Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([N:14]1[C:18]([C:19]2[S:29][C:22]3[N:23]=[CH:24][N:25]=[C:26](SC)[C:21]=3[CH:20]=2)=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:16]=[CH:15]1)[CH3:13].[NH3:36]>C(Cl)Cl>[NH3:14].[CH2:12]([N:14]1[C:18]([C:19]2[S:29][C:22]3[N:23]=[CH:24][N:25]=[C:26]([NH2:36])[C:21]=3[CH:20]=2)=[C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:16]=[CH:15]1)[CH3:13]
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Agent: N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
mCPBA (70-75%, 160 mg) was added to a stirred solution of 6-(1-ethyl-4-phenyl-1H-imidazol-5-yl)-4-(methylthio)thieno[2,3-d]pyrimidine (Intermediate 70) (91 mg) in DCM (8 mL) and allowed to stir at ambient temperature for 45 minutes. NH3 (0.5M in dioxane) (10 mL) was then added and the reaction was allowed to stir for 2 days with further NH3 (0.5M in dioxane) (5 mL) added after 16 hours. The reaction mixture was concentrated in vacuo and the crude product purified by flash chromatography on silica eluting with isohexane:EtOAc (1:1) then 0-10% (7M NH3 in MeOH) in EtOAc to afford the title compound as a solid (40 mg, 48%);
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][C@@H:10](O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.C[I:50]>C1COCC1>[CH3:16][O:15][C:13]([CH:12]1[CH2:11][CH:10]([I:50])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])=[O:14]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CI
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a round-bottom flask equipped with a magnetic stir bar and an addition funnel under N2 is added N-Boc-L-trans-4-hydroxy-proline methyl ester, PPh3 and anhydrous THF. The solution is cooled to 0 centigrade, DEAD in THF is added; followed by the addition of MeI. The reaction mixture is allowed to warm to ambient temperature and stirred for about 10 hours. The solvent is removed and the crude product is purified to afford 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (31).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 180 step C) and methanesulfonyl chloride. White solid. MS (ESI): 393.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[CH:3][C:4]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 4-Chloro-5-methyl-2-nitro-phenol (3.752 g, 20.0 mmol), 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4.83 g, 24 mmol), and triphenylphosphine (6.23 g, 24 mmol) in 75 mL THF is added diisopropyl asodicarboxylate (4.73 mL, 245 mmol) in several portions at 22° C. for 1 h. The reaction is stirred at the same temperature for an additional 2 hrs. The reaction mixture is concentrated in vacuo. The residue is taken up in 50 mL ether, and let stand at 22° C. for 14 hrs. The resulting crystals are removed by filtration. The filtrate is concentrated in vacuo, and the residue is purified over a 330 g SiO2 column (ISCO) using a gradient of 20 to 40% ethyl acetate in hexanes as eluent, affording 4-(4-Chloro-5-methyl-2-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as dark yellow viscous oil. MS (ES+); 315.1 (MH+−C4H8), 393.1 (MNa+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:34]([N:9]1[CH2:8][CH2:7][C:6]([CH2:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:20][CH:21]=2)(=[O:15])=[O:14])([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a solution of 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (0.24 g, 0.576 mmol), triethylamine (0.32 ml) and catalytic amount of 4-Dimethylaminopyridine in 6.0 mL of CH2Cl2 was added a solution of acetyl chloride (0.068 ml, 0.864 mmol) in 1.0 mL of CH2Cl2. The reaction stirred at room temperature for 4 h and washed with H2O, brine, dried over MgSO4, filtered through a pad of silica gel and concentrated to provide 0.242 g (100%) of the desired product as a colorless gum. Electrospray Mass Spec: 422.2 (M+H)+
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:43])[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[N:31]2)=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([C:19]([O:21]C)=[O:20])[CH2:14]2)=[O:8].Cl>C1COCC1.O>[CH3:4][CH:5]([CH3:43])[CH:6]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:35](=[O:36])[CH2:34][O:33][C:32]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[N:31]2)=[CH:25][CH:24]=1)[C:7]([NH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH:13]([C:19]([OH:21])=[O:20])[CH2:14]2)=[O:8]
Reactant: COC(=O)C1Cc2cccc(NC(=O)C(c3ccc(CN4N=C(c5ccccc5)OCC4=O)cc3)C(C)C)c2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)Nc1cccc2c1CC(C(=O)O)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
26 mg (0.63 mmol) of lithium hydroxide monohydrate were added to a solution of 170 mg (0.32 mmol) of methyl 4-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 134A) in 11 ml of THF and 11 ml of water, and the mixture was stirred at 60° C. for 12 h. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and then concentrated to dryness under reduced pressure. This gave 141 mg (content 98%, 0.26 mmol, 84% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([S:17](/[CH:20]=[CH:21]/[CH2:22][CH2:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:19])=[O:18])[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[NH2:32][OH:33].O>C1COCC1>[OH:33][NH:32][CH:21]([CH2:20][S:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:30])([F:1])[F:31])=[CH:10][N:9]=2)[CH2:16][CH2:15]1)(=[O:19])=[O:18])[CH2:22][CH2:23][C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=S(=O)(/C=C/CCc1ncccn1)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Reactant: NO
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of 2-[(3E)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)but-3-en-1-yl]pyrimidine (10.9 g, 23.7 mmol) in THF (200 mL) was added 50% aqueous solution of hydroxylamine (11 mL) and the reaction stirred at room temperature for 2 hours. Water (100 mL) was then added and then this was extracted with EtOAc (3×100 mL) and dried (brine, MgSO4), filtered and concentrated in vacuo to give 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine as a pale yellow solid (11.1 g, 22.6 mmol, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH2:11])=[O:4].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][CH2:17][C:16]1[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=1)=[O:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)[C@H]1CCCC[C@H]1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CCCC[C@H]1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
The crude (1S,2R)-2-amino-cyclohexanecarboxylic acid methyl ester (4.97 mmol) was dissolved in methanol (15 mL) at 25° C. and 4-fluorobenzaldehyde (0.533 mL, 4.97 mmol), glacial acetic acid (1 mL) and sodium cyanoborohydride (0.781 g, 12.4 mmol) were added sequentially. The reaction mixture was stirred at 25° C. for 19 h, and then was partitioned between saturated sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate, decanted, and were concentrated in vacuo to afford the crude product, (1S,2R)-2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester as a yellow oil, which was used directly in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:40])([F:39])[C:10]1[CH:11]=[C:12]([CH2:20][O:21][C@@H:22]2[CH2:28][CH2:27][C@@H:26]3[NH:29][C@@:23]2([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:24][C@H:25]3[C:30]([OH:32])=O)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.[CH2:41]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>>[CH2:41]([N:48]1[CH2:53][CH2:52][N:51]([C:30]([C@@H:25]2[CH2:24][C@:23]3([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:29][C@H:26]2[CH2:27][CH2:28][C@H:22]3[O:21][CH2:20][C:12]2[CH:11]=[C:10]([C:9]([F:39])([F:8])[F:40])[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=2)=[O:32])[CH2:50][CH2:49]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C([C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-2-[3,5-bis(trifluoromethyl)phenyl]methoxy)-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxylic acid trifluoroacetate (Example 122; 100 mg, 0.19 mmol), N-benzylpiperazine (0.1 ml), triethylamine (0.1 ml, 0.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 4-N,N-dimethylaminopyridine (12 mg, 0.1 mmol)was prepared. The mixture was stirred at room temperature for 20 hours and purified by chromatography on silica gel (dichloromethane:methanol) to give the title compound (102 mg, 85%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:10]1[O:13][C@H:11]1[CH3:12].CC(C)([O-])C.[K+].CC(O)(C)C>C1COCC1>[N:1]1([CH2:10][C@H:11]([CH3:12])[OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: c1ccc2[nH]ncc2c1
Reactant: C[C@H]1CO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C[C@H](O)Cn1ncc2ccccc21
Yield: 33.6 %

Procedure:
A mixture of 0.5 g (4.23 mmol) indazole, 0.3 mL (S)-propylene oxide (4.4 mmol), 0.53 g potassium t-butoxide (4.3 mmol) and 15 mL of 25:1 t-BuOH:THF was stirred in a sealed tube at 70° C. overnite. The solvent was removed in vacuo, 50 mL ethyl acetate was added to the residue, the mixture was filtered, concentrated and the residue purified by chromatography over silica eluting with 1:1 EtOAc:hexanes to yield 0.250 g (1.42 mmol, 67%) of the title compound as a viscous oil. MS (APCI) m/z 177 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[NH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][NH:24][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=2)[CH2:28][CH2:27]1
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Reactant: NCC1CC1
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(NCC3CC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for example 85, but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and (aminomethyl)cyclopropane (52 μl; 0.73 mmol; 5.0 eq.) as a white solid (43 mg, 78%). HPLC, Rt: 3.19 min. (purity 78.6%). LC/MS, M+(ESI): 420.0, M−(ESI): 418.0.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+]>CN(C=O)C>[N:36]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[C:21]([C:32]([F:35])([F:34])[F:33])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Oc2ccc(NC(=O)Nc3ccc(CN4CCCCC4)c(C(F)(F)F)c3)cc2)ncn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(3-trifluoromethyl-4-(piperidin-1-ylmethyl)-phenyl)-urea (Example 128; 350 mg, 0.69 mmol) and NaN3 (91 mg, 1.4 mmol) in 7 ml of DMF is stirred for 2 h at 70° C. The resulting mixture is concentrated in vacuo, the residue diluted with AcOEt and water, the aqueous layer separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to yield the title compound: MS: [M+1]+=513.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH2:27]>>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][NH:27][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1Cl
Reactant: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Product: Cc1cc(N2CCCC2)c2ccc(NCCc3ccccc3Cl)cc2n1

Procedure:
In analogy to example 1, on reaction of 7-iodo-2-methyl-4-pyrrolidin-1-yl-quinoline with 2-(2-chlorophenyl)-ethylamine there was obtained [2-(2-Chloro-phenyl)-ethyl]-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-amine as light brown foam. ISP mass spectrum, m/e: 366.2 (M+1 calculated for C22H24ClN3: 366).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:4]1)[CH3:2].[CH3:29][C@H](OC1N=C2C(N=C(OC)N2CCCC2CCNCC2)=C(N)N=1)CCC.ICC>>[CH2:4]([N:3]1[CH2:1][CH2:2][CH:6]([CH2:5][CH2:9][CH2:10][N:11]2[C:19]([O:20][CH3:21])=[N:18][C:17]3[C:12]2=[N:13][C:14]([O:23][C@@H:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[N:15][C:16]=3[NH2:22])[CH2:7][CH2:8]1)[CH3:29]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)=O.Cl[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl>C(O)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]2[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=CN1CCNCC1
Agent: Cl
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
11.2 g (98 mmoles) of 1-formylpiperazine was added to 10 g (49 mmoles) of chlorodiphenylmethane, and the solution was stirred at room temperature for 48 hours, and the mixture was extracted with water and methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and 8.9 g (31.9 mmoles) of the resulting formyl compound was dissolved in 100 ml of ethanol, and 6.5 g (64 mmoles) of conc. hydrochloric acid was added, and the solution was refluxed for 1 hour. Then, the solvent was evaporated under reduced pressure, and the residue was extracted with K2CO3 /water/CH2C2. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 6.8 9 (yield 55 %) of the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C@H:3]1[OH:15].Cl[C:17]1[C:18]2[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:8]([N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[C:18]3[CH:25]=[C:24]([CH2:26][C:27]([F:30])([F:29])[F:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[C@H:3]([OH:15])[CH2:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: FC(F)(F)Cc1cc2c(Cl)ncnc2s1
Reactant: N[C@@H]1CCN(Cc2ccccc2)C[C@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O[C@@H]1CN(Cc2ccccc2)CC[C@H]1Nc1ncnc2sc(CC(F)(F)F)cc12

Procedure:
The mixture of 36.7 mg of trans-4-amino-1-benzylpiperidin-3-ol (0.18 mmol), 30 mg of 4-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine (0.12 mmol) and 46 mg of N,N-diisopropylethylamine (0.36 mmol) was refluxed in 0.75 mL of isopropanol for 18 hs. Then reaction mixture was concentrated and purified on silica gel column eluting with DCM:MeOH 20:1 to afford 45 mf of trans-1-benzyl-4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-3-ol (Compound 165). Its monohydrochloride salt was obtained by adding 1 equivalent of 1N HCl solution in diethyl ether to a solution of compound in ethanol. 1H NMR (600 MHz, CD3OD) of HCl salt, signals are all broadened because of intramolecular H-bond: δ 8.37 (1H), 7.51-7.60 (6H), 4.43 (4H), 4.12 (1H), 3.85 (2H), 3.55 (2H), 3.21 (1H), 2.99 (1H), 2.06 (1H). 13C NMR (150 MHz, CD3OD): δC 165.78, 158.45, 153.97, 132.59, 131.46, 130.51, 130.18, 127.45, 125.62, 122.09, 118.50, 68.02, 61.86, 56.88, 54.15, 52.38, 35.81 (q, J=31.5 Hz), 28.14. ESI MS [MH+]: 423.1458.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([N+:14]([O-])=O)[C:12]=1[CH3:13])[C:9]([CH3:18])([CH3:17])[CH2:8][CH2:7]2)([O-])=O.O>CO.[Pd]>[NH2:1][C:4]1[C:5]([CH3:19])=[C:6]2[C:10](=[C:11]([NH2:14])[C:12]=1[CH3:13])[C:9]([CH3:17])([CH3:18])[CH2:8][CH2:7]2
Reactant: Cc1c2c(c([N+](=O)[O-])c(C)c1[N+](=O)[O-])C(C)(C)CC2
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1c(N)c(C)c2c(c1N)C(C)(C)CC2
Temperature: 55 °C
Reaction time: 84 h
Yield: 92.1 %

Procedure:
175 g (0.662 mol) of the resulted 5,7-dinitro-1,1,4,6-tetramethylindan was dissolved in 500 g of methanol, 17.5 g (50% water content) of 5%-Pd/C was added, then, the mixture was stirred for 84 hours at 50 to 60° C. under a hydrogen atmosphere. After completion of the reaction, the mixture was filtrated and filtrate was concentrated under reduced pressure. The resulted residue was distilled under reduced pressure to obtain 5,7-diamino-1,1,4,6-tetramethyl-indan as a pale yellow crystal. The yielded amount was 124 g (yield: 92.1%), the melting point was 77 to 78.5° C., and the boiling point was 148 to 150° C. (339 Pa).
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[C:31]([F:43])=[CH:32][C:33]([F:42])=[C:34]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:35]=2)[CH2:26][CH2:25]1>>[F:42][C:33]1[CH:32]=[C:31]([F:43])[C:30]([CH:27]2[CH2:26][CH2:25][N:24]([CH2:23][CH2:22][CH2:21][NH:20][C:3](=[O:4])[C:2]([OH:1])([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:6]3[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)[CH2:29][CH2:28]2)=[CH:35][C:34]=1[NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40]
Reactant: CC(C)C(=O)Nc1cc(C2CCN(CCCN)CC2)c(F)cc1F
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Product: Cc1ccc(C(O)(C(=O)NCCCN2CCC(c3cc(NC(=O)C(C)C)c(F)cc3F)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 159 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and N-{5-[1-(3-aminopropyl)-4-piperidinyl]-2,4-difluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.78–8.62 (s, br, 1 H), 8.37 (t, 1 H, J=9.6 Hz), 7.40 (d, 4 H, J=8.4 Hz), 7.28 (s, 1 H), 7.09 (d, 4 H, J=8.0 Hz), 6.84–6.74 (m, 1 H), 5.14–4.82 (br, 1 H), 3.55–3.40 (m, 2 H), 3.11–2.94 (m, 2 H), 2.94–2.78 (m, 1 H), 2.59–2.46 (m, 2 H), 2.46–2.36 (m, 1 H), 2.31 (s, 6 H), 2.11–1.91 (m, 4 H), 1.77–1.61 (m, 4 H), 1.04 (d, 6 H, J=7.2 Hz); ESMS m/e: 578.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH:22](C)C)=[O:20])[CH:3]=1.NC1C(F)=C([Cl:33])N=C(C(OC)=O)C=1Cl>>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:33]
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl

Procedure:
Methyl 4-(amino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate was prepared in analogous fashion to isopropyl 4-(amino)-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoro-picolinate in Example 10 except that methyl 4-amino-3,6-dichloro-5-fluoropicolinate was used in place of isopropyl 4-amino-6-bromo-5-fluoropicolinate: mp=169-171° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.46 (dd, J=8.8, 1.6 Hz, 1H), 7.29 (dd, J=8.8, 7.2 Hz, 1H), 7.10 (s, 2H), 3.93 (s, 3H), 3.87 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 164.8, 154.3, 151.8, 146.2, 144.5, 143.9-143.7 (m), 141.6 (d, JF-C=14.0 Hz), 136.3 (d, JF-C=13.4 Hz), 128.5 (d, JF-C=2.6 Hz), 125.5 (d, JF-C=3.6 Hz), 122.9 (d, JF-C=13.7, 4.0 Hz), 61.6 (d, JF-C=4.2 Hz), 52.7; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.2 (d, JF-F=27.5 Hz), −137.7 (d, JF-F=27.1 Hz); IR: 3482, 3381, 2950, 1741, 1612, 1466, 1423, 1366, 1228, 1202, 1045, 970, 905, 815; MS Calcd. for C14H11Cl2F2N2O3: 362.0. Found: 362 (M+), 304.