Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[O:4].[CH:7]([C:10]1[CH:16]=[CH:15][C:13](N)=[CH:12][CH:11]=1)([CH3:9])[CH3:8].CNC>ClC1C=CC(Cl)=CC=1Cl>[CH:7]([C:10]1[CH:16]=[CH:15][C:13]([NH:5][C:3]([N:2]([CH3:6])[CH3:1])=[O:4])=[CH:12][CH:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CN(C)C(N)=O
Agent: CNC
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CC(C)c1ccc(NC(=O)N(C)C)cc1
Temperature: 205 °C
Reaction time: 5.5 h

Procedure:
3.35 g (0.038 mol) of N,N-dimethylurea and 3.38 g (0.025 mol) of 4-isopropylaniline were added with stirring into 20 ml of 1,2,4-trichlorobenzene. The reaction mixture was heated to 205° C., dimethylamine being introduced from 120° C. After 5.5 hours, 8.8 g (0.19 mol) of dimethylamine had been introduced and the reaction was complete.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.Cl.[NH2:12][OH:13].[OH-].[Na+].Cl>O.CCO>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[N:12][OH:13]
Reactant: NO
Reactant: O=Cc1c(F)cccc1I
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c(F)cccc1I
Temperature: 0 °C
Yield: 59.2 %

Procedure:
To a mixture of 2-iodo-6-fluorobenzaldehyde (45 mmol) in H2O (22.5 ml), EtOH (22.5 ml), and ice (20 g) was added hydroxylamine hydrochloride (3.19 g, 49.5 mmol, 1.1 eq.). Then, 112.5 mmol of 50% NaOH (4.5 g in 4.5 ml H2O, 2.5 eq.) was added with stirring. Enough ice to keep the temperature at 25-30° C. was added. The reaction was stirred for 2 h, acidified with conc. HCl to pH 4 (ice was added to keep the temperature at 25-30° C.), and extracted with Et2O. The combined organic solution was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel using ethyl acetate in hexanes (5%-10%) to give 2-iodo-6-fluorobenzaldehyde oxime (7.06 g, 59% over 2 steps) as an oil that solidified over time.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][CH3:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][CH3:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccccc1CCl
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccccc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(chloromethyl)-2-methoxybenzene and isolated as light-yellow gum (5.7 mg, 34%). MS(m/e): 403.4 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:12])[NH:6][C:7]([CH3:11])=[CH:8][C:9]=1[OH:10])(=[O:3])[CH3:2].[O:13]=[C:14]1[N:18]([C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH:22]=O)[CH2:17][CH2:16][O:15]1>>[OH:10][C:9]1[CH:8]=[C:7]([CH3:11])[NH:6][C:5](=[O:12])[C:4]=1[C:1](=[O:3])[CH:2]=[CH:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([N:18]2[CH2:17][CH2:16][O:15][C:14]2=[O:13])[CH:20]=1
Reactant: CC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: O=Cc1cccc(N2CCOC2=O)c1
Product: Cc1cc(O)c(C(=O)C=Cc2cccc(N3CCOC3=O)c2)c(=O)[nH]1
Yield: 41.2 %

Procedure:
According to the same manner as that of Example 16 except that 0.33 g of 3-acetyl-4-hydroxy-6-methyl-2(1H)-pyridinone was used in place of 3-acetyl-4-hydroxy-1,6-dimethyl-2(1H)-pyridinone, and 0.30 g of 3-(2-oxo-oxazolidin-3-yl)benzaldehyde was used in place of 3-(methoxycarbonyl)benzaldehyde, 0.22 g of 4-hydroxy-3-[3-[3-(2-oxo-oxazolidin-3-yl)phenyl]-1-oxo-2-propenyl]-6-methyl-2(1H)-pyridinone [Compound No. (3a-37)] was obtained as a yellow crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[CH3:39][O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:28])[CH:3]=2)=[CH:31][C:30]=1[F:29])=[O:37]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-fluoro-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e)=552.2 [M+H+].
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>CO>[C:1]1([CH2:7][N:8]2[CH2:9][CH:10]=[C:11]([CH2:14][OH:15])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1=CC(Cl)N(Cc2ccccc2)C=C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCC1=CCN(Cc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
1-(Phenylmethyl)-4-(hydroxymethyl)-pyridinyl chloride (0.87 mol) was dissolved in methanol (2200 ml) and cooled to −20° C. Sodium borohydride (1.75 mol) was added portionwise under a nitrogen atmosphere. The reaction mixture was stirred for 30 minutes and water (200 ml) was added dropwise. The reaction mixture was partially evaporated, water was added and the reaction mixture was extracted with DCM. The organic layer was separated, dried, filtered and evaporated. The residue was purified over silica gel (eluent: DCM), yielding 155 g of 1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[C:9]1(=O)[O:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]2[C:3]=1[CH:10]([CH3:9])[CH2:11][CH2:12][C:13]2=[O:14]
Reactant: O=C1CCCCO1
Reactant: Fc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC1CCC(=O)c2c(F)ccc(F)c21
Temperature: 110 °C
Reaction time: 16 h
Yield: 81.3 %

Procedure:
1,4-Difluorobenzene (22 ml, 210 mmol) was mixed with □-valerolactone (4 ml, 42 mmol) and AlCl3 (28 g, 210 mmol) was added by portions to the stirred reaction mixture. The reaction mixture was then refluxed at stirring for 16 h (oil bath 110° C.). The reaction mixture was cooled down (ice/brine bath) and ice/conc. HCl was added and stirred until homogeneous mixture was obtained. The reaction mixture was then extracted into methylene chloride, washed with water (4×10 ml) and sodium bicarbonate solution (3×100 ml). The organic extract was dried over Na2SO4. Concentration by rotary evaporation gave 6.7 g of product as yellow powder. Yield 81%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[O:4].[CH2:12](O)[CH2:13][OH:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:14]1[C:6]2([CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[C:3]([O:2][CH3:1])=[O:4])[O:11][CH2:12][CH2:13]1
Reactant: OCCO
Reactant: COC(=O)C1CCCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)C1CCCCC12OCCO2
Temperature: 25 °C

Procedure:
A mixture of methyl-2-oxocyclohexanecarboxylate (4-1) (7.0 g, 44.8 mmol), ethylene glycol (3.00 mL, 53.8 mmol) and p-toluenesulfonic acid monohydrate (0.853 g, 4.48 mmol) in Benzene (45 mL) was heated to reflux overnight. The reaction was then cooled to rt and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 3.86-3.99 (m, 4H), 3.69 (s, 3H), 2.69 (dd, 1H, J=4.9 Hz, 9.0 Hz), 1.82-1.97 (m, 3H), 1.58-1.73 (m, 3H), 1.45-1.53 (m, 1H), 1.26-1.37 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH2:8]1[CH2:18]CN2C(=NCCC2)[CH2:10][CH2:9]1.BrC(C(Br)C)C>CN(C=O)C>[C:1]([C:3]1([C:4]([O:6][CH3:7])=[O:5])[CH2:10][CH2:9][CH2:8][CH2:18]1)#[N:2]
Reactant: COC(=O)CC#N
Reactant: C1CCC2=NCCCN2CC1
Agent: CC(Br)C(C)Br
Solvent: CN(C)C=O
Product: COC(=O)C1(C#N)CCCC1
Temperature: -20 °C
Yield: 58 %

Procedure:
A solution of methyl 2-cyanoacetate (30 mL, 340 mmol) in DMF (26 mL) and DBU (112 mL, 748 mmol) was heated to 50° C. for 15 min and then cooled to −20° C. To this stirred solution was added dibromobutane 18. The internal temperature increased to 70° C. during the addition. The reaction was set aside to cool to rt before quenching with H2O (800 mL). The product was extracted with Et2O (3×300 mL). The ether layer was washed with 1N HCl (400 mL) and H2O (400 mL). The combined extracts were dried over magnesium sulfate, and concentrated to a crude oil that was distilled under high vacuum at 80° C. to yield the desired product in 58% yield.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:25])([CH3:24])[CH2:5][O:6][Si:7]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:27][C:28]([NH2:30])=[S:29].O>C(#N)C>[C:20]([Si:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:6][CH2:5][C:4]([C:3]1[N:27]=[C:28]([NH2:30])[S:29][CH:2]=1)([CH3:25])[CH3:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)CBr
Reactant: NC(N)=S
Solvent: O
Solvent: CC#N
Product: CC(C)(CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1csc(N)n1
Temperature: 25 °C
Yield: 6.1 %

Procedure:
A solution of 1-bromo-4-(tert-butyl-diphenyl-silanyloxy)-3,3-dimethyl-butan-2-one (40 g, 92.3 mmol) and thiourea (8.4 g, 110.5 mmol) in 400.0 mL of acetonitrile is heated under reflux for 4 h. After cooling the reaction mixture to room temperature, water is added and the aqueous layer is extracted with ethyl acetate; the organic layer is dried over anhydrous Na2SO4, filtered and the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 2.3 g of 4-[2-(tert-Butyl-diphenyl-silanyloxy)-1,1-dimethyl-ethyl]-thiazol-2-ylamine as a light brown solid. Yield: 4%, over two steps; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (9H, s), 1.25 (6H, s), 3.62 (2H, s), 5.60 (2H, s), 6.15 (1H, s), 7.25-7.40 (6H, m), 7.50-7.60 (4H, m); m/z 411 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH:24]([CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(Cc3ccccc3)C2)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CN2CCC(Nc3ccccc3)C2)cc1
Temperature: 160 °C
Yield: 47.8 %

Procedure:
1-Benzyl-3-(p-toluenesulfonyloxy)pyrrolidine (3.3 g) and aniline (1.3 g) were mixed and stirred under heating at 160° C. for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature, and an aqueous potassium carbonate solution was added thereto. The obtained mixture was extracted with chloroform, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:methanol=40:1). The obtained eluate was concentrated to give 3-anilino-1-benzylpyrrolidine (1.2 g).
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH2:8][C:5]([CH3:10])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.Br[CH2:12][C:13]([N:15]1[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]1[C:21]#[N:22])=[O:14]>>[CH3:10][C:5]12[CH2:8][CH2:9][C:2]([NH:1][CH2:12][C:13]([N:15]3[CH2:19][C@@H:18]([F:20])[CH2:17][C@H:16]3[C:21]#[N:22])=[O:14])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: CC12CCC(N)(CC1)CC2
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CBr
Product: CC12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 75.6 %

Procedure:
Using 4-amino-1-methylbicyclo[2,2,2]octane (56.0 mg) and (2S,4S)-1-(2-bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile (95.0 mg), the same procedure was followed as in Example 1 to obtain (2S,4S)-1-[[N-(4-methylbicyclo[2,2,2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (89.2 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=2)=[CH:16][CH:15]=1.O>CN(C=O)C>[N:1]1([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:24]=[C:23]([C:25]([NH2:27])=[O:26])[O:22][N:21]=3)=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(Cn3ccc4ccccc43)cc2)no1
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
To a mixture of indole (13 mg, 0.11 mmol) in DMF (1 mL) was added NaH (60% dispersion; 5 mg, 0.125 mmol). The mixture was stirred for 20 min and then a solution of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature overnight. H2O was added and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were washed three times with H2O/brine, dried (Na2SO4), evaporated, and purified by chromatography (10-25% acetone/CH2Cl2) to give 3-(4-indol-1-ylmethyl-phenyl)-isoxazole-5-carboxylic acid amide (6 mg, 18%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (br. s., 1H), 7.97 (br. s., 1H), 7.82 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.43 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 6.94-7.14 (m, 2H), 6.49 (d, J=3.0 Hz, 1H), 5.49 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:15][C:16]1[N:24]([C:25]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)=[O:26])[C:23]2[CH:22]=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:18]=2[C:17]=1[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C>CC#N.CCOC(C)=O>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:24]2[C:23]3[C:18](=[CH:19][C:20]([O:34][CH3:35])=[CH:21][CH:22]=3)[C:17]([CH2:36][C:37]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:38])=[C:16]2[CH3:15])=[O:26])=[CH:32][CH:31]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCOCCN
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)c(CC(=O)NCCOCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (150 mg, 0.735 mmol) was then taken up in CH3CN (10 mL) along with indomethacin (263 mg, 0.735 mmol) and EDCI (155 mg, 0.81 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (9:1 CH2Cl2/MeOH) to afford 310 mg of tert-butyl 2-(2-(2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)acetamido)ethoxy)ethylcarbamate (78%).
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Mg]Br)C.[F:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[CH:22][CH:23]=[N:24]2)=[CH:19][C:18]=1[CH:27]=[O:28]>C1COCC1>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH:27]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][C:17]=3[F:16])[N:24]=[CH:23][CH:22]=[CH:21]4)[OH:28])=[CH:3][N:4]=2)[N:7]=1
Reactant: O=Cc1cc2cccnc2cc1F
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Product: OC(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3-Bromo-6-chloro-imidazo[1,2-b]pyridazine (1.327 g, 5.71 mmol) was dissolved THF (40 mL) and under nitrogen conditions, it was cooled down to 0° C. and ethylmagnesium bromide solution (1 M, 6.85 mL) was added. The RM was stirred at rt for 30 min then a solution of 7-fluoro-quinoline-6-carbaldehyde (Intermediate B), (1.0 g, 5.71 mmol) in THF (20 mL) was added by 0° C. The RM was stirred at rt for 2 h. The solvent was partially removed by evaporation and water (40 mL) was added to the residual mash. After 1 h stirring, the crystallized product was filtered and dried overnight under vacuum to afford the title compound as a powder (tR 3.70 min (conditions 3), MH+=329, 1H-NMR in DMSO-d6: 8.90 (dd, 1H); 8.46 (d, 1H); 8.29-8.23 (m, 2H); 7.72 (d, 1H); 7.54-7.49 (m, 2H); 7.40 (d, 1H); 6.56-6.49 (m, 2H)).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH2:24])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(CC)CC.[N:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[C:33]=[O:34]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[NH:24][C:33]([NH:32][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:34])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C=Nc1ccccc1
Reactant: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
To a round bottom flask was added (1R,2R)—N1-(1-(4-nitrophenyl)azepan-4-yl)cyclohexane-1,2-diamine (70 mg, 0.211 mmol), THF (3 mL), and Et3N (0.029 mL, 0.211 mmol). To the resulting solution was added isocyanatobenzene (25.08 mg, 0.211 mmol). The reaction was stirred at rt overnight. After this time, the reaction mixture was concentrated. The resulting crude product was purified by RP prep-HPLC to give a mixture of 2 diastereomers. The mixture of two diastereomers was separated by chiral HPLC (chiral separation method A) to give the desired product, 1-((1R,2R)-2-((S)-1-(4-nitrophenyl)azepan-4-ylamino)cyclohexyl)-3-phenylurea (7 mg, 0.019 mmol, 6.7% yield) as a yellow solid. Anal. Calcd. for C25H33N5O3 m/z 451.5, found: 452.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.10 (d, J=9.35 Hz, 2H), 7.30-7.27 (m, 2H), 7.22 (t, J=7.70 Hz, 2H), 6.99 (t, J=7.15 Hz, 1H), 6.60 (d, J=9.35 Hz, 2H), 4.57 (br. s., 1H), 3.66-3.53 (m, 2H), 3.53-3.45 (m, 1H), 3.44-3.35 (m, 1H), 3.21 (d, J=4.95 Hz, 1H), 2.85-2.73 (m, 1H), 2.24 (td, J=10.31, 3.57 Hz, 1H), 2.09 (d, J=9.35 Hz, 2H), 1.97 (d, J=12.10 Hz, 1H), 1.90 (d, J=11.55 Hz, 2H), 1.73 (d, J=9.90 Hz, 2H), 1.69-1.61 (m, 2H), 1.44-1.34 (m, 2H), 1.23-1.07 (m, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 157.11, 153.29, 139.21, 136.84, 129.12, 126.49, 123.13, 120.06, 110.01, 60.75, 56.99, 56.15, 49.50, 45.82, 34.95, 33.49, 33.29, 32.63, 25.06, 24.85, 23.76.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:24]3[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[I-].[CH3:32][S+](C)C.CC(C)([O-])C.[K+]>O1CCCC1.CS(C)=O>[O:30]1[C:27]2([CH2:26][CH2:25][CH:24]([N:8]3[C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:15][CH:16]=4)=[CH:9]3)[CH2:29][CH2:28]2)[CH2:32]1
Reactant: C[S+](C)C
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC(=O)CC1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCC2(CC1)CO2
Temperature: -5 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixture of 4-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-cyclohexanone (2 g, 5 mmol) in tetrahydrofuran (17.5 mL) were added trimethyl-sulfonium iodide (1.53 g, 7.5 mmol) in dimethyl sulfoxide (25 mL) and potassium-t-butoxide (7.5 mL, 7.5 mmol, 1 M in tetrahydrofuran) under an atmosphere of nitrogen at −5° C. The mixture was stirred at −5° C. for 1 hour. The mixture was poured into ice water (50 mL). The water phase was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with saturated ammonium chloride solution (2×30 mL), water (1×30 mL), and brine (2×30 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (1.9 g, 4.6 mmol, 2:1-mixture of trans and cis). The mixture was suspended in dichloromethane (3 mL). The solid was filtered and was washed with dichloromethane (1 mL) to yield 7-(1-oxaspiro[2.5]oct-6-yl)-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.994 g, 2.4 mmol, 4:1-mixture of trans and cis).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>CN(C)C=O.N1C=CC=CC=1>[Cl:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:17][C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Reactant: O=C(Cl)CCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CCCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCCl)cccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
Dissolve 1,8-diaminoanthraquinone (0.476 g, 2 mmol) in N,N-dimethylformamide (20 ml). Add pyridine (0.5 ml) as catalyst in an ice bath and then add 3-chloropropioyl chloride (0.6 ml, 6 mmol). Remove the ice bath, introduce nitrogen, protect from light, and stir the solution at room temperature for one day. The reacted mixture is poured into ice water and filtered to get precipitate. The precipitate is recrystallized from ethanol to obtain orange compound 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Si](C)(C)C)=[CH:18][C:17]=1[F:26])=[O:5])[CH3:2].[I:27]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:27])=[CH:18][C:17]=1[F:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a cooled (−10° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (140 mg, 0.343 mmol) in DCM (5 mL) was added iodine monochloride (1M in DCM, 0.90 mL) dropwise over 10 minutes. On complete addition the mixture was allowed to stir at ambient temperature for 20 minutes then quenched by the addition of saturated sodium thiosulphate solution (3 mL). The solution was partitioned between DCM (50 mL) and water (10 mL). The organic layer was separated, dried (Na2SO4), filtered and evaporated to give a yellow solid. The solid was triturated with diethyl ether, filtered and left to air dry to provide the title compound as a yellow solid (148 mg, 85%). LCMS (method B): RT=2.37 min, M+H+=426.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](CCC(O)=O)=[CH:16][CH:15]=3)[C:11]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.[Br:38]C1C=CC=CC=1C1NC2C=C(F)C(F)=CC=2N=1.BrCC1CCCCC1>>[Br:38][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]2[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:10]=2[N:9]=1
Reactant: O=C(O)CCc1ccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)cc1
Reactant: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F
Agent: BrCC1CCCCC1
Product: Fc1cc2nc(-c3ccccc3Br)n(CC3CCCCC3)c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate b, from 2-(2-bromo-phenyl)-5,6-difluoro-1H-benzoimidazole and bromomethyl-cyclohexane (2550-36-9). Yellow sticky solid (94%). MS (Turbo Spray): m/z=406.1 (M+H).