Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[CH:3]=1.[CH2:10](I)[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1
Reactant: CCI
Reactant: Oc1cc(Br)c(F)cn1
Solvent: ClCCl
Product: CCOc1cc(Br)c(F)cn1
Temperature: 25 °C

Procedure:
0.20 g (1.04 mmol) 4-bromo-5-fluoro-pyridin-2-ol, 0.83 mL (10.4 mmol) ethyliodide and 0.43 g (1.56 mmol) Ag2CO3 are added to 5 mL DCM and stirred at r.t. over night. The reaction is quenched by the addition of water. DCM is added, the resulting mixture is filtered and the organic layer is separted, dried over MgSO4, filtered again and the solvent is removed in vacuo.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:14][C:15]1[C:16]2[C:21]([CH:22]=[C:23]3[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH3:13])(C)(C)C.[ClH:30]>C(O)C>[ClH:30].[CH:27]1[C:28]2[C:23](=[CH:22][C:21]3[C:16]([C:15]=2[CH2:14][N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][CH2:8][NH2:7])=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:24]=[CH:25][CH:26]=1
Reactant: CCN(CCCNC(=O)OC(C)(C)C)Cc1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CCO
Product: CCN(CCCN)Cc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
A solution of 12b (400 mg, 1.02 mmole) was dissolved in absolute ethanol (13 mL) and stirred at 0° C. for 10 minutes. A 4N HCl solution (22 mL) was added to the reaction mixture dropwise and stirred at 0° C. for 20 minutes and then at room temperature overnight. The solution was concentrated in vacuo to give 12c as a yellow solid in 90% yield. 1H NMR (D2O) δ 8.42 (s, 1H), 8.0 (m, 4H), 7.71 (m, 2H), 7.61 (m, 2H), 4.87 (s, 2H), 3.34 (br q, 2H), 3.14 (br t, 2H), 2.81 (t, 2H), 2.00 (q, 2H), 1.40 (t, 3H); 13C NMR (D2O): δ 133.8, 133.3 (3C), 132.4 (2C), 130.7 (2C), 128.2 (2C), 125.1 (2C), 121.5 (2C), 52.0, 51.9, 39.2 (2C), 24.5, 11.3. HRMS (FAB) calcd for C20H24N2.2HCl (M+H−2HCl)+ 293.2012, Found 293.2009.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=1)[CH:12]([CH3:14])[CH3:13])(C)(C)C.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=[O:37])[CH3:36].[Na+].NC(C1N(CC2C=CC=CC=2)C(=O)C2C(=CC(Cl)=CC=2)N=1)C(C)C.O=CCNC(=O)OC(C)(C)C>C(Cl)Cl>[CH2:25]([N:24]1[C:23](=[O:32])[C:22]2[C:17](=[CH:18][C:19]([Cl:33])=[CH:20][CH:21]=2)[N:16]=[C:15]1[CH:11]([N:10]1[C:35](=[O:37])[CH2:36][CH2:6][NH:7][CH2:8][CH2:9]1)[CH:12]([CH3:14])[CH3:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(C)(C)OC(=O)NCC=O
Agent: CC(C)C(N)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1)N1CCNCCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Preparation of {2-[1-(3-Benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester: Sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added to a solution containing 2-(1-amino-2-methyl-propyl)-3-benzyl-7-chloro-3H-quinazolin-4-one (185 mg, 0.54 mmol) (prepared using the general procedure described in WO 0130768) and tert-butyl N-(2-oxoethyl)carbamate (103 mg, 0.65 mmol) in CH2Cl2 (5.4 mL). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with CH2Cl2 (10 mL), washed with brine, dried and concentrated under vacuum. Purification by flash chromatography on silica gel (5–10% EtOAc in hexane) gave the title compound (105 mg) as a white solid: MS (ES) m/e 485 (M+H)+.
Reaction SMILES: C1(S([C:10]2([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)(=O)=O)C=CC=CC=1.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:10]1([S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH2:11][CH2:12][CH2:13]1
Reactant: O=S(=O)(c1ccccc1)C1(S(=O)(=O)c2ccccc2)CCC1
Reactant: BrCCCCBr
Product: O=S(=O)(c1ccccc1)C1(CCCCBr)CCC1

Procedure:
The title compound was prepared as described in Description 7 from 1,1-bis(phenylsulfonyl)cyclobutane and 1,4-dibromobutane.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH:15]=[C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([CH2:25][CH3:26])[N:17]=2)[CH:13]=[CH:12][C:11]1=[O:27].CI.[C:30]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:25]([N:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:16]([C:14]2[CH:13]=[CH:12][C:11](=[O:27])[N:10]([C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=2)=[N:17]1)[CH3:26]
Reactant: CCn1nc(-c2ccc(=O)n(-c3nc4ccccc4[nH]3)c2)c2ncccc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccc(=O)n(-c3nc4ccccc4n3C)c2)c2ncccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.7 %

Procedure:
A mixture of 1-(1H-benzimidazol-2-yl)-5-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2(1H)-one (20 mg), MeI (11.95 mg) and Cs2CO3 (36.6 mg) in DMF (1 mL) was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and crystallized from hexane/AcOEt to give the title compound (12 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:36]([F:37])=[CH:35][C:34](O)=[CH:33][C:32]=1[F:39].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:40])[C:31]1[C:32]([F:39])=[CH:33][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:35][C:36]=1[F:37]
Reactant: COC(=O)c1c(F)cc(O)cc1F
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1c(F)cc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1F

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 2,6-difluoro-4-hydroxy-benzoic acid methyl ester and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Light yellow oil (85%). MS (Turbo Spray): m/z=561.2 [M+H].
Reaction SMILES: [C:1](=[O:4])([O-:3])[NH2:2].[CH3:5][N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:8]([N+:21]([O-])=O)[CH2:7]1.C(O)(=O)C>CO.[Zn]>[C:1](=[O:3])([O-:4])[NH2:2].[CH3:5][N:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:8]([NH2:21])[CH2:7]1
Reactant: CN1CC(c2ccccc2C(F)(F)F)C([N+](=O)[O-])C1
Agent: NC(=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC(N)C(c2ccccc2C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3S and R,4R and S)-1-Methyl-3-nitro-4-(2-(trifluoromethyl)phenyl) pyrrolidine (296.8 mg, 1.082 mmol) was dissolved in MeOH (5 mL) and the reaction mixture was cooled to 0° C. Acetic acid (5 mL) and zinc (354 mg, 5.41 mmol) were added and the reaction mixture was warmed to room temperature and stirred under N2 for 16 h. The suspension was filtered over Celite and washed with MeOH. The filtrate was concentrated in vacuo, the residue suspended in EtOAc, cooled in an ice bath, and basified with conc. NH4OH. The organic phase was separated, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford (3S and R,4R and S)-1-methyl-4-(2-(trifluoromethyl)phenyl)pyrrolidin-3-amine, which was carried onto the next step without further purification. MS ESI calc'd. For C12H15F3N2 [M+1]+ 245. found 245.
Reaction SMILES: [Cl:1][C:2]1[C:7](=O)[NH:6][CH:5]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:16])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:19]
Reactant: COC(=O)CCC(=O)c1c[nH]c(=O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)CCC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 75 °C

Procedure:
A suspension of 37 g (152 mmol) of methyl 4-(5-chloro-1,6-dihydro-6-oxopyridin-3-yl)-4-oxobutyrate in 230 ml of phosphorus oxychloride was heated at 75° C. for 2.5 hours. The phosphorus oxychloride was subsequently distilled off in vacuo. The pale red residue was taken up in 200 ml of dichloromethane, 100 ml of water was added, and the pH of the aqueous phase was brought to 8.5 using 30 percent sodium hydroxide solution. After phase separation, the aqueous phase was extracted using 100 ml of dichloromethane. The combined organic phases were treated with active charcoal and evaporated. The residue was recrystallized from 300 ml of diisopropyl ether and filtered at 2° C. The yield was 32.83 g of pale pink crystals. A further 1.76 g of product was obtained from the mother liquor in the form of crystals. The total product yield was 87 percent. The melting point of the product was 85.2° to 86° C. Other data concerning the product was:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:26]([CH:28]=1)[NH2:27]>O>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)=[C:26]([NH:27][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:28]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(F)ccc1N1CCCCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)ccc1N1CCCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 67.6 %

Procedure:
Isonicotinoyl chloride hydrochloride (454 mg, 2.55 mmol, commercially available product) and triethylamine (385 μl, 3.83 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 5-fluoro-2-(1-piperidinyl)aniline (248 mg, 1.27 mmol), obtained as described in Referential Example 17-2. The resulting mixture was warmed to room temperature and stirred for 17 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane/ethyl acetate=1.5/1). Thus, N-[5-fluoro-2-(1-piperidinyl)phenyl]isonicotinamide (GIF-0348) (257 mg, 67.6%) was yielded as a colorless solid.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[Cl:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(Cl)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-chloropyridin-3-yl)boronic acid and to afford an off-white solid. UPLC-MS (condition 1) tR=2.51 min, m/z=493.0-495.0 [M+H]+, m/z=494.1-493.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.65 (m, 1H) 1.78-1.92 (m, 1H) 2.23 (ddd, J=13.63, 7.09, 6.91 Hz, 1H) 2.98 (dd, J=10.88, 6.97 Hz, 1H) 3.12-3.22 (m, 2H) 3.21-3.31 (m, 3H, in HDO) 4.62 (br. s, 1H) 7.35 (d, J=8.80 Hz, 2H) 7.61 (d, J=8.31 Hz, 1H) 7.85 (d, J=9.29 Hz, 2H) 7.89 (dd, J=8.31, 2.45 Hz, 1H) 8.03 (d, J=2.44 Hz, 1H) 8.49 (d, J=2.45 Hz, 1H) 8.77 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1.C(N1CCC(OC2C=CC=CN=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cccc(Cl)n1
Agent: CC(C)(C)OC(=O)N1CCC(Oc2ccccn2)CC1
Product: Cc1cccc(OC2CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Prepared from 1-Boc-4-hydroxypiperidine and 2-chloro-6-methylpyridine using methods substantially equivalent to those described for the synthesis of 1-Boc-4-(pyridin-2-yloxy)piperidine. The product was purified by chromatography over silica gel, eluting with a gradient of 0-15% ethyl acetate in hexanes.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[N:34][CH:35]=1>C(#N)CCC>[NH2:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[CH:35]=[N:34][C:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1cnc(N)cn1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCCC#N
Product: CCOC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc2cn1
Temperature: 120 °C

Procedure:
To a mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (245 mg, 0.44 mmol, 1.0 eq) and ethyl 5-aminopyrazine-2-carboxylate (CAS-Nr. 54013-06-8, 81.1 mg, 0.49 mmol, 1.1 eq.) in 2.7 mL butyronitrile was heated at 120° C. for 1.5 h. A substantial amount of the deprotected free amine was detected by UPLC analysis. For isolation, the volatile components were removed using a rotary evaporator and the resulting crude material was purified via MPLC [Biotage Isolera, 25 g Snap-cartridge; eluent: DCM→DCM/ethanol (95/5)] to deliver 38 mg (21%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.C(=O)([O-])[O-].[Na+].[Na+].CI>CN(C=O)C>[CH3:7][C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:11]
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Br)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Yield: 119 %

Procedure:
To stirred solution of 5-bromo-2-methyl-3-nitrobenzoic acid (287 g, 1103 mmol) in DMF (150 mL), sodium carbonate (468 g, 4415 mmol) and methyl iodide (626.63 g, 4415 mmol) were added. The resulting reaction mixture was heated at 60° C. for 8 h. On completion, a solid precipitated was filtered, residue washed with diethyl ether (5 times). The combined organic layers were dried, concentrated under reduced pressure giving desired compound (302 g, 99%) which was used as is in subsequent steps.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.Cl.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.O(C(C)(C)C)[Na].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:30][C:31]1([F:35])[CH2:34][N:33]([C:6]2[CH:5]=[CH:4][C:3]([N:9]3[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]4[N:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[N:21]=[CH:20][CH:19]=4)=[N:10]3)=[C:2]([F:1])[CH:7]=2)[CH2:32]1
Reactant: FC1(F)CNC1
Reactant: COc1cn(-c2ccc(I)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1cn(-c2ccc(N3CC(F)(F)C3)cc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A mixture of 1-(2-fluoro-4-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), 3,3-difluoroazetidine hydrochloride (77.7 mg, 0.6 mmol), NaO-t-Bu (125 mg, 1.3 mmol), Xantphos (46.3 mg, 0.08 mmol) and Pd2(dba)3 (18.3 mg, 0.02 mmol) in 1,4-dioxane (2.5 mL) was heated to 90° C. for 16 h under Ar. The mixture was diluted with NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (123 mg, 54% yield) as a pale yellow solid: mp 204-206° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 4.35 (4H, t, J=12.4 Hz), 6.36 (1H, dd, J=8.9, 2.4 Hz), 6.61 (1H, dd, J=12.8, 2.3 Hz), 6.87-6.99 (2H, m), 7.25-7.49 (5H, m), 7.78 (1H, d, J=1.9 Hz), 8.38 (1H, d, J=1.5 Hz). Anal. Calcd for C23H18F3N5O2: C, 60.93; H, 4.00; N, 15.45. Found: C, 61.00; H, 3.99; N, 15.50.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2ccc(F)cc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
1.20 g of 5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 10 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 1.22 g of 3-chloro-5-(4-chlorophenyl)-4-(2,4-difluorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xv) of the present invention).
Reaction SMILES: N1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)C=CN=N1.[O:55]1CC[CH:57](N)[CH2:56]1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:43][CH:41]([F:42])[C:30]1[C:31]2[C:32]([F:40])([F:39])[CH2:33][CH2:34][C:35]([F:37])([F:38])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:8][CH:7]3[CH2:57][CH2:56][O:55][CH2:6]3)[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NC1CCOC1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NC3CCOC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (25) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with tetrahydrofuran-3-amine and 23B. 1H NMR (400 MHz, CD3OD) δ 8.71 (d, J=7.6 Hz, 1H), 8.06 (s, 1H), 7.43-7.26 (m, 2H), 7.24-7.14 (m, 1H), 6.95-6.63 (m, 2H), 6.42 (d, J=5.9 Hz, 2H), 5.22 (m, 1H), 5.04 (s, 2H), 4.66 (m, 1H), 4.01 (m, 2H), 3.93-3.84 (m, 1H), 3.76 (m, 1H), 3.02 (m, 2H), 2.51 (m, 4H), 2.37 (m, 1H), 1.99 (m, 1H). MS (m/z) 742.15 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][CH:7]=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[OH:21][C:19]1[N:17]=[C:15]([OH:16])[C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=3)[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: NC(=O)c1nc(-c2cccc(F)c2)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Oc1nc(O)c2nc(-c3cccc(F)c3)ccc2n1
Temperature: 25 °C

Procedure:
A mixture of 3-amino-6-(3-fluorophenyl)-pyridine-2-carboxylic acid amide (0.46 g, 2.0 mmol) and triphosgene (0.30 g, 1.0 mmol) in dioxane (10 ml) was heated under reflux for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with diethyl ether. The title compound was obtained as a yellowish solid (410 mg, yield 80%) which was characterised as follows: MS (m/z): 258 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[C:14](=[O:16])=[O:15]>>[Br:8][C:4]1[N:3]=[C:2]([C:14]([OH:16])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C=O
Agent: [Li]CCCC
Product: O=C(O)c1cccc(Br)n1
Yield: 63.4 %

Procedure:
To a suspension of 2,6-dibromopyridine (59 g, 0.25 mol) in ET2O (600 mL) at -70° C. there was added slowly n-BuLi 2.12M in hexanes (118 mL, 0.25 mol); the resulting mixture was stirred in the cold until a solution was obtained (45 min.); this mixture was poured onto a slurry of crushed dry ice (200 g) in ET2O (500 mL). The resulting suspension was allowed to warm up, then it was extracted with H2O (500 mL, then 250 mL). The combined aqueous extracts were extracted with Et2O, then acidified with 12N HCl, affording a precipitate which was filtered. This beige solid was washed with H2O and dried to afford the title acid (32 g), m.p. 186°-189° C.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1(=O)[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1>>[CH:3]1[CH:4]=[CH:5][CH:6]=[C:1]2[NH:7][C:10]3[C:9](=[CH:14][C:13]4[NH:7][C:1]5[C:6]([C:12]=4[CH:11]=3)=[CH:5][CH:4]=[CH:3][CH:2]=5)[C:2]=12
Reactant: O=C1CCC(=O)CC1
Reactant: NNc1ccccc1
Product: c1ccc2c(c1)[nH]c1cc3c(cc12)[nH]c1ccccc13

Procedure:
5,11-Dihydridoindolo[3,2-b]carbazole was synthesized by double Fischer indolization starting from phenylhydrazine and 1,4-cyclohexanedione according to the method described in B. Robinson, J. Chem. Soc. 1963, 3097-3099.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([OH:14])=[O:13])([O-:8])=[O:7].O.[CH2:20](O)[CH3:21]>>[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[F:18])[C:12]([O:14][CH2:20][CH3:21])=[O:13])([O-:8])=[O:7]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 20 °C

Procedure:
2 ml of concentrated sulfuric acid were added to a solution of 10 g of 3-nitro-4-fluoro-benzoic acid in 50 ml of ethanol and the mixture was refluxed for three hours. 8 ml of concentrated sulfuric acid were added to the mixture which was refluxed for 16 hours and was cooled to 20° C. The mixture was poured into water with stirring and was filtered. The solid product was washed and dried to obtain 10.5 g of ethyl 3-nitro-4-fluoro-benzoate melting at 50° C. The said product was reacted as in Example 1 to obtain 0-(4-ethoxycarbonyl-2-nitro-phenyl)-hydroxylamine melting at 102° C.