.260 g, 0.00246 mol). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.066 g, 0.000082 mol) was added and allowed to stir at 80° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic layer was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.587-8.580 (d, J=2.8 Hz, 1H), 8.548 (s, 1H), 7.881-7.856 (d, J=10 Hz, 1H), 7.679-7.658 (d, J=8.4 Hz, 1H), 7.401-7.380 (d, J 8.4 Hz, 1H), 3.237-3.203 (t, J=6.8 Hz, 2H), 3.050-3.016 (t, J=7.2 Hz, 2H), 2.671 (s, 3H), 2.175 (s, 1H), 0.759-0739 (d, J 8 Hz, 2H), 0.034-0.022 (d, J=4.8 Hz, 2H), MS (M+1): 321.2.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22][CH2:23]Cl)[CH3:20]>>[ClH:16].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([Cl:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[N:8][NH:9]2)[CH2:22][CH3:23]
Reactant: Clc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CCC(c1c(Cl)ccc2[nH]nc(-c3ccccc3)c12)N(C)C
Yield: 135.4 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-chloroindazole (4.57 g) and dimethylaminopropyl chloride hydrochloride (4.74 g) were treated to obtain 4.74 g of 1-dimethylaminopropyl-3-phenyl-5-chloroindazole hydrochloride (m.p. 158°-160° C).
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2[C:15]([O:17]C)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CCO>[C:1]1([C:7]2[S:11][C:10]3[CH2:12][CH2:13][CH2:14][C:9]=3[C:8]=2[C:15]([OH:17])=[O:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1c(-c2ccccc2)sc2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)sc2c1CCC2

Procedure:
To a solution of methyl 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylate in EtOH was added a 1 M aqueous NaOH solution, followed by heating under reflux for 5 hours. The reaction mixture was adjusted into pH=2 by addition of 1 M hydrochloric acid, and the solid precipitated was collected by filtration, and washed with water to obtain 2-phenyl-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid as a white solid.
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.[CH3:28][O:29][C:30](=[O:44])[CH:31](C)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([CH3:42])[CH:36]=1)=[O:34].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C@H:33]([OH:34])[CH2:32][CH2:31][C:30]([O:29][CH3:28])=[O:44])=[CH:36][C:37]=1[CH3:42]
Reactant: COC(=O)C(C)CC(=O)c1ccc(F)c(C)c1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CC[C@@H](O)c1ccc(F)c(C)c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
To a solution of BH3.THF (0.9 mmol) in 20 mL anhydrous THF, was added dropwise at room temperature 158 mL (S)-2-methyl-CBS-oxazaborolidine in toluene and the mixture stirred for 5 min. To this mixture was slowly added methyl 4-(4-fluoro-3-methyl-phenyl)-4-oxo-butyric acid methyl ester (354 mg) in 5 mL THF and stirring continued for 30 min at 25° C. Saturated ammonium chloride (30 mL) was slowly added and the resulting mixture extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine (2×20 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure and the product isolated by silica gel chromatography to afford 289 mg of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[C:10](=[O:20])[C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:12][N:13]=2)[CH2:3]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]([CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[C:24]#[N:25])[C:10](=[O:20])[C:11]([C:14]#[CH:15])=[CH:12][N:13]=2)[CH2:3]1
Reactant: C[Si](C)(C)C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cnc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Yield: 71 %

Procedure:
Deprotection of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-trimethylsilylethynyl-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile (168 mg) was carried out by stirring the intermediate in THF (2 mL) with TBAF (1 N in THF, 0.8 mL, 0.8 mmol) for 1 h. The reaction was purified by silica gel chromatography (4 to 8% MeOH/CHCl3) to give 98 mg (71%) of the title compound as a faintly yellow oil/foam. 1H NMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.81 (dd, 1H, J=7.6, 1.2 Hz), 7.63 (dt, 1H, J=7.6, 1.2 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.19 (d, 1H, J=7.6 Hz), 5.22 (AB q, 2H, J=16.4, 15.2 Hz), 4.13 (s, 1H), 3.25-3.46 (m, 2H), 2.82-2.89 (m, 1H), 2.70-2.77 (m, 1H), 2.58-2.63 (m, 1H), 1.74-1.82 (m, 1H), 1.63-1.71 (m, 1H), 1.45-1.57 (m, 1H), 1.11-1.19 (m, 1H). MS (ES) [m+] calc'd for C19H19N5O, 334; found 334.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:20][CH2:19]2)=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:6].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:31]([NH:35][C:25]([CH2:24][CH:21]1[CH2:20][CH2:19][N:18]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=[C:11]([C:14]([F:15])([F:16])[F:17])[N:10]=2)[CH2:23][CH2:22]1)=[O:27])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Reactant: CC(C)(C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)CC1CCN(c2nc(C(F)(F)F)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.8 %

Procedure:
A mixture of 0.100 g (0.226 mmol) of [3′-(3-chloro-benzoylamino)-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.050 g (0.68 mmol) tert-butyl amine, 0.094 g (0.296 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.094 mL (0.68 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is stirred at room temperature for 2 hours. The mixture is diluted with water and purified using preparative reverse phase HPLC to give 0.020 g (18%) of the title compound (283) as colorless foam. [M+H]+=497.2.