Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([CH3:51])[C:45]([CH3:53])([CH3:52])[CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][NH:42][CH:43]2[CH2:48][C:47]([CH3:50])([CH3:49])[N:46]([CH3:51])[C:45]([CH3:53])([CH3:52])[CH2:44]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CN1C(C)(C)CC(NC(=O)CCl)CC1(C)C
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCNC2CC(C)(C)N(C)C(C)(C)C2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 14 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)acetamide (23 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (4.2 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=1)#[N:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH3:17][N:18]([CH:20]=[C:8]([N:6]1[CH:7]=[C:3]([C:1]#[N:2])[N:4]=[CH:5]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:19]
Reactant: CCOC(=O)Cn1cnc(C#N)c1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1

Procedure:
3.8 g (21.4 mmol) of the compound from Example 1A and 7.4 ml (6.3 g, 42.8 mmol) of N,N-dimethylformamide diethyl acetal are stirred at a bath temperature of 100° C. for 16 h. For work-up, the cooled reaction solution is concentrated on a rotary evaporator and the residue is dried under reduced pressure. Yield: 5.0 g (73% pure, 73% of theory)
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH2:23][CH2:22][CH2:21]2>CN1C(=O)CCC1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:2]1[C:3](=[O:16])[NH:4][C:5]3[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:23][CH2:22][CH2:21]2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: Clc1ccc2c(c1)CCCN2
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc(Cl)ccc43)nc2c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (1.0 g, 4.19 mmol) in NMP (10.0 ml) was added 6-chloro-1,2,3,4-tetrahydroquinoline (1.20 g, 7.16 mmol) and the reaction was stirred for 1 h at 150° C. in an oil bath. The reaction mixture was cooled down to room temperature, precipitated with water (100 ml). The solids were collected by filtration and dried in an oven under reduced pressure to afford methyl 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (1.0 g, crude).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[CH:4][C:3]=1[CH3:16].[O-:17][C:18]#[N:19].[K+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCl>[Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([N:9]2[C:18](=[O:17])[NH:19][C:13](=[O:15])[C:10]32[CH2:11][CH2:12]3)=[CH:6][C:7]=1[CH3:8]
Reactant: N#C[O-]
Reactant: Cc1cc(NC2(C(=O)O)CC2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)NC(=O)C23CC3)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a mixture of 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopropane carboxylic acid (198 mg, 0.697 mmol) in acetic acid (3 mL) and dichloromethane (1.5 mL), potassium cyanate (424 mg, 5.23 mmol) was added at room temperature. The mixture was stirred at room temperature for one hour, and then stirred at 60° C. for two hours. A saturated aqueous sodium hydrogen carbonate solution was added to adjust pH to 8, and this mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane) to afford 4-(4-bromo-3,5-dimethylphenyl)-4,6-diazaspiro[2.4]heptane-5,7-dione (49 mg, 23%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:31])[C:17]([N:22]3[CH2:25][C:24]4([CH2:29][CH2:28][CH2:27][N:26]4[CH3:30])[CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]3[CH2:23][C:24]4([CH2:29][CH2:28][CH2:27][N:26]4[CH3:30])[CH2:25]3)=[C:16]([NH:31][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cnn4ccccc34)n2)c(OC)cc1N1CC2(CCCN2C)C1
Reaction time: 3 h
Yield: 64.2 %

Procedure:
A solution of acryloyl chloride (5.71 mg, 0.06 mmol) in CH2Cl2 (1 mL) was added dropwise to a mixture of N′-(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-methoxy-6-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)benzene-1,3-diamine (Intermediate 45, 31 mg, 0.06 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 3 h and then washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 0-2% 7N methanolic ammonia in CH2Cl2 gave the title compound (21 mg, 61%) as a yellow foam; 1H NMR: 1.70 (2H, dd), 1.98-2.11 (2H, m), 2.37 (3H, s), 2.62 (2H, t), 3.65 (2H, d), 3.76 (3H, s), 3.95 (2H, d), 5.67 (1H, d), 6.09-6.27 (2H, m), 6.43 (1H, dd), 7.10 (1H, t), 7.30 (1H, s), 7.34-7.45 (1H, m), 8.35 (2H, s), 8.44 (1H, s), 8.81 (1H, d), 8.92 (1H, s), 9.20 (1H, s); m/z: ES+ MH+ 545.5.
Reaction SMILES: C([O:5][C:6](=[O:52])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:34][C:35]([O:37][CH2:38][CH:39]2[C:51]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[C:45]3[C:40]2=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:15](=[O:33])[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22]2[NH:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>>[CH:50]1[C:51]2[CH:39]([CH2:38][O:37][C:35]([NH:34][CH:14]([C:15](=[O:33])[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]3[C:22]3[NH:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:26]=3)[CH2:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:52])=[O:5])=[CH:8][CH:9]=3)=[O:36])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2c2nc(-c3ccccc3)c[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1ccc(C(=O)O)cc1)C(=O)N1CCCCC1c1nc(-c2ccccc2)c[nH]1)OCC1c2ccccc2-c2ccccc21
Reaction time: 5 h
Yield: 38.5 %

Procedure:
To 670 mg of the product from step A (crude but assumed to be 0.8 mmol based on the previous reaction), cooled in an ice bath under argon, was added 3 mL of trifluroacetic acid. The resulting mixture was allowed to slowly return to room temperature and stir for 5 hours. The mixture was then partitioned between saturated NaHCO3 solution and ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated to 139 mg of a white solid (83% pure by LC). The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were dried over MgSO4 and concentrated to 0.10 g of yellow oil (70% pure by LC). Obtain a total of 239 mg (0.37 mmol, 47% yield) of crude title product.
Reaction SMILES: [CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:4](=[O:6])[CH3:5])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:37][C:38]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[C:39]=1[C:40]([NH2:42])=[O:41]>CC(N(C)C)=O.O>[CH3:50][O:49][C:43]1[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=[C:38]2[C:39]=1[C:40](=[O:41])[NH:42][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH2:12][CH2:11]3)=[CH:18][CH:17]=1)=[N:37]2
Reactant: CCN(C(C)=O)C1CCN(c2ccc(C=O)cc2)CC1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(C(C)=O)C1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.385 g, 1.40 mmol), NaHSO3 (0.162 g, 1.50 mmol), and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2-amino-4,6-dimethoxybenzamide (0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.300 g, 55%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.76 (s, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 3.83 (5, 3H), 3.12-3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07 (s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J=6.7 Hz, 1.5H), 0.99 (t, J=6.7 Hz, 1.5H). ESI MS m/z 451 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][N:19]1[C:23]([NH2:24])=[C:22]([CH3:25])[CH:21]=[N:20]1>>[CH3:18][N:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[C:22]([CH3:25])[CH:21]=[N:20]1
Reactant: Cc1cnn(C)c1N
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Product: COCc1cc2c(C(=O)Nc3c(C)cnn3C)ccc(OC)c2o1
Yield: 28 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran4-carboxylic acid (0.1 g) and 2,4-dimethyl-2H-pyrazol-3-ylamine (56 mg). Purification by column chromatography on silica eluting with 20% heptane in ethyl acetate and gradient preparative HPLC on a PhenomenexLUNA(2)™ C18 column eluting with 0.05% trifluoroacetic acid in20%-65% acetonitrile in water gave the title compound as a pale yellow solid (39 mg).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:22][CH2:23][C:24]1[C:25](=[O:33])[NH:26][C:27]([CH2:31][CH3:32])=[CH:28][C:29]=1[CH3:30].C(O)(C(F)(F)F)=O.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH2:31]([C:27]1[NH:26][C:25](=[O:33])[C:24]([CH2:23][NH:22][C:13]([C:12]2[C:7]3[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=3[N:9]=[C:10]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:11]=2)=[O:15])=[C:29]([CH3:30])[CH:28]=1)[CH3:32]
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21
Reactant: CCc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 9 from 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (403 mg, 1.427 mmol), 3-(aminomethyl)-6-ethyl-4-methyl-2(1H)-pyridinone.TFA (400 mg, 1.427 mmol), HOAT (291 mg, 2.141 mmol), EDC (1094 mg, 5.71 mmol), N-methylmorpholine (0.628 mL, 5.71 mmol), and DMF (6 mL). The final product was collected as a white solid, 232 mg (38%). LCMS E-S (M+H)=432.4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, 3H), 1.56 (d, J=6.57 Hz, 6H), 2.25 (s, 3H), 2.42 (q, J=7.41 Hz, 2H), 4.43 (d, J=4.55 Hz, 2H), 5.29-5.45 (m, 1H), 5.93 (s, 1H), 8.22 (d, J=6.06 Hz, 2H), 8.30 (s, 1H), 8.45 (s, 1H), 8.78 (d, J=5.81 Hz, 2H), 9.01 (t, J=4.55 Hz, 1H), 11.58 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([O:13]CC)=[O:12])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC1c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of ester from step 1 in THF-MeOH (4:1, 0.5M) was added LiOH (3 eq, 2M) and the mixture was stirred at 50° C. for 1 h. The organic solvent evaporated, aqueous was acidified with HCl 1N and the acid extracted with EtOAc (3×). The organic was washed with brine, dried and solvent evaporated to afford 2-(4-bromophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.IC.N1CCOCC1>CN(C)C=O>[Cl:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][N:8]([CH3:1])[CH2:9]2)[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: OC1(c2cc(F)cc(Cl)c2)CCN(Cc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: CI
Solvent: C1COCCN1
Product: CN1CCC(O)(c2cc(F)cc(Cl)c2)C1

Procedure:
Preparation according to Example 34: (−)-1-benzyl-3-(3-chloro-5-fluorophenyl)pyrrolidin-3-ol (0.115 g, 0.38 mmol) and iodomethane (1 mL, 15.9 mmol), dimethyl formamid (2 mL), morpholine (2 mL). Purification by flash chromatography on silica gel (ethyl acetate/methanol, 1:0 to 1:1). Yield: 0.1 g. [α]D=−21.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 117-118° C.; MS m/z (relative intensity, 70 eV) 229 (M+, 6), 129 (7), 109 (6), 58 (28), 57 (bp).
Reaction SMILES: [OH-].[Na+].NC(NCCOC1C=CC([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([C:29]([O:31]CC)=[O:30])[CH:17]=2)=CC=1)=O>C1COCC1.CO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([N:20]2[CH:16]=[CH:17][C:18]([C:29]([OH:31])=[O:30])=[N:19]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc(-c2ccc(OCCNC(N)=O)cc2)n(-c2ccc(OC)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2ccc(C(=O)O)n2)cc1
Temperature: 25 °C
Yield: 175.6 %

Procedure:
1M NaOH (5 ml) was added to a solution of ethyl 5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.75 g) in THF (15 ml) and MeOH (10 ml). The reaction mixture was stirred at ambient temperature and concentrated in vacuo. The residue was dissolved in H2O and acidified by 1M HCl. white precipitates were collected and washed successively with H2O and IPE to give 5-(4–12-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid (1.58 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O-:26])=[O:25].[K+].ClC1C=CC=CC=1CC([O-])=O.[K+]>CS(C)=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: O=C([O-])Cc1ccccc1Br
Agent: O=C([O-])Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
The same procedure as in Example 1 given in Japanese Pat. No. 374/1980 was employed using 3.10 g of 2,6-dichloroaniline, 0.10 g of cuprous bromide, 2.80 g of potassium carbonate and 10 ml of dimethyl sulfoxide except that potassium o-bromophenylacetate was replaced with 4.17 g of potassium o-chlorophenylacetate. o-(2,6-Dichloroanilino)phenylacetic acid was not obtained at all.
Reaction SMILES: [C:1](/[CH:4]=[C:5]1/[CH:6]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]/1)([OH:3])=[O:2].S(Cl)(Cl)=O.Cl[CH2:38]Cl>>[CH3:38][O:2][C:1](/[CH:4]=[C:5]1/[CH:6]([N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[C:19]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)=[N:12]2)[CH2:7][CH2:8][CH2:9][CH2:10]/1)=[O:3]
Reactant: O=C(O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Reactant: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)/C=C1\CCCCC1n1nc(-c2c(-c3ccccc3)nn3ccccc23)ccc1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(E)-3-[2-(2-Carboxymethylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (36.8 mg) was suspended in dichloromethane and the mixture was cooled in an ice bath. To this was added thionyl chloride (0.1 ml). After the reaction mixture was stirred at room temperature for 4 hours, the solvent was evaporated in vacuo. The residue was dissolved in methanol (2 ml), and stirred at room temperature for 10 minutes. Methanol was evaporated in vacuo and the residue was partitioned between dichloromethane (10 ml) and saturated aqueous sodium bicarbonate. After an additional extraction with dichloromethane (10 ml), the combined extracts were washed with brine (10 ml), dried over anhydrous magnesium sulfate, and evaporated in vacuo. The oily residue was crystallized from ethyl acetate to give colorless crystals of (E)-3-[2-(2-methoxycarbonylmethylenecyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (36.3 mg). The spectroscopic data for this compound were identical to those for the authentic sample obtained in Example 31.
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH2:28][CH2:29][CH3:30])[C:4]#[C:5][C:6]1[C:14]2[S:13][CH:12]=[CH:11][C:10]=2[C:9]([C:15]#[C:16][CH:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[S:24][CH:25]=[CH:26][C:7]=12)[CH3:2]>[Pd].C1COCC1>[CH2:22]([CH:17]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15][C:9]1[C:8]2[S:24][CH:25]=[CH:26][C:7]=2[C:6]([CH2:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:27][CH2:28][CH2:29][CH3:30])=[C:14]2[S:13][CH:12]=[CH:11][C:10]=12)[CH3:23]
Reactant: CCCCC(C#Cc1c2ccsc2c(C#CC(CC)CCCC)c2ccsc12)CC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC(CC)CCc1c2ccsc2c(CCC(CC)CCCC)c2ccsc12
Yield: 53.6 %

Procedure:
A dry 250 mL 1-neck flask was flushed with N2 and was charged with 4,8-bis(3-ethylhept-1-ynyl)thieno[2,3-f]benzothiophene (3.04 g, 0.007 mol), Pd/C wet support (0.82 g, 10%) and THF (15 mL, 0.5 M). The flask was evacuated and backfilled with hydrogen. The flask was kept under a hydrogen atmosphere and was monitored by TLC. After the reaction was completed, the mixture was filtered through Celite and solvent was removed by rotary evaporation. The solid was dissolved in hexanes and purified by column chromatography to yield oil (1.66 g, 54%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[C:30]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:30]([C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][N:42]2[CH2:23][CH2:22][C:6]3([CH2:7][CH2:8][N:9]([S:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])(=[O:13])=[O:14])[CH2:10][CH2:11]3)[C:4]2=[O:3])=[CH:38][CH:39]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Reactant: CC(C)(C)c1ccc(CCN)cc1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(CCN2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3)C2=O)cc1

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 2-(4-tert-Butyl-phenyl)-ethylamine. MS (ESI): 489.4 (MH+).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NCc1ccc(Cl)cc1

Procedure:
A mixture of (4.0 g, 25.9 mmol) of phenylacetyl chloride, 3.15 mL (25.9 mmol) of 4-chlorobenzylamine and 5.1 mL of triethylamine in 120 mL of methylene chloride was prepared at 0° C. and then heated to reflux under a nitrogen atmosphere for 18 hours. The solvent was evaporated and the residue was treated with 2 mL of 4-chlorobenzylamine and 3 mL of triethylamine and reheated to reflux overnight. After cooling, the mixture was suspended in 100 mL of methylene chloride, washed with 0.5 N hydrochloric acid, 0.5 N sodium hydroxide and saturated aqueous sodium chloride, followed by drying with magnesium sulfate (MgSO4). The solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to provide N-(4-chlorobenzyl)-phenylacetamide as a white crystalline solid, 4.15 g (62%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20].C(Cl)Cl>CN1CCCC1=O.CO>[NH2:20][CH2:19][CH2:18][NH:21][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCn1cc(C(=O)O)c(=O)c2ccc(NCCN)cc21
Temperature: 130 °C
Yield: 44.6 %

Procedure:
To a solution of 7-chloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (1,7 g) in 1-methyl-2-pyrrolidinone (20 mL) was added ethylenediamine (2.1 g). The mixture was heated at 130° C. for 10 h. The reaction mixture was cooled and poured into DCM (20 mL). The precipitate obtained was dispersed in MeOH, filtered to give the title compound (830 mg).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32](OC)=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].[Na+].C(O)(C(F)(F)F)=O.[CH3:49][CH:50]([OH:52])[CH3:51]>>[C:1]1([S:7]([NH:10][C:11]2[CH:12]=[C:13]([C@@H:17]([OH:38])[CH2:18][NH:19][C:20]([CH3:36])([CH3:37])[CH2:21][CH2:22][N:23]3[C:31]4[C:26](=[CH:27][C:28]([C:32]([O:52][CH:50]([CH3:51])[CH3:49])=[O:33])=[CH:29][CH:30]=4)[CH:25]=[CH:24]3)[CH:14]=[CH:15][CH:16]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)O
Reactant: COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
240 mg (0.36 mmol) methyl 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylate (Example 5) are dissolved in 5 ml 2-propanol and combined with 19 mg (0.36 mmol) sodium methoxide. The mixture is stirred for 17 hours at ambient temperature and then acidified with TFA while cooling with ice. Then the solvent is eliminated in vacuo and the residue is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].