Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=[O:20].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH2:24]([O:23][C:17](=[O:22])[C:18]([C:19](=[O:20])[CH3:21])=[CH:10][C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:8]=1)[CH3:25]
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(OC)c(OC2CCCC2)c1)C(C)=O

Procedure:
A mixture of 3-Cyclopentyloxy-4-methoxybenzaldehyde (7 g, 31.8 mmol), ethyl acetoacetate (4.13 g, 31.8 mmol), piperidine (275 mg, 3.18 mmol) and glacial acetic acid (100 mg) in toluene (350 ml) was heated at reflux with a Dean-Stark trap for 2 days, during which time, at regular intervals, further additions of piperidine (4×275 mg) and glacial acetic acid (4×100 mg) were made. The reaction mixture was then diluted with water and extracted with methylene chloride (3×150 ml), dried over Na2SO4 and the volatiles removed in vacuo. Flash chromatography (SiO2 ; EtOAc:hexane (1:9)) affordedethyl-3-(3-cyclopentyloxy-4-methoxyphenyl)-2-acetyl-prop-2-enoate (2 g, 19%) as a yellow oil.
Reaction SMILES: BrC1N=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=CC=1.COC1C=CC(CN2C(=O)C(C)NC2=O)=CC=1.COC1C=CC(C[N:49]2[C:53](=[O:54])[CH:52]([CH3:55])[N:51]([C:56]3[CH:61]=[CH:60][C:59]([C:62]([N:64]4[CH2:69][CH2:68][N:67]([C:70]5[C:75]([CH3:76])=[CH:74][C:73]([CH3:77])=[C:72]([CH3:78])[N:71]=5)[CH2:66][CH2:65]4)=[O:63])=[CH:58][N:57]=3)[C:50]2=[O:79])=CC=1>>[CH3:55][CH:52]1[N:51]([C:56]2[CH:61]=[CH:60][C:59]([C:62]([N:64]3[CH2:69][CH2:68][N:67]([C:70]4[C:75]([CH3:76])=[CH:74][C:73]([CH3:77])=[C:72]([CH3:78])[N:71]=4)[CH2:66][CH2:65]3)=[O:63])=[CH:58][N:57]=2)[C:50](=[O:79])[NH:49][C:53]1=[O:54]
Reactant: COc1ccc(CN2C(=O)C(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)cn3)C2=O)cc1
Agent: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NC(=O)C4C)nc3)CC2)nc1C

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (311 mg) described in Preparation Example 205 and 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione (187 mg) described in Preparation Example 51 and by the reaction and treatment in the same manner as in Example 508, the title compound (110 mg) was obtained via 3-(4-methoxybenzyl)-5-methyl-1-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}imidazolidine-2,4-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH:14]=1)([O-:3])=[O:2].Cl.[CH2:21]([NH2:23])[CH3:22].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.[OH-].[Na+]>[CH2:21]([NH:23][CH:16]1[CH2:17][CH2:18][C:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[CH:14][CH2:15]1)[CH3:22]
Reactant: O=C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCNC1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 14 h
Yield: 97 %

Procedure:
A solution of compound 79 (1.0 g, 3.902 mmol) in dry 1,2-dichloroethane (10 mL) was treated with ethylamine hydrochloride (0.31 g, 3.902 mmol), glacial acetic acid (0.22 mL, 3.902 mmol) and NaBH(OAc)3 (1.24 g, 5.853 mmol) at room temperature and the resulting mixture was stirred for overnight (14 h). The reaction was diluted with 1 N NaOH (30 mL) and product was extracted into ethyl acetate (2 50 mL). The combined ethyl acetate layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 117 (1.08 g, 97%) as a dark yellow solid. mp 177-179° C.; 1H NMR (DMSO-d6) δ: 1.03 (t, 3H, J=6.9 Hz), 1.39-1.52 (m, 2H), 1.94-2.00 (m, 2H), 2.40-2.80 (m, 3H), 3.16 (s, 2H), 4.07 (brs, 1H), 6.13 (s, 1H), 7.54 (d, 1H, J=9.0 Hz), 7.62 (s, 1H), 8.00 (dd, 1H, J=2.4, 9.0 Hz), 8.67 (d, 1H, J=2.4 Hz), 11.83 (brs, 1H); ESI-MS m/z (%): 286 (MH+, 100).
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]([CH3:33])=[CH:24][C:25]([O:31][CH3:32])=[C:26]([CH:30]=1)[C:27](O)=[O:28].Cl.[N:35]1[CH:40]=[CH:39][C:38]([C:41]2([NH2:44])[CH2:43][CH2:42]2)=[N:37][CH:36]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[C:7]2[C:8]([C:18]([NH:19][CH3:20])=[O:21])=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:30]=[C:26]([C:27](=[O:28])[NH:44][C:41]2([C:38]3[CH:39]=[CH:40][N:35]=[CH:36][N:37]=3)[CH2:43][CH2:42]2)[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[CH3:33]
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)c(F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.185 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF and at 0° C. was added TEA (0.094 g, 0.930 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was warmed to RT, and stirring was continued at RT overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by prep HPLC. Yield: 0.058 g (58.0%). 1H NMR (400 MHz, CD3OD): δ 9.03 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 7.97-7.79 (m., 2H), 7.76 (s, 1H), 7.65 (d, J=5.6 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.31-7.25 (m, 3H), 7.19 (s, 1H), 4.09 (s, 3H), 2.95 (s, 3H), 2.30 (s, 3H), 1.88-1.85 (m, 2H), 1.55-1.52 (m, 2H). 19F NMR (376.57 MHz, CD3OD): δ−77.58 (TFA), −112.32, −122.76. LCMS: (ES+) m/z=569.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13]OCC)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:24]1([NH2:27])[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([C:17]([CH3:22])=[C:18]([F:21])[C:19]=1[F:20])[C:5]([C:7](=[CH:13][NH:27][CH:24]1[CH2:26][CH2:25]1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Reactant: NC1CC1
Product: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Yield: 110.4 %

Procedure:
Employing ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-ethoxyacrylate (360 mg) and cyclopropylamine (60 mg), the procedure of Reference Example 21 is repeated to give ethyl 2-(3-chloro-2,4,5-trifluoro-6-methylbenzoyl)-3-cyclopropylaminoacrylate (410 mg), as brown oil.
Reaction SMILES: C(O[N:5]=[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH2:7][CH3:8])(=O)C.Cl>N1C=CC=CC=1>[CH2:7]([C:6]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][N:5]=1)[CH3:8]
Reactant: CCC(=NOC(C)=O)c1ccccc1O
Agent: Cl
Solvent: c1ccncc1
Product: CCc1noc2ccccc12
Temperature: 0 °C

Procedure:
A mixture of 12.2 g of 1-(2-hydroxyphenyl)-1-propanone-O-acetyloxime and 120 ml of pyridine is refluxed for 3 h. After cooling, the reaction mixture is poured on to a mixture of ice/water and acidified with c. 130 ml of concentrated hydrochloric acid. After extraction with ethyl acetate, the organic phase is washed three times with water and once with a saturated solution of sodium chloride, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3) to give 3-ethyl-1,2-benzisoxazole having a refractive index nD20 of 1.5403.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:20]1
Reactant: Cc1cccc(C(=O)Cl)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(C)c3)C2)c1

Procedure:
The compound of Example 8 was prepared according to the general preparation protocol A from 3-methylbenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([SH:15])=[C:11]2[C:7]=1[CH2:8][CH2:9][CH2:10]2.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:15][C:12]3[CH:13]=[CH:14][C:6]([O:5][CH2:4][C:3]([OH:2])=[O:16])=[C:7]4[C:11]=3[CH2:10][CH2:9][CH2:8]4)=[CH:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: FC(F)(F)c1ccc(-c2ccc(CCBr)cc2)cc1
Product: O=C(O)COc1ccc(SCCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using 12C and 4-(2-bromo-ethyl)-4′-trifluoromethyl-biphenyl (Compound 22B). MS m/z 487 (M+1).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[CH2:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][OH:10])[CH2:13][CH2:14]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.4 %

Procedure:
DIPEA (4.6 mL, 3.4 g, 26 mmol) was added to a solution of 4-(hydroxymethyl)piperidine (2.00 g, 17.4 mmol) dissolved in methylene chloride (20 mL). The solution was cooled in an ice bath and benzyl chloroformate (2.5 mL, 3.0 g, 18 mmol) was added dropwise over 10 min. After warming to rt and stirring for 96 h, the mixture was diluted with ethyl acetate (50 mL) and washed in succession with 25 mL each of saturated aq. sodium bicarbonate, 2N aq. HCl, saturated aq. sodium bicarbonate, and saturated aq. brine. The organic layer was dried (sodium sulfate), decanted, and evaporated to give 4.14 g of 1-(benzyloxycarbonyl)-4-(hydroxymethyl)piperidine.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:9][C:10]1[C:19]([C@H:20]2[CH2:24][CH2:23][O:22][C@H:21]2[CH2:25][OH:26])=[CH:18][CH:17]=[C:16]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([NH:9][C:10]1[C:19]([C@H:20]2[CH2:24][CH2:23][O:22][C@H:21]2[CH2:25][O:26][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][CH:17]=[C:16]([NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])[CH3:7]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2CO)c1NC(C)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2COS(C)(=O)=O)c1NC(C)=O

Procedure:
Methanesulfonyl chloride (0.042 mL) was added to a mixture of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(hydroxymethyl)-tetrahydrofuran-3-yl]benzoate (Intermediate 32, 0.14 g) and triethylamine (0.15 mL) in DCM (5 mL) and the resultant mixture was stirred at room temperature for 30 minutes. The mixture was washed with 1M hydrochloric acid, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(methanesulfonyloxymethyl)-tetrahydrofuran-3-yl]benzoate (0.166 g) as a gum.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[CH:4][CH:3]=[N:2]1.CN1CC[O:11][CH2:10][CH2:9]1.C(Cl)(=O)C.[OH-].[Na+]>C(Cl)Cl>[NH:1]1[C:5]([NH:6][C:10](=[O:11])[CH3:9])=[CH:4][CH:3]=[N:2]1
Reactant: Nc1ccn[nH]1
Reactant: CN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)Nc1ccn[nH]1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.7 %

Procedure:
To a solution of 1H-pyrazol-5-amine (50 g, 0.602 mol) and N-methylmorpholine (160 mL, 1.44 mol) in CH2Cl2 (2 L) was added acetyl chloride (99 mL, 1.38 mol) dropwise at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1 d. Some di-acylated product was observed in an LCMS. The reaction mixture was concentrated in vacuo and the resulting solid was suspended in MeOH (2 L) and cooled to 0° C. 4 M NaOH solution (aq., 440 mL, 1.75 mol) was added slowly and the mixture allowed to warm to room temperature over 1.5 h. The MeOH was removed in vacuo and the solid was collected by filtration, washed with minimal cold water and dried in vacuo to provide the title compound as a solid (60 g).
Reaction SMILES: C([Li])(CC)C.C(O[C:11](=[O:23])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)(C)(C)C.C(OC(=O)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[F:36])=[O:29])C.[Cl-].[NH4+]>C(OCC)(=O)C.O1CCCC1.CCCCCC.C1CCCCC1>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:28]1([OH:29])[C:14]2[C:13](=[CH:18][CH:17]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:15]=2)[NH:12][C:11]1=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: C1CCCCC1
Product: O=C1Nc2ccc(C(F)(F)F)cc2C1(O)c1ccccc1F
Temperature: -40 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
16.8 mL of a hexane-cyclohexane solution of 1.0 mol/L sec-butyllithium was added dropwise under −78° C. cooling to a 15 mL tetrahydrofuran solution of 2 g of tert-butyl[4-(trifluoromethyl)phenyl]carbamate, and the reaction mixture was stirred for 1 hour. The temperature was then raised to −40° C., and the reaction mixture was stirred for 2.5 hours at that temperature. The reaction mixture was cooled back down to −78° C., a 7.5 mL tetrahydrofuran solution of 2.23 g of ethyl(2-fluorophenyl)(oxo)acetate was added dropwise, and the reaction mixture was stirred for 2 hours at the same temperature. The temperature was then raised to room temperature, and the reaction mixture was stirred for 12 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel 60, mobile phase: ethyl acetate/hexane=1/1; v/v) to obtain 389 mg of the titled compound (colorless powder).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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:24]1([C:2]2[CH:6]=[CH:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:3]=2[C:14]([O:16][CH3:17])=[O:15])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1c(Br)ccn1C(=O)OC(C)(C)C
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)ccn1C(=O)OC(C)(C)C
Yield: 65.9 %

Procedure:
To a solution of 1-tert-butyl 2-methyl 3-bromo-1H-pyrrole-1,2-dicarboxylate (17.6 g, 57.9 mmol) in toluene (200 mL) and water (200 mL) was added K2CO3 (64.0 g, 463 mmol), followed by phenylboronic acid (10.6 g, 87.0 mmol) and tetrabutylammonium bromide (1.68 g, 5.21 mmol). The reaction mixture degassed for 10 min with nitrogen and then tetrakis(triphenylphosphine)palladium (1.34 g, 1.16 mmol) was added. The resulting slurry was degassed with nitrogen for 30 min and then heated to reflux for 16 h. The reaction mixture was concentrated under reduced pressure to remove water and toluene. Water was then added to the residue and the mixture extracted by ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 80 g, 20% EtOAc/hexanes) to obtain 1-tert-butyl 2-methyl 3-phenyl-1H-pyrrole-1,2-dicarboxylate (11.5 g, 65.9%) as a tan solid. 1H NMR (400 MHz, CD3OD) δ ppm 1.60 (s, 9H), 3.79 (s, 3H), 6.40 (d, J=3.4 Hz, 1H), 7.37 (m, 6H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH3:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: CNCc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)CBr
Yield: 100.1 %

Procedure:
At 0° C., a solution of 10 g of bromoacetyl bromide in 20 ml of DCM is added to a solution of 6 g of methylbenzylamine and 5 g of triethylamine in 50 ml of DCM. After one night at RT, ether is added, the precipitate formed is filtered off and the filtrate is concentrated to give 12 g of the expected product in crude form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.9 %

Procedure:
10-bromo-2-methoxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (10.2 g) obtained in Example 1 was suspended in anhydrous methylene chloride (1000 ml), and boron tribromide (25 g) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 12 hours, and poured into ice water (500 ml). To this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed in a mixture of methylene chloride and methanol to obtain the title compound (6.4 g, 65%).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]2[S:12][C:13](C([O-])=O)=[CH:14][C:7]=12>CN(C=O)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[Br:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]2[S:12][CH:13]=[CH:14][C:7]=12
Reactant: O=C([O-])c1cc2c(Br)cncc2s1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1cncc2sccc12
Temperature: 120 °C
Reaction time: 24 h

Procedure:
Silver carbonate (28 mg) and acetic acid (0.006 ml) were added to a solution of 4-bromothieno[2,3-c]pyridine-2-carboxylate obtained in the above-described Step 1 (258 mg) in DMF (2.0 ml), and the reaction solution was stirred at 120° C. for 24 hours. The reaction solution was diluted with ethyl acetate and washed successively with an aqueous sodium bicarbonate solution and a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under vacuum. The resultant residue was purified by column chromatography on silica gel (developing solvent:hexane-ethyl acetate) to obtain 4-bromothieno[2,3-c]pyridine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:11]([O:15][C:16]([N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 77.5 %

Procedure:
This compound was prepared in a similar way as described in literature (Journal of Medicinal Chemistry (2005), 48, 2371). A mixture of 1-fluoro-4-nitro-benzene (2.06 g, 14.7 mmol), [1,4]Diazepane-1-carboxylic acid tert-butyl ester (3.52 g, 17.6 mmol) and potassium carbonate (4.85 g, 35.2 mmol) in DMF (100 mL) was heated to 100° C. and stirred for 2 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (100 mL), brine (50 mL), dried with anhydrous sodium sulfate and the solvent was removed. The residue was purified on a flash chromatography column with EtOAc/hexanes to afford 4-(4-nitrophenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.66 g, 78% yield) as a white solid. ES-MS for C16H23N3O4 calcd. (m/e) 321, observed 322 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:31]C(=O)OC(C)(C)C)=[N:6][C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH:17]=[C:16]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:15]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl>O1CCOCC1>[ClH:29].[NH2:31][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:9][CH:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[N:19]3[CH:20]=[CH:21][N:22]=[C:18]3[CH:17]=[C:16]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=3[Cl:30])[N:15]=2)[N:6]=1
Reactant: CC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
32 mg (0.01 mmol) of tert-butyl {3-acetyl-6-[(2-{[7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-yl]amino}ethyl)amino]pyridin-2-yl}carbamate are dissolved in dioxane (2 ml), and 4M hydrogen chloride in dioxane (2 ml) are added. After stirring at RT for 3 h, the solvent is concentrated in a rotary evaporator, and the residue is purified by preparative HPLC. 11 mg (39% of theory) of the product are obtained as a solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]1([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C.O>O1CCCC1>[CH:15]1([CH2:21][NH:22][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NCC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NS(=O)(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 2C (7.70 g) in tetrahydrofuran (35 mL) was added dropwise a solution of cyclohexylmethylamine (6.0 mL, 5.22 g) and diisopropylethylamine (8.0 mL, 5.92 g) in tetrahydrofuran (15 mL). After the addition, tetrahydrofuran (20 mL) was added, and the reaction was stirred at room temperature for 16 hours. The solution was added to water and extracted with a solution of ethyl acetate and dichloromethane (1:1 by volume). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate volume was reduced to isolate the title compound by crystallization.