Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10](F)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-:3])=[O:2].[NH:14]1[CH2:16][CH2:15]1.O>CS(C)=O>[N:14]1([C:10]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:9]=2)[C:6]([NH2:8])=[O:7])[CH2:16][CH2:15]1
Reactant: C1CN1
Reactant: NC(=O)c1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(N2CC2)ccc1[N+](=O)[O-]
Temperature: -5 °C
Yield: 47 %

Procedure:
A stirred solution of 2-nitro-5-fluorobenzamide (Orrin, Eur. Pat. Appl. 19,388; Chem. Abstr. 1981, 94, 156538h) (480 mg, 2.61 mmol) in dry DMSO (2 mL) was treated with aziridine (0.54 mL, 10.4 mmol) at room temperature under N2 for 48 h, then poured into cold water (50 mL). Prolonged cooling at −5° C. gave a crystalline product that was collected and filtered throuhg a column of silica gel in EtOAc to give 11 (256 mg, 47%), mp (EtOAc) 172-174° C. 1H NMR [(CD3)2SO] δ8.01 & 7.61 (2xs, 2H, CONH2), 7.93 (d, J=8.9 Hz, 1H, H-3), 7.17 (dd, J=8.8, 2.4 Hz, 1H, H-4), 7.09 (d, J=2.3 Hz, 1H-6), 2.24 (s, 4H, aziridine-H ). Anal. Calcd. for C9H9N3O3: 52.17;H, 4.38; N, 20.29 Found: C, 52.29;H, 4.27; N, 20.25%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)[O:16]1.C([O-])(=O)C.[K+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O.O>[N:8]1([C:5]2[N:4]=[CH:3][C:2]([OH:16])=[CH:7][N:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cnc(N2CCOCC2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1cnc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
A mixture of 4-(5-bromopyrimidin-2-yl)morpholine (2 g), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.5 g), bis(triphenylphosphine)palladium chloride (180 mg), potassium acetate (2.5 g), and dioxane (20 ml) was stirred at 80° C. overnight under argon atmosphere. Water and EtOAc were added to the reaction mixture, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (10 ml) and water (10 ml), and sodium perborate.tetrahydrate (3.5 g) was added thereto, followed by stirring at room temperature overnight. Then, a saturated aqueous ammonium chloride solution was added thereto. The aqueous layer was extracted with EtOAc, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 2-(morpholin-4-yl)pyrimidin-5-ol (610 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[C:9]([N:15]2[C:19]([C:20]3C=CC=CC=3)=[N:18][N:17]=[N:16]2)[C:10](OCC)=[O:11])=[CH:4][CH:3]=1.FC1C=CC(C(C2C=CC(F)=CC=2)=C(N2C(C)=NN=N2)C(OCC)=O)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[C:9]([N:15]2[C:19]([CH3:20])=[N:18][N:17]=[N:16]2)[CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1C
Product: Cc1nnnn1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
The general procedure of Example 5 was repeated, except that the ethyl 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1 H-tetrazol-1-yl)-2-propenoate utilized therein was replaced by 4.87 g of ethyl 3,3-bis(4-fluorophenyl)-2-(5-methyl-1 H-tetrazol-1-yl)-2-propenoate [prepared in Example 14] and there was thereby produced 4.45 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([N:23]=[N+:24]=[N-:25])=[CH:11][C:10]=1[CH:26]([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:54])[C:32]#[C:33][N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:35]1[CH:40]=[CH:39][C:38]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1.CCOC(C)=O.O>CN(C=O)C>[CH3:29][O:30][C:31]([C:32]1[N:25]=[N:24][N:23]([C:12]2[CH:11]=[C:10]([CH:26]([CH3:28])[CH3:27])[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][C:13]=2[O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:33]=1[N:34]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:35]1[CH:36]=[CH:37][C:38]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][CH:40]=1)=[O:54]
Reactant: COC(=O)C#CN(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Reactant: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nnn(-c2cc(C(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1N(C(=O)OC(C)(C)C)c1ccc(N2CCOCC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
A solution of 1,5-bis-benzyloxy-2-isopropyl-4-azido-benzene (373 mg, 1 mmol) and [t-butoxycarbonyl-(4-morpholin-4-yl-phenyl)-amino]-propynoic acid methyl ester (328 mg, 0.91 mmol) in DMF (2.5 ml) was degassed at RT by means of three vacuum-nitrogen cycles before adding [Cp*RuCl]4 (49 mg, 0.045 mmol) and repeating the three degassing cycles with nitrogen. The reaction mixture was stirred at RT until completion (i.e., monitored by TLC). AcOEt and H2O were then added. The organic phase was extracted four times with AcOEt, washed with water (three times) and brine (once) and dried over Na2SO4. The solvent was removed under reduced pressure and the reaction mixture was purified by column chromatography (PE/AcOEt:60/40). The title compound was obtained as an oil.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)=O.O.[NH2:22][NH2:23]>CCO>[F:13][C:9]1[CH:8]=[C:7]([NH:6][C:4]2[C:3]3[C:2](=[CH:17][CH:16]=[C:15]([N+:18]([O-:20])=[O:19])[CH:14]=3)[NH:23][N:22]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: NN
Reactant: O=C(Nc1cccc(F)c1)c1cc([N+](=O)[O-])ccc1F
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc2[nH]nc(Nc3cccc(F)c3)c2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
2-Fluoro-N-(3-fluoro-phenyl)-5-nitro-benzamide (1.1 μg, 4 mmol) was suspended in EtOH (25 mL) and the mixture heated to ˜60° C. To the resulting solution was added hydrazine monohydrate (1.06 mL, 20 mmol). The mixture was heated at reflux for 5 minutes and a yellow solid was precipitated out. The mixture was allowed to cool to room temperature then the solid was filtered off. The solid was dissolved in phosphorous oxychloride (40 mL) and the mixture heated at 90° C. for 1.5 hr then allowed to cool to room temperature and stirred for overnight. The reaction mixture was concentrated and partitioned between EtOAc and saturated sodium bicarbonate. The organic phase was dried over MgSO4 and concentrated to afford the title compound as a red solid (0.7 g, 64%). MS (ESI) m/z=273 [M+H]+. 1H NMR (400 MHz, d6-DMSO) δ 12.84 (s, 1H), 9.69 (s, 1H), 9.22 (d, J=2.0 Hz, 1H), 8.19 (dd, J=9.2 and 2.0 Hz, 1H), 7.77 (m, 1H), 7.54 (d, J=9.2 Hz, 1H), 7.37 (m, 2H), 6.69 (m, 1H)
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:26])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[C:36]1[N:40]2[CH:41]=[C:42]([O:45][C@@H:46]3[C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C@@H:49]([NH2:56])[CH2:48][CH2:47]3)[CH:43]=[CH:44][C:39]2=[N:38][N:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:56][C@@H:49]2[C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[C@@H:46]([O:45][C:42]3[CH:43]=[CH:44][C:39]4[N:40]([C:36]([N:31]5[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]5[CH3:29])=[N:37][N:38]=4)[CH:41]=3)[CH2:47][CH2:48]2)=[O:26])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCO)c2)n1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 70 °C
Yield: 61.7 %

Procedure:
A mixture of Intermediate 148e (313 mg, 0.7 mmol), Intermediate 186b (262 mg, 0.7 mmol) and DIPEA (182 μL, 1.05 mmol) in dioxane (4 mL) was heated at 70° C. for 20 h. The reaction mixture was cooled to RT and eluted directly on SCX-2 using MeOH and 2M NH3 in MeOH. The basic fractions were evaporated under reduced pressure. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound as a yellow glass (293 mg). LCMS (Method 3): Rt 3.63 min, m/z 679 [MH+].
Reaction SMILES: C(ON=O)CC(C)C.[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1N)=[O:13])[CH3:10].[I:24]CI.O>C(#N)C>[CH2:9]([O:11][C:12]([C:14]1[N:15]([CH3:23])[C:16]([CH3:22])=[C:17]([C:20]#[N:21])[C:18]=1[I:24])=[O:13])[CH3:10]
Reactant: CCOC(=O)c1c(N)c(C#N)c(C)n1C
Reactant: ICI
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C#N)c(C)n1C
Temperature: 55 °C

Procedure:
Add isoamylnitrite (2.5 Eq.) to 3-amino-4-cyano-1,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (prepared in preparation 44) and diiodomethane (3.5 eq.) in acetonitrile (10 mL) with stirring at 55° C. under a nitrogen atmosphere. Slowly heat the reaction mixture to 75° C. and heat at this temperature for 3 hours. Cool to room temperature and pour into water, and extract the quenched reaction with ethyl acetate. Wash the organic extracts with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the residue by silica gel chromatography (Prep.2000) eluting with methylene chloride to provide a solid. Recrystallize from ethyl acetate to provide the title compound as crystals. Mass spectrum (m/e): 318.0 M*). (Bruker 300) 1H NMR (CDCl3) 4.31-4.38 (2H, dd), 3.83-3.86 (3H, s), 2.41-2.44 (3H, s), 1.40-1.44 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Cl[C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[N:15]=[N:16][CH:17]=1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[C:14]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH3:24])[N:15]=[N:16][CH:17]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccccc2Cl)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=285.2 (M+H+), was prepared from 2-chlorophenylboronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][C:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1)([CH3:5])[C:3]#[CH:4]>N1C2C(=CC=CC=2)C=CC=1.CCOCC>[CH3:5][C:2]1([CH3:1])[CH:3]=[CH:4][C:8]2[CH:9]=[C:10]([I:13])[CH:11]=[CH:12][C:7]=2[O:6]1
Reactant: C#CC(C)(C)Oc1ccc(I)cc1
Solvent: CCOCC
Solvent: c1ccc2ncccc2c1
Product: CC1(C)C=Cc2cc(I)ccc2O1
Temperature: 25 °C

Procedure:
A solution of 1-[(1,1-dimethyl-2-propynyl)oxy]-4-iodobenzene (5.97 g, 20.8 mmol) in quinoline (25 mL) was heated at 170° C. for 2 hours. The reaction was cooled to room temperature and diluted with ether. The reaction mixture was washed with 2N HCl (4X eq. vol.), with brine (2X eq. vol.), dried over anhydrous MgSO4 and concentrated to give crude product. This material was combined with product from an identical reaction and purified by flash chromatography, using 100% petroleum ether elution to give 5.58 g, (79% for the two reactions), of product.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1.Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C.O>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7]3[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=3[C@@H:9]3[C@H:14]([NH:15][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:12][CH2:11][N:10]3[C:4]=2[CH:3]=1
Reactant: CN1c2ccccc2[C@@H]2[C@H](N)CCCN2c2cc(Cl)ccc21
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN[C@@H]1CCCN2c3cc(Cl)ccc3N(C)c3ccccc3[C@H]12
Temperature: 60 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a suspension of trans-7-chloro-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[b,f]pyrido[1,2-d][1,4]-diazepin-1-ylamine (100 mg, 0.25 mmol) in DMF (2 mL) was added ethyl bromoacetate (56 μl, 0.51 mmol) and triethylamine (107 ul, 0.76 mmol). The resulting reaction mixture was heated to 60° C. and stirred for 5 h. The mixture was poured into water and extracted with ethyl acetate (3×). The organic layers were washed with sat (aq) NaHCO3 and brine. After drying (MgSO4), the solvents were removed under reduced pressure. The crude product was purified on silica with heptane/ethyl acetate 8:2 to afford 80 mg (80%) of the title compound.
Reaction SMILES: [C@H:1]12[N:8]([C:9]([C:11]3[C:12]([N:18]4[CH:22]=[CH:21][N:20]=[N:19]4)=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[O:10])[CH2:7][C@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.Cl[C:24]1[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:17][C:14]1[N:13]=[C:12]([N:18]2[CH:22]=[CH:21][N:20]=[N:19]2)[C:11]([C:9]([N:8]2[C@H:1]3[C@H:6]([CH2:5][CH2:4][N:3]([C:24]4[N:29]=[C:28]([CH3:30])[C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:2]3)[CH2:7]2)=[O:10])=[CH:16][CH:15]=1
Reactant: Cc1nc(Cl)nc(C)c1C
Reactant: Cc1ccc(C(=O)N2C[C@H]3CCNC[C@H]32)c(-n2ccnn2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(C(=O)N2C[C@H]3CCN(c4nc(C)c(C)c(C)n4)C[C@H]32)c(-n2ccnn2)n1
Temperature: 180 °C
Yield: 53.4 %

Procedure:
To a microwave safe vial was added (1S,6R)-3,8-diazabicyclo[4.2.0]octan-8-yl(6-methyl-2-(1H-1,2,3-triazol-1-yl)pyridin-3-yl)methanone (80 mg, 0.27 mmol), 2-chloro-4,5,6-trimethylpyrimidine (84 mg, 0.54 mmol), ACN (3 mL) and DIPEA (0.093 mL, 0.54 mmol). The resulting mixture was heated to 180° C. in a microwave reactor. After 2 hours the mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue was purified by reverse-phase HPLC (acidic) to yield the title compound (60.3 mg, 42%) as the TFA salt. MS (ESI) mass calcd. for C22H26N8O, 418.2; m/z found, 419.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.44-8.32 (m, 1H), 7.82-7.72 (m, 2H), 7.22-7.16 (m, 1H), 4.52-4.46 (m, 1H), 4.30 (dd, J=10.0, 9.0 Hz, 1H), 4.04 (tt, J=9.6, 4.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.89-3.57 (m, 2H), 3.13-2.83 (m, 2H), 2.65-2.57 (m, 3H), 2.39-2.31 (m, 6H), 2.15-2.02 (m, 4H), 1.99-1.81 (m, 1H).
Reaction SMILES: O=[C:2]([CH3:23])[CH:3]([C:14]1[C:15](=O)[C:16](=[O:21])[C:17]=1[O:18]CC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[NH2:24][CH:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:26].C([O:33]CC)C>C(O)C>[O:33]=[CH:23][CH2:2][CH:3]([C:14]1[C:17](=[O:18])[C:16](=[O:21])[C:15]=1[NH:24][CH:25]([CH3:26])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:9]=1
Reactant: CC(N)C(C)(C)C
Reactant: CCOc1c(C(C(C)=O)c2ccc(C(F)(F)F)cc2)c(=O)c1=O
Reactant: CCOCC
Solvent: CCO
Product: CC(Nc1c(C(CC=O)c2ccc(C(F)(F)F)cc2)c(=O)c1=O)C(C)(C)C
Reaction time: 8 h
Yield: 37 %

Procedure:
3-[2-Oxo-1-(4-trifluoromethyl-phenyl)-propyl]-4-ethoxy-cyclobut-3-ene-1,2-dione (0.350 g, 1.07 mmol) and 2-amino-3,3-dimethylbutane (0.13 mL, 0.998 mmol) were stirred together in ethanol (6 mL) at room temperature overnight. Diethyl ether (25 mL) was added and the precipitated product was collected by filtration. It was stirred in diethyl ether/petroleum ether overnight, filtered and dried in vacuo to afford 0.15 g (37%) of desired product (1H NMR in CDCl3 suggested the presence of both the keto and enol forms in about an 8:1 ratio) as an off-white solid: m.p. 178.2-179.8° C.; 1H NMR (CDCl3) δ 11.74(s,1H), 7.73(ABq,2H), 7.39(ABq,2H), 3.92(m,1H), 1.86(s,3H), 0.93(d,3H), 0.69(s,9H); IR (KBr) 3310, 2970, 2600, 1775, 1710, 1560, 1395, 1260, 1160, 1125, 850 cm−1; MS (m/z) 381 [M+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[F:12][C:10]1[CH:11]=[C:2]([NH:1][C:32]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[NH:33])[CH:3]=[C:4]2[C:9]=1[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1CCCc2cc(N)cc(F)c21)C(=O)Oc1ccccc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a stirred solution of phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (426 mg, 1.241 mmol) in ethanol (12 ml) was added methyl thiophene-2-carbimidothioate hydroiodide (708 mg, 2.481 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was then diluted with water and sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 40-100% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate 52 (422 mg, 0.933 mmol, 75% yield). 1H NMR (DMSO-d6) δ 7.74-7.71 (m, 1H); 7.59-7.57 (m, 1H); 7.41-7.36 (m, 2H); 7.23-7.18 (m, 1H); 7.14-7.07 (m, 3H); 6.50-6.42 (m, 3H); 6.37 (s, 1H); 3.62 (t, J=6 Hz, 1H); 3.51 (t, J=6 Hz, 1H); 3.30 (t, J=6 Hz, 1H); 3.23 (t, J=6 Hz, 1H); 3.15-3.09 (m, 2H); 3.09, 2.97 (2s, 3H); 2.69 (t, J=6 Hz, 2H); 1.83-1.75 (m, 2H). EI-MS (m/z, %): 452 (M+, 8); 288 (60); 179 (100).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[C:16]([O:19][CH3:20])[N:17]=[CH:18][C:11]=3[N:10]=[C:9]2[CH3:21])=[CH:4][CH:3]=1.Br.Br[CH2:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH2:28]1>>[CH3:20][O:19][C:16]1[N:17]=[CH:18][C:11]2[N:10]=[C:9]([CH3:21])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:24][CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:7][CH:6]=3)[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: BrCCCN1C=CC=CC1
Reactant: COc1cc2c(=O)n(-c3ccc(O)cc3)c(C)nc2cn1
Agent: Br
Product: COc1cc2c(=O)n(-c3ccc(OCCCN4CCCCC4)cc3)c(C)nc2cn1

Procedure:
The title compound was synthesized as a white solid (m.p.:145-147° C.) by the method according to Example 63, using 3-(4-hydroxyphenyl)-6-methoxy-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one synthesized in Example 197 and 1-(3-bromopropyl)pyridine hydrobromide as starting materials, followed by recrystallization (ethyl acetate/diethyl ether).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>ClCCCl>[Cl:1][C:2]1[C:7]2[C:8](=[O:10])[C:17]3[C:12](=[CH:13][C:14]([Cl:20])=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:6]=2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2c([N+](=O)[O-])ccc(Cl)c2C(=O)O)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)c1ccccc1
Product: COc1cc2c(=O)c3c(Cl)ccc([N+](=O)[O-])c3[nH]c2cc1Cl

Procedure:
A mixture of 17 g of 6-chloro-2-[(3-chloro-4-methoxyphenyl)amino]-3-nitrobenzoic acid, 35 ml of phosphorus oxychloride, 1 ml of N,N-dimethylaniline and 150 ml 1,2-dichloroethane was heated under reflux for 45 minutes. The resulting solid was collected by filtration from the hot reaction mixture and was washed with chloroform to provide 1,6-dichloro-7-methoxy-4-nitro-9(10H)-acridinone, mp 284°-285° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([CH3:27])=[CH:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[BH3-]C#N.[Na+]>C(O)(C(F)(F)F)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:28])[C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]([CH3:27])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)=[CH:29][CH:30]=1
Reactant: Cc1cn(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(S(=O)(=O)c2ccc(C(=O)NCc3ccc(F)cc3)cc2)c2ccccc21
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 70.7 %

Procedure:
Add N-(4-Fluoro-benzyl)-4-(3-methyl-indole-1-sulfonyl)-benzamide (0.106 g, 0.25 mmol) portionwise to a stirring mixture of NaCNBH3 (0.074 g, 1.2 mmol, in TFA (5.0 mL) at 0 to 5° C. under N2. Stir the mixture for 15 minutes at 0-5° C., allow to warm to ambient temperature and stir for 1 h. add NaCNBH3 (0.074 g, 1.2 mmol) and stir the reaction is for 2 h dilute with H2O (13.0 mL) and work up as described in the above example. Chromatograph and elute with EtOAc-hexane (0-50%) to give 0.075 g of the title compound: Mass spectrum (m/e) (M+H) 425.1335; found 425.1341.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C(N(CC)CC)C.C1[C:36]2[C:35](=[O:37])[C:34]3C(=CC=CC=3)C=2C(C(Cl)=O)=CC=1>ClCCl>[CH:35]([O:37][CH:6]([CH3:5])[CH3:7])([CH3:36])[CH3:34].[NH2:16][C:4]1[CH:3]=[C:2]([F:1])[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][C:5]=1[NH-:15]
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: CN1CCN(c2cc(N)c(N)cc2F)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(C)C
Product: CN1CCN(c2cc([NH-])c(N)cc2F)CC1
Yield: 74.7 %

Procedure:
The procedure used in stage 1 of Example 1 is followed, but starting from 2.69 g of 4-fluoro-5-(4-methylpiperazin-1-yl)benzene-1,2-diamine, which can be prepared according to J. Het. Chem. 2005, 42(1), 67-71, 2.82 ml of triethylamine and 2.43 g of 9H-fluoren-9-one-4-carboxylic acid chloride in 50 ml of dichloromethane for 20 hours at room temperature. After purification by flash chromatography on silica gel (40-63 μm), eluting with a mixture of dichloromethane and methanol (95/5 by volume), and then formation of a paste with diisopropyl ether, in this way we obtain 1 g of [2-amino-4-fluoro -5-(4-methyl piperazin-1-yl)phenyl]amide of 9-oxo-9H-fluorene-4-carboxylic acid, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6])#[CH:2].[CH:12]1C=CC2N(O)N=NC=2C=1.Cl.[NH:23]1[CH2:31][CH2:30][CH:26]([C:27]([OH:29])=O)[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:6][C:27]([CH:26]2[CH2:25][CH2:24][N:23]([CH3:12])[CH2:31][CH2:30]2)=[O:29])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])#[CH:2]
Reactant: O=C(O)C1CCNCC1
Reactant: On1nnc2ccccc21
Reactant: C#Cc1cc(N)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#Cc1cc(NC(=O)C2CCN(C)CC2)ccc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-Ethynyl-4-methoxyaniline (300 mg, 2 mmol) in DCM (20 mL) was treated in a subsequent manner with HOBt (351 mg, 2.6 mmol), isonipecotic acid hydrochloride (467 mg, 2.6 mmol), DIPEA (906 μL, 5.2 mmol) and finally EDCl (498 mg, 2.6 mmol). The reaction was stirred at room temperature for 1.5 h. The organic phase was washed with saturated sodium hydrogen carbonate solution and dried over sodium sulfate. Evaporation of the solvent left a brownish solid which was employed in the following reaction without further purification.