Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:11][C:10](=[CH2:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]>C(O)C.[Pd]>[F:21][C:2]([F:1])([F:20])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:19])=[O:4]
Reactant: C=C1CN(C(=O)C(F)(F)F)C(C)Cc2cc(OC)ccc21
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)CC(C)N(C(=O)C(F)(F)F)CC2C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-4-methyl-1-methylene-2,3,4,5-tetrahydro-1H-3-benzazepine (1.39 g, 4.64 mmol) in ethanol (40 mL) was treated with 10% Pd/C (0.49 g, 0.46 mmol) and stirred overnight under an atmosphere of hydrogen. The product mixture was filtered through a pad of celite and silica and then concentrated. Flash chromatography (20% EtOAc in hexane, silica) resulted in 0.77 g of a clear oil. 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ 7.06 (m, 1H), 6.71 (m, 1H), 6.63 (m, 1H), 4.38 (bm, 1H), 3.8 (s, 3H), 3.6 (m, 1H), 3.25 (m, 1H), 3.18 (bm, 2H), 2.72 (m, 1H), 1.34 (m, 3H) 1.22 (m, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1)=[O:2].S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:18])=[O:10])=[CH:5][CH:4]=1)=[O:2]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
A suspension of 4-formylcinnamic acid (10.0 g), dimethyl sulfate (5.9 ml) and potassium carbonate (11.8 g) in 100 ml dimethylformamide was stirred at room temperature for 17 hours. After removal of inorganic salts by filtration, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted twice with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, and dried over sodium sulfate. The drying agent was filtered off and the filtrate was evaporated and dried under reduced pressure to give methyl 4-formylcinnamate (9.78 g, 91%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.COC[C@@H]1[C@@H](/C=C/C(/C)=C/C(OCC)=O)[C@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@@H:4]1[C@@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)/C=C(C)/C=C/[C@@H]1[C@@H](COC)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@@H]1[C@@H](/C=C/C(C)=C/C(=O)O)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 80 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 19a as the starting material afforded the title compound (26 mg, 80% yield) as a white solid:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:20])[C:10]([C:13]2([C:17]([OH:19])=O)[CH2:16][CH2:15][CH2:14]2)=[N:11][N:12]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[C:54]12([NH2:64])[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:54]12([NH:64][C:17]([C:13]3([C:10]4[N:9]([CH3:20])[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])=[N:12][N:11]=4)[CH2:14][CH2:15][CH2:16]3)=[O:19])[CH2:61][CH:60]3[CH2:59][CH:58]([CH2:57][CH:56]([CH2:62]3)[CH2:55]1)[CH2:63]2
Reactant: Cn1c(-c2ccccc2Cl)nnc1C1(C(=O)O)CCC1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(-c2ccccc2Cl)nnc1C1(C(=O)NC23CC4CC(CC(C4)C2)C3)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
1-[5-(2-Chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxylic acid (200 mg) was suspended in methylene chloride (7 ml) and then diisopropylethylamine (0.72 ml) and bromotris(pyrrolidino)phosphonium hexafluorophosphate salt (416 mg) were added thereto, followed by stirring at room temperature for 30 minutes. Then, 1-adamantanamine (104 mg) was added to the reaction solution and the whole was stirred at room temperature for 15 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution (30 ml), followed by extraction with chloroform (20 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtrated and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=2:98) and the resulting solid washed with hexane and diethyl ether to obtain 212 mg of N-1-adamantyl-1-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]cyclobutanecarboxamide (white solid).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Si:16]([O:23][CH2:24][C@@H:25]1[C@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@H:28]2[C@H:27]([N:35]2[CH:43]=[N:42][C:41]3[C:36]2=[N:37][CH:38]=[N:39][C:40]=3[Cl:44])[O:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[CH2:45]([Sn:49](Cl)([CH2:54][CH2:55][CH2:56][CH3:57])[CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46][CH2:47][CH3:48].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>O1CCCC1.O>[Si:16]([O:23][CH2:24][C@@H:25]1[C@H:29]2[O:30][C:31]([CH3:34])([CH3:33])[O:32][C@H:28]2[C@H:27]([N:35]2[CH:43]=[N:42][C:41]3[C:36]2=[N:37][C:38]([Sn:49]([CH2:50][CH2:51][CH2:52][CH3:53])([CH2:54][CH2:55][CH2:56][CH3:57])[CH2:45][CH2:46][CH2:47][CH3:48])=[N:39][C:40]=3[Cl:44])[O:26]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:17])[CH3:18]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nc(Cl)c2ncn([C@@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of 2,2,6,6-tetramethylpiperidine (17.6 g, 125 mmol) in dry tetrahydrofuran (350 ml) was cooled to −50° C., under an atmosphere of nitrogen gas, and treated with n-butyllithium (78 ml, 1.6M solution in hexanes, 125 mmol) over 15 minutes. The reaction mixture was then cooled to −70° C. and a solution of 9-[(3aR,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine (Bioorg. Med. Chem. Lett., 8, 695-698, (1998)) (11.0 g, 25 mmol) in dry tetrahydrofuran (150 ml) was added, dropwise, keeping the temperature below −70° C. The reaction mixture was stirred for 30 minutes. Tri-n-butyl tin chloride (40.7 g, 125 mmol) was then added to the reaction and the mixture stirred at −70° C. for 30 minutes. A saturated solution of ammonium chloride in water (100 ml) was added to the reaction which was then warmed to 0° C. A saturated aqueous solution of sodium hydrogen carbonate was added (150 ml) and the mixture extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (95:5, by volume) gradually changing to hexane:ethyl acetate (80:20, by volume) to afford the title compound (13.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].C([Li])CCC.CCCCCC.CN(C)[CH:27]=[O:28].Cl>O1CCCC1>[CH:27]([C:11]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:28]
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cnccc1C=O
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,2-dimethyl-N-(3-pyridinyl)propanamide (3.56 gm, 20 mmol) (prepared as described in J. Org. Chem. 48, 3401 (1983)) in anhydrous tetrahydrofuran (40 mL) was cooled to −70° C. and a solution of 2.5 M n-butyl lithium/hexane (20 mL, 50 mmol) was added dropwise maintaining the temperature at −70° C. This reaction was slowly warmed to −5° C. giving a copious precipitate. This mixture was cooled to −70° C. and dry dimethyl formamide (4.64 mL, 60 mmol) was added. The reaction was allowed to warm to room temperature giving a clear yellow solution. This reaction was poured into 8 N aqueous HCl (16 mL) and ice. After stirring for 10 minutes the pH of the solution was adjusted to 7 and extracted with diethyl ether. The organic layer was dried (Na2SO4), filtered and the solvent evaporated. The residue was purified by column chromatography eluting with 30-100% ethyl acetate/hexane. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a solid. 1H-NMR (500 MHz, CDCl3): δ 10.92 (1H, br s), 10.15 (1H, s), 10.05 (1H, s), 8.62 (2H, d, J=4.9 Hz), 7.56 (1H, d, J=4.9 Hz),), 1.39 (9H, s). m/e (m+1): 235.3.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[NH2:16][CH:17]([C:19]1[CH:20]=[C:21]([CH3:31])[C:22]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:23][CH:24]=1)[CH3:18]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:16]([CH:17]([C:19]3[CH:24]=[N:23][C:22]([NH:25][CH2:26][C:27]([F:30])([F:28])[F:29])=[C:21]([CH3:31])[CH:20]=3)[CH3:18])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1NCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1NCC(F)(F)F
Yield: 62 %

Procedure:
The title compound is prepared in 62% yield (220 mg, pale yellow solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (260 mg, 0.93 mmol, Step-1 of Intermediate-1) and 5-(1-aminoethyl)-3-methyl-N-(2,2,2-trifluoroethyl)pyridin-2-amine hydrochloride (250 mg, 0.93 mmol, Amine-46, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH2:24])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)COc1ccc(C[C@H](N)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(2S)-2-Amino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step G (40 mg, 0.072 mmol) is stirred in pyridine (0.5 mL) at 0° C. under N2. Benzenesulfonyl chloride (20 mg, 0.11 mmol) is added and the reaction is stirred overnight at RT. The mixture is then diluted with CH2Cl2 (20 mL), washed with 2N HCl (2×20 mL) and then with saturated NaHCO3 (2×20 mL). The organics are dried over MgSO4, filtered, concentrated and purified by flash column chromatography to provide 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: CON(C)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1.O1CCCC1.C(OCC)(=O)C.Cl>O1CCCC1>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([CH:14]1[CH2:16][CH2:15]1)=[O:12]
Reactant: CON(C)C(=O)c1ccccc1C
Reactant: Br[Mg]C1CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-methoxy-2,N-dimethylbenzamide (3.55 g) obtained in Step 1 in tetrahydrofuran (40 ml) was added dropwise a solution of 1M cyclopropylmagnesium bromide-tetrahydrofuran (29.7 ml) under ice-cooling, and the mixture was stirred at room temperature for 12 hr. To the reaction mixture was added a 4N hydrogen chloride-ethyl acetate solution (10 ml), and the resulting mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:5) to give the title compound (1.05 g).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[OH:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18](=O)[CH2:19][C:20]#[N:21])=[CH:12][C:11]=1[O:23][CH3:24]>C(O)(=O)C>[NH2:21][C:20]1[N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[N:2]=[C:18](/[CH:17]=[CH:16]/[C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[C:11]([O:23][CH3:24])[CH:12]=2)[CH:19]=1
Reactant: NNc1ccccn1
Reactant: COc1cc(/C=C/C(=O)CC#N)ccc1O
Solvent: CC(=O)O
Product: COc1cc(/C=C/c2cc(N)n(-c3ccccn3)n2)ccc1O
Temperature: 120 °C
Yield: 20 %

Procedure:
2-hydrazinopyridine (62 mg, 0.57 mmol) was added to a solution of Compound 10 (113 mg, 0.520 mmol) synthesized in Step 1 of Example D in acetic acid (3 mL), followed by stirring under reflux at 120° C. for 30 minutes. The reaction solution was concentrated by distillation under reduced pressure, and ethyl acetate (5 mL) and water (5 mL) were added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then separated by column chromatography (n-Hex/EtOAc=3/1 (v/v)) to afford the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][O:17][C:13]=3[C:12]=2[CH2:24][CH2:25][CH3:26])[CH2:5][CH2:4][N:3]1[CH:27]([CH3:32])[C:28]([O:30]C)=[O:29].[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:23]=[CH:22][C:14]3[C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][O:17][C:13]=3[C:12]=2[CH2:24][CH2:25][CH3:26])[CH2:5][CH2:4][N:3]1[CH:27]([CH3:32])[C:28]([OH:30])=[O:29]
Reactant: CCCc1c(OCCCN2CCN(C(C)C(=O)OC)C2=O)ccc2c(C(F)(F)F)noc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCN2CCN(C(C)C(=O)O)C2=O)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a MeOH solution (0.6 mL) of methyl 2-[2-oxo-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidin-1-yl]propanoate as prepared in Example 40 (17.6 mg, 0.039 mmol), was added NaOH (0.6 mL, 0.154 mmol) and the mixture stirred at room temperature overnight. The reaction mixture was neutralized with 1N HCl and purified by preparative HPLC and the title compound was obtained.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:16](OC=C)(=O)[CH3:17]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH:16]=[CH2:17])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: C=COC(C)=O
Product: C=COC(=O)C(C)c1ccc(CC(C)C)cc1
Reaction time: 8 h
Yield: 82 %

Procedure:
100 g of 2-(4'-isobutylphenyl)propionic acid (ibuprofen) were taken up in 1 l of vinyl acetate and heated under reflux to boiling in the presence of 2 g of Li2PdCl4 and 20 g of active carbon. The reaction was followed by thin layer chromatography. After 8 hours, the catalyst was filtered off and the filtrate was concentrated to dryness. After filtration through silica gel using hexane:ethyl acetate (10:1), 92.7 g (39.9 mmol; 82%) of vinyl 2-(4'-isobutylphenyl)propionate were obtained as a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[O:15]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:27]=1)=[O:11]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc(Oc2ccccc2)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 4-phenoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][C@@H:2]([C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)[CH2:3][N:4]([CH2:17][C@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19])[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6].FC(F)(F)C(O)=O>ClCCl>[NH2:20][C@H:18]([CH3:19])[CH2:17][N:4]([CH2:3][C@@H:2]([OH:1])[C:28]1[CH:32]=[CH:31][S:30][CH:29]=1)[S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])(=[O:6])=[O:7]
Reactant: C[C@H](CN(C[C@@H](O)c1ccsc1)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)CN(C[C@@H](O)c1ccsc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
602 mg of tert-butyl (R)-1-[N—{(S)-2-hydroxy-2-(thiophen-3-yl)ethyl}-2-nitrophenylsulfonamido]propan-2-ylcarbamate was dissolved in 4 mL of dichloromethane. To the solution, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 4 mL of methanol. 1 g of sodium bicarbonate was added thereto, and the mixture was stirred for 1 hour. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=8:1) to obtain 338 mg of the title compound as a colorless oil (71%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:3]=1.[CH:14]1(/[C:17](/O)=[CH:18]/[C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>C(O)(=O)C>[CH:14]1([C:17]2[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:6]3[C:2]([CH3:1])=[N:3][N:4]([CH:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[C:5]=3[N:7]=2)[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(=O)/C=C(\O)C1CC1
Reactant: Cc1cc(N)n(C2CCOCC2)n1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCOCC1
Temperature: 117 °C

Procedure:
A mixture of 3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-amine (380 mg, 2.097 mmol), ethyl (3Z)-4-cyclopropyl-4-hydroxy-2-oxo-3-butenoate (386 mg, 2.097 mmol) and acetic acid (50 mL) were heated at 117° C. for 2 hours. The solvent was removed in vacuo, and the crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex). The desired product was collected as a solid, 300 mg (43%). LCMS E-S (M+H)=330.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00-1.12 (m, 4H), 1.37 (t, J=7.20 Hz, 3H), 1.82 (dd, J=12.51, 2.40 Hz, 2H), 2.16 (qd, J=12.21, 4.55 Hz, 2H), 2.29-2.42 (m, 1H), 2.54 (s, 3H), 3.47-3.60 (m, 2H), 3.99 (dd, J=11.37, 3.79 Hz, 2H), 4.42 (q, J=7.24 Hz, 2H), 4.92 (tt, J=11.59, 4.20 Hz, 1H), 7.46 (s, 1H).
Reaction SMILES: Cl.Cl[C:3]1[NH:4][C:5](=[O:14])[C:6]2[CH:12]=[CH:11][C:10]([CH3:13])=[N:9][C:7]=2[N:8]=1.[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:13][C:10]1[CH:11]=[CH:12][C:6]2[C:5](=[O:14])[NH:4][C:3]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:8][C:7]=2[N:9]=1
Reactant: OCCCCCc1ccccc1
Reactant: Cc1ccc2c(=O)[nH]c(Cl)nc2n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc2c(=O)[nH]c(OCCCCCc3ccccc3)nc2n1

Procedure:
In analogy to the procedure described in example 97.3, 2-chloro-7-methyl-3H-pyrido[2,3-d]pyrimidin-4-one hydrochloride was reacted with 5-phenyl-1-pentanol in DMSO in the presence of molecular sieves and potassium tert-butylate to give 7-methyl-2-(5-phenyl-pentyloxy)-3H-pyrido[2,3-d]pyrimidin-4-one as yellow crystals. MS: m/e=324.4 [M+H+].
Reaction SMILES: O[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5].S(Cl)([Cl:29])=O>>[Cl:29][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]3[CH2:19][CH2:20][C:21]4[NH:22][C:23](=[O:26])[CH:24]=[CH:25][C:16]([C:17]=43)=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CC(O)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Product: CC(C)CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1

Procedure:
This compound was prepared from intermediate 228 and thionyl chloride according to the procedure used in Example 171. Received 8.36 g (91%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](=[O:28])(=[O:27])[NH:13][C:14]3[C:19]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:26])[N:11]=[C:4]2[N:3]=1.[H-].[Na+].O1CCC[CH2:32]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12](=[O:28])(=[O:27])[N:13]([CH3:32])[C:14]3[C:19]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:26])[N:11]=[C:4]2[N:3]=1
Reactant: C1CCOC1
Reactant: CCOCCOc1cccc(Cl)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Agent: [H-]
Agent: [Na+]
Product: CCOCCOc1cccc(Cl)c1N(C)S(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
1.5g of 5,7-dimethyl-2-(N-[2-chloro-6-(2-ethoxyethoxy)phenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (prepared using the procedures described in Preparation Example 1, Variant A, were stirred in dry tetrahydrofuran under dry nitrogen at ambient temperature. To the pale yellow solution was added 60% sodium hydride and a white floccular solid formed over 60 minutes. The tetrahydrofuran was removed and the sodium salt resuspended in dry dimethyl formamide. 0.5g of methyl iodide was added and the mixture stirred under nitrogen overnight at ambient temperature. After concentration of the reaction mixture the residue was treated with water and extracted twice with 20ml of ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and concentrated. The crude product was then purified by flash chromatography to give 1.1g (71% yield) of 5,7-dimethyl-2-(N-methyl-N-[2-chloro-6-(2-ethoxyethoxy)phenyl]-sulphamoyl)-1,2,4-triazolo[1,5-a]pyrimidine (Compound No. 26) as a white solid.