Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[Cl:20]N1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>ClCCl.O>[F:19][C:2]([F:18])([F:1])[C:3]([N:5]1[CH2:11][C@@H:10]([CH3:12])[C:9]2[C:13]([Cl:20])=[C:14]([Cl:17])[CH:15]=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)cc21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)C(F)(F)F)CCc2ccc(Cl)c(Cl)c21
Temperature: 20 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A solution of (S)—N-Trifluoroacetyl-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.62 g, 2.1 mmol) in dichloromethane (10 mL) was treated with N-chlorosuccinimide (0.284 g, 2.1 mmol) and trifluoromethanesulfonic acid (0.639 g, 4.2 mmol). The reaction was stirred for 16 h at 20° C., diluted with water (20 mL) and extracted with dichloromethane (25 mL). The organics were dried with MgSO4, filtered and concentrated. HPLC purification was done to provide 0.078 g of a white solid. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.32-7.25 (m, 1H), 6.97-6.93 (m, 1H), 4.27-4.24 (m, 0.6H), 4.19-4.13 (m, 1H), 4.08-4.01 (m, 1H), 3.91-3.86 (0.8H, m), 3.74-3.69 (m, 0.8H), 3.45-3.37 (m, 1H), 3.31-3.21 (m, 1H), 2.96-2.80 (m, 1H), 1.28-1.22 (m, 3H). MS calculated for C13H12Cl2F3NO+H: 326, observed: 326.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27])[CH3:15].C(=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:14][CH3:15])=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)[N:5]=[C:4]([C:9]#[N:10])[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOc1ccc(B(O)O)cc1C(F)(F)F
Reactant: N#Cc1nc(Cl)cc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccc(-c2cc(N)c([N+](=O)[O-])c(C#N)n2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 50.7 %

Procedure:
A stirred mixture 4-amino-6-chloro-3-nitro-pyridine-2-carbonitrile (1 g, 5.04 mmol), 4-ethoxy-3-trifluoromethylphenylboronic acid (1.33 g, 6.04 mmol), tetrakis-(triphenylphosphine)palladium(0) (˜500 mg,10 mol %), potassium carbonate (2.09 g, 15.12 mmol) and THF (10 ml) was degassed under a stream of nitrogen before heating in the “Smith” microwave at 150° C. for 10 minutes. The crude mixture was concentrated under reduced pressure to remove THF before partitioning between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a dark brown oil. Trituration with diethylether gave a light brown solid which was filtered and dried under a stream of air to afford 4-amino-6-(4-ethoxy-3-trifluoromethyl-phenyl)-3-nitro-pyridine-2-carbonitrile (900 mg). 1H NMR (DMSO): δ 8.25-8.1 (m, 3H), 7.63 (s, 1H), 7.44 (d, 2H), 4.27 (q, 2H), 1.38 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31](O)=[O:32])[CH2:27][CH2:26]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:38][N:39](C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:38][NH:39][C:31]([C@H:28]1[CH2:29][CH2:30][C@H:25]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)[N:9]=2)[CH2:26][CH2:27]1)=[O:32]
Reactant: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General procedure to EXAMPLES 37 and 38: A DMF solution (2 mL) of acid trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid (100 mg, 0.23 mmol) and methylamine hydrochloride (153 mg, 2.26 mmol) in a sealed tube was charged with DIEA (394 μL, 2.26 mmol), 0.6 M HOAt in DMF (377 μL, 0.23 mmol), and then EDC (65 mg, 0.34 mmol). The reaction mixture stirred at rt for 16 h. The reaction mixture was concentrated to solids, taken up in CH2Cl2, charged with silica, and concentrated to brown solids. The crude material was purified by silica gel column chromatography [Jones Flashmaster, 20 g/70 mL cartridge, eluting with 2% ˜7 N NH3 in MeOH/CH2Cl2 to 5% ˜7 N NH3 in MeOH/CH2Cl2] to afford trans-4-[8-amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methylamide as an off-white solid (60 mg, 57%).
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C:22]=3[CH2:27]/[CH:28]=[CH:29]/[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:65])([F:64])[C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])[C:37]([N:39]3[C@H:43]([C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([O:68]CC3C=CC=CC=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)C1C=CC=CC=1.C(OC1C=CC2C3[C@H]([C@H]4[C@@](CC=3C/C=C\CCCCCC[C@H](CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(N3[C@H](C5C=CC=CC=5)[C@H](C)N(C)C3=O)=O)(C)[C@@H](OCC3C=CC=CC=3)CC4)CCC=2C=1)C1C=CC=CC=1>CO.O1CCCC1.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][C@@H:22]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C@H:36]([CH2:53][CH2:54][C:55]([F:67])([F:66])[C:56]([F:64])([F:65])[C:57]([F:62])([F:63])[C:58]([F:59])([F:60])[F:61])[C:37]([N:39]3[C@H:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C@H:42]([CH3:50])[N:41]([CH3:51])[C:40]3=[O:52])=[O:38])([CH3:20])[C@@H:18]([OH:68])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C/CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [Pd+2]
Agent: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCC/C=C\CC2=C3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]3CC[C@H](OCc4ccccc4)[C@@]3(C)C2)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)[C@H](CCCCCCCCC[C@H]2C[C@]3(C)[C@@H](O)CC[C@H]3[C@@H]3CCc4cc(O)ccc4[C@@H]23)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
The mixture of (4S, 5R)-1-{(2R, 9E)-11-[3,17β-bis-(benzyloxy)estra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one and (4S, 5R)-1-{(2R, 9Z)-11-[3,17β-bis(benzyloxy)estra-1,3,5(10), 9(11)-tetraen-11-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)-9-undecenoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (283 mg, 0.27 mmol) was dissolved in a mixed solvent of methanol (12 ml) and tetrahydrofuran (1.2 ml), followed by addition of palladium hydroxide/carbon (85 mg) at room temperature. After purging with hydrogen, the reaction mixture was stirred for 1 day at room temperature. After the reaction mixture was filtered, the solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=3/7) to give (4S, 5R)-1-{(2R)-11-[3,17β-dihydroxyestra-1,3,5(10)-trien-11β-yl]-2-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)undecanoyl}-3,4-dimethyl-5-phenylimidazolidin-2-one (164 mg, Yield 70%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][CH2:9][C:10]1([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.F[B-](F)(F)F.[H+].O>C(Cl)Cl>[CH3:1][O:8][CH2:9][C:10]1([N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])[CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1c2ccccc2C(=O)N1C1(CO)Cc2ccccc2C1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Solvent: ClCCl
Product: COCC1(N2C(=O)c3ccccc3C2=O)Cc2ccccc2C1
Reaction time: 0.33 h

Procedure:
(Trimethylsilyl)diazomethane (2 M hexanes, 0.51 ml, 1.03 mmol) is added dropwise to a cooled (0° C.) solution of 2-(2-hydroxymethylindan-2-yl)-isoindole-1,3-dione (0.150 g, 0.511 mmol) and fluoroboric acid (48% aqueous, 93.5 μl, 0.511 mmol) in CH2Cl2 (4 ml). The reaction is stirred for 20 minutes, then three further portions of (trimethylsilyl)diazomethane (2 M hexanes, 0.128 ml, 0.25 mmol; 64 μl, 0.12 mol; 64 μl, 0.12 mmol)) are made at 20 minute intervals. The reaction is stirred for a further 40 minutes after the final addition, poured into water and extracted with dichloromethane. The organic phase is washed with brine, dried (MgSO4) and evaporated. The crude product is purified by flash chromatography (CH2Cl2 elution) to afford 2-(2-methoxymethylindan-2-yl)-isoindole-1,3-dione, MH+308.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:26]3[C:25]([NH2:27])=[N:24][CH:23]=[N:22][C:21]=3[N:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)=[CH:14][C:13]=1[O:33][CH3:34].C(N(CC)C(C)C)(C)C>ClCCl>[NH2:27][C:25]1[C:26]2[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:11][C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])=[C:13]([O:33][CH3:34])[CH:14]=3)=[CH:19][N:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: O=C=NCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)NCc1ccccc1
Reaction time: 24 h

Procedure:
Benzylisocyanate (24 uL, 0.194 mmol) in dichloromethane (1 mL) was added dropwise to a stirring solution of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.155 mmol) in N,N-diisopropylethylamine (153 uL, 0.881 mmol) and methylene chloride (2 mL) under nitrogen. The resulting mixture was stirred for 24 hours. The solvent was evaporated and the solid was purified by preparative TLC using dichloromethane/methanol (95:5) as the mobile phase to give N-(4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl)-N′-benzylurea. 1H NMR (CDCl3) δ 1.78 (m, 2H), 1.90 (m, 4H), 2.26 (m, 2H), 3.86 (s, 3H), 4.48 (d, J=6 Hz, 3H), 5.24 (m, 4H), 6.93 (s, 1H), 6.98 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=8 Hz, 1H), 7.29 (m, 5H), 8.17 (d, J=8 Hz, 1H), 8.31 (s, 1H); LC/MS (MH+=457).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C([O-])([O-])=O.[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[N+:29]([O-:31])=[O:30]>CS(C)=O.O>[NH2:28][C:24]1[C:23]([N+:29]([O-:31])=[O:30])=[C:22]([O:14][C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]([NH2:3])=[CH:13][CH:12]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Nc1ccc(O)c2ncccc12
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(N)c3cccnc23)c1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred solution of 5-aminoquinolin-8-ol dihydrochloride (2.00 g, 8.60 mmol) in DMSO (30 mL) under N2 was added K2CO3 (3.79 g, 27.5 mmol) and after 1 hr at RT the mixture was treated with 4-chloro-3-nitropyridin-2-amine (1.34 g, 7.72 mmol) in a single portion. The reaction mixture was heated to 70° C. for 2 hr and was then cooled to RT and diluted with water (500 mL). A precipitate formed which was isolated by filtration, washed with water (2×20 mL) and then dried in vacuo at 40° C. to afford the title compound, Intermediate H1 as a dark brown solid (1.50 g, 53%); Rt 0.99 min (Method 2); m/z 298 (M+H)+ (ES+).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C(Cl)(Cl)Cl.O>[Br:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][O:23]1
Reactant: C1=COCCC1
Reactant: Brc1ncnc2[nH]cnc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Brc1ncnc2c1ncn2C1CCCCO1
Temperature: 20 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
A solution of 6-bromo-9H-purine (2.0 g, 10 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) in chloroform (45 mL) at 0° C. was treated with dihydropyran (1.4 mL, 15 mmol) and stirred at 20° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with saturated sodium bicarbonate, water and brine, dried with sodium sulfate, filtered, and concentrated to give a crude residue. Purification by flash column chromatography using ethyl acetate in hexanes (0%-70%) gave the desired product (2.7 g, 94%). LCMS for C10H12BrN4O (M+H)+: m/z=283.0, 285.0; Found: 283.0, 285.0.
Reaction SMILES: I.[C:2](=[S:5])(S)[NH2:3].[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH2:16].[Na]>C(O)C>[CH3:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[CH2:12][S:13][CH2:14][CH2:15][NH:16][C:2]([NH:3][CH2:15][CH2:14][S:13][CH2:12][C:11]1[NH:10][CH:9]=[N:8][C:7]=1[CH3:6])=[S:5]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: NC(=S)S
Agent: I
Agent: [Na]
Solvent: CCO
Product: Cc1nc[nH]c1CSCCNC(=S)NCCSCc1[nH]cnc1C

Procedure:
A solution prepared from S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio))ethyl]dithiocarbamate hydriodide (15.6 g.), 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (6.8 g.) in ethanol (200 ml.) containing sodium (0.9 g.) was heated under reflux for 8 hours. Concentration followed by chromatographic purification of the product on a column of silica gel with ethyl acetate-isopropyl alcohol (5:1) as eluant gave the title compound which was converted to the dihydrochloride (2.5 g., m.p. 115°-120° ) with ethanolic hydrogen chloride.
Reaction SMILES: N[C:2](N)=[S:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])CBr.[OH-].[Na+].Cl>C(O)C.C(OCC)C>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:2][SH:3])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: NC(N)=S
Reactant: COc1ccc(CBr)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(CS)cc1Cl
Temperature: 80 °C
Yield: 83 %

Procedure:
Thiourea (3.04 g, 0.04 mol) was added to a solution of 3-chloro-4-methoxybenzyl bromide (4.0 g, 0.02 mol) in ethanol (200 ml) and refluxed for 16 hours. The reaction mixture was concentrated in vacuo and the residue was subsequently dissolved in aqueous sodium hydroxide solution (30 g, 0.75 mol in 300 ml water) and heated at 80° C. for one hour. The reaction mixture was cooled with an ice bath and acidified by addition of concentrated hydrochloric acid. The product was isolated by extraction three times into diethyl ether. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo, to give the sub-title compound as a colourless oil in 83% yield (3.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15]Cl)=[O:4].C(Cl)Cl.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O>[CH3:1][O:2][C:3]([C:5]1[C:6]([Cl:21])=[N:7][C:8]2[CH:9]=[C:10]3[O:20][CH2:19][CH2:18][O:17][C:11]3=[CH:12][C:13]=2[C:14]=1[CH2:15][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1c(Cl)nc2cc3c(cc2c1CCl)OCCO3
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(Cl)nc2cc3c(cc2c1CN1CCN(C)CC1)OCCO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 4-necked 5-L round-bottom flask is equipped with a mechanical stirrer and 250-mL addition funnel. Under nitrogen, the flask is charged with 7-chloro-9-chloromethyl-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester (340 g, 1.04 mol), prepared as in example 13c, and methylene chloride (2 L). To the stirred solution is added N-methylpiperazine (237 mL, 2.14 mol) over 10 min. After the addition is complete, the reaction mixture is stirred at ambient temperature for 15 h. The reaction mixture is poured into water (3 L) and the organic layer is separated. The aqueous layer is extracted with methylene chloride (3×2 L). The combined organic layers are washed with brine (2 L), dried over anhydrous sodium sulfate and concentrated in vacuo. The resultant thick brown slurry is successively treated with methylene chloride (300 mL) and hexane (1.5 L). The mixture is swirled at 0° C. for 30 min. The precipitate is collected on a Buchner funnel, washed with hexane (1 L) and dried in vacuo. at 30° C. yielding [7-chloro-9-(4-methyl-piperazin-1-yl-methyl)-2,3-dihydro[1,4]dioxino[2,3-g]quinoline-8-carboxylic acid methyl ester as a yellow powder: mp 143° C. 1H NMR (CDCl3, 200 MHz) δ2.28 (s, 3H), 2.38-2.49 (m, 8H), 3.81 (s, 2H), 3.96 (s, 3H), 4.59 (s, 2H), 4.40 (s, 4H), 7.45 (s, 1H), 7.65 (s, 1H). Elemental analysis: Calculated for C19 H22ClN3O4 : C 58.24, H 5.66, N 10.72. Found: C 58.08, H 5.72, N 10.63.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1cccc2cccnc12
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
2-Nitrobenzenesulfonyl chloride (1.15 g, 5.21 mmol) was added to a stirred solution of 8-aminoquinoline (500 mg, 3.47 mmol) and TEA (0.72 ml, 5.21 mmol) in DCM (5 ml), at 0° C., under argon. The reaction was allowed to warm to room temperature and was stirred for 5 h. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water and a sat. sodium bicarbonate solution. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (980 mg, 86%).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8].S(Cl)([Cl:20])=O>N1C=CC=CC=1.C(OCC)C>[Cl:20][CH2:2][C:3]1[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]([CH3:11])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CCc1ccc(OC(C)C(=O)OC)c(CO)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCc1ccc(OC(C)C(=O)OC)c(CCl)c1
Yield: 100.8 %

Procedure:
By the method of Example 1, Step H, 26.0 grams (0.109 mole) of methyl 2-(2-hydroxymethyl-4-ethylphenoxy)propionate and 14.3 grams (0.12 mole) of thionyl chloride were reacted in the presence of two drops of pyridine in 120 mL of diethyl ether, yielding 28.21 grams of methyl 2-(2-chloromethyl-4-ethylphenoxy)propionate. The NMR spectrum was consistent with the proposed spectrum.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]=[N+]=[N-])[O:10][C:9]2=[O:17])[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:22][CH:21]2[CH2:23][C:24]3([CH2:29][CH:20]2[CH2:19]1)[O:28][CH2:27][CH2:26][O:25]3.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(OCC)(=O)C.[Pd]>[C:36]([NH:14][CH2:13][C@@H:11]1[O:10][C:9](=[O:17])[N:8]([C:6]2[CH:5]=[CH:4][C:3]([N:18]3[CH2:22][CH:21]4[CH2:23][C:24]5([CH2:29][CH:20]4[CH2:19]3)[O:28][CH2:27][CH2:26][O:25]5)=[C:2]([F:1])[CH:7]=2)[CH2:12]1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 5 h
Yield: 51 %

Procedure:
10 g (24.8 mmol) of 2-[2-fluoro-4-[(5R)-5-(azidomethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 9 was dissolved in 100 ml of ethyl acetate, and 1 g of 10% palladium/active carbon, 4.01 ml (45.6 mmol) of pyridine and 3.5 ml (37.2 mmol) of acetic anhydride were added, and then, the mixture was stirred for 5 hours under hydrogen gas balloon. After the reaction was completed, the reaction mixture was filtered to remove solid and concentrated under reduced pressure. The concentrate was separated by column chromatography to obtain 5.30 g (51%) of the title compound, of which NMR data is as follows.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[CH3:38][O:39]C1C=C(B(O)O)C=CC=1>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:13]4[N:12]=[CH:11][N:10]=[C:9]([NH2:37])[C:8]=4[C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([O:39][CH3:38])[CH:4]=4)[CH2:15][CH2:16]3)[N:21]([CH3:36])[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:33])([F:34])[F:35]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)c1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 3-methoxyphenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=527, obsd.=527).
Reaction SMILES: S(O[C@@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)(C)(=O)=O.[N-:29]=[N+:30]=[N-:31].[Li+].CO>CN(C)C=O>[N:29]([C@H:6]1[C@H:10]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:9][C@H:8]([N:20]2[CH:27]=[C:26]([F:28])[C:24]([NH2:25])=[N:23][C:21]2=[O:22])[CH2:7]1)=[N+:30]=[N-:31]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1O[C@H](n2cc(F)c(N)nc2=O)C[C@H]1N=[N+]=[N-]
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a solution of 9 (520 mg, 1.19 mmol) in anhydrous dimethylformamide (12 mL) was added lithium azide moistened with 10% methanol (300 mg, 5.31 mmol). The reaction mixture was stirred at 100° C. during 2.5 h, and then cooled to room temperature, poured onto ice/water (200 mL) and extracted with chloroform (3×100 mL). Combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution (2×100 mL), with water (5×100 mL), and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent : methanol (4%) in chloroform] to give pure 10 (327 mg, 72%), which was crystallized from a diethyl ether/methanol mixture: mp 146-147° C.; UV (ethanol): λmax 243 nm (ε 8700), 283 nm (ε8400), λmin 226 nm (ε 7200), 264 nm (ε 6700); 1H NMR (DMSO-d6): δ 7.90 (d, 1H, H-6, J6-F5=7.0 Hz), 7.8-7.5 (br d, 2H, NH2), 6.0 (m, 1H, H-1′), 4.3 (m, 1H, H-3′), 3.9-3.7 (m, 3H, H-4′, H-5′ and H″-5), 2.4-2.2 (m, 2H, H-2′ and H-2″), 0.87 (s, 9H, (CH3)3C—Si), 0.05 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 769 (2M+H)+, 385 (M+H)+, 130 (BH2)+; FAB<0 m/z 383 (M−H)−; [α]D20=−67 (c, 0.96 DMSO).