Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([N:8]([CH:9]2[CH2:10][CH2:11]2)[S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(c2ccc(Cl)cc2[N+](=O)[O-])C2CC2)cc1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
To a suspension of sodium hydride (60%, 0.10 g (2.50 mmol)) in DMF (3.0 ml), 4-chloro-N-cyclopropyl-2-nitroaniline (0.40 g (1.88 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, p-toluenesulfonyl chloride (0.38 g (1.99 mmol)) was added. After one hour's stirring at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.42 g (61%) of the title compound as yellow crystals
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ncc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Yield: 78.3 %

Procedure:
Add, at 0° C., 1 g of 5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde, then 0.27 g of sodium hydride to 10 cm3 of anhydrous tetrahydrofuran. Stir the reaction mixture for fifteen minutes at 0° C. before adding 1.87 g of tosyl chloride in solution in 1.7 cm3 of tetrahydrofuran. Continue stirring the reaction mixture for two hours, allowing it to return to room temperature. Pour the reaction mixture into 100 cm3 of iced water. Extract the mixture obtained with two times 100 cm3 of ethyl acetate. Dry the organic phases over magnesium sulphate and then evaporate to dryness under vacuum in a rotary evaporator. 1.32 g of 5-bromo-1-[(4-methylphenyl)sulphonyl]-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde is obtained in the form of a beige powder with the following physical characteristics:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16](C(OC(C)(C)C)=O)[CH2:17][C@@H:18]([NH:31]C(=O)OC(C)(C)C)[C@H:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[CH3:20])=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.FC1C=C(C2SC(NC(=O)[O:63][C:64](C)(C)[CH3:65])=NN=2)C=CC=1[N+]([O-])=O.[F:69][C:70]([F:92])([F:91])[C:71]1[CH:76]=[CH:75][C:74]([C@@H:77]([C@H:79]2[CH2:83][O:82][S:81][N:80]2[C:84]([O:86][C:87]([CH3:90])([CH3:89])[CH3:88])=[O:85])[CH3:78])=[CH:73][CH:72]=1>>[NH2:31][C@@H:18]([C@H:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[CH3:20])[CH2:17][NH:16][C:14]1[S:15][C:11]([C:4]2[CH:3]=[C:2]3[C:7](=[CH:6][CH:5]=2)[NH:8][C:64](=[O:63])[CH2:65]3)=[N:12][N:13]=1.[F:92][C:70]([F:69])([F:91])[C:71]1[CH:76]=[CH:75][C:74]([C@@H:77]([C@H:79]2[CH2:83][O:82][S:81][N:80]2[C:84]([O:86][C:87]([CH3:89])([CH3:88])[CH3:90])=[O:85])[CH3:78])=[CH:73][CH:72]=1
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1nnc(-c2ccc([N+](=O)[O-])c(F)c2)s1
Agent: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H]1COSN1C(=O)OC(C)(C)C
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](N)CNc1nnc(-c2ccc3c(c2)CC(=O)N3)s1

Procedure:
LCMS (API-ES) m/z (%): 448.1 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.41 (d, J=7.03 Hz, 3H) 2.93-3.02 (m, 1H) 3.26-3.31 (m, 4H) 3.58-3.69 (m, 1H) 6.97 (d, J=8.53 Hz, 1H) 7.51 (d, J=8.03 Hz, 2H) 7.64 (t, J=7.28 Hz, 3H) 7.70 (s, 1H). The title compound was synthesized in a similar manner as Example 2 starting with tert-butyl (2S,3S)-1-(5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-Boc-amino)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate, which was synthesized in a similar manner to described for Example 1 using tert-butyl 5-(3-fluoro-4-nitrophenyl)-1,3,4-thiadiazol-2-ylcarbamate to react with (S)-tert-butyl 4-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3-oxathiazolidine-3-carboxylate, 2,2-dioxide. (S)-tert-Butyl 4-((S)-1-(4-(trifluoromethyl)phenyl)ethyl)-1,2,3-oxathiazolidine-3-carboxylate, 2,2-dioxide was synthesized as shown in Scheme 4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[C:5]([C:17]#[N:18])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[C:5]([C:17]#[N:18])=[C:4]([C:19]2[O:20][C:21]([Br:24])=[CH:22][CH:23]=2)[N:3]=1
Reactant: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccco1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccc(Br)o1

Procedure:
From 2-amino-4-(2-bromo-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 451 (M{81Br}+H+, 100), 449 (M{79Br}+H+, 95).
Reaction SMILES: Br[CH:2]1[CH2:5][C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:3]1.[I:10][C:11]1[CH:12]=[N:13][NH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:3]1[C:4]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:5][CH:2]1[N:13]1[CH:12]=[C:11]([I:10])[CH:15]=[N:14]1
Reactant: Ic1cn[nH]c1
Reactant: BrC1CC2(C1)OCCO2
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Ic1cnn(C2CC3(C2)OCCO3)c1
Temperature: 87.5 °C
Reaction time: 48 h
Yield: 28.7 %

Procedure:
To a solution of 2-bromo-5,8-dioxa-spiro[3.4]octane (Compound 100F, 19 g, 100 mmol) and 4-iodopyrazole (38.6 g, 200 mmol) in DMF (100 mL) was added powdered K2CO3 (41.4 g, 300 mmol) and 18-crown-6 ether (5.3 g, 20 mmol). The reaction mixture was stirred at 85-90° C. for 2 days. The reaction mixture was diluted with ethyl acetate (400 mL) and washed with water (4×100 mL). The combined organic layers were washed with brine and concentrated, the residue was purified by column chromatography (ethyl acetate/DCM: 5:95) to give 8.8 g (29%) of 1-(5,8-dioxa-spiro[3.4]oct-2-yl)-4-iodo-1H-pyrazole. 1H NMR (CDCl3, 300 MHz): δ=2.87-2.89 (m, 4H), 3.92-3.96 (m, 4H), 4.64-4.68 (m, 1H), 7.53 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:18]=[C:19]=S)[CH2:17][CH2:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[CH:13]1([NH:18][C:19]2[NH:1][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[S:9](=[O:11])(=[O:10])[N:12]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: S=C=NC1CCCC1
Reactant: Nc1cc(F)ccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Product: O=S1(=O)N=C(NC2CCCC2)Nc2cc(F)ccc21
Temperature: 140 °C
Yield: 23.2 %

Procedure:
A mixture of 2-amino-4-fluorobenzenesulfonamide (1.71 g, 9 mmol) and cyclopentyl isothiocyanate (4.6 ml, 36 mmol) was heated at 140° C. for 4 h. The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate. The precipitate was isolated by filtration and recrystallised from ethanol to give 591 mg (23%) of the title compound; m.p. 295-298° C.; 1H-NMR (DMSO-d6): δ 1.37-2.02 (m, 8H, cyclopentyl), 4.05 (sext, 1H, CH), 6.97-715 (m, 2H, ArH), 7.32 (br.s, 1H, NH), 7.72 (dd, 1H, ArH), 10.35 (br.s, 1H, NH; MS: m/e 283 (M+, 21%); (C12H14N3F1O2S1) calc. C, 50.87; H, 4.98; N, 14.83; found C, 50.75; H, 5.12; N, 14.93.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO>C1COCC1>[OH:16][CH2:15][C@@H:14]1[CH2:13][CH2:12][CH:11]2[CH:9]([CH2:10]2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1C2CC2CC[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C2CC2CC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of D6 (8 g, 45.6 mmol) in THF (250 mL) cooled at 0° C., BH3 1M in THF (66 mL, 66 mmol) was added and the mixture was stirred at room temperature for 2 hours. Methanol was added, the solution was concentrated in vacuum and co-evaporated twice from methanol to give the title compound as 1/1 diasteroisomeric mixture. Yield (7.6 g, 100%)
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[NH2:6].Cl[CH2:8][C:9]1[C:10]([CH3:15])=[N:11][O:12][C:13]=1[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH3:15][C:10]1[C:9]([CH2:8][N:2]2[N:3]=[N:4][C:5]([NH2:6])=[N:1]2)=[C:13]([CH3:14])[O:12][N:11]=1
Reactant: Nc1nn[nH]n1
Reactant: Cc1noc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(C)c1Cn1nnc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
2H-tetrazol-5-amine (1.29 g, 12.5 mmol), 4-(chloromethyl)-3,5-dimethylisoxazole (1.56 mL, 12.5 mmol) and potassium carbonate (1.73 g, 15.5 mmol) in DMF (20 mL) were heated to 80° C. with stirring for 16 hours. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL) and washed consecutively with brine and water. The organics were dried over sodium sulfate and concentrated with rotary evaporation. The crude product was purified by silica gel chromatography (0-10% gradient ethyl acetate/dichloromethane) affording 2-((3,5-dimethylisoxazol-4-yl)methyl)-2H-tetrazol-5-amine as a white crystalline solid (970 mg, 40% yield) MS M+H calculated 195.1, found 195.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH:13]([CH3:15])[CH3:14])[N:7]=1)=O)C.[BH4-].[Na+].O>CO>[CH:13]([S:12][C:8]1[N:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][N:9]=1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1ccnc(SC(C)C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Sc1nccc(CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
After 2-isopropylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester (0.1 g, 0.44 mmol) obtained in Step B was dissolved in MeOH (4 mL), NaBH4(0.033 g, 0.9 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The separated organic layer was dried with MgSO4 and separated by column chromatography to obtain the title compound (0.063 g, 77%).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1)([OH:10])=[O:9].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH:1]1([NH:7][C:19]([CH2:18][C:14]2[CH:13]=[C:12]([CH2:11][C:8]([OH:10])=[O:9])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(O)Cc1cccc(CC(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)Cc1cccc(CC(=O)NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44.2 %

Procedure:
Cyclohexylamine (510 mg), (3-carboxymethyl-phenyl)-acetic acid (1.0 g), 1-hydroxybenzotriazole (700 mg) and Hunigs base (0.9 mL) were added to a round bottomed flask and dissolved in dichloromethane (40 mL) at room temperature. The mixture was stirred at room temperature for 5 minutes then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (990 mg) was added. The reaction was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (40 mL) and washed with 2M hydrochloric acid (2×40 mL). The organic layer was isolated and extracted with 2M sodium hydroxide (2×40 mL). The basic extract was isolated, acidified with 2M hydrochloric acid and extracted with dichloromethane (2×40 mL). The dichloromethane extracts were combined, dried over anhydrous sodium sulphate, filtered and concentrated to give 626 mg of the sub-titled product as a white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>CN(C=O)C.O>[C:25]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:16][C:14]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([F:7])[CH:15]=2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc(O)cc1F
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)cc1F
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Potassium tert-butoxide (0.217 g, 1.93 mmol) was added to a solution of 2-fluoro-4-hydroxy-benzaldehyde (0.246 g, 1.76 mmol) in anhydrous DMF (5 mL) at 0° C., and the mixture was stirred for 30 min. 4-(3-Bromo-propoxy)-biphenyl (0.564 g, 1.93 mmol, Example 132, Step D) was added, and the mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with EtOAc (5×15 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 4:1) to give 4-[3-(biphenyl-4-yloxy)-propoxy]-2-fluoro-benzaldehyde as a white solid (540 mg, 88%). 1H NMR (200 MHz, CDCl3): δ 10.19 (s, 1H), 7.80 (t, 1H, J=8.4); 7.55–7.48 (m, 4H); 7.42–7.27 (m, 3H); 6.99–6.93 (m, 2H); 6.78 (dd, 1H, J=8.8, 2.6); 6.64 (dd, 1H, J=12.4, 2.2); 4.27–4.15 (m, 4H); 2.30 (qn, 2H, J=5.9)ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([Cl:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>C(Cl)Cl.CO>[Cl:38][C:32]1[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=[C:30]([NH:29][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=2)[CH:31]=1
Reactant: Cn1cc(N)cc(Cl)c1=O
Reactant: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 1.4 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(4-methoxybenzyl)-1H-pyrazole-3-carboxylate (Step 9.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.91 min (HPLC 1); tR: 1.08 min (LC-MS 2); ESI-MS: 541/543 [M+H]+ (LC-MS 2); Rf=0.32 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([Cl:24])[CH:26]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Nc1cccc(Cl)c1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cccc(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 using 2-bromo-5-[(4-chloro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-imidazole-4-carboxylic acid ethyl ester (intermediate B) and 3-chloro-aniline as starting materials. tR: 1.45 min (LC-MS 2); ESI-MS: 510.1/512.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (373 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (120 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (806 mg) in DMF (20 ml) was added and the mixture was further stirred at room temperature for 13 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=99:1) to provide the title compound as white powder (615 mg, yield 68%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:25]=1)[N:7]=[C:8]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11]2.[C:26]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)#[N:27].[F-].[Cs+].O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([O:20][C:18]([NH:17][C:8]1[CH2:9][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([C:26]#[N:27])[CH:33]=3)=[CH:25][C:6]=2[N:7]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2ccc(-c3cccc(C#N)c3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A mixture of (1E,4E)-ethyl 8-bromo-2-(tert-butoxycarbonylamino)-3H-benzo[b]azepine-4-carboxylate (2.05 g, 5 mmol), 3-cyanophenylboronic acid (1.47 g, 10 mmol), CsF (2.28 g, 15 mmol), and Pd(PPh3)4 (0.345 g, 0.3 mmol) in anhydrous THF (100 mL) was refluxed for 12 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude material that was purified by silica gel flash column chromatography to afford 1.12 g (52%) of (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(3-cyanophenyl)-3H-benzo[b]azepine-4-carboxylate.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=[O:4].[CH2:26]=O>C(O)(=O)C>[F:25][C:2]([F:1])([C:21]([F:23])([F:24])[F:22])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:11][C:12]2[N:17]3[C:18](=[CH:19][N:20]=[C:16]3[CH:15]=[CH:14][CH:13]=2)[CH2:26]1)=[O:4]
Reactant: C=O
Reactant: O=C(NCCCCNCc1cccc2nccn12)C(F)(F)C(F)(F)F
Solvent: CC(=O)O
Product: O=C(NCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)C(F)(F)F
Temperature: 100 °C

Procedure:
To a solution of 2620 mg (7.19 mmol) of 5-[N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 10 ml of acetic acid was added 8.1 ml (107.88 mmol) of a 37% aqueous solution of formalin. The mixture was heated for 30 minutes at 100° C. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 ml of purified water. To this solution was added 2N sodium hydroxide to adjust the pH to 8, and extracted with 100 ml of dichloromethane. The organic layer was washed with 100 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography to afford 2250 mg of the desired compound (83.2%, a pale yellow liquid).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][CH:14]=[C:13]([Mg]Cl)[CH:12]=1>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH3:19])[CH:12]=1)[CH3:9]
Reactant: Cc1cccc([Mg]Cl)c1
Reactant: CC(=O)c1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1cccc(C(C)(O)c2cccc(O)c2)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of m-tolylmagnesium chloride in tetrahydrofuran (4.4 ml) as starting materials, the title compound (329.0 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:25]([SH:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([S:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1SCc1ccccc1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
A solution of the product of Example 2A (7.72 g, 31.26 mmol), sodium carbonate (3.31 g, 31.26 mmol) and benzyl mercaptan (3.90 mL, 30.21 mmol) in absolute ethanol (50 mL) was stirred at reflux for 6 hours, cooled to 25° C. and added to water (200 mL). The precipitate was collected by filtration, washed with water and dried to give the title compound (10.71 g, 98%). 1H NMR (300 MHz, CDCl3): δ 8.26 (d, J=9.19 Hz, 1 H), 7.36 (m, 10 H), 6.91 (d, J=2.57 Hz, 1 H), 6.78 (dd, J=9.19, 2.57 Hz, 1 H), 5.06 (s, 2 H), 4.12 (s, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][C:3]=1[C:16]1[NH:17][C:18]2[CH:24]=[C:23]([C:25](O)=[O:26])[CH:22]=[CH:21][C:19]=2[N:20]=1.Cl.Cl.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)[CH:35]=[CH:34][C:33]=1[NH2:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([N:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)[CH:35]=[CH:34][C:33]=1[NH:45][C:25]([C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([C:3]3[CH:4]=[C:5]([C:8]4[C:9]([O:14][CH3:15])=[N:10][CH:11]=[CH:12][CH:13]=4)[CH:6]=[CH:7][C:2]=3[OH:1])[NH:17][C:18]=2[CH:24]=1)=[O:26]
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.8 %

Procedure:
To a solution of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid (containing 1 equivalent of DMA, 44 mg, 0.1 mmol), 2-methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine di HCl salt (29.4 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (1.2 mL) was added DIEA (45 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 2 h and heated at 60° C. for 3 h, and then evaporated under reduced pressure. The residue was diluted with DMSO (1.5 mL), filtered and then purified with using HPLC (TFA/H2O/CH3CN) to afford the title compound (26.4 mg, 39%). ESI-MS m/z 565.5 (MH+).