Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CSC[C@@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 77.3 %

Procedure:
To a stirred solution of (3R)-3-(benzylthio)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2320 g, 0.755 mmol) in dichloromethane (3 ml), under argon, was added trifluoroacetic acid (1 ml) and the mixture was stirred at room temperature for 65 minutes before quenching with anhydrous methanol (2 ml) and evaporating in vacuo. More methanol (2 ml) was added to the residue and removed in vacuo. The residual oil was then dissolved in dichloromethane (25 ml) and washed with 2N NaOH solution (10 ml). The aqueous layer was reextracted with more dichloromethane (15 ml) and the combined dichloromethane extracts were washed with saturated NaCl solution (10 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, CH2Cl2 /MeOH/NH3, 85:15:1.5) to give 0.1210 g (77%) of the title compound as a colourless oil. δH (250 MHz,CDCl3) 1.41 (1H, m), 1.90-2.00 (1H, m), 2.24 (1H, m), 2.42-2.50 (2H, m), 2.57 (1H, dd, J=6.5 and 11.0 Hz), 2.82-2.99 (2H, m), 3.07 (1H, dd, J=7.3 and 11.0 Hz), 3.72 (2H, s), 7.20-7.36 (5H, m); m/e (ES) 208 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.N1C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C=Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Yield: 29.1 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.640 g, 2.45 mmol) in dichloromethane (2 ml) was added to a mixture of aniline (0.465 g, 4.99 mmol) and pyridine (1 ml), and the resultant solution was stirred at 50° C. for one hour. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 10% HCl. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform-ethyl acetate (7:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.226 g, 29%). 1H NMR (CDCl3, HMDSO), δ: 3.72 (3H, s); 6.34 (1H, d, J=16.0 Hz); 6.68 (1H, br s); 6.92-7.89 (10H, m).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(C1C=CC=CC=1)(=O)C.[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([OH:34])=[CH:31][C:32]=1[OH:33])=[O:26]>>[CH3:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]([O:34][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:31][C:32]=1[OH:33])=[O:26]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)c1ccccc1
Product: CC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
The reaction of (1) above is repeated using 1.1 molar equivalents of benzyl chloride, 1.0 molar equivalent of K2CO3, and substituting for the above acetophenone 2,4-dihydroxyacetophenone ##STR17##
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:12][C:3]1[C:2]([NH:1][C:21]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Br:13])=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: Nc1cc2ccccc2cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1cc2ccccc2cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 3-amino 2-hydroxy napthalene (0.320 g, 2 mmol) and 2-bromo phenyl isocyanate (0.40 g) by general Method B. It was purified by dilution of the with methylene chloride and precipitation with hexane (0.339, 47%). EI-MS m/z 357 (M+H)+
Reaction SMILES: [Cl:1][C:2](=[CH2:7])[CH2:3][N:4]=[C:5]=[S:6].[CH2:8]([SH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N12CCN(CC1)CC2>C(#N)C.C1(C)C=CC=CC=1>[CH2:8]([S:15][C:5](=[S:6])[NH:4][CH2:3][C:2]([Cl:1])=[CH2:7])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: SCc1ccccc1
Reactant: C=C(Cl)CN=C=S
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C=C(Cl)CNC(=S)SCc1ccccc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
47 g of 2-chloro-allyl isothiocyanate and 40 g of benzyl mercaptan are dissolved in 150 ml of acetonitrile and 150 ml of toluene. Then 1 g of 1,4-diazabicyclo[2.2.2]octane is added and the mixture is heated to 75° C. and stirred for one hour. After cooling to room temperature, the solvent is removed by evaporation and the residue is crystallised from ether/hexane. In that manner the title product having a melting point of 46-48° C. (compound A) is obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:25])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:38](=[O:39])[C:37]([C:40](O)=[O:41])=[CH:36][N:35]([CH2:43][CH3:44])[C:34]2=[O:45])=[CH:29][CH:28]=1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:25][C:40]([C:37]3[C:38](=[O:39])[N:33]([C:30]4[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=4)[C:34](=[O:45])[N:35]([CH2:43][CH3:44])[CH:36]=3)=[O:41])[CH:7]=[CH:8][C:9]=2[O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C3CC3)c2cc1OC
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(C3CC3)c2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
1-Ethyl-3-(4-fluoro-phenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid [3-cyclopropyl-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-amide was synthesized from 3-cyclopropyl-4-(6,7-dimethoxyquinolin-4-yloxy)phenylamine (0.06 g, 0.20 mmol) and 3-(4-fluoro-phenyl)-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.06 g, 0.21 mmol) in an analogous manner to Example 1. mp 183-185° C.; LCMS m/z=597 (M+1). 1H NMR (DMSO-d6) δ: 10.84 (s, 1H), 8.86 (s, 1H), 8.44 (d, 1H, J=5.2 Hz), 7.71 (d d, 1H, J=2.53 Hz, J=8.73 Hz), 7.58 (s 1H), 7.31-7.46 (m, 5H), 7.27 (d, 1H, J=2.53 Hz), 7.17 (d, 1H, J=8.73 Hz), 6.33 (d, 1H, J=5.2 Hz), 4.00 (q, 2H, J=7.04 Hz), 3.94 (s, 6H), 1.77-1.87 (m, 1H), 1.29 (t, 3H, J=7.04 Hz), 0.72-0.82 (m, 2H), 0.62-0.71 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:50]2)[CH2:45][CH2:44]1>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([N:43]3[CH2:44][CH2:45][CH:46]([N:49]4[CH2:54][CH2:53][CH2:52][C@@H:51]([C:55]([O:57][CH2:58][CH3:59])=[O:56])[CH2:50]4)[CH2:47][CH2:48]3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCNCC2)C1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)C34CCC(N(CC(=O)N5C[C@@H](F)C[C@H]5C#N)C(=O)OCc5ccccc5)(CC3)CC4)CC2)C1
Yield: 96.2 %

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (101 mg) and ethyl (3R)-1-(piperidin-4-yl)piperidine-3-carboxylate (84.3 mg) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-[4-[(3R)-3-ethoxycarbonylpiperidin-1-yl]piperidine-1-yl]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (115 mg).
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[Cl:27])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Reactant: Oc1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2ccccc2Cl)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 69.4 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 71 mg (0.55 mmol) of 2-chlorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, diethyl ether/heptane 1:1) to yield 160 mg (69%) product as a white solid. MS (ISP) 461.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].O>CN(C)C=O>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=1
Reactant: CCCCCCCCBr
Reactant: Ic1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCn1cc(I)cn1
Reaction time: 0.5 h

Procedure:
To a slurry of NaH (60% in mineral oil, 271 mg, 6.77 mmol) in N,N-dimethylformamide (20 mL) was added 4-iodo-1H-pyrazole (1.25 g, 6.44 mmol), and the reaction was stirred for 30 minutes. 1-Octyl bromide (1.22 mL, 7.08 mmol) was then added and the reaction stirred for 24 hours. The mixture was poured into water (200 mL), and the resulting solution was extracted three times with ether. The combined ether extracts were washed three times with water and brine, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)([O-:19])=[O:18].Cl>O1CCCC1.O>[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:19])=[O:18]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccccc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a suspension of 60% sodium hydride/mineral oil (1.11 g) in tetrahydrofuran (40 mL) was added ethyl diethylphosphonoacetate (6.29 mL) dropwise under ice cooling. After stirring the mixture under ice cooling for 30 minutes, a solution of 2-nitrobenzaldehyde (3.0 g) in tetrahydrofuran (30 mL) was added thereto under ice cooling. The solution was stirred at room temperature for 8 hours. Water and 3N hydrochloric acid were then added to the solution and it was extracted with diethyl ether. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=3:2) to give the title compound (3.74 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[F:21])=[O:4].Cl.[C:23](Cl)(=[O:25])[CH3:24].C(N(CC)CC)C>O>[C:23]([NH:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:8][C:7]=1[F:21])=[O:4])(=[O:25])[CH3:24]
Reactant: NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1F
Yield: 99 %

Procedure:
A solution of 2-amino-N-[2-fluoro-4-(4-fluoro-benzyloxy)-phenyl]-acetamide (1:1) hydrochloride (50 mg, 0.15 mmol), acetyl chloride (14.4 mg, 0.18 mmol), triethylamine (31 mg, 0.30 mmol) was stirred at 0° C. for 4 h. Then the mixture was diluted with water and the mixture extracted with DCM. The organic layer was then washed with brine, dried, filtered and evaporated to leave the title compound (50 mg, 99%) as a white solid. MS: m/e=335.2 (M++H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:43][N:44]1[C:52]2[CH:51]=[C:50]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][NH:62][CH2:63][CH3:64])=[C:55]([C:65]([F:68])([F:67])[F:66])[CH:54]=3)[N:49]=[C:48]([C:69]#[N:70])[C:47]=2[N:46]=[CH:45]1>ClCCl>[C:69]([C:48]1[C:47]2[N:46]=[CH:45][N:44]([CH3:43])[C:52]=2[CH:51]=[C:50]([C:53]2[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH2:61][N:62]([CH2:63][CH3:64])[C:7]([C@@H:3]3[CH2:4][CH2:5][CH2:6][N:2]3[CH3:1])=[O:9])=[C:55]([C:65]([F:68])([F:66])[F:67])[CH:54]=2)[N:49]=1)#[N:70]
Reactant: CCNCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Reactant: CN1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)[C@@H]1CCCN1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 64.5 %

Procedure:
To a solution of (S)-1-methylpyrrolidine-2-carboxylic acid (16 mg), DIPEA (60 ul) and HBTU (51.7 mg) in dichloromethane (2 ml) was added 1-methyl-6-(4-(2-(ethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (55 mg). The reaction was left stirring at room temperature for 60 hrs. Reaction mixture was diluted with dichloromethane, washed with sodium bicarbarbonate and water. Organic layer was dried over magnesium sulphate and solvent removed under reduced pressure. The residue was purified by acidic prep HPLC and cationic ion exchange column to yield (S)—N-(2-(4-(4-cyano-1-methyl-1H-imidazo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)-N-ethyl-1-methyl-pyrrolidine-2-carboxamide (40 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][OH:31])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
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: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CO)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and 4-(hydroxymethyl)phenylboronic acid (96 mg, 0.63 mmol) in dioxane (2.5 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (130 mg, 62%). LCMS: 504.15 (M+1)+; HPLC: 98.86% (@254 nm) (Rt; 4.240; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.39 (s, 1H), 7.37 (d, 2H), 7.21 (s, 1H), 5.85 (s, 1H), 5.20 (t, 1H, J=5.2 Hz), 4.52 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.84 (m, 2H), 3.22-3.32 (m, 2H), 3.08-3.09 (m, 2H), 3.01 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: C1CCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC2)ncn1
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 71 mg of pyrrolidine was added therein, and the mixture was stirred for 4 hours at 55-60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 170 mg of 4-(2-butynyloxy)-6-(1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (17)).
Reaction SMILES: C(O[C:4]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])C.C(OC1(O[Si](C)(C)C)CC1)C.[C:37]1(=O)[CH2:40][CH2:39][CH2:38]1>>[CH:17]1([N:14]2[CH2:13][CH2:12][CH:11]([O:10][C:9]3[CH:8]=[CH:7][C:6]([CH:4]=[O:5])=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)[CH2:39][CH2:38][CH2:37][CH2:40]1
Reactant: CCOC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: O=C1CCC1
Agent: CCOC1(O[Si](C)(C)C)CC1
Product: O=Cc1ccc(OC2CCN(C3CCCC3)CC2)cc1

Procedure:
Compounds of Reference Examples 2 and 3 can be produced according to the method of Reference Example 1 but starting from tert-butyl 4-[4-(ethoxycarbonyl)phenoxy]tetrahydro-1(2H)-pyridinecarboxylate and [(1-ethoxycyclopropyl)oxy](trimethyl)silane or cyclobutanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].CC1(C)COC2=CC3OC[C:32]4([C:42]=3[CH:43]=C12)[C:40]1[C:35](=CC=CC=1)NC4=O.BrCC1CC1C.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:35][CH:40]1[CH2:32][CH:42]1[CH2:43][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: CC1CC1CBr
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CC1CC1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 1-(bromomethyl)-2-methylcyclopropane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound was obtained (37%) as a white solid: MS (ES+) m/z 350.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([NH2:14])[N:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)[CH3:2].C(O)(=O)C.[Br:19]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:19][C:5]1[C:4]([O:3][CH2:1][CH3:2])=[N:13][C:12]([NH2:14])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: CCOc1cc2cccnc2c(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCOc1nc(N)c2ncccc2c1Br
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a 250 mL round bottom flask was added 6-ethoxy-1,7-naphthyridin-8-amine (0.65 g, 3.43 mmol), glacial acetic acid (20 mL), followed by the dropwise addition of bromine (0.60 g, 3.78 mmol) dissolved in carbontetrachloride (40 mL). After addition was complete, the mixture was stirred for 2 h then neutralized with saturated NaHCO3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The resultant residue was purified by silica gel to yield 5-bromo-6-ethoxy-1,7-naphthyridin-8-amine as a pale yellow solid (0.6 g, 2.24 mmol, 65%). 1H NMR (400 MHz, CDCl3): δ ppm 8.53 (d, J=3.95 Hz, 1H), 8.22 (d, J=8.79 Hz, 1H), 7.50 (dd, J=8.57, 4.17 Hz, 1H), 5.87 (br. s., 2H), 4.48 (q, J=7.03 Hz, 2H), 1.44 (t, J=7.03 Hz, 3H). LC/MS m/z 270 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10].C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:34][CH2:35][CH2:36][OH:37])(=[O:10])=[O:11]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc(Cl)c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
To a solution of 3-(2,3-dichlorophenylsulfonyloxy)-5-methylphenol (642 mg, 2.0 mnol), as prepared in the preceding step, tri-n-butylphosphine (607 mg, 3.0 mmol) and 1,3-propanediol (760 mg, 10 mmol) in anhydrous tetrahydrofuran (20 mL) was added 1,1'-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (30 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (690 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 7.92 (d, J=8.0 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.34 (t, J=8.0 Hz, 1 H), 6.62 (s, 1 H), 6.55 (s, 1 H),6.50(s, 1 H),4.02(t,J=6.0Hz,2H),3.82(t,J=5.7Hz,2H),2.26(s,3 H), 1.99 (m, 2 H), 1.58 (s, 1 H).