Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([CH:29]=O)=[CH:21]1>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1csc2ccccc12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4csc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-benzothiophene-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1-benzothiophen-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([O:9][C:10]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:11]=1[C:12]([OH:14])=O)(=[O:8])[CH3:7].[NH2:20][C:21]1[S:22][C:23]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[N:25]=1.Cl>O1CCCC1.N1C=CC=CC=1>[C:6]([O:9][C:10]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:11]=1[C:12]([NH:20][C:21]1[S:22][C:23]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([C:26]([CH3:29])([CH3:27])[CH3:28])[N:25]=1)=[O:14])(=[O:8])[CH3:7]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Reactant: CC(C)(C)c1nc(N)sc1N1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)c(N2CCCCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
Under argon atmosphere, phosphorus oxychloride (46 μl, 0.50 mmol) was added to a mixture of 2-acetoxy-5-bromobenzoic acid (90.3 mg, 0.35 mmol), 2-amino-4-[(1,1-dimethyl)ethyl]-5-piperidinothiazole (80.7 mg, 0.34 mmol), pyridine (0.1 mL) and tetrahydrofuran (3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=3:1) to give the title compound (84.3 mg) as a crude product.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH2:15][C@@H:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH2:12][C@@H:11]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[N:46]1[C:50](=[O:51])CC[C:47]1=[O:52].[N:53](C(C)(C)C#N)=[N:54]C(C)(C)C#N.CCCCCC>O1CCCC1>[C:16]1([N:46]2[C:50](=[O:51])[N:54]=[N:53][C:47]2=[O:52])[CH:17]=[CH:21][CH:23]=[CH:24][CH:25]=1.[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][CH2:30][CH2:31][C:32]([N:34]([CH3:35])[CH3:36])=[O:33])[CH2:12][C@@H:11]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C(=O)CCOC[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCOC[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Product: O=C1N=NC(=O)N1c1ccccc1
Temperature: 25 °C
Yield: 140.2 %

Procedure:
To 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(N,N-dimethylaminocarbonylethoxymethyl)androst-5-ene (15 g), were added N-bromosuccinimide (5.36 g), 2,2′-azobis isobutyronitrile (1.06 g), hexane (120 ml) and tetrahydrofuran (30 ml), followed by reflux under heating for 15 min. After cooling to room temperature, the mixture was filtered to remove insoluble material and the filtrate was concentrated under reduced pressure. To the resultant, were added toluene (50 ml) and γ-collidine (9.8 ml), followed by reaction under reflux for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was washed with 0.5M hydrochloric acid, a saturated aqueous sodium bicarbonate solution and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure. To the thus obtained residue, were added dichloromethane (70 ml) and 4-phenyl-1,2,4-triazoline-3,5-dione, followed by reaction at room temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by column chromatography (hexane:ethyl acetate=1:2) to give the titled compound (7.43 g).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[C:21]([CH3:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)[C:23]#[N:24].C1COCC1.C1C(=O)N([Br:42])C(=O)C1>O1CCOCC1.[Pd].O>[Br:42][CH2:8][C:6]([C:20]1[C:21]([CH3:29])=[C:22]([C:25]([F:28])=[CH:26][CH:27]=1)[C:23]#[N:24])=[O:7]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)ccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)CBr)ccc(F)c1C#N
Temperature: 100 °C
Reaction time: 22 h

Procedure:
Degassed tributyl(1-ethoxyvinyl)tin (200 mL, 591 mmol) was added to a stirred, room temperature mixture of 3-Bromo-6-fluoro-2-methyl-benzonitrile (115 g, 537 mmol) and cis-PdCl2(PPh3)2 (18.9 g, 26.9 mmol) in degassed Dioxane (1149 mL) and the mixture was stirred at 100° C. for 22 hours. By this time HPLC showed complete conversion of starting material (requires at least 12 hours), completion of the reaction can be seen by plating of palladium metal onto the side of the flask. At this time the reaction was cooled to 0° C. and THF (575 mL) and Water (230 mL) were added followed by NBS (110 g, 618 mmol) (added portionwise over 15 min, maintaining internal temperature<5° C.). After 30 minutes, HPLC showed full consumption of the intermediate enol ether. The solution was diluted with MTBE (1000 mL) and washed with 0.5% aqueous HBr (3×500 mL), then washed with water. The organics were dried over MgSO4, filtered and concentrated. A precipitate was generated, and the solid was filtered and washed several times with hexanes. It was dried by nitrogen sweep, providing 3-(2-Bromo-acetyl)-6-fluoro-2-methyl-benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[Br:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=3)[CH2:36][CH2:35]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 80.6 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[CH:12][C:11]=2[CH3:17])=[C:5]([CH3:18])[CH:4]=1.[I:19][CH3:20]>C(Cl)Cl>[I-:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:18])[C:6]([C:10]2[C:15]([CH3:16])=[CH:14][N+:13]([CH3:20])=[CH:12][C:11]=2[CH3:17])=[C:7]([CH3:9])[CH:8]=1
Reactant: CI
Reactant: COc1cc(C)c(-c2c(C)cncc2C)c(C)c1
Solvent: ClCCl
Product: COc1cc(C)c(-c2c(C)c[n+](C)cc2C)c(C)c1
Product: [I-]
Temperature: 60 °C

Procedure:
To a solution of 4 (0.241 g, 1.00 mmol) in dry CH2Cl2 (5 mL) was added dropwise iodomethane (0.32 mL, 0.729 g, 5.10 mmol) at room temperature under N2. The reaction mixture was then refluxed at 60° C. under N2 for 1 h. After cooling to room temperature, the mixture was concentrated in vacuo to give the corresponding methyl pyridinium iodide salt as an analytically pure yellow solid (0.382 g, 99.8%). mp 220-221° C.; 1H NMR (400 MHz, CD2Cl2): δ 9.079 (s, 2H), 6.751 (s, 2H), 4.579 (s, 3H), 3.881 (s, 3H), 2.135 (s, 6H), 1.854 (s, 6H); 13C NMR (100 MHz, CD2Cl2): δ 160.512, 159.866, 143.124, 138.802, 135.527, 125.927, 114.217, 55.692, 48.686, 20.188, 17.331; Anal. Calcd. For C17H22INO: C, 53.27; H, 5.79; N, 3.65. Found: C, 53.15; H, 5.79; N, 3.57.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:14])=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:15])[C:5]([NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: Nc1cc(N2CCOCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCOCC2)cc1N
Yield: 97.9 %

Procedure:
35 g of 4-fluoro-5-morpholin-4-yl-2-nitrophenylamine in solution in 618 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 3.4 g of palladium-on-charcoal at 22° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 30 g of 4-fluoro-5-morpholin-4-ylbenzene-1,2-diamine in the form of a brown solid are isolated. 1H NMR (400 MHz, (CD3)2SO, δ in ppm): 2.78 (m: 4H); 3.68 (m: 4H); 4.25 (broad s: 2H); 4.35 (broad s: 2H); 6.27 (d, J=8 Hz: 1H); 6.31 (d, J=14 Hz: 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[C:8]2[C:9]([O:11][C:12](=O)[NH:13][C:7]2=[CH:6][CH:5]=1)=O)([O-:3])=[O:2].CSC(=N)[NH:19][S:20]([CH2:23]Cl)(=[O:22])=[O:21].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(#[N:41])C>CN(C1C=CN=CC=1)C>[N+:1]([C:4]1[CH:15]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[C:12]1[NH:19][S:20](=[O:21])(=[O:22])[CH2:23][N:41]1[C:9]2=[O:11])([O-:3])=[O:2]
Reactant: CSC(=N)NS(=O)(=O)CCl
Reactant: CC#N
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)o1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: O=c1c2cc([N+](=O)[O-])ccc2nc2n1CS(=O)(=O)N2

Procedure:
To a stirred solution of 5-nitroisatoic anhydride (1.04 g, 5.0 mmol) and S-methyl-N-(chloromethanesulfonyl)isothiourea (1.04 g, 5.0 mmol) in acetonitrile (10 ml) under nitrogen is added 4-(N,N-dimethylamino)-pyridine (0.61 g, 5.0 mmol). The solution is refluxed for 16 hr, cooled, and poured into 10% aqueous citric acid. The resulting solid is collected by filtration and recrystallized twice from isopropanol/DMF, then from DMSO, to provide the title compound as a light yellow solid, mp >300° C. (225 mg, 16%).
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH:8]=1>CN(C)C=O>[CH3:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[S:1]([Cl:5])(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1cc2ccccc2s1
Solvent: CN(C)C=O
Product: Cc1sc2ccccc2c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.4 %

Procedure:
Sulfuryl chloride (9.5 mmoles, 0.76 ml) was added to a stirred solution of dimethylformamide (DMF; 11.2 mmoles, 0.87 ml) at 0° C., and the resulting feint yellow solution was stirred for 20 min at 0° C. 2-Methylbenzo[b]thiophene (5.6 mmoles, 0.83 g) was then added, the reaction mixture was diluted with 2 ml of DMF, and then heated to 85° C. After 2.5 hrs at 85° C., the brown reaction mixture was cooled to ambient temperature and added to ice (≈100 ml). The aqueous phase was extracted with ethyl acetate (100 ml), and the organic phase was dried (MgSO4), filtered and concentrated to collect an orange-brown solid. Flash chromatography (4% ethyl acetate/hexanes) provided 0.89 g (64%) of 2-methylbenzo[b]thiophene-3-sulfonyl chloride as a yellow solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[C:21]([O:22][CH3:23])=[C:20]2[C:15]([CH:16]=[C:17]([C:25]([OH:27])=O)[C:18](=[O:24])[O:19]2)=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:52]1[C:53]([C:61]2[CH:62]=[C:63]([NH2:67])[CH:64]=[CH:65][CH:66]=2)=[CH:54][N:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=12>CN(C=O)C>[N:52]1[C:53]([C:61]2[CH:62]=[C:63]([NH:67][C:25]([C:17]3[C:18](=[O:24])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[C:21]=4[O:22][CH3:23])=[O:27])[CH:64]=[CH:65][CH:66]=2)=[CH:54][N:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: COc1ccc2cc(C(=O)O)c(=O)oc2c1OC
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: COc1ccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc2c1OC
Temperature: 25 °C
Yield: 77.8 %

Procedure:
DIEA (38.3 μL, 0.22 mmol) was added to 7,8-dimethoxy-3-carboxy-coumarin (500 mg, 0.20 mmol) and HATU (83.6 mg, 0.22 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (41.8 mg, 0.20 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 68.7 mg of product in 78% yield: LCMS (ESI) m/z 442 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][CH2:11][CH2:10][CH:9]2[C:14]([OH:16])=O)([O-:3])=[O:2].[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])[CH3:18].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:17]([C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:14]([CH:9]2[C:8]3[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=3)[O:12][CH2:11][CH2:10]2)=[O:16])=[CH:22][CH:21]=1)([CH3:19])[CH3:18]
Reactant: O=C(O)C1CCOc2c1cccc2[N+](=O)[O-]
Reactant: CC(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccc(NC(=O)C2CCOc3c2cccc3[N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
To a solution of 8-nitrochroman-4-carboxylic acid (3.0 g) and 4-isopropylaniline (2.0 g) in dimethylformamide (30 mL) were added N-hydroxybenzotriazole hydrate (2.0 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.8 g), and the mixture was stirred at room temperature. After the completion of the reaction, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give N-(4-isopropylphenyl)-8-nitrochroman-4-carboxamide (4.1 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[NH2:11][C@H:12]1[CH2:15][N:14]([S:16]([OH:19])(=[O:18])=[O:17])[C:13]1=[O:20]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:11][C@H:12]2[CH2:15][N:14]([S:16]([OH:19])(=[O:18])=[O:17])[C:13]2=[O:20])=[O:10])[N:6]=1
Reactant: Nc1nc(CC(=O)O)cs1
Reactant: N[C@H]1CN(S(=O)(=O)O)C1=O
Product: Nc1nc(CC(=O)N[C@H]2CN(S(=O)(=O)O)C2=O)cs1

Procedure:
Following the procedure of Example 1 but substituting an equivalent amount of 2-amino-4-thiazoleacetic acid for the formyl protected reactant and (3S)-3-amino-2-oxo-1-azetidinesulfonic acid, inner salt for the 4-methyl reactant, one obtains as a result of the enzymatic coupling (3S)-3-[[[2-amino-4-thiazolyl]acetyl]amino]-2-oxo-1-azetidinesulfonic acid, zwitterion. Again, the structure is confirmed by analytical and bioassay techniques.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[S:20][C:21]([C:25](=[O:35])[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=3)=[C:22]([NH2:24])[N:23]=2)=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:24][C:22]1[N:23]=[C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:13][CH:14]=2)[S:20][C:21]=1[C:25]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=1)=[O:35]
Reactant: COc1ccc(C(=O)c2sc(Nc3ccc(OCCCNC(=O)OC(C)(C)C)cc3)nc2N)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)c2sc(Nc3ccc(OCCCN)cc3)nc2N)cc1F
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of (3-[4-[4-Amino-5-(3-fluoro-4-methoxy-benzoyl)-thiazol-2-ylamino]-phenoxy]-propyl)-carbamic acid tert-butyl ester (254 mg) (from Step A above) in dichloromethane (6 mL) at 0° C. was added trifluoroacetic acid (3 mL). After stirring for 1 hour, the mixture was concentrated and the residue was purified on HPLC to give [4-Amino-2-[4-(3-aminopropoxy)-phenylamino]-thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)-methanone (180.9 mg, 88% yield) as a light yellow solid. HRMS, Observed: 417.1394; Calcd for M+H+: 417.1391.
Reaction SMILES: [NH2:1][C:2]1[C:10]([I:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:14])=[N-]>CO.C(OCC)C>[CH3:14][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([I:11])[C:2]=1[NH2:1]
Reactant: Nc1c(I)cccc1C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccc(I)c1N

Procedure:
A solution of 2-amino-3-iodo-benzoic acid (2.5 g, 9.5 mmol) in methanol and diethyl ether mixture (15 mL, 8:2) was added a freshly prepared solution of diazomethane gas in diethyl ether until all the starting material is consumed. Reaction mixture was then evaporated under reduced pressure to obtain a yellow solid which was purified by flash column using. 5% ethylacetate in hexane as an eluent. 1.5 g of the required product was isolated as a yellow viscous liquid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]3[CH2:24][CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.CO.[C].[Pd]>[NH2:29][C:27]1[CH:26]=[CH:25][C:3]([O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][N:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1)N1CCC(CN2CCC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc(NC(=O)N3CCC(CN4CCC4)CC3)ncn2)c(F)c1
Reaction time: 13 h
Yield: 69.9 %

Procedure:
4-(Azetidin-1-ylmethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (340 mg) was dissolved in tetrahydrofuran (8 ml) and methanol (8 ml), and then 10% palladium carbon (170 mg) was added, followed by stirring under a hydrogen atmosphere for 13 hrs. The catalyst was filtered off and washed with methanol. The filtrate and washings were concentrated under reduced pressure to give the titled compound (221 mg) as pale yellow solid.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.Br[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Cl-].[NH4+]>>[CH:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCCC1
Reactant: Br[Mg]c1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Product: c1ccc(C2CCCCC2)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A mixture of phenyl magnesium bromide (1.25 mL of 0.96-M THF solution, 1.2 mmol) and TMEDA (181.1 μL, 1.2 mmol) was added to a mixture of bromocyclohexane (163.1 mg, 1.0 mmol) and FeCl3 (0.5 mL of 0.1-M THF solution, 5 mol %) at 0° C. over 20 minutes using an injection pump. After the addition of the mixture of Grignard reagent and TMEDA was completed, the reaction mixture was stirred at the temperature for 10 minutes. After treating with saturated aqueous ammonium chloride solution in a conventional manner, the reaction mixture was filtered through a pad of Florisil® and concentrated in vacuum. Using the internal standard (tetrachloroethane, 79 mg, 0.47 mmol), the crude product was analyzed by 1H NMR to give cyclohexylbenzene in a yield of 99%. GC analysis gave cyclohexylbenzene in a yield of 99%.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([C:28]([N:30]3[CH2:33][CH:32]([O:34][CH3:35])[CH2:31]3)=[O:29])[N:27]=2)[CH2:20]1
Reactant: COC1CN(C(=O)c2coc(N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)n2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (1.49 g, 3.23 mmol) (obtained as described in Reference Example 72(1)) in anhydrous tetrahydrofuran (75 ml) was added a solution of 1.0 M tetra-n-butylammonium fluoride in tetrahydrofuran (3.88 ml, 3.88 mmol) in an ice bath and the mixture was stirred in an ice bath for 1 hour. After checking the completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (95:5→9:1) as the eluant to afford 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (486 mg, yield 60%) as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=3[O:34][CH3:35])[CH:15]=[CH:16][C:17]=2[F:21])[CH2:12]1)=O)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[F:21][C:17]1[CH:16]=[CH:15][C:14]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:24][C:23]=2[O:34][CH3:35])=[C:13]2[C:18]=1[CH2:19][CH2:20][NH:11][CH2:12]2
Reactant: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CN(C(=O)OCc2ccccc2)CC3)c(OC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-c2ccc(F)c3c2CNCC3)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of 8-(4-ethoxycarbonylmethyl-2-methoxy-phenyl)-5-fluoro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (770 mg, 1.61 mmol, 1 eq.) in AcOEt (60 mL), palladium on activated carbon (10 wt. %, 80 mg) was added. The flask was evacuated and backfilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The suspension was filtered through Celite, the Celite rinsed with AcOEt. The filtrate was concentrated in vacuo to give ethyl 2-(4-(5-fluoro-1,2,3,4-tetrahydroisoquinolin-8-yl)-3-methoxyphenyl)acetate as an yellow oil. The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22]O)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.Cl.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:46][CH:45]=1>C(#N)CC>[C:1]([O:5][C:6]([N:8]1[CH2:21][CH2:20][N:19]2[CH:10]([C:11](=[O:24])[NH:12][C:13]3[C:18]2=[N:17][CH:16]=[C:15]([CH2:22][N:53]2[CH2:52][CH2:51][N:50]([C:47]4[CH:46]=[CH:45][C:44]([Cl:43])=[CH:49][CH:48]=4)[CH2:55][CH2:54]2)[CH:14]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncc(CO)cc3NC(=O)C2C1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)N1CCN2c3ncc(CN4CCN(c5ccc(Cl)cc5)CC4)cc3NC(=O)C2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
7-Hydroxymethyl-10-oxo-1,3,4,9,10,10a-hexahydro-2,4a,5,9-tetraaza-phenanthrene-2-carboxylic acid tert-butyl ester (22.0 mg, 0.598 mmol) was suspended in propionitrile (1.5 mL) and (cyanomethyl)trimethylphosphonium iodide (174.0 mg, 0.718 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (313 ul, 1.794 mmol). To the stirred mixture was then added 1-(4-chlorophenyl)piperazine hydrochloride (139 mg, 0.598 mmol). The reaction was heated to 90° C. with stirring for 16 h. The crude reaction was cooled to room temperature and purified on silica column (24 g, 25% THF in ethyl acetate). The fractions were combined and concentrated to afford 250.9 mg (82%) of the title compound as a brown solid in 80% purity. [M+H] calc'd for C26H33ClN6O3, 513; found, 513.