Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(N(CC)CC)C.[C:20](=O)([O:26]C(C)(C)C)[O:21][C:22]([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:21][C:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:26])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
Ethyl 2-amino-4-thiazole-acetate (5.0 g, 26.8 mmol) and triethylamine (3.8 ml, 26.8 mmol) were dissolved in a dichloromethane (20 ml). Di-t-butyl carbonate (7.0 g, 32.2 mmol) was added to the solution under cooling with ice water. The mixture was stirred overnight at room temperature. After 18 hours, additional di-t-butyl carbonate (1.4 g, 13.4 mmol) was added, and the resultant mixture was stirred at room temperature for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resultant residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1) to obtain 3.1 g of ethyl 2-t-butoxycarbonylamino-4-thiazole-acetate. A part (2.0 g, 7.0 mmol) of this compound was dissolved in a mixed solvent of ethanoltetrahydrofuran (3:2, 50 ml). Lithium chloride (592 mg, 14.0 mmol) and sodium borohydride (528 mg, 14.0 mmol) were added to the solution at room temperature, and the mixture was stirred at room temperature for 6 hours. After 6 hours, sodium borohydride (530 mg, 14.1 mmol) and lithium chloride (592 mg, 14.0 mmol) were additionally added, and the resultant mixture was stirred further for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water, diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=1:1 to 2:3) to obtain 959 mg of the title compound (oil).
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][C:8]1([OH:16])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.[NH2:25][NH2:26]>C(Cl)Cl.CO>[OH:16][C:8]1([CH2:7][C:6]([NH:25][NH2:26])=[O:5])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: NN
Reactant: CC(C)(C)OC(=O)CC1(O)CN2CCC1CC2
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NNC(=O)CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.5 g of the compound of step (a) in 15 ml of methylene chloride was added trifluoroacetic acid (39 ml) and the mixture was stirred at ambient temperature for three hours. The mixture was then concentrated in vacuo. The residue was dissolved in methanol (30 ml) and 18M H2SO4 (3 ml) was added and the mixture was stirred overnight. The mixture was then poured into a solution of sodium carbonate in water, extracted three times with chloroform, dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid. The solid was dissolved in methanol (10 ml) and hydrazine (2 ml) was added to this solution and the mixture was heated to reflux for one hour. The mixture was then concentrated in vacuo. The resulting solid was suspended in toluene (50 ml) and heated to reflux in an apparatus equipped with a Dean-Stark trap for two hours. The reaction mixture was then allowed to cool, and the product was filtered off to give 1.82 g of the subtitle compound as a tan solid.
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)C4)=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]1([C:5]2[N:13]3[C:8]([C:9]([NH2:14])=[N:10][CH:11]=[N:12]3)=[C:7]([C:26]3[CH:25]=[C:24]4[C:29]([CH:30]=[CH:31][C:22]([C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)=[N:23]4)=[CH:28][CH:27]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncnn2c(C3CCC3)nc(I)c12
Reactant: CC1(C)CB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1ncnn2c(C3CCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Temperature: 75 °C

Procedure:
A flask was charged with 7-cyclobutyl-5-iodo-imidazo[5,1-f][1,2,4]triazin-4-ylamine (30 mg, 0.095 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[2,3,2]dioxaborolan-2-yl)-quinoline (38 mg, 0.110 mmol), and sodium carbonate (Na2CO3) (30 mg, 0.286 mmol) was evacuated and charged with nitrogen (N2) (3×). To this mixture was quickly added tetrakis(triphenylphosphine)palladium(0) and evacuated and charged with N2 (2×). This mixture was charged with a previously degassed solvent DME/H2O (5:1) (2 mL) and heated overnight at 75° C. The reaction mixture was filtered through an autovial (0.45 μM frit) and washed with MeOH (3×). The filtrate was concentrated in vacuo and purified by mass directed purification (MDP) resulting in the title compound as a pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 1.96-2.10 (m, 1H), 2.10-2.25 (m, 1H); 2.40-2.56 (m, 2H); 2.60-2.78 (m, 2H); 4.12-4.29 (m, 1H); 5.99 (brs, 2H); 7.42-7.58 (m, 3H); 7.84-8.05 (m, 4H); 8.18 (d, J=7.2 Hz, 2H); 8.28 (d, J=8.4 Hz, 1H); 8.39 (s, 1H); MS (ES+): m/z 393.14 (100) [MH+], HPLC: tR=3.51 min (MicromassZQ, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][C@H:39]([CH3:43])[CH2:40][O:41][CH3:42])[CH:37]=1)[N:34]=[C:33]([CH:44]=O)[CH:32]=[CH:31]2.C(O)C.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:44]([C:33]3[CH:32]=[CH:31][C:30]4[C:35](=[C:36]([O:38][C@H:39]([CH3:43])[CH2:40][O:41][CH3:42])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:34]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COC[C@@H](C)Oc1cc(F)cc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Agent: O=C([O-])O
Agent: O=Ic1ccccc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COC[C@@H](C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
A solution of tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.16 g, 0.43 mmol) and (R)-6-fluoro-8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (0.11 g, 0.43 mmol) in ethanol (2.2 mL, 0.43 mmol) was allowed to stir at ambient temperature for 12 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (2.2 mL) and iodosobenzene diacetate (0.15 g, 0.47 mmol) was added. The reaction mixture was stirred at ambient temperature for 1 hour. Ethyl acetate (20 mL) and saturated sodium bicarbonate (10 mL) were added. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography on C18 (0-100% acetonitrile/water) to give the title compound (0.12 g, 44%).
Reaction SMILES: [NH:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][C:19](Br)=[O:20].O>C(Cl)Cl>[Br:17][CH2:18][C:19]([N:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[O:20]
Reactant: C1CCC2NCCCC2C1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CCCC2CCCCC21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.6 %

Procedure:
To an ice cooled suspension of 2.15 g (15 mmol) of decahydroquinoline, 5.20 g (37.5 mmol) of potassium carbonate in 30 ml of methylene chloride was added 3.10 g (15 mmol) of bromoacetylbromide. Then the reaction mixture was stirred at RT for 20 h, Water was added, the mixture extracted by methylene chloride, the organic phase washed by water, dried over sodium sulphate and evaporated to dryness. Flash chromatography using methylene chloride as eluant afforded 2.6 g of compound as uncolorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22](Cl)=[O:23])[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:22](=[O:23])[CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH3:13])[CH:16]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: COc1cccc(CC(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(CC(=O)Nc2ccc3sc(C)nc3c2Cl)c1
Yield: 44 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with 3-methoxyphenylacetyl chloride (47 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-2-(3-methoxy-phenyl)-acetamide (40 mg, 0.11 mmol, 48% yield) as a white powder after crystallisation in hexane/DCM.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(#N)C.[NH2:28][C:29]1[CH:56]=[CH:55][CH:54]=[CH:53][C:30]=1[O:31][CH2:32][C:33]([OH:52])([CH3:51])[CH2:34][N:35]1[CH2:40][CH2:39][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[NH:43][C:42]2=[O:50])[CH2:37][CH2:36]1.[N:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1[C:63](O)=[O:64].CCN(C(C)C)C(C)C>C1COCC1>[OH:52][C:33]([CH3:51])([CH2:34][N:35]1[CH2:36][CH2:37][CH:38]([N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[NH:43][C:42]2=[O:50])[CH2:39][CH2:40]1)[CH2:32][O:31][C:30]1[CH:53]=[CH:54][CH:55]=[CH:56][C:29]=1[NH:28][C:63]([C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][N:57]=1)=[O:64]
Reactant: O=C(O)c1ccccn1
Reactant: CC(O)(COc1ccccc1N)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(O)(COc1ccccc1NC(=O)c1ccccn1)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
HATU in acetonitrile (0.2 M, 0.375 ml, 0.075 mmol) was added to a solution of 1-{1-[3-(2-aminophenoxy)-2-hydroxy-2-methylpropyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one (0.020 g, 0.05 mmol), 2-pyridinecarboxylic acid (0.006 g, 0.05 mmol) and Hünigs base (0.013 ml, 0.075 mmol) in THF (0.5 ml). After 0.5 h at 40° C. and 2 h at room temperature the reaction mixture was concentrated, and the residue purified on silica (dichloromethane-methanol, 12:1, containing 1% of NH4OH (25%)). Yield 20 mg of the title compound.
Reaction SMILES: [Cl-:1].[NH4+].[CH3:3][O:4][C:5](=[O:29])[C@H:6]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([OH:17])[CH:9]=1>[Fe]>[ClH:1].[CH3:3][O:4][C:5](=[O:29])[C@H:6]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([OH:17])[CH:9]=1
Reactant: COC(=O)[C@@H](Cc1ccc([N+](=O)[O-])c(O)c1)NC(=O)OCc1ccccc1
Reactant: [Cl-]
Agent: [Fe]
Agent: [NH4+]
Product: COC(=O)[C@@H](Cc1ccc(N)c(O)c1)NC(=O)OCc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Powdered iron (3.7 g, 66.4 mmol) and ammonium chloride (5.9 g, 111 mmol) were added at 0° C. to a solution of (R)-2-benzyloxycarbonylamino-3-(3hydroxy-4-nitro-phenyl)-propionic acid methyl ester (2.07 g, 5.53 mmol) in degassed 1:1 methanol/water (400 mL). The resulting mixture was stirred at room temperature for 48 h. Trifluoroacetic acid (7 mL) was added, and the mixture was swirled until it was a clear dark red solution containing a suspension of unreacted iron powder. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was extracted with ethyl acetate (2×150 mL), the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, hydrochloric acid (4.2 mL, 4M in dioxane) was added. Solvents were removed in vacuo, and the title compound was obtained as a tan foamy solid (80%). 1H-NMR (CD3OD, 500 MHz) δ 7.34-7.28 (m, 5H), 7.20 (d, J=8.0 hz, 1H), 6.88 (s, 1H), 6.78 (d, J=7.5 Hz, 1H), 5.05-5.00 (m, 2H), 4.42 (dd, J=8.5, 5.0 Hz, 1H), 3.70 (s, 3H), 3.65 (s, 1H), 3.33 (br s, 2H), 3.11 (dd, J=14.0, 5.0 hz, 1H), 2.90 (dd, J=13.5, 9.0 Hz, 1H). 13CNMR (CD3OD, 125 MHz) 172.5, 157.4, 151.2, 140.2, 137.0, 128.5, 128.0, 127.7, 123.8, 120.9, 117.0, 116.9, 67.2, 55.7, 52.0, 37.2. Mass spec.: 345.20 (MH)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28])=[O:6])[CH:2]=[CH2:3].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([S:31][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:9]1)(=[O:32])[CH3:30]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A solution of (2S,4R)-1-allyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (12.4 g: 30.46 mmole) and 90% potassium thioacetate (5.22 g: 45.69 mmole) in dimethylformamide (130 ml) is heated with stirring at 60° C. for 4 hours. The reaction mixture is diluted with ethyl acetate (200 ml) and ice water (200 ml). The organic layer is taken, successively washed with water (3 times) and saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel chromatography to give crude (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-phthalimidomethylpyrrolidine (9.33 g). Yield: 81%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCC)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: NCc1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(NCc1cccnc1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred two-phase solution of 3-nitrobenzoyl chloride (9.3 g) in a mixture of diethyl ether (50 ml) and saturated sodium bicarbonate solution (50 ml) was added 3-aminomethylpyridine (5.4 g) in an ice-cooled bath. The mixture was stirred vigorously at ambient temperature for 30 minutes. The reaction mixture was filtered, and the resulting solid was washed with water. The solid was further solidified with diisopropyl alcohol-water to afford 3-nitro-N-(3-pyridylmethyl)benzamide (5.91 g) as a pale yellow amorphous solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.[CH:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([CH3:24])[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:25]1[CH:30]=[C:29]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:28]=[CH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(C)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of tert-butyl 4-[(trifluoromethyl)sulfonyl]oxy-3,6-dihydropyridine-1(2H)-carboxylate (11.0 g, 0.0332 mol), (3-isopropylphenyl)boronic acid (5.44 g, 0.0332 mol) and potassium phosphate (21.1 g, 0.0996 mol) in tetrahydrofuran (150.0 mL, 1.849 mol) was degassed for 15 min, then tetrakis(triphenylphosphine)palladium(0) (2 g, 0.002 mol) was added and the resulting mixture was refluxed overnight. After evaporation of most of THF, the residue was diluted with water, extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dry. The residue was applied on silica gel column, eluting with 0 to 20% EtOAc in hexane (9.1 g, 91%). MS (ESI): (M−Bu) 246.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Br:29][CH2:30][C:31](Cl)=[O:32]>C(OCC)C.CC(OC)(C)C>[Br:29][CH2:30][C:31]([N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: O=C(Cl)CBr
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)CBr)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (220 mg, 0.75 mmol) in diethylether (2 mL) was cooled to 0° C. and triethylamine (114 μL, 0.82 mmol) and bromoacetyl chloride (81 μL, 0.97 mmol) were added. After stirring for 15 min. at this temperature the ice bath was removed and the suspension was stirred for 2 h at ambient temperature. Further bromoacetyl chloride (16 μL, 0.2 mmol) was added and the resulting suspension was stirred for 1 h at this temperature. It was diluted with TBME (10 mL) and washed with water (15 mL) and brine (15 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 70:30) afforded the title compound (134 mg, 43%) as a light brown oil. MS m/e: 417.1 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22]C3N(C)C=NC=3)[CH:20]=2)[CH:4]=1.[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38]C#C)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]>>[CH:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:22]#[C:21][C:19]2[CH:20]=[C:15]([C:5]3[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH:6]=3)[CH:16]=[N:17][CH:18]=2)[CH2:34][CH2:33]1)([CH3:31])[CH3:30]
Reactant: C#CCN1CCN(C(C)C)CC1
Reactant: CNc1cc(-c2cncc(C#Cc3cncn3C)c2)cc(-c2ccccn2)n1
Product: CNc1cc(-c2cncc(C#CCN3CCN(C(C)C)CC3)c2)cc(-c2ccccn2)n1

Procedure:
This compound is prepared analogously to Methyl-[5″-(3-methyl-3H-imidazol-4-ylethynyl)-[2,2′;4′,3″]terpyridin-6′-yl]-amine (Example 2.182) by replacing 1-methyl-5-((trimethylsilyl)ethynyl)-1H-imidazole with 1-isopropyl-4-(prop-2-ynyl)piperazine (Intermediate D1)
Reaction SMILES: C1(C)C=CC=C(CC[O:9][C:10]([C:12]2[CH:20]=[C:19]([O:21][CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=2)=[O:11])C=1.[OH-].[Na+].C1COCC1.O>CO>[C:26]1([CH3:30])[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][CH2:22][O:21][C:19]2[C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:20]=2)[CH:25]=1
Reactant: Cc1cccc(CCOC(=O)c2cc(OCCc3cccc(C)c3)c3c(c2)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cccc(CCOc2cc(C(=O)O)cc3c2OCO3)c1
Temperature: 50 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
4.5 g of 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid 2-m-tolyl-ethyl ester and 650 mg of sodium hydroxide were dissolved in 50 ml of methanol, 50 ml of THF and 5 ml of water. The mixture was kept at room temperature for 20 h, then stirred at 50° C. for 5 h and evaporated. The residue was dissolved in 300 ml of a 0.1 M aqueous solution of sodium hydroxide and washed three times with 50 ml each of diisopropyl ether. The pH was adjusted to 2 with sodium hydrogensulfate and the mixture stirred for 30 min at room temperature. The product was collected by filtration, washed and dried in vacuo to yield 3.1 g of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11](O)[C:10]=2[CH:21]=1)(=[O:5])=[O:4].O1CCOCC1.[ClH:29]>CCOCC>[Cl:29][CH:11]1[C:10]2[CH:21]=[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:22])[CH3:1])[CH:7]=[CH:8][C:9]=2[CH:15]=[CH:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]1=2
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2
Reactant: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(Cl)c1ccccc1C=C2
Reaction time: 5 h

Procedure:
A solution of 1.0 g. (0.00317 mole) of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol in a mixture of 2 ml. of dry dioxane and 2 ml. of absolute ether is cooled in ice and saturated with dry hydrogen chloride. The mixture is allowed to stand at room temperature for 5 hours and then is refrigerated overnight. The white crystalline product is collected, washed with petroleum ether, and dried in a vacuum desiccator over calcium chloride. The yield of 5-chloro-3-dimethylsulfamoyl-5H-dibenzo[a,d]cycloheptene is 600 mg., m.p. 139.5°-143.5° C. Dilution of the mother liquor with petroleum ether gives a second crop which is recrystallized from a mixture of ether and a petroleum ether affording 250 mg., m.p. 138.5°-142.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH:18]=O)[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].Cl.[CH3:21][O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25].C(N(CC)CC)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][NH:25][C@H:24]([C:23]([O:22][CH3:21])=[O:27])[CH3:26])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:4]
Reactant: COC(=O)C1(CC=O)CCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@H](C)NCCC1(C(=O)OC)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
271 mg (1 mmol) 2-(2-oxo-ethyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester and 154 mg (1.1 mmol) L-alanine methyl ester hydrochloride are suspended in 10 mL toluene and treated with 0.073 mL (1 eq.) triethylamine. The reaction mixture is stirred 10 minutes at room temperature and slowly evaporated in a rotary evaporator. The residue is taken up in 15 mL acetonitrile and 95 mg (1.5 mmol) sodium cyanoborohydride in 2 mL methanol added dropwise. Upon completion of the reaction (TLC, EtOAc/petroleum ether 4:1), the reaction mixture is evaporated and the residue taken up in ethyl acetate and treated with an ice-cold, saturated aqueous ammonium chloride solution, then extracted with ethyl acetate and saturated aqueous sodium bicarbonate. The combined organic phases are dried over sodium sulfate, filtered and evaporated to yield the crude desired product as a thick oil.