Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=1)#[CH:2].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]#[C:1][C:3]2[C:8]([NH2:9])=[CH:7][CH:6]=[C:5]([CH3:10])[N:4]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: C#Cc1nc(C)ccc1N
Reactant: Clc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N)c(C#Cc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.6 %

Procedure:
To a solution of Cul (5.0 mg, 28 μmol) in triethylamine (5 ml) were added (2-ethynyl-6-methyl-pyridin-3-yl)amine (75 mg, 0.57 mmol described in Example 7), (PPh3)2PdCl2 (20 mg, 28 μmol), and 1-chloro-3-iodobenzene (135 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 4 h. The solvent was evaporated to afford a brown oil which was taken up in DCM and the solution was washed with water. The aqueous phase was extracted twice with DCM. The organic phases were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to yield 54 mg (0.22 mmol, 39%) of (2-(3-chloro-phenylethynyl)-6-methyl-pyridin-3-yl)amine as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][CH2:8][C@@H:9]([N:11]1[CH2:16][CH2:15][N:14]2[C:17](=[O:27])[C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[CH:19][CH:20]=[C:13]2[C:12]1=[O:28])[CH3:10].F[C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=1[S:39]([F:44])([F:43])([F:42])([F:41])[F:40]>O1CCCC1.O>[CH3:26][C:24]1[N:23]=[CH:22][N:21]([C:18]2[C:17](=[O:27])[N:14]3[CH2:15][CH2:16][N:11]([C@@H:9]([CH3:10])[CH2:8][O:7][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:31]=4[S:39]([F:42])([F:43])([F:44])([F:40])[F:41])[C:12](=[O:28])[C:13]3=[CH:20][CH:19]=2)[CH:25]=1
Reactant: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)CO)C3=O)cn1
Reactant: O=[N+]([O-])c1ccc(F)c(S(F)(F)(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn(-c2ccc3n(c2=O)CCN([C@@H](C)COc2ccc([N+](=O)[O-])cc2S(F)(F)(F)(F)F)C3=O)cn1
Reaction time: 0.17 h

Procedure:
A solution of potassium tert-butoxide in tetrahydrofuran (1 M, 1.97 mL, 1.97 mmol) was added to a slurry of 2-[(2S)-1-hydroxypropan-2-yl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (C54) (541 mg, 1.79 mmol) in tetrahydrofuran (6 mL), and the mixture was allowed to stir for 10 minutes. A solution of 1-fluoro-4-nitro-2-(pentafluoro-λ6-sulfanyl)benzene (P15) (478 mg, 1.79 mmol) in tetrahydrofuran (4 mL) was added, and the reaction mixture was stirred at room temperature for 18 hours. At that point, it was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: ethyl acetate, then 10% methanol in ethyl acetate) afforded the product as a yellow foam. Yield: 695 mg, 1.26 mmol, 70%. LCMS m/z 550.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.53 (d, J=7.1 Hz, 3H), 2.34 (d, J=1.0 Hz, 3H), 3.73-3.85 (m, 2H), 4.30-4.47 (m, 4H), 4.99-5.08 (m, 1H), 7.16-7.21 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.52 (d, J=7.7 Hz, 1H), 8.40 (dd, J=9.2, 2.7 Hz, 1H), 8.44 (br s, 1H), 8.71 (d, J=2.6 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:31])[C:24]1[CH:25]=[C:26](O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][N:23]([CH3:31])[C:24]1[CH:29]=[C:28]([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: CN(C)c1cccc(O)c1
Product: CN(C)c1cccc(OC(=O)COc2ncc(C(=O)Nc3ccc(F)cc3)cn2)c1
Yield: 76 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3-dimethylaminophenol (21 mg, 0.15 mmol) as the coupling partner. Concentration (no chromatography) yielded 53 mg (76%) of the titled compound as a pink-purple solid. ESI-MS m/z 411 (MH+), 409 (M−H−).
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([OH:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH3:24]>CC(C)=O>[CH2:23]([O:14][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])[C:4]([NH:3][CH2:1][CH3:2])=[O:15])[CH3:24]
Reactant: CCNC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCNC(=O)c1ccc([N+](=O)[O-])c(OCC)c1
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of N-ethyl-3-hydroxy-4-nitrobenzamide (2.1 g) obtained in Example 74a) in acetone (100 ml) were added potassium carbonate (1.4 g) and bromoethane (0.75 ml), and the mixture was heated under reflux overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue, and the organic layer was fractionated. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown solid (0.72 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@:12]2([F:20])[CH3:19])=[C:4]([O:21][CH3:22])[N:3]=1.[C:23](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:32]1[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=1)[C:24]1[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=1>N1C=CC=CC=1>[CH3:29][O:28][C:27]1[CH:30]=[CH:31][C:24]([C:23]([C:32]2[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:17][CH2:16][C@@H:14]2[C@@H:13]([OH:18])[C@:12]([F:20])([CH3:19])[C@H:11]([N:8]3[CH:7]=[N:6][C:5]4[C:9]3=[N:10][C:2]([NH:1][C:23]([C:24]3[CH:31]=[CH:30][C:27]([O:28][CH3:29])=[CH:26][CH:25]=3)([C:32]3[CH:39]=[CH:38][C:35]([O:36][CH3:37])=[CH:34][CH:33]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[N:3][C:4]=4[O:21][CH3:22])[O:15]2)=[CH:25][CH:26]=1
Reactant: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](O)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (2R,3R,4R,5R)-5-(2-amino-6-methoxy-9H-purin-9-yl)-4-fluoro-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (2, 4 g, 12.8 mmol) in anhydrous pyridine (100 mL) cooled at 0° C. was added DMT-Cl portion-wise under nitrogen. The brown solution was stirred at ambient temperature for 24 hours. The mixture was concentrated under reduced pressure to remove most of solvent and sat. NaHCO3 (20 mL) was added. The mixture was diluted with water (150 mL) and EtOAc (120 mL). The organic layer was separated and washed with water (5×120 mL), brine and dried over Na2SO4. After removal of solvent, the residue was purified via column chromatography (20% EA in hexanes to 80% EA in hexanes) to afford 11.6 g of product, 3, as a white foam solid (quantitative yield). 1H-NMR (DMSO-d6): δ 7.94 (s, 1H), 7.39-7.37 (m, 3 H), 7.26-7.14 (m, 17H), 6.84-6.80 (m, 8H), 5.58 (s, 1H), 4.04 (br, 1H), 3.71-3.70 (m, 14H), 3.68 (m, 1H), 3.48 (br, 2H), 3.20 (d, 1H), 0.88 (br, 3H).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:2]1.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>C(O)C>[OH:24][CH2:23][CH2:22][N:21]([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:20]
Reactant: CCCCCCCCCCCCCCCCC1CO1
Reactant: CNCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)CN(C)CCO
Temperature: 80 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A 300-ml flask equipped with a stirrer was charged with 26.85 g (0.1 mol) of 1,2-epoxyoctadecane, 7.51 g (0.1 mol) of N-methylethanolamine and 50 ml of ethanol, and the contents were stirred at 80° C. for 18 hours. After the solvent was distilled off under reduced pressure, the resultant residue was purified by column chromatography on silica gel, thereby obtaining 23.0 g (yield: 67%) of the title compound (IIc-2).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:26]2([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]2)[O:25][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[C@H:19]([OH:22])[C:18](=[O:23])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:24])[CH2:11]2.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34].N1C=CN=C1>CN(C=O)C>[Si:37]([O:24][C@H:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C@@H:10]([CH2:9][CH2:8][C@@H:7]3[C@@H:17]2[C:18](=[O:23])[C@@H:19]([OH:22])[C@@:20]2([CH3:21])[C@H:6]3[CH2:5][C@@H:4]3[O:25][C@@:26]4([O:32][CH2:31][C@H:29]([CH3:30])[CH2:28][CH2:27]4)[C@@H:2]([CH3:1])[C@@H:3]32)[CH2:11]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]5(C)[C@H]4C(=O)[C@@H](O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
Using the procedure described in J. Am. Chem. Soc., 1972,94, 6190, (3β,5α,12β,25R)-spirostan-3,12-diol-11-one (see preparation G6) was silylated with t-butyldimethylchlorosilane and imidazole in DMF to give the title compound.
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20].[F:21][C:22]([F:30])([S:28][CH3:29])[C:23](OCC)=[O:24].Cl>CCOCC>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:23](=[O:24])[C:22]([F:30])([F:21])[S:28][CH3:29]
Reactant: CCOC(=O)C(F)(F)SC
Reactant: Fc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CSC(F)(F)C(=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
A hexane solution (13.7 ml, 21.6 mmol) of 1.58 M n-butyllithium was added dropwise to a solution of 1-bromo-2,4-difluorobenzene (4.2 g, 21.8 mmol) in absolute ether (60 ml) at −70° C., and the mixture was stirred for 15 minutes at the same temperature. A solution of ethyl 2,2-difluoro-2-(methylthio)acetate (3.7 g, 21.6 mmol) in absolute ether (20 ml) was added to this solution at −70° C. After the resultant mixture was stirred for 1 hour at the same temperature, the temperature of the reaction mixture was raised to 0° C. for 1 hour. The reaction mixture was poured into diluted hydrochloric acid-containing ice to conduct extraction with ether. After the resultant ether solution was washed with water and dried, the solvent was distilled off. The resultant residue was purified by distillation under reduced pressure to obtain 1-(2,4-difluorophenyl)-2,2-difluoro-2-(methylthio)-1-ethanone (4.1 g, yield: 90.0%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20](Cl)=[O:21].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[CH:13][CH:12]=2)[C:8]([C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=2)=[CH:9]1)=[O:21]
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(C(=O)c3c(Cl)cccc3Cl)c3ccncc23)CC1

Procedure:
from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)5-azaindole (20 mg, 0.094 mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:12][CH2:11][CH2:10][C@@H:9]([NH:13][C:14]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:20])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCO)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCOS(C)(=O)=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To a mixture of (S)-tert-Butyl 1-(4-chlorophenyl)-4-hydroxybutan-2-ylcarbamate (686 mg, 2.3 mmol) and TEA (399 μl, 2.9 mmol) in DCM (10 mL) at −8° C. was added methanesulfonyl chloride (214 μl, 2.7 mmol). The resulting mixture was stirred for 2 hours. After warming to room temperature, the mixture was diluted with DCM and washed with H2O (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the product as a light yellow solid (815 mg, 94%). LCMS (API-ES) m/z: 400 (M+Na+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](N)[C:7]=1[Br:13])(=[O:3])[CH3:2].N(OC(C)(C)C)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([Br:13])=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cccc(N)c1Br
Reactant: c1ccccc1
Agent: CC(C)(C)ON=O
Product: CC(=O)OCc1cccc(-c2ccccc2)c1Br
Reaction time: 48 h

Procedure:
A stirred solution of (3-amino-2-bromophenyl)methyl acetate (8.5 g, 0.035 mole) in 31.1 ml of benzene was heated at reflux. During a 40 minute period t-butyl nitrite (8.03 ml, 0.07 mole) was added to the reaction mixture. The mixture was refluxed for four hours, then held at room temperature for two days. The solvent was distilled from the reaction mixture under reduced pressure and 100 ml of n-heptane added to the residue. The solvent was removed by distillation under reduced pressure to give (2-bromo-[1,1'-biphenyl)-3-yl)methyl acetate (10.2 g) as an oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[C:25]([O:27][C@@H:28]([CH3:38])[CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH:26]=2)[C:21](O)=[O:22])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:63]([N:65]1[CH:69]=[CH:68][C:67]([NH2:70])=[N:66]1)[CH3:64]>CN(C=O)C>[CH3:35][C:34]([Si:31]([CH3:33])([CH3:32])[O:30][CH2:29][C@@H:28]([O:27][C:25]1[CH:24]=[C:20]([CH:19]=[C:18]([O:17][CH2:16][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:26]=1)[C:21]([NH:70][C:67]1[CH:68]=[CH:69][N:65]([CH2:63][CH3:64])[N:66]=1)=[O:22])[CH3:38])([CH3:37])[CH3:36]
Reactant: CCn1ccc(N)n1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.3 %

Procedure:
DIPEA (3.11 mL, 18.03 mmol) was added to a solution of 3-{(phenylmethyl)oxy}-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (3.00 g, 7.21 mmol), HATU (3.41 g, 9.01 mmol) and 1-ethyl-1H-pyrazol-3-amine [Chem. Heterocycl. Compd. (Engl. Transl.), 11, 1975, 212] (1.20 g, 10.8 mmol) in DMF (10 mL). The resulting mixture was stirred at ambient temperature for 3 hours. The DMF was removed in vacuo. The solvent was evaporated and the residue was dissolved in 5% w/v citric acid (50 mL), ethyl acetate (30 mL) and diethyl ether (30 mL) and the organic layer was further washed with sat. aqueous NaHCO3 (30 mL) and brine (30 mL). The organic layer was separated, then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:5 to 1:2 ethyl acetate:hexanes, afforded the title compound as a colourless oil (2.40 g, 65%).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:3]1([N:2]([CH3:1])[C:9]2[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]([CH3:33])[C:28]([NH:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: CNC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCNC(=O)C(C)c1ccc(C2CCN(c3ccnc(N(C)C4CCCC4)n3)CC2)cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To 26 mg (0.26 mmol) N-methyl-cyclopentylamine in 2.5 mL NMP are added 80 mg (0.22 mmol) 2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-N-ethyl-propion-amide (XII.1) and 110 (0.65 mmol) DIPEA. The mixture is stirred at 100° C. for 1 h and at 120° C. for 1 h under microwave irradiation. After that time, the mixture is directly purified by HPLC (XBridge 100; water, 0.3% NH4OH/MeOH) to yield the desired product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][OH:34])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:36][CH2:37][O:38][CH3:39]>CN(C=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][O:34][CH2:36][CH2:37][O:38][CH3:39])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(CO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Reactant: COCCBr
Solvent: CN(C)C=O
Product: COCCOCc1cccc2c1nc(C(=O)NC1CCN(C(C)C)CC1)n2CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
81.6 mg (0.065 mmol) 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-hydroxymethyl-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 5 mL abs. DMF. At 0° C. 21.9 mg (0.195 mmol) potassium tert.butylate were added. After 5 min 12 μl (0.13 mmol) 1-bromo-2-methoxy-ethane were added and the reaction mixture was allowed to come to room temperature. After 3 h further 12 μl (0.13 mmol) 1-bromo-2-methoxy-ethane were added and the reaction mixture was stirred for 16 h. The solvent was distilled off and the resulting residue was purified by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) to give 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-methoxy-ethoxymethyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as a light brown amorphous solid. The title compound was obtained as its formiate. Yield: 12 mg MS (ES+): m/e=543, chloro pattern.
Reaction SMILES: [ClH:1].NC(=O)[C@@H]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])C1C=CC=CC=1.[CH:34]1(N)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Reactant: NC1CCCCC1
Agent: Cl
Product: Nc1cc(Oc2ccc(NC(=O)CC(=O)NC3CCCCC3)cc2F)ccn1
Yield: 52 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with cyclohexanamine (Aldrich, 20 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-cyclohexylmalonamide, hydrochloride salt (22 mg, 52% yield). 1H NMR (DMSO-d6) δ 14.00 (s, 1H), 10.72 (s, 1H), 8.10 (d, 1H, J=7.0 Hz), 7.97 (d, 1H, J=7.0 Hz), 7.88 (m, 3H), 7.44 (m, 2H), 6.70 (m, 1H), 6.14 (d, 1H, J=2.0 Hz), 3.54 (m, 1H), 3.27 (s, 2H), 1.66-1.75 (m, 4H), 1.52 (m, 1H), 1.15-1.25 (m, 5H); MS (ESI+) m/z 387.32 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13][C:12]([CH3:15])([CH3:14])[O:11][C@@H:8]32)[O:3]1.[CH3:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][C:21]=1/[CH:26]=[C:27]1\[C:28](=[O:39])[N:29]([C:36](Cl)=[O:37])[C:30]2[C:35]\1=[CH:34][CH:33]=[CH:32][CH:31]=2>N1C=CC=CC=1.C1COCC1>[CH3:15][C:12]1([CH3:14])[O:13][C@H:7]2[O:6][CH:5]([CH2:16][O:17][C:36]([N:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)/[C:27](=[CH:26]/[C:21]4[NH:22][C:23]([CH3:25])=[CH:24][C:20]=4[CH3:19])/[C:28]3=[O:39])=[O:37])[C@@H:4]3[O:3][C:2]([CH3:18])([CH3:1])[O:10][C@@H:9]3[C@H:8]2[O:11]1
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC3O[C@@H]4OC(C)(C)O[C@@H]4[C@H]4OC(C)(C)O[C@@H]34)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1,2,3,4-di-O-isopropylidene-D-galactopyranose (650 mg, 2.5 mmol) in 1.0 mL of pyridine and 2.0 mL of THF was added a suspension of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) at 0° C. The reaction mixture was then gradually warmed to room temperature, stirred for 4 h, and concentrated. The residue was triturated with water and washed with ether to give 170 mg (65%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid (3aR, 5aS, 8aS, 8bR)-2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4′,5′-d]pyran-5-ylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:55][CH2:56][C:57]([O:59][CH3:60])=[O:58]>>[CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[CH2:55][CH2:56][C:57]([O:59][CH3:60])=[O:58])=[CH:13][CH:12]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COC(=O)CCc1ccccc1O
Product: COC(=O)CCc1ccccc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method F, 0.30 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and methyl 3-(2-hydroxyphenyl)propionate are used to prepare the title compound as a colourless oil. Rf=0.23 (1:2 EtOAc-heptane); Rt=6.20.