Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:17]([OH:20])(=[O:19])=[O:18])[CH2:11][C:12]([O:14]CC)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([S:17]([OH:20])(=[O:18])=[O:19])[CH2:11][C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(CNC(=O)OC(C)(C)C)S(=O)(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CC(=O)O)S(=O)(=O)O
Reaction time: 8 h
Yield: 89.8 %

Procedure:
1-(tert-Butoxycarbonylamino)-4-ethoxy-4-oxobutane-2-sulfonic acid (402 mg, 1.29 mmol) in the mixture of THF/H2O (1:2, 60 ml) was added lithium hydroxide monohydrate (2.0 g, 47.6 mmol). The mixture was stirred under Ar overnight, concentrated, purified on C-18 column (2×30 cm) eluted with from 100% water to 10% methanol in water to afford 328 mg (90%) of the title compound. 1H NMR (DMSO), 6.78 (s, 1H), 4.03 (m, 1H), 3.57 (dd, 1H, J=4.2, 13.4 Hz), 3.41 (m, 1H), 2.89 (m, 1H), 2.61 (m, 1H), 1.39 (s, 9H); 13C NMR 174.21, 155.82, 79.85, 59.95, 42.06, 32.52, 28.88, 14.55; ESI MS 281.8 (M−H);
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.[CH3:41][N:42](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.CN>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:42][CH3:41])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.5 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-156), 0.06 g (0.17 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.06 mL (0.33 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.17 mL (0.33 mmole) of 2M methylamine in tetrahydrofuran was then added. The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes to give 0.018 g of 4-(9-cyclopentyl-5-ethyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-methyl-benzamide (I-158).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)([C:8]1[CH:14]=[CH:13][C:11]([CH3:12])=[CH:10][CH:9]=1)(=[O:7])=[O:6].O>CN(C=O)C>[C:11]1([CH3:12])[CH:10]=[CH:9][C:8]([S:5]([O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:6])=[O:7])=[CH:14][CH:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 110 °C
Yield: 16.5 %

Procedure:
Sodium azide (0.47 g, 7.24 mmol) added to a solution of diethyleneglycol ditosylate (3 g, 7.24 mmol) in DMF (30 mL) and the resulting mixture was heated to 110° C. for 5 hours. The reaction mixture was poured into chilled water (125 mL) and the product was extracted with ethyl acetate (3×100 mL), the collected organic extracts were washed with water (3×100 mL), brine and dried over MgSO4. The crude product was purified on SiO2 and DCM/MeOH 0-100% gradient as eluant to yield 0.34 g (16%) of 7 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.16 (t, J=4.8 Hz, 2H), 3.60 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H), 4.17 (t, J=4.8 Hz, 2H), 7.35 (d, J=8 Hz, 2H), 7.81 (d, J=8 Hz, 2H); 13C NMR (100.6 MHz, CDCl3): δ 21.6, 50.6, 68.7, 69.1, 70.2, 128.0, 129.9, 133.0, 144.9; MS ESI (m/z): [M+H]+ calcd. for C11H15N3O4S, 286.08. found 286.1
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:37][CH:38]([C:48]1[O:49][C:50]([C:53]2[C:54](=[O:64])[N:55]([CH3:63])[C:56]3[C:61]([CH:62]=2)=[CH:60][CH:59]=[CH:58][CH:57]=3)=[CH:51][N:52]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46]>CN(C=O)C.C(Cl)Cl>[CH3:63][N:55]1[C:56]2[C:61](=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:62]=[C:53]([C:50]2[O:49][C:48]([C@@H:38]([NH:37][C:12]([CH:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]3)=[O:14])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44](=[O:47])[CH2:45][CH3:46])=[N:52][CH:51]=2)[C:54]1=[O:64]
Reactant: CCC(=O)CCCCCC(N)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)CCCCC[C@H](NC(=O)C1CN(C(=O)OC(C)(C)C)C1)c1ncc(-c2cc3ccccc3n(C)c2=O)o1
Temperature: 25 °C

Procedure:
A solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (1.3 eq), HOBt (1.3 eq) and EDC.HCl (1.3 eq) in DMF (premixed for 10 min) was added to S)-3-(2-(1-amino-7-oxononyl)oxazol-5-yl)-1-methylquinolin-2(1 H)-one (1 eq), obtained as described above. The mixture was stirred o/n at room temperature. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated. The mixture was purified by flash chromatography on silica, eluting with EtOAc/petroleum ether (from 50% of EtOAc to 100% of EtOAc). MS (ES) C31H40N4O6 requires: 564.67, found: 565.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=2[C:29]#[N:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=CC=CC=1C#N>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=3[C:29]#[N:30])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2ccccc2C#N)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: N#Cc1ccccc1Br
Product: N#Cc1ccccc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 81 %

Procedure:
2-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzonitrile. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (60 mg, 0.091 mmol) and 2-bromobenzonitrile following General Procedure A. Flash chromatography (2-5% EtOAc/hexanes) yielded the title compound as a clear oil (35 mg, 81%): 1H NMR (CDCl3, 600 MHz) δ 7.90 (s, 1H), 7.85 (d, 1H, J=7.8 Hz), 7.74 (d, 1H, J=7.8 Hz), 7.66 (t, 1H, J=7.8 Hz), 7.40 (t, 1H, J=7.8 Hz), 7.27-7.25 (m, 2H), 7.16-7.15 (m, 3H), 4.87 (t, 1H, J=6.0 Hz), 2.59 (t, 2H, J=7.8 Hz), 1.96-1.90 (m, 2H), 1.62-1.60 (m, 2H), 1.38-1.36 (m, 6H), 0.90 (s, 9H), 0.10 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 150 MHz) δ 166.7, 148.06, 143.6, 135.0, 134.1, 131.7, 129.2, 129.1, 129.0, 127.3, 126.9, 126.4, 124.2, 119.2, 108.3, 69.5, 37.3, 36.8, 32.3, 30.0, 26.6, 26.6, 26.0, 19.1, −4.1, −4.2.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=4)=[CH:16][CH:15]=3)[CH2:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(F)cn1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(F)cn3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 56.1 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-(5-fluoropyridin-2-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (65 mg) in acetic acid (3 mL) was added ammonium acetate (170 mg), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (35 mg, yield 56%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 455 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1>CCOCC>[CH2:9]([O:8][C:7]1[C:2]([NH:1][C:23]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[S:24])=[N:3][CH:4]=[CH:5][CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 2-amino-3-benzyloxypyridine (5.0 g, 25 mmol), phenyl isothiocyanate (3.72 g, 25 mmol) and toluene (20 ml) was heated at reflux for 1.5 hours, then left at room temperature overnight. The solution was diluted with ether, and the product filtered off; yield 5.6 g (67%), m.p. 107°-109° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Si:15]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[N:7][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(F)nc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Fluoropyridin-3-yl)methanol (9.54 g, 75.0 mmol) and imidazole (5.11 g, 75.0 mmol) were placed into a round-bottomed flask with CH2Cl2 (300 mL). tert-butyldimethylsilyl chloride (10.9 g, 72.8 mmol) was dissolved in CH2Cl2 (75 mL) and added drop-wise to the reaction mixture, which was then allowed to stir overnight at rt. The reaction was quenched by adding water (100 mL). The biphasic mixture was then separated and the aqueous layer was washed with CH2Cl2 (2×30 mL). The combined organic layer was then washed with H2O (3×50 mL), brine (50 mL), dried over MgSO4, filtered, and concentrated to give 5-((tert-butyldimethylsilyloxy)methyl)-2-fluoropyridine as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([N+:24]([O-])=O)=[CH:16][CH:15]=2)[N:10]=[CH:9][N:8]=1)=[O:5].CC(O)=O.[H][H]>CO.C(Cl)Cl.[Pt]>[NH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([O:13][C:11]2[N:10]=[CH:9][N:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH:12]=2)=[CH:15][CH:16]=1
Reactant: COCC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ncn1

Procedure:
A solution of 2-methoxy-N-(6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-yl)acetamide (400 mg, 1.13 mmol) in a mixture of MeOH and DCM and AcOH (2:2:1 v/v/v, 15 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 55 mm CatCart, 10% Pt/C, full hydrogen mode) and was then evaporated in vacuo to afford the title compound, Intermediate M1, as a brown oil (400 mg, 90% purity, 98%); Rt 3.57 min (Method 1 basic); m/z 325 (M+H)+ (ES+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)C(C)C)C>C(O)C>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:27]2[CH2:28][CH2:29][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[N:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 4-phenyl-piperidine in ethanol in the presence of N-ethyl-diisopropylamine at 80° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+383.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:37])[NH:26][CH2:27][CH2:28][O:29]CC4C=CC=CC=4)=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:38]>CO.[Pd]>[ClH:38].[ClH:38].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25](=[O:37])[NH:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3ccc(C(=O)NCCOCc4ccccc4)cc3)cc3ccccc23)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCN1CCN(c2nc(-c3ccc(C(=O)NCCO)cc3)cc3ccccc23)CC1
Reaction time: 48 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-{4-[N-(2-benzyloxyethyl)carbamoyl]phenyl}isoquinoline (0.17 g) was converted into a hydrochloride in a conventional manner. The resulting hydrochloride was dissolved in methanol (10 ml), followed by the addition of 10% palladium/carbon catalyst (0.03 g), and the catalytic reduction was conducted at atmospheric pressure for 2 days. The catalyst was filtered off, and the solvent was evaporated. Water was added to the resulting residue, to which was then added sodium carbonate to adjust the resulting solution to pH 8, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.05 g of the free compound of the title compound as a pale brown amorphous.
Reaction SMILES: CN(C)C=O.Cl.[F:7][C:8]([F:19])([F:18])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH2:17])[CH2:13][CH2:12]1)=[O:10].Br[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:22](=[O:23])[CH2:21][NH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[C:8]([F:7])([F:18])[F:19])[CH2:12][CH2:13]1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=C(CBr)Nc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CNC1CCN(C(=O)C(F)(F)F)CC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 15 mL of an N,N-dimethylformamide solution containing 1.5 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride, 1.4 g of 2-bromo-N-(pyridin-2-yl)acetamide and 1.8 g of potassium carbonate were added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to obtain 1.1 g of a light brown oily substance, N-(pyridin-2-yl)-N2-(1-(trifluoroacetyl)piperidin-4-yl)glycinamide.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]2[NH:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]2[N:21]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2C(=O)NCCN2C(=O)CCl)cc1OC
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: a solution of 11.5 g (0.1 mol) of chloroacetyl chloride in 50 ml of chloroform is added, while cooling, to 23.6 g (0.1 mol) of 3-(3,4-dimethoxyphenyl)-piperazin-2-one (Example 1), 150 ml of chloroform and 10.1 g of triethylamine. The mixture is stirred for a further hour at room temperature and is concentrated in vacuo, the residue is taken up in aqueous potassium carbonate solution, and the solution is extracted by shaking with ethyl acetate. Distilling off the ethyl acetate gives 17.5 g≈56% of theory of 3-(3,4-dimethoxyphenyl)-4-chloroacetylpiperazin-2-one.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([Cl:28])[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>C(O)C.O1CCCC1>[Cl:28][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Cl)cc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(Cl)cc(N2CCOCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 30.6 %

Procedure:
A mixture of 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.7 g, 1.63 mmol), lithium hydroxide hydrate (0.69 g, 16.3 mmol), water (5 mL) in ethanol (20 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-chloro-5-morpholin-4-yl-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 31%) as a white solid: LC/MS m/e calcd for C22H25ClN2O3 M+: 400.9, observed: 401.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][S:8][C:6]=2[N:7]=1.NC1N=C(N)C2C(C)=CSC=2N=1.C1C2NC3C(=CC=CC=3)C=2C=CC=1>>[NH2:1][C:2]1[N:3]=[C:4]([NH2:25])[C:5]2[C:10]([CH2:11][N:12]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:18]4[C:13]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Nc1nc(N)c2c(CN(c3ccccc3)c3ccccc3)csc2n1
Agent: Cc1csc2nc(N)nc(N)c12
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: Nc1nc(N)c2c(Cn3c4ccccc4c4ccccc43)csc2n1

Procedure:
N-[(2,4-Diaminothieno[2,3-d]pyrimidin-5-yl)methyl]carbazole (Formula I: Ar=2,4-diaminothieno[2,3-d]pyrimidin-5-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-[(2,4-diaminothieno[2,3-d]pyrimidin-5-yl)methyl]-N,N-diphenylamine as disclosed in Example 11 above by using 2,4-diamino-5-methylthieno[2,3-d]pyrimidine (1.3 g, 7.2 mmol) in Step 1 and carbazole (129 mg, 0.8 mmol) in Step 3. The final product and its intermediates can be purified by chromatography.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:27][CH2:26][C:11]2([C:15](=O)[N:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[Cl:29][C:30]1[C:31]([C:40]([F:43])([F:42])[F:41])=[N:32][N:33]([CH2:36]C(O)=O)[C:34]=1[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CCOC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:14]2[CH2:13][CH2:12][C:11]3([CH2:10][CH2:9][N:8]([C:6](=[O:7])[CH2:36][N:33]4[C:34]([CH3:35])=[C:30]([Cl:29])[C:31]([C:40]([F:42])([F:43])[F:41])=[N:32]4)[CH2:27][CH2:26]3)[CH2:15]2)=[CH:18][C:19]=1[O:24][CH3:25]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCC3(CCN(C(=O)Cn4nc(C(F)(F)F)c(Cl)c4C)CC3)C2)ccc1Cl
Temperature: 0 °C

Procedure:
2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (90 mg, 1 equiv) was treated with 4 mL of 4N HCl in dioxane at rt for 1 h. The volatile was removed and to the residue were added 3 mL of THF and 3 mL of dichloromethane. After cooling to 0° C., the solution was treated with 2 mL of 1M LiAlH4 in THF over night (allowed to warm to room temperature). 10 drops of water, 10 drops of 1N NaOH, and then 10 drops of water were added. The organic layer was collected and dried under vacuum. The residue was taken up in 1 mL of DMF, and to the solution were added (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (55 mg, 1 equiv), HATU (95 mg, 1.1 equiv), TEA (150 μL, 3 equiv). After stirring at rt over night, the mixture was taken up in EtOAc, washed with saturated sodium NaHCO3. Purification by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) gave 1-[2-(4-Chloro-3-methoxy-phenyl)-2,8-diaza-spiro[4.5]dec-8-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone. LCMS observed for (M+H)+: 505. Retention time: 5.28 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using a 4.5 minutes gradient of 20% to 95% B with a 1.1 minutes wash at 95% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/99.9% acetonitrile).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[N:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=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>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:14])[CH:8]=2)[N:3]=[C:2]([C:18]2[CH:19]=[N:20][CH:21]=[C:16]([F:15])[CH:17]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2ccc(F)cc2c1Cl
Reactant: OB(O)c1cncc(F)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: Cc1ccccc1
Solvent: O
Product: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Cl

Procedure:
Prepared according to general Procedure F using 2,4-dichloro-6-fluoro-3-methylquinoline (300 mg, 1.3 mmol), 5-fluoropyridin-3-ylboronic acid (160 mg, 1.3 mmol), tetrakis(triphenylphosphine)palladium(0) (151 mg, 0.13 mmol), sodium carbonate (242 mg, 2.28 mmol) in toluene:water (5 mL:2 mL) and heating at 130° C. overnight. After purification 4-chloro-6-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline was obtained as a white solid. Mass Spectrum (ESI) m/e=291.0 (M+1).