Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>CC(C)=O>[Cl:22][C:23]1[N:28]=[C:27]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:7][C:8]([F:14])([F:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.1 %

Procedure:
Compound Ethyl 3-(cyclopentylamino)-2,2-difluoropropanoate (396 mg, 1.79 mmol) was solubilized in acetone (40 mL, dry). The solution was cooled in an ice salt bath under a nitrogen atmosphere and K2CO3 (495 mg, 3.58 mmol) added. To this, a solution of 2,4-dichloro-5-nitropyrimidine (378 mg, 1.97 mmol) in acetone (10 mL, dry) was added dropwise. Upon completion of addition the reaction mixture abandoned and allowed to slowly warm to room temperature and stir overnight. The mixture was then filtered through paper, the filter pad washed with acetone, and the filtrate concentrated. The concentrate was then solubilized in EtOAc (10 mL). Hexanes (70 mL) were then added and the solution was put on the rotovap to slowly concentrate. Yellow crystals form and are collected by filtration to yield 360 mg of the desired product Ethyl 3-((2-chloro-5-nitropyrimidin-4-yl)(cyclopentyl)amino)-2,2-difluoropropanoate (53%). The filtrate was found to contain a 1:1:1 mixture of the product, dichloronitropyrimidine, and the 2-addition product. This material was concentrated and set aside for future use. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (t, J=7.20 Hz, 3H) 1.36-1.98 (m, 8H) 3.64 (q, 1H) 4.25 (q, J=7.24 Hz, 2H) 4.35 (t, J=13.77 Hz, 2H) 8.94 (s, 1H). [M+H] calc'd for C14H17F2N4O4, 379. found 379.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]#[N:29])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:10][CH2:9]2)[CH2:3]1.[OH:30][Li].O.OO>CO>[O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([CH:8]2[CH2:9][CH2:10][CH:11]([O:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]4[C:26]=3[C:25]3[C@@H:24]([CH2:27][C:28]([NH2:29])=[O:30])[CH2:23][CH2:22][C:21]=3[S:20]4)[CH2:12][CH2:13]2)[CH2:3]1
Reactant: [Li]O
Reactant: N#CC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Agent: OO
Solvent: CO
Solvent: O
Product: NC(=O)C[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetonitrile (330 mg, 0.80 mmol, 1.00 equiv) in methanol (10 mL) was added LiOH.H2O (101 mg, 2.40 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. The resulting solution was stirred for 2 h at room temperature and quenched with Na2SO3 (aq.), extracted with DCM (80 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to give 50 mg (15%) of 2-[(3R)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]acetamide as a white solid. [Note: The product was found to decompose during column purification].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=CC=5)NC4=O)[CH2:32][O:31][C:29]3=[CH:30]C=2ON=1.BrCC1CCCCO1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:30][CH:29]1[CH2:36][CH2:41][CH2:33][CH2:32][O:31]1)[C:10]3=[O:18]
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, J=7.5, 7.5 Hz, 1H), 7.20-6.98 (m, 3H), 6.66-6.49 (m, 2H), 6.41-6.33 (m, 1H), 4.99-4.91 (m, 1H), 4.74-4.66 (m, 1H), 4.02-3.31 (m, 8H), 1.92-1.19 (m, 6H); MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:17][CH2:16][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=1)=[CH2:19].[OH-].[K+]>CN1C(=O)CCC1>[C:26]([C:23]1[N:24]=[CH:25][C:20]([CH2:18][CH2:19][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:17][CH2:16][C:5]2=3)=[CH:21][CH:22]=1)([OH:28])=[O:27]
Reactant: CN1CCc2[nH]c3ccc(C(=O)O)cc3c2C1
Reactant: C=Cc1ccc(C(=O)O)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(C(=O)O)ccc3n2CCc2ccc(C(=O)O)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole-8-carboxylic acid, 5-vinylpyridine-2-carboxylic acid and a KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:33][C:34]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-methoxyphenyl isocyanate (0.160 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and ethyl acetate to give 133 mg (41.4%) of the desired product as a solid.
Reaction SMILES: BrC1C=C[C:5]([N:8]2[CH2:13][C@H:12](C)[NH:11][C@H:10]([CH3:15])[CH2:9]2)=CC=1.I[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.CN(C)[C@@H]1CCNC1>>[I:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]2[CH2:10][CH2:15][C@@H:13]([N:8]([CH3:5])[CH3:9])[CH2:12]2)=[CH:18][CH:19]=1
Reactant: Ic1ccc(I)cc1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Agent: CN(C)[C@@H]1CCNC1
Product: CN(C)[C@@H]1CCN(c2ccc(I)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine, except reacting 1,4-diiodobenzene (2.41 g, 7.30 mmol) with (R)—N,N-dimethylpyrrolidin-3-amine (1.0 g, 8.8 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 2:98 to 12:88) as a yellow solid (1.17 g, 51%). 1H NMR (400 MHz, MeOD) δ 7.42 (d, J=8.2 Hz, 2H), 6.39 (d, J=8.0 Hz, 2H), 3.51-3.47 (m, 1H), 3.44-3.39 (m, 1H), 3.29-3.24 (m, 1H), 3.13-3.09 (m, 2H), 3.00-2.87 (m, 1H), 2.35 (s, 6H), 2.35-2.26 (m, 1H), 1.96-1.86 (m, 1H); MS ESI 317.0 [M+H]+, calcd for [C12H17IN2+H]+ 317.04.
Reaction SMILES: [CH3:1][C@@:2]12C(=O)CC[C@H:15]1[C@H:14]1[C@@H:5](C3C(CC1)=CC(O)=C(OC)C=3)[CH2:4][CH2:3]2.[C:23]([O-:26])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:26][CH2:23][C:2]1[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:14][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 379.6 %

Procedure:
The 2-Methoxy estrone (0.521 g, 0.00173 mol) was dissolved in anhydrous DMF under nitrogen atmosphere, added K2CO3 (0.718 g, 0.00225 mol) and stirred at r.t. for approximately 40 h. The crude mixture was diluted with EtOAc, washed with water and brine. The organics were dried (MgSO4) and concentrated. The crude product was pre-absorbed onto silica gel, purified using Flash Master-2 system to give the benzylated compound 32 (0.651 g, 96%) as a chalky white solid: TLC (Rt, 0.4, EtOAc:Hexane, 3:7); 1H NMR (270 MHz, CDCl3) δ 0.90 (s, 3H, 18-CH3 diastereomeric methyl signals), 1.24-1.27 (t, J=3.4 Hz, 3H, CH2—CH3), 1.24-1.29 (t, J=7.1 Hz, 3H, CH2—CH3), 1.39-2.44 (broad m, 12H), 2.44-2.54 (dd, J=18.8 and 8.6 Hz, 1H), 2.77-2.83 (m, 2H), 3.84-3.87 (s, 3H, OMe), 5.0 (s, 2H, PhCH2), 6.6 (s, 1H, aromatic), 6.77 (s, 1H, aromatic), 3.87-3.84 (s, 3H, OMe), 4.10-4.16 (q, J=7.0 Hz, 2H, CH3—CH2—O), 5.09 (s, 2H, CH2-phenyl), 6.61 (s, 1H, 4-CH), 6.82 (s, 1H, aromatic 1-CH), 7.41-7.43 (m, 5H).
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH2:36][CH2:37][CH2:38][CH2:39]O)[CH3:35])=[CH:29][CH:28]=2)[CH3:19])[CH2:12][CH2:11]1.[CH2:50]([N:52](CC)CC)C.CS(Cl)(=O)=O.CN.CO>ClCCl>[C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:43])[O:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]([CH3:19])[C:20](=[O:42])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[O:41])[N:34]([CH3:35])[CH2:36][CH2:37][CH2:38][CH2:39][NH:52][CH3:50])=[CH:29][CH:28]=2)[CH2:14][CH2:15]1
Reactant: CCN(CC)CC
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCNc1ccc(C(=O)N(C)CCCCO)cc1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CNCCCCN(C)C(=O)c1ccc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reaction time: 0.17 h
Yield: 77.1 %

Procedure:
The compound (107 mg, 0.159 mmol) obtained in Example 80a was dissolved in dichloromethane (6 mL), triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. Triethylamine (0.044 mL, 0.32 mmol) and methanesulfonyl chloride (0.018 mL, 0.24 mmol) were further added under ice cooling, then a 40% methyl amine-methanol solution (6 mL) was added, and the mixture was stirred at room temperature for 14 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel column chromatography (elution solvents, n-hexane:ethyl acetate:methanol=1:1:0→0:1:0→0:9:1, v/v/v) to give the title compound (84 mg; yield, 77%) as a colorless oily substance.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][NH:45][CH2:44]1)[CH3:42]>CN(C=O)C>[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][N:45]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:6][CH3:7])[CH2:44]1)[CH3:42]
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Reactant: CC[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H]1CN(C(=O)[C@@H](O)CC)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of (S)-2-hydroxybutanoic acid (3.54 mg, 0.034 mmol) in DMF (181 μl) were added DIEA (28.5 μl, 0.163 mmol) and HATU (25.9 mg, 0.068 mmol). After 15 minutes, 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.027 mmol) was added. The reaction was stirred at room temperature for 3 hrs. The product mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation to yield the title compound (7.9 mg, 0.017 mmol, 64.0% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12-8.09 (m, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.5 Hz, 2H), 6.92-6.88 (m, 1H), 4.42-4.34 (m, 2H), 4.24-4.13 (m, 1H), 3.95 (s, 3H), 3.12-3.03 (m, 1H), 2.41-2.34 (m, 1H), 1.84-1.73 (m, 2H), 1.70-1.58 (m, 3H), 1.43-1.32 (m, 1H), 1.06-0.97 (m, 7H). LCMS (Method K) m/z 454.249 ([M+H]+). HPLC (Method F) Rt: 1.12 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH:12]C(=O)OCC1C=CC=CC=1)=[O:8])(=[O:3])[CH3:2].C1CCCCC1>[Pd].C(O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][NH2:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCC(=O)NCCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CCO
Product: CC(=O)NCCC(=O)NCCN
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 1.3 g of [2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]carbamic acid, phenylmethyl ester, 25 ml of cyclohexane and 180 mg of 10% palladium on carbon in 50 ml of ethanol was heated for 15 hours under argon and then stirred at room temperature for 12 hours. The mixture was filtered through a pad of celite and washed with methanol. The combined filtrate and wash was evaporated, giving 670 mg of the desired compound as a white solid.
Reaction SMILES: C(OC(=O)N[C@H]1C[C@H](NC2SC3C=CC=CC=3N=2)C1)(C)(C)C.Cl.[NH2:24][C@H:25]1[CH2:28][C@H:27]([N:29]2[C:33]3=[N:34][CH:35]=[CH:36][CH:37]=[C:32]3[N:31]([CH3:38])[C:30]2=[O:39])[CH2:26]1.Cl[C:41]1[S:42][C:43]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][C:44]=2[N:45]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1.CS(C)=O>[F:50][C:47]1[CH:48]=[CH:49][C:43]2[S:42][C:41]([NH:24][C@H:25]3[CH2:28][C@H:27]([N:29]4[C:33]5=[N:34][CH:35]=[CH:36][CH:37]=[C:32]5[N:31]([CH3:38])[C:30]4=[O:39])[CH2:26]3)=[N:45][C:44]=2[CH:46]=1
Reactant: Fc1ccc2sc(Cl)nc2c1
Reactant: Cn1c(=O)n([C@H]2C[C@H](N)C2)c2ncccc21
Agent: CC(C)(C)OC(=O)N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n([C@H]2C[C@H](Nc3nc4cc(F)ccc4s3)C2)c2ncccc21

Procedure:
The title compound was synthesized following the procedure described for INTERMEDIATE 10, using 3-(trans-3-aminocyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one hydrochloride (0.147 g, 0.577 mmol), 2-chloro-5-fluorobenzo[d]thiazole (0.108 g, 0.577 mmol), diisopropylethylamine (1 ml, 5.75 mmol), and 4-dimethylaminopyridine (7.05 mg, 0.058 mmol) in DMSO (0.5 mL) and purified by ISCO on silica gel column using 0-80% EtOAc/hexanes to afford 3-(trans-3-((5-fluorobenzo[d]thiazol-2-yl)amino)cyclobutyl)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (0.030 g, 0.081 mmol, 14.07% yield). m/z: 370.1 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ: ppm 8.07 (d, J=4.89 Hz, 1 H), 7.43-7.60 (m, 1 H), 7.23-7.34 (m, 1 H), 7.17 (d, J=7.43 Hz, 1 H), 6.98-7.10 (m, 1 H), 6.84 (t, J=8.71 Hz, 1 H), 6.18 (br. s., 1 H), 5.40 (quin, J=8.36 Hz, 1 H), 4.62 (br. s., 1 H), 3.50-3.67 (m, 2 H), 3.43 (s, 3 H), 2.55 (t, J=10.07 Hz, 2 H).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19][OH:20])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24]O>>[CH3:24][O:8][C:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2=[N+:10]([O-:22])[C:11]3[C:16]([N+:17]([O-:21])=[C:18]2[CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=3
Reactant: O=C(c1ccccc1)c1c(CO)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: CO
Agent: Cl
Product: COC1(c2ccccc2)OCc2c1[n+]([O-])c1ccccc1[n+]2[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A stirred suspension of 0.25 g. (0.84 mmol.) of 2-benzoyl-3-hydroxymethylquinoxaline 1,4-dioxide, in 10 ml. of methanol, was saturated with dry hydrogen chloride. The reaction mixture was stirred at room temperature overnight and then the suspended solid was collected by filtration. This afforded 0.16 g. (60% yield) of 1-methoxy-1-phenyl-1,3-dihydrofuro[3,4-b]quinoxaline 4,9-dioxide, m.p. 150°-151° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Sodium hydride (554 mg, 13.84 mmol) is added to a solution of 4-fluorophenol (1.60 g, 14.20 mmol) in DMF (20 ml) and the mixture is stirred at room temperature for 2 minutes. 3-Methanesulphonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester is added and the mixture heated at 60° C. for 18 hours. Water (50 ml) is then added and the resulting product is extracted using diethyl ether (3×30 ml). The organic extracts are dried (using MgSO4), filtered and evaporated to give a white solid, which is purified using column chromatography over silica gel (ethyl acetate/isohexane 1:9 v/v) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10]C(C)=O.C(=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cc(F)ccc1F
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COc1cc(F)ccc1F

Procedure:
35.0 g of the product of Step A, 350 ml of acetone, 44.6 g of potassium carbonate and 40.7 g of dimethyl sulfate (neutralized on potassium bicarbonte) and was allowed to return to ambient temperature. Water was added and extraction was carried out with ether. The extracts were washed, dried and concentrated to dryness under reduced pressure to obtain 39.8 g of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:30]2[C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:22]([NH2:31])[C:21]=2[N:20]=[C:19]1[CH2:32][O:33][CH2:34][CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH2:31][C:22]1[C:21]2[N:20]=[C:19]([CH2:32][O:33][CH2:34][CH3:35])[N:18]([CH2:17][CH2:16][CH2:15][NH:14][CH2:1][C:3]3[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=3)[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: COC(=O)Cc1cccc(C=O)c1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCCNCc1cccc(CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.9 %

Procedure:
Methyl 2-(3-formylphenyl)acetate (199 mg) was added to the product of step (iv) (334 mg) in THF (20 mL) at 25° C. under nitrogen. The resulting solution was stirred at rt for 6 h. Sodium triacetoxyborohydride (1183 mg) was added to the reaction mixture at rt under nitrogen and the mixture was stirred at rt for 15 h. The reaction mixture was quenched with water and dissolved in MeOH. The product was purified via RPHPLC, which afforded 25 mg of the desired product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=O)([O-:3])=[O:2].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:10][C:9]1[N:8]=[C:6]([C:5]2[CH:30]=[CH:31][CH:32]=[CH:33][C:4]=2[N+:1]([O-:3])=[O:2])[N:16]2[C:11]=1[CH:12]=[N:13][C:14]([NH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4[N+](=O)[O-])n3n2)cc(OC)c1OC
Yield: 0.7 %

Procedure:
In a similar manner as described for Example 1, 2-nitro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 10) (0.50 g, 1.5 mmol) in 1,2-dichloroethane (20 mL) and phosphorus oxychloride (1.1 mL, 12 mmol) gave 5-methyl-7-(2-nitrophenyl)-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.0046 g) as a yellow solid. 1H NMR (CDCl3): δ8.82 (s, 1H), 8.09 (dd, J=8.0, 1.1 Hz, 1H), 7.90 (dd, J=7.7, 1.3 Hz, 1H), 7.76 (ddd, J=7.7, 7.5, 1.3 Hz, 1H), 7.64 (ddd, J=8.2, 7.5, 1.5 Hz, 1H), 6.89 (s, 1H), 6.67 (s, 2H), 3.79 (s, 3H), 3.66 (s, 6H), 2.63 (s, 3H). MS m/z 437 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[CH2:16](I)[CH3:17].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1.O>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([C:13]#[N:14])([CH2:16][CH3:17])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C#N)CC2CN(C(=O)N(C)C)CC2C1
Yield: 48.1 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (3.0 g, 14.5 mmol) was dissolved in 60 mL of tetrahydrofuran with stirring followed by addition of ethyl iodide (4.52 g, 29 mmol) and lithium hexamethyldisilazide (29 mL, 29 mmol) under nitrogen atmosphere. The reaction mixture was reacted at room temperature for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was diluted with 20 mL of water and extracted with ethyl acetate (200 mL×3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain an oil. TLC showed that there are two adjacent spots, and then the oil was purified by silica gel column chromatography to obtain the title compound 5-cyano-5-ethyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 19a (1.64 g) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].N12CCN(CC1)CC2>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:14]([C:15]([OH:17])=[O:16])=[CH:18]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
A solution of 25 g 4-Amino-3-Iodo-benzoic acid methyl ester, 19 ml 2-Oxo-propionic acid, 30.4 g 1,4-Diaza-bicyclo[2.2.2]octane and 1 g Pd(OAc)2 in 200 ml DMF was heated under argon to 100° C. After 5 h the reaction mixture was concentrated under reduced pressure and the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to yield a yellow solid (6.4 g). From the aqueous layer additional product slowly precipitated as a white solid (7.9 g) which was collected by filtration. Both fractions were combined, dried in vacuo and used in the next reaction without further purification. Yield: 14.3 g. MS (ES+): m/e=220.