Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]1=[O:21].Br[C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1>>[CH:35]1([CH2:34][O:33][C:24]2[CH:23]=[CH:28][C:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][C:25]=2[C:10]2[C:9]3[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=3[C:3](=[O:21])[N:2]([CH3:1])[CH:11]=2)[CH2:36][CH2:37]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2c(c1=O)CCCC2

Procedure:
The title compound of Example 163, step 3 and 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene were reacted in a similar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 7.92 (dd, J1=8.4 Hz, J2=2.0 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 3.92-3.87 (m, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H), 1.77-1.64 (m, 4H), 1.21-1.17 (m, 1H), 0.63-0.61 (m, 2H), 0.29-0.27 (m, 2H). LCMS: 388.1 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH2:12][CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][S:15]([CH2:14][CH2:13][CH2:12][Cl:11])(=[O:17])=[O:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(NS(=O)(=O)CCCCl)cc1

Procedure:
A solution of 5.00 g (36.2 mmol) of 4-nitroaniline and 6.41 g (36.2 mmol) of 3-chloropropanesulfonyl chloride in 20 ml of pyridine is stirred overnight at room temperature. The reaction mixture is then poured onto ice. The precipitate which deposits in the process is filtered off with suction and dried, giving N-(4-nitrophenyl)-3-chloropropane-1-sulfonamide as a yellowish solid; ESI 279.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)ccc4ccccc34)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 75 h
Yield: 85.2 %

Procedure:
To a solution of methyl 3-(4-{[3-(2-methyl-1-naphthyl)benzyl]oxy}phenyl)propanoate (0.648 g, 1.58 mmol) in a mixture of methanol (6 mL) and tetrahydrofuran (6 mL) was added 2 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 75 hrs. Water was added to the reaction mixture, acidified with 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.534 g, yield 85%) as colorless needle crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([O:22]C)=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([O:5][C:6]([N:8]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:9]1[C:10]2[C:11]3[C:12](=[N:24][N:25]([CH2:27][C:28]4[C:33]([CH3:34])=[C:32]([O:35][CH3:36])[C:31]([CH3:37])=[CH:30][N:29]=4)[N:26]=2)[CH:13]=[C:14]([CH2:19][C:20]([OH:22])=[O:21])[C:15]=3[CH2:16][S:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cc2nn(Cc3ncc(C)c(OC)c3C)nc3c-2c1CSN=C3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)cnc(Cn2nc3cc(CC(=O)O)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture composed of the above methyl {4-[bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl}acetate (69 mg), methanol (2 ml) and a 1 N sodium hydroxide solution (0.22 ml) was stirred at room temperature for 16 hours. A 1 N sodium hydroxide solution (0.5 ml) was added, followed by stirring for three hours. Then, a 1 N sodium hydroxide solution (0.3 ml) was further added, followed by stirring for three hours. A 1 N hydrochloric acid solution (1.5 ml) was added dropwise to the reaction mixture. Then, water was added, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. An oil (60 mg, 89%) was obtained as a residue. Although the product contained a by-product, it was directly used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClCCl.C(N(CC)CC)C>CO>[CH3:1][O:5][C:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[O:20][C:19]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:8]3([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:36])[CH2:11][CH2:10][CH2:9]3)=[CH:13][CH:14]=1)[C:27]2=[O:28])=[O:36]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 50 °C
Yield: 200.1 %

Procedure:
{1-[4-(8-Bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (200 mg, 0.367 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dischloropalladium(II) complex with dichloromethane (60 mg, 0.073 mmol) were loaded into a microwave vial. The vial was sealed and a solution of triethylamine (0.102 mL, 0.732 mmol) in MeOH (4 mL) was added. The vial was evacuated and flushed twice with argon, followed by carbon monoxide. The reaction mixture was heated conventionally at 50° C. under an atmosphere of carbon monoxide for 18 h. The reaction mixture was allowed to cool to RT and was concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% EtOAc in DCM) to give the title compound as a gum (193 mg, 100%). LCMS (Method G): RT=4.41 min, [M+H]+=526.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.[Cl:31]C1C=CC(CBr)=CC=1.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:31])=[CH:17][CH:18]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=1
Reactant: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: Cl
Product: NCCCn1c(COCc2ccc(Cl)cc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Yield: 45 %

Procedure:
The compound (313 mg) obtained in Example 208 (2) and 4-chlorobenzyl bromide (216 mg) were treated in a similar manner to in Example 208 (3), (4) to give the title compound (152 mg) as hydrochloride.
Reaction SMILES: [Mg:1].[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].C([Cl:15])CCC>>[CH2:2]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH3:5].[CH2:2]([Mg:1][Cl:15])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCCl
Reactant: [Mg]
Solvent: CCCCOCCCC
Product: CCCC[Mg]Cl
Reaction time: 5 h

Procedure:
To a 1-liter flask equipped with a stirrer, a reflux condenser and a dropping funnel was added magnesium chip (12 g) for Grignard reagent. After replacing atmosphere in the flask by argon, di-n-butyl ether (250 ml) was added, and then n-butyl chloride (62 ml, 1.2 times by mole based on magnesium) was added dropwise to start reaction with the contents of the falsk kept at 50° C. After addition over 2 hours at 50° C., reaction was continued at this temperature for further 5 hours to obtain a di-n-butyl ether solution of n-butylmagnesium chloride. The concentration of this solution was 1.45 mole/liter.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C@@H:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([NH:21][CH3:22])=[O:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([NH:17][C@@H:18]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, MS (EI): m/e=374.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:54][OH:55])[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])[CH2:52][OH:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)O[C@@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 27 %

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 12j (1.09 g, 1.42 mmol) was dissolved in 30 mL of mixed solution (THF and MeOH, v:v=1:2), followed by addition of sodium borohydride (108 mg, 2.83 mmol) in batch. The reaction mixture was stirred for 30 minutes before 20 mL water and 30 mL water were added. The aqueous phase was extracted with ethyl acetate (30 mL×3) and the organic extract was washed with saturated sodium chloride solution (30 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyl-oxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 12k (293 mg, yellow grease), yield: 27.0%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)([CH3:22])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1)([CH3:22])[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1cccc(Br)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 38.1 %

Procedure:
3-(4-Benzyloxy-phenyl)-2-(3-bromo-phenoxy)-3-hydroxy-2-methyl-propionic acid ethyl ester (10.0 g, 20.7 mmol) was added slowly to a −20° C. solution of triethylsilane (9.9 mL, 62.0 mmol, d=0.728) and boron trifluoride etherate (15.3 mL, 124.0 mmol, d=1.154) in anhydrous CH2Cl2 (370 mL). The mixture was stirred for 6 h, gradually warming to 0° C. The reaction mixture was quenched with a saturated solution of aqueous sodium carbonate and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by flash column chromatography to provide the titled compound (3.7 g, 38%). 1H NMR (400 MHz, CDCl3): δ 7.46-7.33 (m, 5H), 7.18 (d, 2H, J=8.60 Hz), 7.15-7.05 (m, 3H), 6.94 (dt, 2H, J=8.60 Hz), 6.78 (dt, 1H, J=7.82 Hz, 2.35 Hz), 4.23 (q, 2H, J=7.04 Hz), 3.28 (d, 1H, J=13.69 Hz), 3.19 (d, 1H, J=13.69 Hz), 1.45 (s, 3H), 1.23 (t, 3H, J=7.04 Hz). Rf=0.46 in 25% ethyl acetate in hexanes.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O-:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na+].[C:12]1([CH2:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1OCCOCCOCCOCCOC1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCCCc1ccccc1
Reactant: [O-]CCCN1CCCCC1
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCOCCCN2CCCCC2)cc1

Procedure:
Sodium 3-piperidinopropanolate (20 mmol), 20 mmol of 3-phenylpropyl bromide, and 0.5 mmol of 15-crown-5 in 30 ml of dry toluene were refluxed for 4 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (eluent: methylene chloride/methanol/aqueous ammonia (90/10/0.5)). After removing the solvent under reduced pressure the residue was crystallized with oxalic acid from diethyl ether/ethanol.
Reaction SMILES: C(N(CC)CC)C.NC1C2C(=CC=CC=2)C(Br)=CC=1.[OH-].[Na+].[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([O:35]C)=[O:34])=[CH:25][CH:24]=1>[C]=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C.CN(C)C=O.CO>[NH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([OH:35])=[O:34])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(N)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Nc1ccc(Br)c2ccccc12
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: Nc1ccc(C(=O)O)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.60 g (2.3 mmol) of bis(triphenylphosphine)dichloropalladium, 7.0 ml (50.6 mmol) of triethylamine and 60 ml of methanol were successively added to a mixture of 5.00 g (22.5 mmol) of 1-amino-4-bromonaphthalene and 60 ml of dimethylformamide, and they were stirred in carbon monoxide atmosphere at 80° C. for 2 days. After the concentration under reduced pressure, water was added to the reaction mixture and the product was extracted with ethyl acetate and concentrated. 20 ml of ethanol and 10 ml (40.0 mmol) of 4 N aqueous sodium hydroxide solution were added to crude methyl 4-amino-1-naphthalenecarboxylate thus obtained. They were stirred at 80° C. overnight. Ethanol was evaporated, and the residue was washed with ethyl acetate. The aqueous layer was neutralized with hydrochloric acid. After the extraction with ethyl acetate, the product was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.CCO.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:9]1([C:2]2[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1cc(Br)co1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc(-c2ccccc2)co1
Yield: 97 %

Procedure:
In a screw cap pressure tube, 4-bromofuran-2-carbaldehyde (504 mg, 2.88 mmol) and phenyl boronic acid (491.7, 4.03 mmol) were suspended in a mixture of toluene:EtOH (4:1). Na2CO3 (sat) (6.0 ml) was added. N2 was bubbled through the mixture for 5 minutes. Pd(PPh3)4 (166.4 mg, 0.05 mmol) was added. The tube was sealed and the mixture heated to reflux for 4.0 h. The mixture was allowed to cool. H2O was added and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography (Pet. Ether/EtOAc 90/10→85/15) to afford the title substance in 97% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])=[CH:7]1.[CH3:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22]([N:30]([CH3:31])[CH3:29])=[CH:23][CH:24]=2)=[O:18])=[CH:7]1
Reactant: CNC
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Product: CN(C)c1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1

Procedure:
Experimental conditions analogous to those described for Example 141, from 151 mg (0.37 mmol) of 1-(3-chloro-benzyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 2 mL 2 M dimethylamine solution. Yield: 127 mg of a yellow powder. LC-MSD, m/z for C24H20ClN3O2 [M+H]+=418.1, 420.1; HPLC retention time: 1.6 min.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([CH2:13][CH2:14]Br)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C(=O)([O-])O.[Na+].CN(C=O)C.[NH2:26][C:27]1[C:28]([CH3:42])=[C:29]([CH3:41])[C:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32](=[O:37])[C:31]=2[C:38]=1[CH:39]=[CH2:40]>C(OCC)(=O)C.O>[CH:39]([C:38]1[C:31]2[C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[O:34][C:30]=2[C:29]([CH3:41])=[C:28]([CH3:42])[C:27]=1[N:26]1[CH2:14][CH2:13][N:4]([C:5]2[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1)=[CH2:40]
Reactant: C=Cc1c(N)c(C)c(C)c2c1C(=O)C(C)(C)O2
Reactant: COc1ccc(N(CCBr)CCBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=Cc1c2c(c(C)c(C)c1N1CCN(c3ccc(OC)cc3)CC1)OC(C)(C)C2=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 8.4 %

Procedure:
N,N-bis(2-bromoethyl)-4-methoxyaniline (2.45 g, 7.63 mmol) and sodium hydrogencarbonate (1.25 g, 1.40 mmol) were added to a solution of DMF (36 mL) containing 5-amino-4-ethenyl-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (1.47 g, 6.36 mmol) synthesized in Reference Example 22, and the mixture was stirred at 120° C. for 16 hours. After cooled to room temperature, water was added to the mixture, and extraction was performed using ethyl acetate. It was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate: 100:0 to 90:10) to give 217 mg of the title compound (yield: 8%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[C:21]([CH2:29][C:30]([O:32]CC)=[O:31])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[C:21]([CH2:29][C:30]([OH:32])=[O:31])=[N:20]2)=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccc(F)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccc(F)cc12
Yield: 95.4 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-5-fluoro-1H-indazol-3-yl]acetate (100 mg, 0.208 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (44 mg, 1.05 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 90 mg, at a yield of 95.7%.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=2)[N:3]=1.C([Si](C(C)C)(C(C)C)[N:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[CH3:16][N:14]1[CH:15]=[C:11]([C:4]2[N:3]=[C:2]([C:23]3[CH:24]=[CH:25][NH:21][CH:22]=3)[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=2)[CH:12]=[N:13]1
Reactant: Cn1cc(-c2cc3nccn3c(Cl)n2)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1cc(-c2cc3nccn3c(-c3cc[nH]c3)n2)cn1
Temperature: 75 °C
Reaction time: 8 h
Yield: 129.6 %

Procedure:
To a flask charged with 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation J; 0.150 g, 0.642 mmol), 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (0.257 g, 0.963 mmol), and potassium phosphate (0.321 mL, 0.642 mmol) was added 6 mL of dioxane and argon was bubbled through the mixture for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.0742 g, 0.0642 mmol) was added and argon was bubbled through the reaction for 15 minutes. The flask was sealed under argon and the mixture was heated at 75° C. with stirring overnight. The reaction was then concentrated under reduced pressure and then taken up in DCM (5 mL). A precipitate was formed and collected by means of vacuum filtration and washed with DCM (10 mL). The solid contained product without the triisopropylsilyl protection as well as inorganic salts. Further purification was not attempted and so was obtained 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrrol-3-yl)imidazo[1,2-c]pyrimidine (0.220 g, 0.832 mmol, 130% yield). MS (apci) m/z=265.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([SH:22])[CH2:20][CH3:21]>CN(C=O)C>[Cl:1][C:2]1[C:7]([S:22][CH2:19][CH2:20][CH3:21])=[CH:6][C:5]([NH2:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: CCCS
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Yield: 98.1 %

Procedure:
To a mixture of 4,5-dichloro-2-nitro-phenylamine (3.50 g, 16.9 mmol), potassium carbonate (4.67 g, 33.8 mmol), and DMF (85 mL) was added 1-propanethiol (2.30 mL, 25.4 mmol). The reaction mixture was heated at 90° C. for 1.5 h, and allowed to cool to 23° C. The mixture was poured into ice/brine (600 mL) and the resulting precipitate was collected to yield the titled compound (4.09 g, 98%). 1H NMR (600 MHz, CDCl3): 8.11 (s, 1H), 6.46 (s, 1H), 6.10 (br s, 2H), 2.91 (t, J=7.3 Hz, 2H), 1.85-1.76 (m, 2H), 1.12 (t, J=7.4 Hz, 3H).