Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C@@H:8]2[C:17](=[O:18])[C@@:4]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])([C:5]([O:20][CH3:21])=[CH:6][C:7]2=[O:19])[CH2:3]1.[CH3:27][O:28][CH2:29]COC.C(N(C(C)C)CC)(C)C.COCCl>CCCCCC>[CH3:21][O:20][C:5]1[C@:4]2([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:17](=[O:18])[C@@H:8]([C@:9]([CH3:16])([CH2:10][CH2:11][CH:12]=[C:13]([CH3:14])[CH3:15])[C@@H:2]([O:1][CH2:27][O:28][CH3:29])[CH2:3]2)[C:7](=[O:19])[CH:6]=1
Reactant: COC1=CC(=O)[C@H]2C(=O)[C@]1(CC=C(C)C)C[C@H](O)[C@@]2(C)CCC=C(C)C
Reactant: COCCOC
Agent: COCCl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H]1C[C@@]2(CC=C(C)C)C(=O)[C@H](C(=O)C=C2OC)[C@]1(C)CCC=C(C)C
Temperature: 60 °C
Yield: 97 %

Procedure:
A flame-dried round-bottom flask under argon atmosphere is charged with 458 mg (1.22 mmol, 1 equiv.) of starting material 20, 1.3 mL 1,2-dimethoxyethane, and 953 μL (5.34 mmol, 5.5 equiv.) diisopropylethylamine. With stirring, 376 μL (4.95 mmol, 5.1 equiv.) methoxymethyl chloride is added dropwise. The stirring reaction is heated to 60° C. for four hours before being allowed to cool to room temperature. Once the reaction has cooled, it is transferred to a separatory funnel in 50 mL hexane and the organic layer is washed sequentially with 10% aqueous hydrochloric acid, water, and brine. The organic solution is then dried with MgSO4 and concentrated in vacuo to give a clear to yellow oil. The crude product is purified by silica gel chromatography (Rf=0.25 in 4:1 hexane:ethyl acetate) to give 380 mg (97% yield) of 50 as a clear oil. 1H NMR (500 MHz, CDCl3) δ ppm 5.67 (s, 1H), 5.07 (tt, J=7.1, 1.4 Hz, 1H), 4.97 (tt, J=6.2, 1.3 Hz, 1H), 4.58 (dd, J=36.8, 7.0 Hz, 2H), 3.75 (s, 3H), 3.60 (dd, J=11.2, 5.5 Hz, 1H), 3.32 (s, 3H), 3.18 (s, 3H), 2.48 (dd, J=14.4, 6.2 Hz, 1H), 2.29-2.42 (m, 2H), 2.21 (dd, J=13.4, 5.4 Hz, 3H), 1.87 (ddt, J=18.3, 12.1, 5.5, 5.5 Hz, 3H), 1.78 (dd, J=13.3, 11.4 Hz, 3H), 1.65 (s, 12H), 1.57 (ddd, J=12.9, 4.6 Hz, 1H), 1.27 (ddd, J=12.9, 4.5 Hz, 1H), 0.92 (s, 3H). 13C NMR (126 MHz, CDCl3) δ ppm 205.2, 193.0, 177.3, 134.3, 131.8, 124.3, 119.1, 106.0, 97.1, 77.4, 76.9, 69.2, 57.1, 55.9, 55.8, 46.3, 37.6, 37.4, 29.6, 26.0, 25.9, 21.6, 18.1, 17.8, 16.5. HRMS-ESI (m/z): [M+H]+ calculated for C24H36O5, 405.2636. found 405.2637.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][C:10](O)=[C:9]2O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[CH2:11][CH2:10][CH2:9]2)[CH:2]=[CH2:3]
Reactant: O=C1CC(O)=C(O)c2cc(O)ccc21
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2c(c1)CCCC2=O
Temperature: 25 °C

Procedure:
3.30 ml of allyl bromide was added to a mixture consisting of 5.62 g of 6-hydroxy-3,4-dihydroxynaphthalen-1(2H)-one, 5.27 g of potassium carbonate, and 60 ml of acetone. The obtained mixture was heated to reflux under nitrogen atmosphere overnight. The reaction solution was cooled to a room temperature, and the precipitate was removed by filtration. The solvent was removed under a reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 6.35 g of the subject compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[NH:8][N:7]=1)=[O:5])[CH3:2].[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][Si:16]([C:29]([CH3:31])([CH3:30])[CH3:32])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:13]=2)[N:8]([CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-tert-butyldiphenylsilyloxyindazole-3-carboxylate (1.461 g) which can be prepared according to the method described in Reference example 18, etc. was dissolved in toluene (16.5 mL; manufactured by Wako Pure Chemical Industries, Ltd.), added with 3,4-dihydro-2H-pyran (0.6 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) and toluene sulfonic acid-monohydrate (0.1293 g), followed by stirring overnight at 60° C. under nitrogen atmosphere. The reaction solution was poured to a saturated aqueous solution of sodium hydrogen carbonate and extracted once with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=96:4→75:25) to obtain the title compound (1.334 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C1COCC1.[CH2:17]([N:19]=[C:20]=[O:21])[CH3:18]>CCOCC>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH:9][C:20]([NH:19][CH2:17][CH3:18])=[O:21])=[O:7])=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCNC(=O)NNC(=O)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
A stirred suspension of 4-chlorobenzoic acid, hydrazide (17.1 g, 1.00×10-1 mole), and THF (425 ml) was warmed until homogeneous, at which time ethyl isocyanate (8.7 ml, 1.1×10-1 mole) was added via syringe. A precipitate soon formed. After stirring overnight the reaction was diluted with Et2O and the precipitate was collected by filtration affording a colorless powder: 23.7 g (98%). Crystallization from ethanol gave a colorless solid: 21.4 g (88%), Mp 237°-239° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:25]1([NH:24][C:21]([C:8]2[CH:9]=[N:10][C:11]3[C:16]([C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:19])[F:20])=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of 4-phenyl-8-trifluoromethyl-quinoline-3-carboxylic acid (0.24 g, 0.757 mmole) in 15 mL DMF was added aniline (0.137 mL, 1.51 mmole), EDCI-HCl (0.218 g, 1.13 mmole), and DMAP (0.184 g, 1.51 mmole). After stirring at room temperature overnight, the solution was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded onto silica gel and chromatographed with hexanes:ethyl acetate (9:1) to afford 0.211 g (71%) of the title compound as a white solid: mp 207-208° C.; Calculated mass for C23H15N2F3O is 392.38, found by ESI MS, 393 (M+H)+, found by HRMS (ESI), 393.12056 (M+H)+; 1H NMR (DMSO-d6) δ 10.40 (bs, 1H), 9.25 (bs, 1H), 8.31 (d, 1H, J=6.9 Hz), 7.90 (d, 1H, J=8.3 Hz), 7.77 (t, 1H, J=7.5 Hz), 7.47 (m, 7H), 7.28 (t, 2H, J=7.5 Hz), 7.06 (t, 1H, J=7.06 Hz). Anal. Calcd for C23H15N2F3O: C, 70.40; H, 3.85; N, 7.14. Found: C, 70.00; H, 3.61; N, 6.96.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:12]=1[C:13](Cl)=[O:14]>>[OH:9][C:3]1[CH:4]=[CH:5][C:6]([Br:8])=[CH:7][C:2]=1[NH:1][C:13](=[O:14])[C:12]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:11]=1[F:10]
Reactant: Nc1cc(Br)ccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(Nc1cc(Br)ccc1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-4-bromophenol (752 mg, 4.0 mmol) and 2-fluoro-5-nitrobenzoyl chloride (814 g, 4.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>CN(C=O)C>[CH:27]1([CH2:26][N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([F:1])=[N:3][C:4]=3[NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:29][CH2:28]1
Reactant: BrCC1CC1
Reactant: Fc1nc(NCc2cccnc2)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1nc(NCc2cccnc2)c2ncn(CC3CC3)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-fluoro-6-[(pyridin-3-ylmethyl)-amino]purine (1 g, 4.10 mmol) in DMF (12 ml) under argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 2.84 g, 5 eq, 20.52 mmol) followed by (bromomethyl)cyclopropane (5.53 g 10 eq, 41 mmol). The reaction mixture was stirred at RT for 24 h, when TLC (CHC13: Me0H; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (50 ml) and EtOAc (50 mL); the aqueous phase was separated and extracted with more EtOAc (2×50 ml). The bulked organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient flash column chormoatography on silica gel, eluted with CHCl3:MeOH (100:0→95:5), to afford the product as a colorless gum; Yield 0.8 g (68%) δH (250 MHz, CDCl3) 0.24-0.15 (2 H, m, CHH and CHH of Cp), 0.48-0.38 (2 H, m, CHH and CHH of Cp), 1.11-0.95 (1 H, m, CH of Cp), 2.56 (1 H, s, br, NH), 3.69 (2 H, d, J 7.5, HCH2Cp), 4.58 (2 H, s, br, HCH2Ar), 7.04-6.96 (1 H, m, ArH), 7.51-7.45 (2 H, m, ArH), 8.26-8.24 (1 H, m, ArH), 8.37 (1 H, s, br, ArH); δc (250 MHz, CDCl3) 156.32 (C), 156.01 (C), 149.29 (CH), 148.97 (CH), 139.85 (CH), 139.8 (C), 135.54 (CH), 133.81 ©, 123.51 (CH, 117.86 (C), 48.52 (CH2), 42.09 (CH2), 11.06 (CH3), 5.28 (2×(CH2); m/z 299.2 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH2:11]([N:13]1C(=O)O[C:16](=[O:17])[C:15]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:14]12)[CH3:12]>>[CH2:11]([NH:13][C:14]1[CH:24]=[CH:23][CH:22]=[CH:21][C:15]=1[C:16]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:17])[CH3:12]
Reactant: CCn1c(=O)oc(=O)c2ccccc21
Reactant: Oc1n[nH]c2ccccc12
Product: CCNc1ccccc1C(=O)n1nc(O)c2ccccc21
Yield: 47.7 %

Procedure:
1H-Indazol-3-ol was reacted with N-ethylisatoic anhydride according to the general procedure A above and afforded the desired amine as a canary yellow solid, in 47.7% yield; m.p. 163°-165° C.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][CH2:16][CH2:17]O.O1CCCC1.[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:54]=[C:53]([F:55])[CH:52]=[CH:51][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH2:17][CH2:16][O:15][CH3:14])[S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])=[CH:30][C:29]=1[C:40]1[C:41]2[CH:50]=[CH:49][NH:48][C:42]=2[C:43](=[O:47])[N:44]([CH3:46])[CH:45]=1
Reactant: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Reactant: COCCO
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(CCOC)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Yield: 4.24 %

Procedure:
To a 4 mL vial was added (azidocarbonyl) dipiperidine (ADDP) (25.9 mg, 0.102 mmol) in anhydrous toluene. The vial was introduced into a dry box and tributylphosphine (41.5 mg, 3 eq, 0.205 mmol) was added to the vial. This mixture was shaken until the solution turned clear. To this solution was added a solution of 2-methoxyethanol in anhydrous tetrahydrofuran (1.2 equivalents, 0.082 mmol, 6.24 mg). This mixture was stirred for 10 minutes at ambient temperature. To this mixture was added a solution of Example 36e (0.068 mmol, 31.4 mg) in anhydrous toluene/anhydrous tetrahydrofuran (1:1 v/v) (1 mL). The reaction mixture was stirred at room temperature overnight in the dry box. The reaction mixture was concentrated to dryness and the residue purified by reverse phase HPLC (C18, 10-100% acetonitrile in 0.1% TFA/water) to provide the title compound (4.24%, 1.5 mg). 1H NMR (400 MHz, DMSO d6/D2O) δ ppm 7.49 (d, J=2.75 Hz, 1H), 7.38-7.43 (m, 1H), 7.37 (d, J=2.75 Hz, 1H), 7.35-7.36 (m, 1H), 7.34 (d, J=2.75 Hz, 1H), 7.22-7.27 (m, 1H), 7.05-7.11 (m, 1H), 6.87 (d, J=8.54 Hz, 1H), 6.30 (d, J=2.75 Hz, 1H), 3.78-3.81 (m, 2H), 3.57 (s, 3H), 3.37 (t, J=5.65 Hz, 2H), 3.20 (s, 3H), 3.16 (t, J=7.32 Hz, 2H), 1.26 (t, J=7.48 Hz, 3H). ESI+ m/z=518.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][O:14][C:15]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][C:18]([CH:19]=O)=[C:17]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:16]=1>>[CH3:13][O:14][C:15]1[C:22]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:21][C:18](/[CH:19]=[CH:2]/[C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][CH:5]=2)=[O:3])=[C:17]([O:28][CH2:29][CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:16]=1
Reactant: CC(=O)c1ccc(C(N)=O)cc1
Reactant: COc1cc(OCCCN2CCOCC2)c(C=O)cc1-c1cccs1
Product: COc1cc(OCCCN2CCOCC2)c(/C=C/C(=O)c2ccc(C(N)=O)cc2)cc1-c1cccs1

Procedure:
The title compound was prepared by condensing 4-Acetyl-benzamide (Ex-92A) and 4-methoxy-2-(3-morpholin-4-yl-propoxy)-5-thiophen-2-yl-benzaldehyde (Ex-66A) in a similar manner as described in Ex-92. Orange solid, mp 81–83° C. 1H-NMR (CDCl3) δ 8.08 (m, 3H), 7.94 (d, 2H), 7.86 (s, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 7.32 (d, 1H), 7.10 (m, 1H), 6.55 (s, 1H), 4.19 (t, 2H), 3.99 (s, 3H), 3.72 (t, 4H), 2.59 (t, 2H), 2.12 (t, 4H), 1.98 (quintet, 2H). MS m/z=506 ([M]+, 34%), 100 (100%). 28%. Anal. calculated for C28H30N2O5S.2/5H2O: C, 65.45; H, 6.04; S, 6.24; found C, 65.30; H, 6.16; S, 6.17.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:16])=[CH:13][N:14]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([NH:8][C:10]1[S:11][C:12]([C:15]([NH:17][C:18]2[S:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:16])=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cnc(Br)s3)s2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cnc(NC(=O)c3cnc(NCc4ccccc4)s3)s2)cc1
Yield: 70.8 %

Procedure:
Benzylamine (0.143 mL, 1.32 mmol) was added to a solution of 2-bromo-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (250 mg, 0.66 mmol) in DMF (4 mL). The reaction mixture was stirred at reflux for 2 hrs. Then it was diluted with AcOEt and washed with water, dried with Na2SO4 and concentrated. The crude product was purified by precipitation (AcOEt/PE), yielding 2-(benzylamino)-N-(5-p-tolylthiazol-2-yl)thiazole-5-carboxamide (190 mg, 71%) as a solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:24][CH2:23][CH2:22][CH2:21]1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccccc1N1CCCC1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccc2N2CCCC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 2-pyrrolidin-1-yl-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[N+:10]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:14]=1)([O-:12])=[O:11].[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>ClCCl>[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:18]=[CH:17][N:16]=2)[CH2:21][CH2:22]1)=[O:30]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccnc(OC2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1c(F)cccc1F)N1CCC(Oc2cc([N+](=O)[O-])ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
Add triethylamine (2.57 mL, 18.5 mmol) to a suspension of 1.1 g (3.7 mmol) of 4-nitro-2-(piperidin-4-yloxy)-pyridine dihydrochloride in dry dichloromethane (50 mL). Then add 2,6-difluorobenzoyl chloride, 0.512 mL (4.07 mmol). Stir the mixture at room temperature overnight. Add water (50 mL) and separate organic layer. Dry with MgSO4 and filter. Evaporate solvents to obtain 1.22 g (91% yield) of (2,6-difluoro-phenyl)-[4-(4-nitro-pyridin-2-yloxy)-piperidin-1-yl]-methanone as a yellow solid (ES+(m/z)=364 [M+H].
Reaction SMILES: C([O:4][C:5](=[O:62])[C@@H:6]([O:59][CH2:60][CH3:61])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([O:48][CH2:49][CH3:50])[C:42]([O:44]C(C)C)=[O:43])=[CH:36][CH:35]=4)=[CH:26][C:25]=3[C:51]([F:54])([F:53])[F:52])=[C:20]([C:55]([F:58])([F:57])[F:56])[CH:19]=2)=[CH:10][CH:9]=1)(C)C.[OH-].[Na+]>C(O)C>[C:5]([C@@H:6]([O:59][CH2:60][CH3:61])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][O:33][C:34]4[CH:39]=[CH:38][C:37]([CH2:40][C@H:41]([O:48][CH2:49][CH3:50])[C:42]([OH:44])=[O:43])=[CH:36][CH:35]=4)=[CH:26][C:25]=3[C:51]([F:54])([F:53])[F:52])=[C:20]([C:55]([F:56])([F:58])[F:57])[CH:19]=2)=[CH:12][CH:13]=1)([OH:62])=[O:4]
Reactant: CCO[C@@H](Cc1ccc(OCCCc2ccc(-c3ccc(CCCOc4ccc(C[C@H](OCC)C(=O)OC(C)C)cc4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1)C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(-c3ccc(CCCOc4ccc(C[C@H](OCC)C(=O)O)cc4)cc3C(F)(F)F)c(C(F)(F)F)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (S,S)-2-ethoxy-3-{4-[3-(4′-{3-[4-(2-ethoxy-2-isopropoxycarbonyl-ethyl)-phenoxy]-propyl}-2,2′-bis-trifluoromethyl-biphenyl-4-yl)-propoxy]-phenyl}-propionic acid isopropyl ester (example 13) in ethanol (4 ml) was added 1 N NaOH (0.6 ml) at room temperature. The reaction was stirred for 48 hours at room temperature and evaporated. The residue was treated with 1 N HCl and extracted with methylene chloride (2×15 ml). The combined organic phases were dried and evaporated to give the title compound in 105 mg (78%) yield.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](Cl)=[O:8].[NH2:10][C:11]1[C:12]([I:29])=[C:13]([C:22]([NH:24][CH2:25][CH:26]([OH:28])[CH3:27])=[O:23])[C:14]([I:21])=[C:15]([C:19]=1[I:20])[C:16]([OH:18])=[O:17].CC(N(C)C)=O>O>[OH:28][CH:26]([CH3:27])[CH2:25][NH:24][C:22](=[O:23])[C:13]1[C:14]([I:21])=[C:15]([C:19]([I:20])=[C:11]([NH:10][C:7](=[O:8])[CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=1[I:29])[C:16]([OH:18])=[O:17]
Reactant: CC(O)CNC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: COCCOCC(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COCCOCC(=O)Nc1c(I)c(C(=O)O)c(I)c(C(=O)NCC(C)O)c1I
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At a maximum of 10° C. (ice cooling), 16.5 ml. of methoxyethoxyacetyl chloride is added dropwise within 30 minutes with agitation to 30.8 g. (50 mmol) of 5-amino-(2-hydroxypropyl)2,4,6-triiodoisophthalamic acid in 60 ml. of dimethylacetamide. The mixture is stirred for 1 hour at 0° C. and then for 16 hours at room temperature. Thereafter, another 2 ml. of the acid chloride is added thereto, and the mixture is stirred at room temperature for 4 hours. Then, 10 ml. of water is added and the mixture is concentrated under vacuum. The residue is dissolved in 350 ml. of water and neutralized with 32% sodium hydroxide solution. The mixture is combined with another 5 ml. of 32% sodium hydroxide solution and then stirred for some time after adding 5 g. of active carbon. After the carbon has been removed, the mixture is acidified with concentrated hydrochloric acid, allowed to stand for a period of time and vacuum-filtered. The resulting precipitate is dried under vacuum. Yield: 21.3 g. (58%), m.p. 275° C., with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[C:4]([CH:15]=O)[CH:3]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)=[O:7])=[C:4](/[CH:15]=[CH:22]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(Br)ccc1C(=O)N1CCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(Br)ccc1C(=O)N1CCCC1

Procedure:
A solution of 1.27 g (4.5 mmol) of N-(4-bromo-2-formyl-benzoyl)-pyrrolidine and 1.65 g (4.5 mmol) of carboethoxymethylene triphenylphosphorane in 45 ml of toluene is heated to 80° C. for 4 hours. After removal of the solvent the residue is purified by flash chromatography (silica gel; methylene chloride/ethanol 99:1 to 99:2).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:18]([F:17])=[CH:19][CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(F)cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(F)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-fluorobenzoic acid
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NCC1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: C[C@H](O)C(=O)N1CCCC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-3-ylmethyl)-amide (example A145) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.