Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([C:26]([CH3:31])([CH3:30])[C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:13]=1.[C:32](=[O:40])([O:37][CH2:38][CH3:39])[O:33][CH:34](Cl)[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:34]([O:33][C:32]([O:37][CH:38]([O:28][C:27](=[O:29])[C:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:14]2[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:17]=[C:16]([O:18][CH3:19])[N:15]=2)[CH:21]=1)([CH3:31])[CH3:30])[CH3:39])=[O:40])[CH3:35]
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Reactant: CCOC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C(C)(C)c1cccc(-c2cc(NCCc3ccc(Cl)cc3Cl)nc(OC)n2)c1
Temperature: 110 °C

Procedure:
To a solution of 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [100 mg, 0.218 mmol, Example 49(b)] in dimethylformamide (2 mL) is added 1-chloroethyl ethyl carbonate (0.053 mL, 0.392 mmol) and Cs2CO3 (142 mg, 0.436 mmol). The mixture is heated under microwave at 110° C. for 10 minutes, quenched with water, and extracted with ethyl acetate. Combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography eluting with 0 to 40% EtOAc in heptane to obtain 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 1-ethoxycarbonyloxy-ethyl ester as an oil which is treated with 1M hydrogen chloride in ether affording 2-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid 1-ethoxycarbonyloxy-ethyl ester hydrochloride [80 mg, 64%, Example 50] as a solid. LC/MS: RT=2.94 minutes, MS: 576 (M+H). 1H NMR [300 MHz. (CD3)2SO]: □7.36-7.8 (7H, m), 6.64 (1H, q), 6.64 (1H, s), 4.05 (2H, q), 3.96 (3H, s), 3.68 (2H, m), 3 (2H, m), 1.57 (6H, s), 1.38 (3H, d), 1.15 (3H, t). IC50=4 nM
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](=[O:11])[N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)NC(CC(=O)Cl)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Reactant: CCNCC
Solvent: ClCCCl
Product: CCN(CC)C(=O)CC(NC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.7 %

Procedure:
A solution 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionyl chloride (100 mg, 0.19 mmol) in 1,2-dichloroethane (3 mL) is treated with diethylamine (28 mg, 0.38 mmol) in one portion and stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel (eluted with 1 to 4% MeOH/CH2Cl2) to afford 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(3-bromo-phenyl)-2-diethylcarbamoyl-ethyl]-amide as a white foam (6.0 mg, 6.0%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=2)[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(O)cc2)cc(O)c1SCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-hydroxyacetophenone (0.722 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (1.95 g, 11.6 mmol), chlorotrimethylsilane (1.48 mL, 11.6 mmol), THF (116 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. dec. 204° C.; 1H NMR (250 MHz, DMSO-d6) δ 3.96 (s, 2 H), 6.55 (s, 1 H), 6.88 (d, 2 H), 7.39 (m, 5 H), 7.63 (d, 2 H), 10.28 (s, 1 H), 11.75 (bs, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([OH:26])[CH2:25][CH2:24][C:16]3([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17]3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16](=[O:21])[CH2:24][CH2:25]3)[O:26][C:28]2=[O:30])[CH3:9])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16]4([O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][O:21]4)[CH2:24][CH2:25]3)[O:26][C:28]2=[O:30])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Cl)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: C[C@@H](c1ccc(Cl)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Product: C[C@@H](c1ccc(Cl)cc1)N1CCC2(CCC3(CC2)OCC(C)(C)CO3)OC1=O
Yield: 35 %

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-chloro-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2; besides the title compound the intermediate 3-[(S)-1-(4-chloro-phenyl)-ethyl]-12,12-dimethyl-1,10,14-trioxa-3-aza-dispiro[5.2.5.2]hexadecan-2-one (35% of theory) is also isolated. Yield: 23% of theory; LC (method 4): tR=1.51 min; Mass spectrum (ESI+): m/z=322/324 (Cl) [M+H]+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]4[N:32]=[CH:31][N:30](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:29]=4)[CH:26]=3)[N:21](C3CCCCO3)[N:20]=2)[CH:14]=1)=[O:12].Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:29]1[C:28]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[C:19]3[C:15]2[CH:14]=[C:13]([C:11]([NH:10][CH:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[O:12])[CH:18]=[CH:17][CH:16]=2)=[N:32][CH:31]=[N:30]1
Reactant: O=C(NC1Cc2ccccc2C1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NC1Cc2ccccc2C1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 21.5 %

Procedure:
To a stirred solution of N-indan-2-yl(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.342 g, 0.458 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 5.5 h. The mixture was cooled and poured into saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) followed by washing with saturated sodium bicarbonate and extraction with ethyl acetate gave the title compound (0.0414 g, 22% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.50 (m, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 7.91 (d, 1H), 7.69 (m, 2H), 7.25 (m, 2H), 7.17 (m, 2H), 4.83 (m, 1H), 3.34 (dd, 2H), 3.07 (dd, 2H). ES-MS (m/z) 421 [M+1]+
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([OH:24])(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=O)[CH:15]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl.CN(C=O)C>[F:25][C:26]([F:34])([F:35])[C:27]1[CH:28]=[C:29]([NH:33][C:17]([C:16]2[CH:15]=[C:14]([CH:22]=[CH:21][CH:20]=2)[C:13]([OH:24])=[O:23])=[O:19])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(O)c1cccc(C(=O)Nc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.34 g, 7 mmol) was added to a stirring solution of isophthalic acid (1.66 g, 10 mmol) and 3-(trifluoromethyl)benzenamine (0.8 g, 5 mmol) in anhydrous CH2Cl2 (10 mL) and DMF (10 mL). The mixture was stirred at room temperature under argon for 2 h. The solvent was removed under reduced pressure and recrystalized from water to afford the title compound as a white solid after washed by CHCl3 (1.5 g, 49%).
Reaction SMILES: [CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([OH:28])=O)[CH2:5][CH2:4]1)=[O:2].S(Cl)(Cl)=O.[CH3:33][N:34]([CH:36]=O)[CH3:35]>>[CH:1]([N:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:16][CH:15]=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:26]([NH:3][C:9]2[CH:10]=[CH:11][C:12]([CH2:36][N:34]([CH3:33])[CH:35]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:13][CH:8]=2)=[O:28])[CH2:5][CH2:4]1)=[O:2]
Reactant: CN(C)C=O
Reactant: O=CN1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Solvent: O=S(Cl)Cl
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCOCC5)cc4)ccc3N(C=O)CC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (14 ml) was dissolved 1- formyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.18 g). To the solution was added, under ice-cooling, thionyl chloride (0.1 ml), and the mixture was stirred at room temperature for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was suspended in THF (50 ml). The suspension was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.13 g) and triethylamine (0.33 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethanol/hexane to give 1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.16 g) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[N+:10]([O-:13])([OH:12])=[O:11].[NH2:14][NH:15][C:16]([NH2:19])=[N:17][NH2:18].[N+]([O-])(O)=O>C(O)C.O>[N+:10]([O-:13])([OH:12])=[O:11].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:18][NH:17][C:16]([NH:15][N:14]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)=[NH:19])=[CH:4][CH:3]=1
Reactant: NN=C(N)NN
Reactant: O=Cc1ccc(Br)cc1
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: O
Product: N=C(NN=Cc1ccc(Br)cc1)NN=Cc1ccc(Br)cc1

Procedure:
A boiling solution of 20.0 grams of 4-bromobenzaldehyde in 250 milliliters of ethanol is stirred vigorously as a solution of 6.1 grams of 1,2-diaminoguanidine nitrate and 0.5 milliliters of concentrated nitric acid in 50 milliliters of water is added in one portion. The reaction mixture is stirred as the temperature recedes to room temperature. The reaction mixture is allowed to stand for several hours. The precipitate which forms is collected, washed with hot ethanol, air dried and finally dried at 60° C. under reduced pressure. The yield is 16.5 grams of product and the melting point is 178°-180° C. with decomposition.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[CH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:9][CH2:8]1)[CH3:2]>[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C=C[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Product: CCOC(=O)CC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 6 g (19.26 mmol) trans-3-[4-(tert-Butoxy carbonyl methyl-amino)-cyclohexyl]-acrylic acid ethyl-ester and 600 mg of Pd/C (10%) was stirred over H2-atmosphere for 20 h. After filtration of the solution, the methanol was evaporated under reduced pressure to yield 5.82 g of clean trans-3-[4-(tert-Butoxycarbonyl methyl-amino)cyclohexyl]-propanoic acid ethyl-ester. To a solution of this ester in 60 ml of THF was added 917 mg (40 mmol) LiBH4. The solution was refluxed for 8 h and then cooled with an ice-bath to 0° C. At this temperature was dropped slowly 1N HCl to the reaction-mixture to destroy excess of LiBH4. The reaction-mixture was diluted with Et2O and then washed with water: The organic layers were evaporated to dryness to yield 3.39 g (73%) of clean trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 271 (M).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:3]=1[NH:18][C:19](=S)[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]2[N:18]=[C:19]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([Cl:28])=[CH:23][N:22]=3)[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:4]=2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2ncc(Cl)cc2Cl)c1NCCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ncc(Cl)cc3Cl)n(CCCCO)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A suspension of methyl 4-chloro-3-{[(3,5-dichloropyridin-2-yl)carbamothioyl]amino}-2-[(4-hydroxybutyl)amino]benzoate (2.76 g, 5.78 mmol), triethylamine (886 μL, 6.36 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.22 g, 6.36 mmol) in tetrahydrofuran (25 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (2.45 g, 5.52 mmol, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: NCCN1CCOCC1
Product: CN(C)C(=O)Cn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 4-(2-aminoethyl)morpholine employing methods similar to those described in Example 9. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.15 (1H, br t), 8.54 (1H, s), 7.15 (2H, dd, J=9, 6 Hz), 7.05-7.01 (3H, m), 4.96 (2H, s), 4.11 (2H, s), 3.74 (4H, m), 3.56 (2H, q, J=6 Hz), 3.13 (3H, s), 2.97 (3H, s), 2.59 (2H, t, J=6 Hz), 2.52 (4H, m); HRMS calcd for C26H30FN5O5+H+: 512.2309. Found: 512.2296.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26](N[C@H](C#C)CC(O)=O)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1.Cl.C[O:39][C:40](=[O:48])[C@H:41]([CH2:43][C:44]([O:46]C)=[O:45])[NH2:42]>>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]([S:26]([NH:42][C@H:41]([C:40]([OH:39])=[O:48])[CH2:43][C:44]([OH:46])=[O:45])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)C[C@H](N)C(=O)OC
Reactant: C#C[C@H](CC(=O)O)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H](NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1)C(=O)O

Procedure:
The procedure for the preparation of the product of EXAMPLE 17 was repeated using L-aspartic acid dimethyl ester hydrochloride (Aldrich) in the place of ethyl (3S)-3-aminopent-4-ynoate hydrochloride to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.42 (3H, m); 7.13 (1H, m); 7.05 (1H, d); 6.87 (1H, t); 4.20 (1H, t); 4.12 (2H, t); 3.44 (2H, t); 2.71 (2H, m); 1.93 (4H, m).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[NH2:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN1CCOCC1>ClCCl>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]([NH:26][S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:14])([F:13])[F:1])(=[O:11])=[O:10])[CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: Cc1cc(N)cc(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(NS(=O)(=O)c2ccccc2C(F)(F)F)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
2-Trifluoromethylbenzenesulfonyl chloride (490 mg, 2.0 mmol) was added to a solution of 3-benzyloxy-5-methylaniline (426 mg, 2.0 mmol), as prepared in the preceding step, and N-methylmorpholine (0.5 mL) in dichloromethane (10 mL). The mixture was stirred at ambient temperature overnight. After adding additional dichloromethane (100 mL), the dichloromethane solution was washed with saturated aqueous NaHCO3 (2×50 mL), 10% HCl (2×50 mL), and brine (2×50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (4:1 dichloromethane/hexane) to give the title compound as white solid (700 mg, 83%). 1H-NMR (300 MHz, CDCl3) δ 7.93 (d, J=7.8 Hz, 1 H), 7.85 (d, J=7.3 Hz, 1 H), 7.63 (t, J=7.7 Hz, 1 H), 7.53 (t,J=7.7 Hz, 1 H), 7.38 (m, 5 H), 6.60 (s, 1 H), 6.55 (s, 2 H), 6.40 (s, 1 H), 4.98 (s, 2 H), 2.20 (s, 3 H).
Reaction SMILES: C(Cl)(Cl)=O.[Cl:5][C:6]1[S:10][C:9]([NH:11]C(=O)C)=[C:8]([S:15](=[O:24])(=[O:23])[NH:16][C:17](=S)[NH:18][CH:19]([CH3:21])[CH3:20])[CH:7]=1.C(N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1[S:10][C:9]2[NH:11][C:17]([NH:18][CH:19]([CH3:20])[CH3:21])=[N:16][S:15](=[O:23])(=[O:24])[C:8]=2[CH:7]=1
Reactant: CC(=O)Nc1sc(Cl)cc1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)NC1=NS(=O)(=O)c2cc(Cl)sc2N1
Temperature: 0 °C

Procedure:
Phosgene (0.416 ml, 20% in toluene) was added dropwise to a solution of N-[5-chloro-3-(isopropylthiocarbamoyl)sulfamoylthiophen-2-yl]acetamide(261 mg, 0.73 mmol) and dry triethylamine (0.209 ml, 1.5 mmol) in dry tetrahydrofuran (5 ml) with stirring at 0° C. The mixture was stirred for 1 h at 0° C., and evaporated to dryness. The residue was triturated with 10 ml of water, and the precipitate was isolated by filtration, washed with water and finally deacetylated by stirring in 2 ml of 2 N sodium hydroxide for 90 min at room temperature. The solution was acidified to pH 2 with 4 M hydrochloric acid and the precipitate was filtered off and recrystallised from ethyl acetate with decolorising charcoal affording 44 mg (21%) of the pure title compound; mp 272-274° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ1.16 (d, 6H, 2×CH3), 3.85 (m, 1H NCH), 7.23 (s, 1H, H-7), 7.48 (br d, 1H, NH), 11.12 (s, 1H, NH); MS: m/e 279/281 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[NH:20][S:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22].Cl[C:33]1C=C(S(Cl)(=O)=O)C=C(Cl)[CH:38]=1>>[CH2:33]([O:14][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:18]=[CH:19][C:2]([Cl:1])=[C:3]([NH:20][S:21]([C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)(=[O:22])=[O:23])[CH:4]=2)=[CH:17][CH:16]=1)[CH3:38]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(Cl)c(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)c2)cc1

Procedure:
4-[4-Chloro-3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=499.0 (M−H), was prepared in analogy to example 21, steps A to D. Step C was performed using 3,5-dichloro-benzenesulfonyl chloride and yielded 4-[4-chloro-3-(3,5-dichloro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: C([O:5][C:6](=[O:22])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17]2[NH:18][CH:19]=[CH:20][N:21]=2)=[N:9]1)(C)(C)C>FC(F)(F)C(O)=O>[NH:21]1[CH:20]=[CH:19][N:18]=[C:17]1[C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]([CH2:7][C:6]([OH:22])=[O:5])[N:9]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid tert-butyl ester (977 mg) was dissolved in trifluoroacetic acid (TFA) (10 mL) and stirred at room temperature for 1 hr. The mixture was evaporated in vacuo to provide 2-(3-(1H-imidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)acetic acid as a brown oil, which was used without further purification.
Reaction SMILES: [N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:31]1[S:32][CH:33]=[CH:34][N:35]=1>>[N:1]1([C@@H:6]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[C:22]([O:27][C:31]6[S:32][CH:33]=[CH:34][N:35]=6)[CH:23]=5)[C:18]4=[O:28])=[CH:13][C:12]=3[F:29])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Brc1nccs1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1
Product: O=c1c2ccc(Oc3nccs3)cc2ccn1-c1ccc(N2CC[C@@H](N3CCCC3)C2)c(F)c1

Procedure:
According to Method AB, 2-((R)-4-[1,3′]bipyrrolidinyl-1′-yl-3-fluorophenyl)-6-hydroxy-2H-isoquinolin-1-one was reacted with 2-bromothiazole. In this way the product was obtained with molecular weight 476.58 (C26H25FN4O2S); MS (ESI): 477 (M+H+).
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1>>[F:18][C:17]1[CH:16]=[C:15]([O:19][CH3:20])[C:14]([F:21])=[CH:13][C:12]=1[N:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cc(F)c(Br)cc1F
Agent: COc1ccc(Br)cc1C
Product: CCOC(=O)C1CCN(c2cc(F)c(OC)cc2F)CC1

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 4-bromo-2,5-difluoroanisole (4.460 g) and ethyl isonipecotate (3.70 mL), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=6:1) to provide ethyl 1-(2,5-difluoro-4-methoxyphenyl)piperidine-4-carboxylate (2.465 g).