Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[CH2:19][S:20]([CH3:22])=[O:21])=[C:14]([NH:24][CH3:25])[CH:13]=1>O>[F:11][C:12]1[CH:13]=[C:14]2[C:15]([C:18](=[O:23])[C:19]([S:20]([CH3:22])=[O:21])=[CH:25][N:24]2[CH3:1])=[CH:16][CH:17]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: O
Product: Cn1cc(S(C)=O)c(=O)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
A mixture of acetic anhydride (66.0 ml) and formic acid (45.0 ml) was stirred and heated at 50°-60° under nitrogen for 2 hours and then cooled to ambient temperature. 1-(4-Fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (69.0 g), prepared in a similar manner to that described in Example 1, was added slowly below 30° and the mixture stirred for a further 2 hours. The mixture was cooled in an ice/salt bath to 0° and water (500 ml) added whilst maintaining the temperature below 30°. The mixture was filtered and the filtrate cooled in an ice/salt bath to 0°. Toluene (100 ml) and aqueous sodium hydroxide solution (specific gravity 1.5; 140 ml) were added sequentially, again maintaining the temperature below 30°. The mixture was stirred for 30 minutes at ambient temperature and the product collected by filtration, washed with water (200 ml), toluene (3×50 ml) and hexane (2×50 ml) and then dried at 50° in vacuo to give 7-fluoro-1-methyl-3-methylsulphinyl-4-quinolone, m.p.228.5°-230.5° (53.7 g).
Reaction SMILES: N[C@@](C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)CO.[C:38]([C@H:42]1[CH2:47][CH2:46][C@H:45]([O:48][C:49]2[C:50]([C:66]3[CH:67]=[N:68][CH:69]=[N:70][CH:71]=3)=[C:51]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([C@:59]2([CH3:65])[CH2:63][O:62]C(=O)[NH:60]2)[CH:53]=[CH:52]3)[CH2:44][CH2:43]1)([CH3:41])([CH3:40])[CH3:39]>>[NH2:60][C@@:59]([C:54]1[CH:53]=[CH:52][C:51]2[C:56](=[CH:57][CH:58]=[C:49]([O:48][C@H:45]3[CH2:44][CH2:43][C@H:42]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:47][CH2:46]3)[C:50]=2[C:66]2[CH:67]=[N:68][CH:69]=[N:70][CH:71]=2)[CH:55]=1)([CH3:65])[CH2:63][OH:62]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2-c2cncnc2)CC1
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2ccc(OC(F)(F)F)cc2)CC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2-c2cncnc2)CC1

Procedure:
(R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)propan-1-ol was synthesized as per (R)-2-amino-2-(6-(trans-4-tert-butylcyclohexyloxy)-5-(4-(trifluoromethoxy)phenyl)naphthalen-2-yl)propan-1-ol (Example 221) in 48% yield using (R)-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(pyrimidin-5-yl)naphthalen-2-yl)-4-methyloxazolidin-2-one as starting material. MS: m/z 417.28 [M−16]+. 1H NMR (MeOD) δ: 9.21 (s, 1H), 8.79 (s, 2H), 7.99-8.05 (m, 2H), 7.59 (dd, J=9.0, 2.0 Hz, 1H), 7.52 (d, J=9.3 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 4.26-4.35 (m, 1H), 3.73 (d, J=10.8 Hz, 1H), 3.69 (d, J=10.8 Hz, 1H), 2.08-2.15 (m, 2H), 1.80-1.87 (m, 2H), 1.52 (s, 3H), 1.14-1.23 (m, 4H), 0.96-1.06 (m, 1H), 0.88 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Cl:37]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]([Cl:37])=[N:10][N:9]=[C:8]2[C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nncn1Cc1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1nnc(Cl)n1Cc1ccc(Cl)cc1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
To a solution of Boc-protected triazole from Example 3 (4.344 g, 12 mmol) in 20 mL of THF at −60° C. under argon was slowly added a solution of n-butyl lithium (1.6M) in hexane (7.5 mL, 1.2 eq.) and stirred at −60° C. for 30 minutes. To the mixture was added a suspension of N-chlorosuccinimide (4.67 g, 2.9 eq.) in 20 mL of THF and the mixture was kept at −60° C. for 1 hr before warming up to RT overnight. The reaction mixture was treated with sat. aqueous NaHCO3 (30 mL), then extracted with EtOAc (2×40 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Flash chromatography purification ((Hex/EtOAc) provided the desired product (1.011 g, 21.2%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:24]#[N:25].[OH:26][C:27]1[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=1[CH3:34])[NH2:30].Cl.N1C=CC=CC=1.C(OC(O)C)C>>[ClH:1].[OH:26][C:27]1[CH:28]=[C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:24]#[N:25])[CH:31]=[CH:32][C:33]=1[CH3:34]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCc1ccncc1
Agent: CCOC(C)O
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2cc1OCCCc1ccncc1
Yield: 65.9 %

Procedure:
A mixture of 0.090 g of 4-chloro-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile, 0.050 g of 3-hydroxy-4-methylaniline, 0.039 g of pyridine hydrochloride and 3 ml of ethoxyethanol was stirred under nitrogen at reflux temperature for 20 minutes. The mixture was cooled and filtered. The product was washed with saturated sodium bicarbonate, water, then dried to give 0.080 g of 4-(3-hydroxy-4-methyl-phenylamino)-6-methoxy-7-(3-pyridin-4-yl-propoxy)-quinoline-3-carbonitrile hydrochloride as a solid, dec >153° C. ; mass spectrum (electrospray, m/e): M+H 440.9.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:11]([C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc[nH]1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1ccccc1)(C(=O)OCC)C(=O)c1ccc[nH]1
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
2-(1H-Pyrrole-2-carbonyl)-malonic acid diethyl ester (0.79 mmol, 0.21 g) in DME (3 ml) was treated with lithium bis-trimethylsilylamide (0.79 mmol, 133 mg). The resulting solution was held at room temperature for 30 minutes, then treated with benzyl bromide (0.79 mmol, 0.10 ml). The resulting solution was held at room temperature overnight, then diluted with ethyl acetate (30 ml), and washed with saturated ammonium chloride (10 ml), followed by brine (20 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 0.23 g (84%) of 2-benzyl-2-(1H-pyrrole-2-carbonyl)-malonic acid diethyl ester. 1H NMR (CDCl3) δ10.01 (1H, s), 7.25-7.17 (4H, m), 7.14 (1H, dt, J=2.7, 1.3), 7.03-6.98 (1H, m), 6.86 (1H, ddd, J=3.8, 2.4, 1.3), 6.29-6.25 (1H, m), 4.22 (4H, q, J=7.1), 3.47 (2H, s), 3.39 (2H, s), 1.25 (6H, t, J=1.7).
Reaction SMILES: O=[S:2]1(=[O:29])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([O:18]CC3C=CC([N+]([O-])=O)=CC=3)=O)[CH:13]=[CH:14][C:3]1=2.O=S1C2C=CC=CC=2C2C=C(NC(OCC3C=CC([N+]([O-])=O)=CC=3)=O)C=CC1=2.[CH3:58][NH:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=1>CCOC(C)=O>[O:29]=[S:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]2[CH:11]=[C:12]([NH:15][C:16]([N:59]([CH2:60][CH2:61][C:62]3[CH:67]=[CH:66][N:65]=[CH:64][CH:63]=3)[CH3:58])=[O:18])[CH:13]=[CH:14][C:3]1=2
Reactant: CNCCc1ccncc1
Reactant: O=C(Nc1ccc2c(c1)-c1ccccc1S2(=O)=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(Nc1ccc2c(c1)-c1ccccc1S2=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: CN(CCc1ccncc1)C(=O)Nc1ccc2c(c1)-c1ccccc1S2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5,5-Dioxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene contaminated with 5-oxo-2-(4-nitrobenzoxycarbonylamino)dibenzothiophene (Examples 24 and 25; 396 mg, 1.0 mmol) was suspended in EtOAc (10 ml) and 4-[2-(methylamino)ethyl]pyridine (272 mg, 2.0 mmol) was added in one portion. The resulting mixture was stirred at ambient temperature for 16 hours then further EtOAc (100 ml) was added and the solution was washed with 1 M sodium hydroxide (2×25 ml), water (2×25 ml) and brine (25 ml), dried and evaporated in vacuo. The resulting mixture was separated by preparative HPLC (Dynamax C-18 60A column eluted with 20-90% acetonitrile in water plus 0.1% trifluoroacetic acid). Two products were obtained:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13].[N:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:20]=[O:21].CO>O1CCCC1>[CH2:26]([O:25][C:23]([CH2:22][NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:14]1[NH:15][CH:16]=[CH:17][CH:18]=1)[CH3:13])=[O:24])[CH3:27]
Reactant: CCOC(=O)CN=C=O
Reactant: CC(=C1C(=O)Nc2ccc(N)cc21)c1ccc[nH]1
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Reaction time: 8 h

Procedure:
A solution of 5-amino-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (360 mg, 1.5 mmol) in tetrahydrofuran (15 mL) was treated with ethyl isocyanatoacetate (195 mg, 1.5 mmol) at ambient temperature. After stirring overnight, methanol (5 mL) was added and the reaction was concentrated. Chromatography on SiO2 (7.2 g) using 1:2 hexane/ethyl acetate afforded 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, 3H), 2.82 (s, 3H), 3.96 (d, 2H), 4.22 (q, 2H), 6.44 (m, 2H), 6.88 (d, 1H), 7.16 (m, 1H), 7.28 (d, 1H), 7.40 (m, 1H), 7.96 (m, 1H), 8.76 (s, 1H), 11.02 (s, 1H) ppm; (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:16]N(C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[O:29]1CCCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:27])[C:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:16][OH:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1CCOC1
Reactant: COc1ccc(CCNC(=O)C(=CN(C)C)c2ccc(Cl)cc2)cc1OC
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6.60 g (17.2 mmol) of crude N-[2-(3,4-dimethoxyphenyl)ethyl]-3-dimethylamino-2-(4-chlorophenyl)acrylamide, 80 ml of 5% hydrochloric acid and 100 ml of tetrahydrofuran were mixed and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was followed by extracted with ethyl acetate twice, washed with saturated brine twice, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was washed with hexane and dried to give 4.46 g of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:11][CH2:12][O:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:30]=O)=[CH:20]2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.C(OP([CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])(OCC)=O)C.Cl>CN(C)C=O>[CH3:3][N:4]([CH2:11][CH2:12][O:13][C:14]1[CH:33]=[CH:32][C:17]([CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21](/[CH:30]=[CH:42]/[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:20]2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: CN(CCOc1ccc(Cn2cc(C=O)c(-c3ccccc3)c2)cc1)c1ccccn1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Sodium hydride (60%, oily, 200.0 mg) was added to a solution of 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenylpyrrole-3-carbaldehyde (1.35 g) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, then neutralized using 2N hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl (E)-3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propenoate (1.35 g, yield: 85%) was obtained as an oily substance from the fraction eluted with acetone-hexane (1:2, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].[CH2:14]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[NH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][O:24][C:23](=[O:26])[N:22]1[C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Product: COC(=O)c1ccc(N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Yield: 6.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 22 and using p-(methoxycarbonyl)phenylboronic acid (2.45 g) and (S)-4-benzyloxazolidin-2-one (1.205 g), the title compound (0.142 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22]O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:21][CH:20]([CH2:22][O:9][C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([Br:1])=[C:3]([CH3:10])[CH:4]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(OCC2CN(C(=O)OC(C)(C)C)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-3,5-dimethylphenol (3.7 g, 18.16 mmol), 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester (commercially available, EP1889836 A1, 3.40 g, 18.16 mmol), di-tert-butylazodicarboxylate (4.6 g, 19.97 mmol) and triphenylphosphine (5.24 g, 19.97 mmol) are suspended in dichloromethane (100 mL) and stirred for 2 hours at room temperature. The solvent is removed under vacuum and the residue suspended in diethyl ether, cooled and the precipitate is filtered off. The solvent is removed under vacuum to give the title compound
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C1COCC1.[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[C:35]([O:37][CH:38]3[CH2:43][CH2:42][N:41]([C:44](N4C=CN=C4)=[O:45])[CH2:40][CH2:39]3)[N:34]=[CH:33][N:32]=1)[CH2:26][CH2:25]2)(=[O:21])=[O:20])[CH3:18]>O>[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([O:37][CH:38]3[CH2:39][CH2:40][N:41]([C:44]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:45])[CH2:42][CH2:43]3)[CH:36]=1)[CH2:26][CH2:25]2)(=[O:20])=[O:21])[CH3:18]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Cyclobutanol (90 μL, 1.15 mmol) and potassium tert-butoxide (50 mg, 0.446 mmol) were added to a THF (2.5 mL) suspension of the 5-(ethylsulfonyl)-1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)indoline (109 mg, 0.226 mmol) produced in Reference Example 31, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:ethyl acetate=50:50, V/V; (ii) ethyl acetate]. The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (34.6 mg, yield: 32%).
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:42])C=1.O>C(Cl)Cl>[CH:1]1([S:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH:25]([F:27])[F:26])[N:13]=[C:12]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:11]=2)=[O:42])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(NCCSC2CCCC2)nc(N2CCOCC2)n1
Solvent: O
Solvent: ClCCl
Product: O=S(CCNc1nc(N2CCOCC2)nc(-n2c(C(F)F)nc3ccccc32)n1)C1CCCC1
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
N-[2-(Cyclopentylsulfanyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (60 mg) was dissolved in methylene chloride (1.2 mL), and m-chloroperbenzoic acid (75% wet) (32 mg) was added thereto at 0° C., followed by stirring for 10 minutes. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2-90:10) to obtain N-[2-(cyclopentyl sulfinyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (53 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:59][CH2:58][C@@H:57](O)[CH2:56][CH2:55]1)([CH3:49])([CH3:48])[CH3:47]>O1CCCC1.O>[C:46]([O:50][C:51](=[O:61])[NH:52][CH2:53][C@H:54]1[CH2:55][CH2:56][C@H:57]([O:12][C:7]2[C:6]3[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH2:58][CH2:59]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](O)CC1
Reactant: Oc1ccnc2c(F)cccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Oc2ccnc3c(F)cccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Fluoroquinolin-4-ol (948 mg, 5.81 mmol), triphenylphosphine (1.52 g, 5.81 mmol) and DIAD (1.17 g, 5.81 mmol) were dissolved in tetrahydrofuran (140 mL). After adding tert-butyl-N-[(cis-4-hydroxycyclohexyl)methyl]carbamate (1.11 g, 4.84 mmol), the reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate and the combined organic phases were dried over sodium sulphate. After removal of the solvent residues and chromatographic purification of the residue, the product was obtained at 42% yield (960 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8](O)=[O:9].P(Cl)(Cl)(Cl)(Cl)Cl.[C:31]([O:40][CH2:41][CH3:42])(=[O:39])[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH2:34]>ClCCl>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([NH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[C:31]([O:40][CH2:41][CH3:42])=[O:39])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccccc1N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1NC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
Under an ice-cooled condition, 332 mg (1 mmol) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl) pyridine-3-carboxylic acid was suspended in dried dichloromethane. The mixture was stirred with addition of 229 mg (1.1 mmol) of phosphorus pentachloride little by little for one hour. At -30° C., 1650 mg (10 mmol) of ethyl anthranilate was added to the reaction mixture. The reaction mixture was further stirred at room temperature for one hour. After washing with water, the reaction mixture was dried over anhydrous sodium sulfate. The thus obtained mixture was chromatographed on a silica gel column for purification, whereby 486 mg (100%) of the captioned compound was obtained as an oily material.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([C@@H]2C[C@H]2C(O)=O)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][C@@H:9]2[CH2:32][C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C[C@@H]2C[C@H]2c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexy)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-2-phenylcyclopropanecarboxylic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25](=[O:37])[CH2:26]C(NC2C=CC(F)=CC=2)=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:15]CCN2CCOCC2)C=1.[CH2:38]([O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.COCCOCCOC>O>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]([NH:50][C:13]2[N:12]=[CH:11][N:15]=[C:9]([O:8][C:7]3[CH:6]=[CH:5][C:4]([NH:24][C:25](=[O:37])[CH3:26])=[CH:3][C:2]=3[F:1])[CH:14]=2)=[CH:51][CH:52]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(CC(=O)Nc1ccc(Oc2ccnc(NCCN3CCOCC3)c2)c(F)c1)Nc1ccc(F)cc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Solvent: COCCOCCOC
Solvent: O
Product: CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Temperature: 160 °C
Yield: 45 %

Procedure:
A mixture of N-(4-(6-chloropyrimidin-4-yloxy)-3-fluorophenyl)acetamide (Compound B of Example 13, 281 mg, 1.00 mmol), 4-benzyloxyaniline (Aldrich, 398 mg, 2.00 mmol), and 2-methoxyethyl ether (2 mL) was heated at 160° C. for 45 min. The cooled mixture was treated with H2O (50 mL) and extracted with EtOAc (100 mL). The EtOAc extract was washed with brine (3×25 mL), dried (MgSO4) and concentrated in vacuo to give the title compound (200 mg, 22%) as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.43 (s, 1H), 8.23 (s, 1H), 7.72 (dd, 1H, J=12.5, 2.0 Hz), 7.44-7.42 (m, 4H), 7.38 (dd, 2H, J=8.0, 6.9 Hz), 7.33-7.23 (m, 3H), 6.98 (d, 2H, J=9.0 Hz), 6.07 (s, 1H), 5.07 (s, 2H), 2.05 (s, 3H); MS (ESI+) m/z 445.13 (M+H)+.