Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:56][O:57][CH2:58][C@@H:59]1[CH2:63][CH2:62][CH2:61][NH:60]1>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:60]2[CH2:61][CH2:62][CH2:63][C@@H:59]2[CH2:58][O:57][CH3:56])=[O:32])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: COC[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC[C@H]1CCCN1C(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (S)-(+)-2-(methoxymethyl)pyrrolidine (46 mg, 2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:48])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37](=[O:47])[CH2:38][NH:39][C:40](OC(C)(C)C)=[O:41])=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)[N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].Cl.CCN(C(C)C)C(C)C.[C:59]([O:63][C:64]([N:66]1[CH2:70][CH:69]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:68][CH:67]1C(O)=O)=[O:65])([CH3:62])([CH3:61])[CH3:60].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O1CCOCC1.CN(C=O)C.CCOC(C)=O>[C:59]([O:63][C:64]([N:66]1[CH2:70][CH:69]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH2:68][CH:67]1[C:40](=[O:41])[NH:39][CH2:38][C:37]([C:34]1[CH:35]=[CH:36][C:31]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:19]4[N:20]=[C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:48])[CH:6]([CH3:8])[CH3:7])[NH:17][CH:18]=4)[CH:22]=3)[CH:27]=2)=[CH:32][CH:33]=1)=[O:47])=[O:65])([CH3:61])([CH3:62])[CH3:60]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)CC1C(=O)O
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc3cc(-c4ccc(C(=O)CNC(=O)C5CC(c6ccccc6)CN5C(=O)OC(C)(C)C)cc4)ccc3c2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 174.4 %

Procedure:
{1-[2-(4-{6-[4-(2-tert-Butoxycarbonylamino-acetyl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (61.0 mg, 0.095 mmol) was dissolved in DCM (1 mL) and HCl in dioxane (4M, 1 mL) was added and stirring at room temperature was continued. After 90 minutes, all volatiles were removed in vacuo. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (1.0 mL) and DIEA (23.7 mg, 0.183 mmol) was added. A solution of 4-Phenyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (17.8 mg, 0.061 mmol), HATU (23.3 mg, 0.061 mmol) and DIEA (7.9 mg, 0.061 mmol) in DMF (0.5 mL) was added. The reaction was stirred at room temperature. After 20 minutes, the reaction was diluted with EtOAc and was washed with brine, saturated sodium bicarbonate solution, brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material (88 mg), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2](=[C:4]([C:25]([O:27][CH2:28]C)=[O:26])[CH:5]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](=O)[CH2:8][Cl:9])[CH3:3].Cl.[C:31]([O-])(O)=O.[Na+]>CCO>[Cl:9][CH2:8][C:7]1[NH:1][C:2]([CH3:3])=[C:4]([C:25]([O:27][CH3:28])=[O:26])[CH:5]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)[C:6]=1[C:11]([O:13][CH2:14][CH3:31])=[O:12]
Reactant: CCOC(=O)C(=C(C)N)C(c1cccc(C(F)(F)F)c1)C(C(=O)CCl)C(=O)OC
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(CCl)NC(C)=C(C(=O)OC)C1c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-amino-7-chloro-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl)-6-oxo-2-heptene (5 g) and aqueous concentrated HCl (0.2 ml) in EtOH (50 ml) is stirred at 0° C. for 2 hours then it is neutralized with a drop of a saturated NaHCO3 solution and evaporated to dryness. The residue is dissolved in AcOEt (50 ml), washed with water (3×15 ml), dried on Na2SO4 and concentrated in vacuum. The residue is dissolved in Et2O/diisopropylether to give 3.6 g of 2-chloromethyl-3-carboethoxy-5-carbomethoxy-4-(m-trifluoromethylphenyl)-6-methyl-1,4-dihydropyridine, m.p. 115°-116° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[S:37])=[C:31]([CH:39]([CH3:41])[CH3:40])[CH:30]=1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[N:16]=[CH:15][N:14]([C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:3])=[S:37])=[C:31]([CH:39]([CH3:41])[CH3:40])[CH:30]=1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: CC(C)c1cc(F)ccc1NC(N)=S
Product: CC(C)c1cc(F)ccc1NC(=S)NC(=O)NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(4-fluoro-2-isopropylphenyl)thiourea isolated as a white solid (0.085 g, 27%): 1H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.17 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.95 (m, 2H), 7.68-7.58 (m, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 2H), 7.15 (dd, J=10.3, 3.0 Hz, 1H), 7.03 (td, J=8.3, 2.9 Hz, 2H), 3.47 (q, J=6.6 Hz, 2H), 3.01-2.82 (m, 3H), 1.14 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.97, −114.40; ESIMS m/z 587 ([M+H]+), 585 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[CH3:14].B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)(O)O>>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:12][C:11]([CH3:13])=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1ccc(-c2ccc(Br)c(C)c2)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1

Procedure:
5-(4-Bromo-3-methylphenyl)-2-methylfuran (D118) (600 mg, 2.39 mmol) and 4-boronobenzoic acid (397 mg, 2.39 mmol) were converted to the title compound using a method similar to that of Description 11, as a pale yellow solid (207 mg, 30%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17](=O)[C:16]2[C:15]([C:19](OC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:10][CH:9]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:2].O.[NH2:30][NH2:31]>CO>[CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]1[C:17]2=[N:30][NH:31][C:19](=[O:20])[C:15]3[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=32)[NH:10][CH:9]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:2]
Reactant: NN
Reactant: CCn1ccnc1C1C(=O)c2c(cccc2C(=O)OC)NC1c1ccccc1
Solvent: O
Solvent: CO
Product: CCn1ccnc1C1c2n[nH]c(=O)c3cccc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
Methyl 3-(1-ethyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (190 mg, 0.49 mmol) and hydrazine monohydrate (2 mL) were added to methanol (15 mL) and the mixture was stirred room temperature for 3 hrs. Methanol was evaporated and then filtered. The filtrate was concentrated to give 9-(1-ethyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one as a white solid (50 mg, yield 28%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm); 0.96 (t, 3H), 3.74-3.79 (m, 2H), 4.61 (d, 1H), 4.95 (d, 1H), 6.78 (dd, 1H), 6.91 (dd, 1H), 7.16 (d, 1H), 7.23-7.31 (m, 4H), 7.37 (s, 3H), 7.57 (t, 1H). LC-MS (ESI) m/z: 358 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[CH2:16]1[CH2:21][NH:20][CH2:19][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:20]1[CH2:21][CH2:16][CH2:17][CH:18]([C:22]([F:25])([F:24])[F:23])[CH2:19]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: FC(F)(F)C1CCCNC1
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCCC(C(F)(F)F)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and DL-3-(trifluoromethyl)piperidine (9.2 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C16H14ClF3N2O2: 358.0696, found 358.0702.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:31])[N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][C:22](=[O:31])[N:23]3[CH2:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=COCc1ccccc1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CNCCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O)cc3)cc21

Procedure:
Analogously to Example 10f, 0.190 g of 7-[4-(4-hydroxyphenyl)piperidin-3-yloxymethyl]-1-(3-methoxypropyl)-3,4-dihydro-1H-quinolin-2-one and 0.070 ml of benzyl formate are reacted. The title compound is obtained as a white foam. Rf=0.19 (2:1 EtOAc-heptane); Rt=6.03.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1)#[CH:9].[CH3:19][C:20]1([CH3:27])[C:24]([CH3:26])([CH3:25])[O:23][BH:22][O:21]1>[H-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Zr+2].CCCCCC>[CH3:19][C:20]1([CH3:27])[C:24]([CH3:26])([CH3:25])[O:23][B:22](/[CH:9]=[CH:8]/[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[O:21]1
Reactant: C#Cc1ccc(C(C)C)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: [Zr+2]
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(/C=C/B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
A mixture of triethylamine (246 mg), 1-ethynyl-4-isopropylbenzene (3500 mg), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3417 mg) and zirconocene chloride hydride (626 mg) was stirred at 80° C. overnight. To the reaction mixture was added hexane, and the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6030 mg) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[NH2:12][C:13]1[CH:18]=[C:17]([C:2]2[C:6]3[N:7]=[C:8]([NH2:11])[N:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncc2scc(Br)c2n1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2csc3cnc(N)nc23)c1
Yield: 75.9 %

Procedure:
7-(3-Aminophenyl)thieno[3,2-d]pyrimidin-2-amine (160 mg, 75% yield) was prepared in the same manner as Step 6 of Example 1 using 7-bromothieno[3,2-d]pyrimidin-2-amine (200 mg, 0.87 mmol) and 3-aminophenylboronic acid (120 mg, 0.87 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:23]1([C:29]2[O:30][C:31]([CH3:47])=[C:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:22])[C@:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][C:32]2[N:33]=[C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:30][C:31]=2[CH3:47])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)[C@@](C)(Cc1ccc(O)cc1)Oc1ccccc1
Product: CCOC(=O)[C@@](C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)Oc1ccccc1

Procedure:
(R)-3-(4-hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester, shown below, from Example 1, Step C, and toluene-4-sulfonic acid 2-(2-phenyl-5-methyloxazol-4-yl)-ethyl ester were reacted, as described in Example 1, Step D, to provide (R)-3-{4-[2-(2-phenyl-5-methyl-oxazol-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxypropionic acid ethyl ester, shown below, as a colorless oil (61%). 1H NMR (300 MHz, CDCl3): δ 7.96 (m, 2H), 7.41 (m, 3H), 7.19 (t, 2H), 7.12 (d, 2H), 6.93 (t, 1H), 6.82 (m, 4H), 4.20 (q, 2H), 4.18 (t, 2H), 3.23 (d, 1H), 3.06 (d, 1H), 2.95 (t, 2H), 2.37 (s, 3H), 1.33 (s, 3H). MS [EI+] 486 (M+H)+, [EI−] 484 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: CC(C)CNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NCC(C)C)CC2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
14.40 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 9.20 g of 1-[1-(isobutylaminocarbonyl)ethyl]piperazine and 5.70 g of triethylamine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:7]1[C:8]([O:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Oc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1nc2ccccc2o1
Product: CCc1c(Oc2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 54.9 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (215 mg, yield: 54.9%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14].[C:31](Cl)(=[O:34])[CH2:32][CH3:33]>C(Cl)Cl.N1C=CC=CC=1>[C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([F:30])[CH:21]=3)[N:16]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH3:14])(=[O:34])[CH2:32][CH3:33]
Reactant: COC(=O)c1ccc(-c2noc(-c3ccc(N4CCCCC4C)c(N)c3)n2)cc1F
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1N1CCCCC1C
Temperature: 40 °C

Procedure:
Methyl 4-{5-[3-amino-4-(2-methylpiperidin-1-yl)phenyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate, prepared as in example 67, Steps 1 and 2, (100 mg; 0.24 mmol) was suspended in a DCM/Pyridine mixture (4 mL, 1:1). Propionyl chloride (25 μL, 0.29 mmol) was added and the mixture was heated to 40° C. for 18 h. After this time, solvents were removed under vacuum and title compound was obtained as an off-white powder after trituration with MeOH (96 mg; 83%). LC/MS (Method B): 467.4 (M+H)+. HPLC (Method A) Rt. 5.69 min (purity: 93.6%).
Reaction SMILES: [C:1]1([C:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+:10].[C:11](=[O:13])=[O:12]>>[C:11]([O-:13])(=[O:12])[C:4]1[CH:5]=[CH:6][C:1]([C:7]([O-:9])=[O:8])=[CH:2][CH:3]=1.[K+:10].[K+:10]
Reactant: O=C([O-])c1ccccc1
Reactant: O=C=O
Agent: [K+]
Product: O=C([O-])c1ccc(C(=O)[O-])cc1

Procedure:
isomerizing said dried potassium benzene carboxylic acid salt mixture by heating under an atmosphere comprising carbon dioxide to produce a dipotassium terephthalic acid salt;
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:31][C:30](=O)[CH:29]=[C:28]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([N:39]3[CH:43]=[N:42][CH:41]=[N:40]3)[CH:34]=2)[O:27]1>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:31])[CH2:29][C:28](=[O:27])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[CH:43]=[N:42][CH:41]=[N:40]2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3cncn3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example G33) and 2,2-dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example J13) according to the general procedure K. Obtained as a yellow solid (230 mg).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:10]([O:14][CH2:15][CH:16](O)[CH3:17])(=[O:13])[CH:11]=[CH2:12].C(Cl)CCl>C(Cl)Cl>[C:10]([O:14][CH2:15][CH:16]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH3:17])(=[O:13])[CH:11]=[CH2:12]
Reactant: O=C(O)CCCCCBr
Reactant: C=CC(=O)OCC(C)O
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CC(=O)OCC(C)OC(=O)CCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. cooled mixture of 6-bromohexanoic acid (9.89 g), 2-hydroxypropyl acrylate (6 g), in CH2Cl2 (30 ml), EDC (7.89 g) was added. After being stirred for 30 min the reaction mixture was diluted with additional 20 ml of CH2Cl2 and stirring was continued for 16 h at room temperature. It was then filtered over celite and the filtrate was evaporated to dryness. The obtained beige-yellow residue was purified by silica column chromatography to give nearly pure material as transparent oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:21]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][CH:6]=[C:5]2[CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])(=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)C(C)c1cccc2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc2c(C(=O)C(C)C)cccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under vigorous magnetic stirring, CH2Cl2 (125 cc) followed by AlCl3 (60 g) are added to a 500 cc three-necked flask provided with a cooling device with CaCl2 trap, a dropping funnel and a thermometer (said three-necked flask being immersed in a water-bath maintained at room temperature). Methyl 2-(1-naphthyl)-propionate (32.1 g) and isobutyryl chloride (18 cc) dissolved in CH2Cl2 (100 cc) are added thereto dropwise. The addition takes 2.5 hours. On completion of the addition, the ingredients are maintained in contact, with continued stirring. Hydrolysis is effected by pouring the reaction mixture over ice-water. The material is extracted with ether. The organic phase is washed over Na2SO4 ; the ether and CH2Cl2 are distilled off and the residual oil is distilled, to give the product named in the title.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:8]([C:10]([OH:12])=[O:11])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:45](C1SC(CNC2C=CC=C(C3C=C(NC4NN=C(C5CC5)C=4)C(=O)N(C)C=3)C=2CO[Si](C(C)(C)C)(C)C)=C(C(OC)=O)N=1)(C)(C)C>>[C:1]([C:5]1[S:6][C:7]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[C:25]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][N:29]=4)[C:24](=[O:34])[N:23]([CH3:35])[CH:22]=3)[C:16]=2[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:8]([C:10]([O:12][CH3:45])=[O:11])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3cc(C4CC4)n[nH]3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C
Reactant: Cn1cc(-c2cccc(NCc3sc(C(C)(C)C)nc3C(=O)O)c2CO[Si](C)(C)C(C)(C)C)cc(Nc2ccncn2)c1=O
Product: COC(=O)c1nc(C(C)(C)C)sc1CNc1cccc(-c2cc(Nc3ccncn3)c(=O)n(C)c2)c1CO[Si](C)(C)C(C)(C)C

Procedure:
Following the procedures as described for compound 125e and starting with methyl 2-tert-butyl-5-((2-((tert-butyldimethylsilyloxy)methyl)-3-(5-(3-cyclopropyl-1H-pyrazol-5-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenylamino)-methyl)thiazole-4-carboxylate, 125d was obtained as a yellow solid (crude). LCMS: (M+H)+ 663.
Reaction SMILES: [Br:1][CH:2](Br)[CH3:3].[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[OH:17])([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:5]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH2:3][CH2:2][Br:1])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCBr)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 35.2 %

Procedure:
Dibromoethane (5.25 g, 0.049 mol) and 2,4-dinitrophenol (3 g, 0.016 mol) were added to dimethylformamide (20 ml) and, after adding a fine powder of potassium carbonate (2.24 g), the mixture was heated at 85° C. for 1.5 h. Thereafter, the solvent was evaporated and three extractions were conducted with ethyl acetate. The organic extracts were combined and dried with sodium sulfate, with the residue being subjected to column chromatography on silica gel using methylene chloride as an eluent. The fractions containing the end product were collected and the solvent was evaporated to yield the end compound 2,4-dinitrophenoxyethly bromide (1.64 g).