Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:19][CH3:20])[C:13]=3[C:12]([C:21]3[CH:22]=[N:23][N:24](COCC[Si](C)(C)C)[CH:25]=3)=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:1][C:2]1[C:3]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([O:19][CH3:20])[C:13]=3[C:12]([C:21]3[CH:25]=[N:24][NH:23][CH:22]=3)=[N:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: COc1nccc2c1c(-c1cnn(COCC[Si](C)(C)C)c1)nn2-c1c(F)cccc1C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1nccc2c1c(-c1cn[nH]c1)nn2-c1c(F)cccc1C#N
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a solution of 3-fluoro-2-(4-methoxy-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile (400 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added aqueous sodium carbonate solution. The organic layer was separated, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give the title compound (115 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[CH3:14][N:13]([CH3:15])[C:11](=[O:12])[C:10]1[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=1[NH:8][C:6]1[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=[C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: CN(C)C(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Nc4ccccc4C(=O)N(C)C)n3)cc2)CC1
Yield: 12 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-((2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N,N-dimethylbenzamide and 4-((4-methylpiperazin-1-yl)methyl)aniline in 12% yield (pale yellow oil that solidifies on standing) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.28 (s, 1H), 8.15 (d, 1H, J=8.2 Hz), 7.44 (d, 2H, J=8.5 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.21 (t, 1H, J=7.5 Hz), 7.02 (t, 1H, J=7.4 Hz), 6.81 (s, 1H), 3.50 (s, 2H), 3.09 (s, 3H), 2.96 (s, 3H), 2.49 (bs, 8H), 2.30 (s, 3H); MS (ESI): 514.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13]([C:17]#[N:18])=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1.Cl.[OH-].[Na+]>C(OCC)C.C1COCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:17](=[NH:18])[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:14]=2[CH:15]=[CH:16][C:7]([NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=2[O:2][CH3:1])=[N:8]3)=[CH:26][CH:25]=1
Reactant: COc1ccccc1CNc1ccc2c(C#N)cccc2n1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1CNc1ccc2c(C(=N)c3ccc(F)cc3)cccc2n1
Temperature: 0 °C
Yield: 41.3 %

Procedure:
To a cooled (ice bath) and stirred suspension of 2-(2-methoxy-benzylamino)-quinoline-5-carbonitrile (289 mg, 1.0 mmol) in diethylether (3 ml) and THF (1 ml) was added drop wise a 1M solution of 4-fluorophenyl-magnesium bromide (4 ml, 4.0 mmol), the reaction mixture was heated under reflux conditions for 24 h and poured into ice-water (15 ml). 2N HCl (5 ml) was added, the mixture was stirred at room temperature for 10 min, 3 N NaOH (5 ml) was added and the mixture was extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (2×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white solid (159 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[CH:5]=[N:6][OH:7].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([Cl:12])=[N:6][OH:7])[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: ON=C(Cl)c1ccc(Cl)c(Cl)c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 132.7 %

Procedure:
The title compound of Step A (3.7 g) was dissolved in 100 mL of dimethylformamide and 2.6 g of N-chlorosuccinimide was added. The reaction mixture was stirred at about 30° C. for 2 h and then at room temperature overnight. The mixture was diluted with 200 mL of water and extracted with three 100 mL portions of diethyl ether. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 5.8 g of the title compound of Step B as an oil. 1H NMR (CDCl3): δ 10.41 (s,1H), 7.95 (d,1H,J=2 Hz), 7.69 (dd,1H,J=2, 8 Hz), 7.46 (d,1H,J=8 Hz). The crude oil also contained DMF. The crude material was triturated in hexane and collected by filtration to yield 5.2 g of white solid, still containing DMF, which was used in the next step without additional purification or characterization.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O.CCOC(C)=O>[Si:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5](=[O:6])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:1]1(=[O:2])=[O:3])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:25])[CH3:24]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCCCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a solution of saccharin (92 mg, 0.5 mmol) in anhydrous DMF (4 mL), at room temperature, under a nitrogen atmosphere, was added NaH (60% dispersion in mineral oil, 21 mg, 0.52 mmol). The mixture was stirred at the same temperature for additional 15 min, a solution of (6-bromohexyloxy)-tert-butyldimethylsilane (177 mg, 0.6 mmol) in DMF (1 mL) was added and the resulting mixture microwaved at 150° C. for 10 min. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and AcOEt (10 mL). The organic layer was separated and the aqueous layer extracted with AcOEt (2×10 mL). The combined organic layer was washed with brine, dried (MgSO4) and the solvent removed in vacuum. The residue was purified by flash column chromatography on silica gel (20% ethyl acetate-petroleum ether) to give 83.8 (89 mg, 45% yield), as a viscous liquid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23]C)=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC2CCCCC=2C=1C(OC)=O.[Cl:39]C1C=CC(S(Cl)(=O)=O)=CC=1>>[Cl:39][C:4]1[CH:5]=[CH:6][C:1]([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH3:23])=[O:21])(=[O:9])=[O:8])=[CH:2][CH:3]=1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: COC(=O)c1c(N)sc2c1CCCC2
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(Cl)cc2)sc2c1CCCC2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from methyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate and 4-chlorobenzene-sulphonyl chloride
Reaction SMILES: [N:1](=[C:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](=O)[CH3:5])O.[CH3:11][C:12](=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[N:19](Cl)=O.N=C=O>C(O)(=O)C>[CH3:11][C:12]1[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])=[N:19][C:4]([CH3:5])=[C:3]([CH2:7][CH2:8][CH2:9][CH3:10])[N:1]=1
Reactant: CCCCC(=NO)C(C)=O
Reactant: CCCCCC(C)=O
Reactant: O=NCl
Agent: N=C=O
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(CCCC)nc1C

Procedure:
e. 2,5-Dimethyl-3,6-dibutyl-pyrazine was prepared by first forming 3-oximino-2-heptanone by reacting 2-heptanone with nitrosyl chloride according to the method of BOUVEAULT, Bull. [3] 31, 1163 (1904). The autocondensation of two moles of the imino-ketone in the presence of zino and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-dibutyl-pyrazine which had a b.p. of 18°C./0.002 mm. Hg.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N-:22]=[C:23]=[O:24].[K+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:23]([NH2:22])=[O:24])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (100 mg, 0.36 mmol) and potassium isocyanate (32 mg, 0.40 mmol) were stirred in a 1:1 mixture of water and acetic acid (3 mL) at ambient temperature for 2 h. Then a satured solution of sodium bicarbonate was added, the aqueous phase was extracted with ethyl acetate, the organic phase washed with brine and dried over sodium sulfate. Over night the desired product precipitated and subsequently the crystals were collected and dried under vacuum. [2-((R)-Indan-1-ylamino)-quinolin-6-yl]-urea was obtained as a white solid (44 mg; 38%); MS: m/e=319.3 (M+H+).
Reaction SMILES: [CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH2:35])=[N:31]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:1]1([O:6]/[N:7]=[C:8](\[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)/[C:9]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cn1ccc(N)n1
Reactant: O=C(O)/C(=N/OC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
(E)-Cyclopentyloxyimino-(3,4-dichloro-phenyl)-acetic acid (100 mg, 0.33 mmol) was dissolved in methylene chloride (1.6 mL). N,N-diisopropylethylamine (173 μL, 0.99 mmol) and 1-methyl-1H-pyrazol-3-ylamine (32 μL, 0.33 mmol) were added and the reaction mixture was cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (126 mg, 0.33 mmol) was added and the reaction mixture was allowed to warm to 25° C. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 40% ethyl acetate/hexanes) to afford (E)-2-cyclopentyloxyimino-2-(3,4-dichloro-phenyl)-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (103 mg, 82%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C17H18Cl2N4O2 [M+] 380.08, found 381 [M+H+]; H1-NMR (400 MHz, CDCl3) □ ppm 1.64 (m, 4 H, 2×CH2), 1.85 (m, 4 H, 2×CH2), 3.83 (s, 3 H, NCH3), 4.84 (m, 1 H, OCH), 6.70 (d, J=2.3 Hz, 1 H, Ar), 7.26 (d, J=2.3 Hz, 1 H, Ar), 7.33 (dd, Jo=8.3, Jm=1.9 Hz, 1 H, Ar), 7.47 (d, Jo=8.3 Hz, 1 H, Ar), 7.61 (d, Jm=1.9 Hz, 1 H, Ar), 9.15 (s, 1 H, NH).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O-:3])=[O:2].[C:13](Cl)(=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[N+:1]([CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])CCCc1ccccc1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)c1ccc(CCC[N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 3-nitropropylbenzene (16) and octanoyl chloride, according to example 2, affording compound (17) with 73% yield, which was used at the next step without additional purification.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH:12]([CH2:24][OH:25])[NH:11][C:10]1=[O:26].Cl[C:28](OC1C=CC([N+]([O-])=O)=CC=1)=[O:29].Cl.Cl.[O:42]=[C:43]1[NH:51][C:46]2=[N:47][CH:48]=[CH:49][CH:50]=[C:45]2[N:44]1[CH:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>O1CCCC1.C(Cl)(Cl)Cl>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH:12]([CH2:24][OH:25])[NH:11][C:10](=[O:26])[C@H:9]([NH:8][C:28]([N:55]2[CH2:56][CH2:57][CH:52]([N:44]3[C:45]4[C:46](=[N:47][CH:48]=[CH:49][CH:50]=4)[NH:51][C:43]3=[O:42])[CH2:53][CH2:54]2)=[O:29])[CH2:15][CH2:14]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)C(CO)NC1=O
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NC(CO)[C@H](c2cccc(F)c2F)CC[C@H]1NC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
Triethylamine (0.68 mL, 0.49 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-7-(hydroxymethyl)azepan-2-one (57 mg, 0.21 mmol) and 4-nitrophenyl chloroformate (47 mg, 0.23 mmol) in tetrahydrofuran (10 mL) at 0° C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (98 mg, 0.34 mmol), triethylamine (0.84 mmol) and chloroform (10 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was stirred overnight, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1%→12% methanol/dichloromethane) gave the title compound (17 mg). MS 515.2203 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][OH:20]>>[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH2:19][O:20][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccc(Cl)cc1Cl
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccc(Cl)cc3Cl)c21
Yield: 76.5 %

Procedure:
The title compound was prepared as white crystals in 76.5% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-dichlorobenzyl alcohol.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)[N:7]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:26][CH2:27][C:28]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:29]=1[O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[N:36]([CH2:40][CH2:41][OH:42])[N:35]=[CH:34]2.C([N:50](CC)CC)C>CC(N(C)C)=O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:26][CH2:27][C:28]2[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:29]=2[O:30][C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[N:36]([CH2:40][CH2:41][OH:42])[N:35]=[CH:34]3)=[O:18])[N:7]([C:19]2[CH:20]=[CH:21][C:22]([C:25]#[N:50])=[CH:23][CH:24]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(CC)CC
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: NCc1cc(F)ccc1Oc1ccc2c(cnn2CCO)c1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1cc(NC(=O)NCc2cc(F)ccc2Oc2ccc3c(cnn3CCO)c2)n(-c2ccc(C#N)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.6 %

Procedure:
2,2,2-Trichloroethyl 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (0.22 g, 0.529 mmol), 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)ethanol (prepared as in Example 1, Steps E1-E6; 0.175 g, 0.582 mmol), and triethylamine were combined in a minimal amount of DMA and stirred at ambient temperature overnight. The reaction mixture was concentrated, and the residue was diluted with DCM. The DCM was washed with aqueous NH4Cl and aqueous Na2CO3. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography, eluting with 1% MeOH in ethyl acetate to provide 100 mg (32.6%) of the desired product. MS M+1 (568).
Reaction SMILES: [CH2:1]([N:3]1[C:10]2[CH:9]=[C:8]([C:11]([O:13]CC)=[O:12])[NH:7][C:6]=2[C:5]([N:16]([CH3:25])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])=[CH:4]1)[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:1]([N:3]1[C:10]2[CH:9]=[C:8]([C:11]([OH:13])=[O:12])[NH:7][C:6]=2[C:5]([N:16]([CH3:25])[S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc2c([nH]1)c(N(C)S(=O)(=O)c1cccs1)cn2CC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCn1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 84.2 %

Procedure:
To a mixture of ethyl 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylate (1.0 g), tetrahydrofuran (8 mL) and ethanol (8 mL) was added 8N aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was concentrated, 6N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was crystallized from diethyl ether to give 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid (780 mg, yield 85%) as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])[C:3]#[N:4].[O:14]1[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1.[Si](OC(C)(C)CC(NC(C1C=C(Cl)C=CC=1OC)C#N)=O)(C(C)(C)C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([CH:2]([C:3]#[N:4])[NH:1][C:20]([CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[O:21])[CH:10]=1
Reactant: O=C(O)C1CCOCC1
Reactant: COc1ccc(Cl)cc1C(N)C#N
Agent: COc1ccc(Cl)cc1C(C#N)NC(=O)CC(C)(C)O[Si](C)(C)C(C)(C)C
Product: COc1ccc(Cl)cc1C(C#N)NC(=O)C1CCOCC1

Procedure:
Using amino-(5-chloro-2-methoxy-phenyl)-acetonitrile and tetrahydro-2H-pyran-4-carboxylic acid, the title compound was prepared following the synthetic procedures described for 3-(tert-butyldimethylsilyloxy)-N-((5-chloro-2-methoxyphenyl)(cyano)methyl)-3-methylbutanamide to give N-((5-chloro-2-methoxyphenyl)(cyano)methyl)tetrahydro-2H-pyran-4-carboxamide as a white solid. LCMS (ESI) m+H=309.3.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([O:11][CH3:12])(=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].C(N(CC)CC)C.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[N:28]=1)[CH2:24]Cl.Cl.[OH2:31]>C(#N)C.ClCCl>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[N:28]=1)[C:24]([CH:5]([C:4]([O:11][CH3:12])=[O:10])[C:6]([O:8][CH3:9])=[O:7])=[O:31]
Reactant: ClCc1cc(Cl)nc(Cl)c1
Reactant: O
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C(=O)OC)C(=O)c1cc(Cl)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.2 %

Procedure:
2312 g (24.28 mol) of magnesium chloride are introduced with cooling into 18 l of acetonitrile. After the exothermic reaction has subsided, the solution is cooled to 0° C. and 3210 g (24.3 mol) of dimethyl malonate are added dropwise with stirring in the course of 45 minutes. After this, 4920 g (48.62 mol) of triethylamine are added dropwise at 0° C. with stirring in the course of 1.5 hours. After addition is complete, the mixture is stirred at 0° C. for a further 15 minutes. A solution of 4742 g (22.53 mol) of 2,6-dichloro-isonicotinyl chloride in 6670 ml of acetonitrile is then added dropwise at 0° C. with stirring in the course of 20 hours. The mixture is first stirred for 1 hour at 0° C. and then for 16 hours while slowly warming to room temperature. 15.9 l of concentrated hydrochloric acid are then added dropwise with stirring to the reaction mixture with cooling to 0 to 10° C. After this, 15.9 l of dichloromethane and 6.4 l of water are added with stirring and the organic phase is then separated off. The aqueous phase is extracted once more with 7.9 l of dichloromethane. The combined organic phases are washed twice with 4 l of water each time and then concentrated under reduced pressure. The residue which remains is stirred with 9.5 l of water, then filtered off with suction and washed successively, first with 6.3 l of water and then twice with 7.9 l of petroleum ether each time. The product obtained is dried at 40° C. under reduced pressure. In this manner, 6.17 kg (89.2% of theory) of dimethyl 2,6-dichloro-isonicotinoyl-malonate are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C@@H:14]([CH2:15][CH2:16][OH:17])[O:13][CH2:12][CH2:11][N:10]2[C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:29])[CH3:28])[CH:21]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:31][S:32]([O:17][CH2:16][CH2:15][C@H:14]1[O:13][CH2:12][CH2:11][N:10]([C:18](=[O:30])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH:27]([CH3:28])[CH3:29])[CH:21]=2)[CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:34])=[O:33]
Reactant: CC(C)Oc1cccc(CC(=O)N2CCO[C@H](CCO)C2c2ccc(Cl)c(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cccc(CC(=O)N2CCO[C@H](CCOS(C)(=O)=O)C2c2ccc(Cl)c(Cl)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
1.81 g (4.00 mmole) of 2-{(2R)-(3,4-dichlorophenyl)-4-[(3-isopropoxyphenyl)acetyl]morpholin-2yl}ethanol [prepared as described in step (a) above] were dissolved in 5 ml of pyridine, and 45 mg (0.40 mmole) of 4-dimethylaminopyridine and 0.46 ml (6.00 mmole) of methanesulfonyl chloride were added to the resulting solution, whilst ice-cooling. The mixture was then stirred at 0° C. for 2 hours under a nitrogen atmosphere. At the end of this time, the reaction mixture was poured into ice-cooled 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 1:1 to 1:2 by volume as the eluent, to give 2.00 g of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[C:22](C)[CH:21]=1.[C:30](O)(=O)C.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:24]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([NH2:18])=[O:17])=[C:28]([CH3:30])[CH:27]=1)([OH:26])=[O:25]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: Cc1cc(N)ccc1C(=O)O
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncc(C(N)=O)c(Nc3ccc(C(=O)O)cc3C)c2cc1OC
Temperature: 100 °C
Yield: 47 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.046 g, 0.17 mmol), 4-amino-2-methylbenzoic acid (0.036 g, 0.24 mmol) and acetic acid (40 μl) in DMF (0.8 ml) was heated at 100° C. for 12 h. After cooling, the mixture was diluted with water (15 ml) and made alkaline with saturated NaHCO3 and was then weakly acidified with acetic acid. The precipitate was filtered of and suspended in warm methanol. After cooling, the precipitate was filtered off and dried to give the title compound (31 mg, 47%).