Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH2:17])=[CH:13][N:12]([CH2:18][C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:11]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:42][CH2:43][CH2:44][CH2:45][C:46](Cl)=[O:47]>ClCCl>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([NH:17][C:46](=[O:47])[CH2:45][CH2:44][CH2:43][Cl:42])=[CH:13][N:12]([CH2:18][C:19]2[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=2[F:25])[C:11]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(NC(=O)CCCCl)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of {(R)-2-[5-amino-3-(2,6-difluoro-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (42 mg, 0.089 mmol) in dichloromethane (2 mL) were added triethylamine (25 μl, 0.178 mmol) and 4-chloro-butyryl chloride (11 μl, 0.097 mmol) in the order. The solution was stirred at room temperature for 2 hrs and concentrated. The residue was purified using silica gel chromatography (eluent: hexane/ethyl acetate/dichloromethane, 2/1/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 78%). 1H NMR (300 MHz, CDCl3) δ 1.33 (9H, s), 2.17 (2H, p), 2.57 (2H, t), 3.63 (2H, t), 4.10 (1H, m), 4.34 (1H, t), 4.99-5.14 (3H, m), 5.47 (1H, d), 6.96 (2H, m), 7.24-7.39 (6H, m), 7.72 (1H, s), 8.65 (1H, s)
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>CCOCCO>[CH2:16]([NH:20][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CS(=O)(=O)c1cc(C(=O)O)c(Cl)cc1Cl
Solvent: CCOCCO
Product: CCCCNc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Yield: 34 %

Procedure:
A mixture of 2,4-dichloro-5-methylsulfonylbenzoic acid (6.0 g.; 0.0224 mole), butylamine (9 ml.) and ethyl cellosolve (20 ml.) is heated at reflux in a nitrogen atmosphere for 5 hours. The solvent is distilled at reduced pressure and the residue is dissolved in water (75 ml.) then treated with dilute hydrochloric acid which causes the product to precipitate. After recrystallization from butyl chloride there is collected 2.3 g. (34% yield) of 2-butylamino-4-chloro-5-methylsulfonylbenzoic acid, m.p. 187°-9° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:22][CH2:21]1)[N:14]=2)[C:5](O)=[O:6].Cl.[CH2:30]([O:32][C:33](=[O:37])[CH2:34][CH2:35][NH2:36])[CH3:31]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[C:15]([C:20]1([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:22]1)[N:14]=2)[C:5]([NH:36][CH2:35][CH2:34][C:33]([O:32][CH2:30][CH3:31])=[O:37])=[O:6]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoic acid (0.080 g, 0.20 mmol) and beta-alanine ethyl ester hydrochloride, according to Reference S and the general procedure for amide formation afforded ethyl 3-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzamido)propanoate. MS (ESI) m/z: Calculated: 489.2; Observed: 490.0 (M++1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([CH2:31][CH3:32])[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH:44]=1)[CH3:35]
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
3-Benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 11, Step 4 to provide {5-[2-(3-benzyl-1-ethyl-ureidomethyl)-4-trifluoromethyl-phenyl]-6-methoxy-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>>[CH:10]1[C:11]2[N:12]([CH2:15][CH2:16][CH2:17][C:18]#[N:19])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: N#CCCCBr
Product: N#CCCCn1c2ccccc2c2ccccc21

Procedure:
Carbazole (10 g, 0.060 mol) was reacted with 4-bromobutyronitrile (11.9 ml, 0.12 mol) by working in a similar manner to Example 1a).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][N:16]1[CH2:21][C@H:20]([CH3:22])[NH:19][C@@H:18]([CH3:23])[C:17]1=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][C@H:18]1[C:17](=[O:24])[N:16]([CH3:15])[CH2:21][C@H:20]([CH3:22])[N:19]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@@H]1N[C@@H](C)CN(C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3[C@@H](C)CN(C)C(=O)[C@@H]3C)nc12
Yield: 19.1 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (342 mg, 1.62 mmol), (3S,5S)-1,3,5-trimethylpiperazin-2-one (230 mg, 1.62 mmol) and potassium carbonate (670 mg, 4.85 mmol), in DMF (10 mL), was stirred at ambient temperature for 16 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (2×40 mL). The combined organic layers were washed with 0.5 N HCl (10 mL), H2O (10 mL), brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was triturated with diethyl ether and the solids were removed by filtration. The filtrate was concentrated and purified by column chromatography (silica gel, 10% CH2Cl2 in EtOAc to 100% EtOAc) to give methyl 2-((2S,6S)-2,4,6-trimethyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (98 mg, 19%): 1H NMR consistent.
Reaction SMILES: [N:1]1[N:2]([C:10]2[N:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][CH:15]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]([OH:20])[C:17](O)=[O:18])=[O:13])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:17](=[O:18])[CH:16]([OH:20])[CH:15]([NH:14][C:12](=[O:13])[C:11]1[CH:28]=[CH:29][CH:30]=[N:31][C:10]=1[N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[CH:7][CH:6]=[CH:5]2)=[N:1]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH3:33]
Reactant: CCN
Reactant: O=C(NC(Cc1ccccc1)C(O)C(=O)O)c1cccnc1-n1cc2ccccc2n1
Product: CCNC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1

Procedure:
The reaction was carried out in analogy to reaction step 1.4 by reacting 3-(2-(2H-indazol-2-yl)nicotinamido)-2-hydroxy-4-phenylbutanoic acid and ethylamine.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=O)[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCOC(C)=O>[C:11]([O:15][C:16](=[O:23])[NH:17][CH:18]1[CH2:21][C:20](=[CH2:1])[CH2:19]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a three necked flask equipped with additional funnel which was cooled to −78° C. was added a solution of methyl(triphenyl)phosphonium bromide (43 g, 121 mmol) in anhydrous tetrahydrofuran (200 mL) under nitrogen protection. 1 M KHMDS in tetrahydrofuran (105 mL, 105 mmol) was then introduced dropwise over 40 minutes while the internal temperature was kept below −60° C. After addition, the mixture was stirred at −78° C. for 15 minutes. Then a solution of tert-butyl(3-oxocyclobutyl)carbamate (14 g, 81 mmol) in 100 mL of tetrahydrofuran was added slowly while the internal temperature was kept below −60° C. The resulting mixture was then warmed naturally to room temperature and stirred overnight. The resulting reaction mixture was diluted with EtOAc, and then washed with saturated aqueous solution of ammonium chloride and brine, then dried over anhydrous Na2SO4 and then concentrated in vacuo. The residue was purified by flash chromatography (EA:PE=1:10 to 1:2) to afford tert-butyl(3-methylidenecyclobutyl)carbamate (7.5 g).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH2:30]>>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][CH2:29][NH:30][C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Reactant: COc1ccccc1CCN
Product: COc1ccccc1CCNc1nccc(-n2cnc3ccccc32)n1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-(2-methoxyphenyl)ethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound. Mass Spectrum (ESI): m/e 346.1 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.66 (br s, 1H); 8.38 (br s, 1H); 8.22 (br s, 1H); 7.88 (d, J=6.7 Hz, 1H); 7.40 (m, 2H); 7.22 (m, 2H); 6.92 (m, 2H); 6.78 (d, J=5.4 Hz, 1H); 5.60 (br s, 1H); 3.88 (s, 3H); 3.78 (m, 2H); 3.03 (t, J=6.7 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.C(N(S(F)(F)[F:31])CC)C.C(N(CC)CC)C>ClCCl>[F:13][C:7]1[C:4]([CH2:5][F:31])=[C:3]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:2]([F:1])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CF)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3,6-Difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (1.5 g) is dissolved in dichloromethane (18 ml), and thereto is added dropwise a solution of diethylaminosulfur trifluoride (DAST) (0.7 ml) and triethylamine (0.78 ml) in dichloromethane (3 ml) over a period of 5 minutes while stirring at 0° C. in ice bath. The mixture is stirred at 0° C. for 1.2 hour, and thereto is further added DAST (0.3 ml). After 5 minutes, the reaction mixture is poured into ice water, and the organic layer is separated. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:10→1:5 v/v) to give 2,5-difluoro-3-fluoromethyl-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene (1.1 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10](Cl)[N:9]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:19]=[C:18]([O:20][CH3:21])[NH:17][N:16]=2)[C:11]([F:22])=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: C1COCCN1
Reactant: COc1cc(Nc2nc(Cl)nc(Cl)c2F)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2nc(Cl)nc(N3CCOCC3)c2F)n[nH]1
Temperature: 90 °C

Procedure:
To a solution of 2,4,6-trichloro-5-fluoropyrimidine (2.01 g) in absolute ethanol (50 mL) was added DIEPA (4.4 mL) and 5-methoxy-1H-pyrazol-3-amine (2.24 g). The resulting solution was stirred at room temperature for over night. The solvent was removed by reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine as solid (0.776 g). m/z 278. A mixture of morpholine (0.256 mL), 2,6-dichloro-5-fluoro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (776 mg) and DIPEA (0.742 ml) in n-butanol (14.0 ml) was heated at 90° C. for 5 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (310 mg). 1H NMR 9.80 (s, 1H) 5.66 (s, 1H) 3.77 (s, 3H) 3.64-3.71 (m, 4H) 3.53-3.64 (m, 4H); m/z 329.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.C[Li].C([Li])(C)(C)C.[C:20](=[O:22])=[O:21].Cl>CCOCC>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]([OH:22])=[O:21])[CH:11]=[CH:10]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O=C(O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a slurry of 5.00 g (22.4 mmol, Aldrich) of 6-bromo-2-naphthol in 150 ml of dry ether at -78° was added dropwise, 16 ml (1.4M in ether, 22 mmol, Aldrich) of methyllithium solution over 10 minutes. The reaction mixture was stirred for 10 minutes, then 28 ml (1.8M in pentane, 50 mmol, Aldrich) of t-butyllithium solution was added dropwise over 15 minutes. The resulting slurry was stirred at -78° for 30 minutes then at 0° for 15 minutes. The reaction mixture was re-cooled to -78°, added into 100 g of crushed dry ice via cannula, and allowed to warm to room temperature over about ~2 hours, then added to 200 ml of 1M aqueous HCl solution and extracted with 100 ml of ethyl acetate. The organic extract was separated, washed with an additional 200 ml of H2O and concentrated in vacuo to give a pale yellow solid. The crude material was dissolved in 125 ml of warm, saturated aqueous NaHCO3 solution and extracted with two 50 ml portions of ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated HCl. The solid which precipitated was collected on a Buchner funnel then dried under vacuum at 110° to afford 2.95 g (70%) of title compound as an off-white powder, m.p. 237°-241°.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH2:21]([N:28]1[CH:36]=[C:35]2[C:30]([CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:34]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:1][C:2]1[C:7]2=[C:8]([C:32]3[CH:33]=[CH:34][C:35]4[C:30]([CH:31]=3)=[N:29][N:28]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:36]=4)[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(-c2cc(Br)c3c(N)ncnn23)ccc1O
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: COc1cc(-c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)ccc1O
Yield: 9 %

Procedure:
Using a procedure similar to that of Example 4 with 4-(4-Amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-phenol and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole as starting materials, 21.5 mg (9%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.80 (s, 3 H); ES-MS m/z 463.49 [M+H]+, HPLC RT (min) 2.99.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16]([OH:19])[CH2:17]O)[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.CS(Cl)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2=[N:11][C:12]3[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[C:13]=3[N:14]2[CH2:15][CH:16]([OH:19])[CH2:17]1
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc3n(c12)CC(O)CN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 47 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propane-1,2-diol (Reference Example 88; 46.2 mg, 0.109 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.0127 mL, 0.164 mmol) at 0° C. After 5 hr, the mixture was warmed up to room temperature. After 1 hr, methanesulfonyl chloride (0.0042 mL, 0.0545 mmol) was added, and the mixture was stirred for additional 1 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on NH-silica gel eluting with a 20-80% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (20.6 mg, 0.0512 mmol, 47%). Analytically pure material was obtained by recrystallization from methanol/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[H-].[Na+].Cl.Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2cc(Cl)ccc12
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CCN(C)C)c2cc(Cl)ccc12
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
To a stirred solution of 80 mg (0.38 mol) of 6-chloro-1H-indole-3-carboxylic acid methyl ester in 5 ml of DMF were added 50 mg of NaH (3 eq, 55H in oil) at RT. After 20 min, 66 mg (0.45 mmol, 1.2 eq.) of (2-chloro-ethyl)-dimethyl-amine hydrochloride were added and stirring was continued overnight at 60° C. Extraction with EtOAc/aq. NH4Cl followed by flash chromatography yielded 45 mg of crude 6-chloro-1-(2-dimethylamino-ethyl)-1H-indole-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]([OH:24])=[C:16]3[OH:25])[N:12]=1)=[O:7].B.[Na]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18](=[O:23])[C:17]([OH:24])=[C:16]4[OH:25])[N:12]=2)[OH:7])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)c2nc(-c3ccc4[nH]c(=O)c(O)c(O)c4c3)cs2)cc1OC
Agent: B
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)c2nc(-c3ccc4[nH]c(=O)c(O)c(O)c4c3)cs2)cc1OC
Reaction time: 1 h
Yield: 51.8 %

Procedure:
In 6 ml of chloroform was dissolved 100 mg of 2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl)thiazole. Thereto was added sodium boron hydride at room temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off. The residue was extracted with chloroform. The extract was water-washed, dried and then subjected to solvent removal by distillation. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=99/1) and then recrystallized from ethyl acetate to obtain 52 mg of 2-[1-(3,4-dimethoxyphenyl)-1-hydroxymethyl]-4-(3,4-dihydroxycarbostyril-6-yl)thiazole as light brown prismatic crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4](/[N:19]=[N:20]/[C:21]2[CH:26]=[CH:25][C:24]([N:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:23][CH:22]=2)[S:5][C:6]=1[CH:7]=[C:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>O1CCCC1>[CH2:28]([N:27]([CH2:30][CH3:31])[C:24]1[CH:25]=[CH:26][C:21](/[N:20]=[N:19]/[C:4]2[S:5][C:6]([CH:7]=[C:8]3[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]3=[O:18])=[C:2]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[N:3]=2)=[CH:22][CH:23]=1)[CH3:29]
Reactant: CN1CCNCC1
Reactant: CCN(CC)c1ccc(/N=N/c2nc(Cl)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Solvent: C1CCOC1
Product: CCN(CC)c1ccc(/N=N/c2nc(N3CCN(C)CC3)c(C=C3C(=O)c4ccccc4C3=O)s2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.00 g (2.20 mmol) 2-[(4-chloro-2-{(E)-[4-(diethylamino)phenyl]diazenyl}-1,3-thiazol-5-yl)methylene]-1H-indene-1,3(2H)-dione and 0.30 g (2.70 mmol) 1-methylpiperazine were dissolved in 40 ml tetrahydrofurane (THF) and heated under stirring for 5 hours when thin layer chromatography (TLC) analysis indicated complete consumption of the starting material. After cooling to room temperature the formed precipitate was filtered off, washed with THF and dried in vacuum at 40° C. to obtain a dark green powder.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.ClC1C=C2C([O:34][C:35](=O)[NH:36]C2=CC=1)=O>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:35]([NH2:36])=[O:34])=[N:3][CH:4]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 177.8 %

Procedure:
To a solution of 2-amino-5-chloropyridine (328 mg, 2.55 mmol) in tetrahydrofuran (5 ml) was 0.5M potassium bis(trimethylsilyl)amide in toluene (10 ml, 5.05 mmol) dropwise at −78° C. After stirred for additional 0.5 hr at −78° C., the mixture was added 5-chloroisatoic anhydride (0.5 g, 2.55 mmol) at −78° C. The mixture was warmed up to r.t gradually and stirred overnight. After quenched by saturated ammonium chloride solution, the mixture was extracted by ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl)carboxamide (0.71 g. 100%). MS found for C12H9Cl2N3O M+=282, (M+2)+=284. Step 2: To a solution of the compound of (2-amino-5-chlorophenyl)-N-(5-chloro(2-pyridyl)carboxamide (0.71 g, 2.52 mmol) in dichloromethane (10 ml) was added 3-cyanobenzoly chloride (417 mg, 2.52 mmol) and pyridine (0.611 ml, 7.55 mmol). The mixture was stirred at r.t. overnight. The precipitate was filtered and washed with dichloromethane to give N-[4-chloro-2-[N-(5-chloro(2-pyridyl)carbamoyl]phenyl](4-cyanophenyl)carboxamide as a solid (683 mg, 66%). MS found for C20H12Cl2N4O2 M+=411, (M+2)+=413. Step 3: To a solution of the compound of N-{4-chloro-2-[N-(5-chloro(2-pyridyl)carbamoyl]phenyl}(4-cyanophenyl)carboxamide (683 mg, 1.66 mmol) in anhydrous pyridine (10 ml) and triethyl amine (1 ml) was saturated with hydrogen sulfide gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous acetone (5 ml) and iodomethane (1 ml, 16.6 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the residue was dissolved in anhydrous methanol (5 ml) and added a solution of N-methylethylenediamine (0.732 ml, 8.3 mmol) and acetic acid (1.5 ml) in anhydrous methanol (5 ml). The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{4-chloro-2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder. MS found for C23H19Cl2N5O2 M+=468 (M+2)+=470.