Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4](NN)[C:3]=1[Cl:12].Cl[O-].[Na+]>O1CCOCC1>[Cl:8][C:6]1[C:5]([Cl:9])=[CH:4][C:3]([Cl:12])=[C:2]([Cl:1])[N:7]=1
Reactant: NNc1c(Cl)c(Cl)nc(Cl)c1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1COCCO1
Product: Clc1cc(Cl)c(Cl)nc1Cl

Procedure:
To a reaction vessel containing 10 milliliters of dioxane was added ~0.5 gram (~0.002 mole) of tetrachloro-4-hydrazinopyridine. To this mixture was added portionwise 10 milliliters of a 5.25 percent sodium hypochlorite solution (0.07 mole). The mixture was held until the dark color cleared and was poured over ice. The solid 2,3,5,6-tetrachloropyridine was recovered by filtration and found to be pure by infrared and vapor phase chromatographic analyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][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:26][CH2:27][CH2:28][O:29][CH2:30][CH3:31])=[O:25])[C:6]1=[O:32].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39]>>[CH2:30]([O:29][CH2:28][CH2:27][NH:26][C:24]([C:7]1[C:6](=[O:32])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:38]([C:34]2[S:33][CH:37]=[CH:36][CH:35]=2)=[O:39])[C:14]2[C:9]([C:8]=1[OH:23])=[N:10][CH:11]=[C:12]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH:13]=2)=[O:25])[CH3:31]
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN)c1=O
Reactant: O=C(Cl)c1cccs1
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCNC(=O)c2cccs2)c1=O

Procedure:
This compound was prepared from 1-(3-aminopropyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide and 2-thiophenecarbonyl chloride employing methods similar to those described in Example 400 and was obtained as a white solid: ES+ MS: 553 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C(=O)OC)cc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 80 °C
Yield: 65.3 %

Procedure:
In a sealed tube, a solution of dimethyl 5-bromoisophthalate (5.0 g, 18.3 mmol), N-benzylpiperazine (4.0 mL, 23.0 mmol), and cesium carbonate (8.4 g, 25.7 mmol) in toluene (36 mL) was degassed with nitrogen at room temperature for 20 minutes. Palladium (II) acetate (225 mg, 0.92 mmol) and BINAP (1.7 g, 2.74 mmol) were quickly added under nitrogen and the solution heated to 80° C. overnight to yield a yellow solution with a white suspension. The reaction mixture was cooled to room temperature, vacuum filtered, and the solid rinsed with fresh toluene. The filtrate was then concentrated under reduced pressure to yield a yellow oil. Purification by flash chromatography (silica, 80:20 hexanes/ethyl acetate) gave the desired dimethyl 5-(4-benzylpiperazin-1-yl)isophthalate (4.40 g): ESI MS m/z 369 [M+H]+.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:13]=[C:12]([Cl:14])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+].COC(=O)C1C=C(Cl)C=C(C(O)=O)C=1.Cl.[CH3:33][N:34](C)[CH2:35][CH2:36][CH2:37]N=C=NCC.ON1C2C=CC=CC=2N=N1.CNCCC.[OH-].[Li+].Cl>CC(C)=O.CO.CN(C=O)C.C(OCC)(=O)C>[Cl:14][C:12]1[CH:13]=[C:4]([C:3]([N:34]([CH3:33])[CH2:35][CH2:36][CH3:37])=[O:15])[CH:5]=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CCCNC
Agent: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCN(C)C(=O)c1cc(Cl)cc(C(=O)O)c1
Reaction time: 3 h

Procedure:
Dissolve commercially available 5-chloroisophthalic acid dimethyl ester (1.0 g, 4.37 mmol) in acetone (10 mL) and add a solution of NaOH (192 mg, 4.81 mmol) in methanol (2 mL). Stir 3 h and concentrate. Partition the residue between diethyl ether and water. Acidify the water layer to about pH=1 and collect the precipitate, 5-chloro-isophthalic acid monomethyl ester (675 mg, 72%). Dissolve 5-chloro-isophthalic acid monomethyl ester (459 mg, 2.13 mmol) in DMF (20 mL), add 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (513 mg, 2.67 mmol) and 1-hydroxybenzotriazole (360 mg, 2.67 mmol). Stir at room temperature 1 h and add methyl propylamine (584 mg, 8.0 mmol). Stir at room temperature 3 h, dilute with ethyl acetate, wash with 10% aqueous potassium carbonate, 0.1 N citric acid, 1 N lithium chloride and saturated aqueous sodium chloride and concentrate. Dissolve the residue in THF (30 mL) and add 1 N lithium hydroxide (10 mL, 10 mmol). Stir at room temperature 3 h and acidify to about pH=1 by addition of 1 N HCl. Extract with diethyl ether, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [OH:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH2:15]=[C:16]1[O:20][C:18](=[O:19])[CH2:17]1>C1(C)C=CC=CC=1>[O:20]=[C:16]([CH3:15])[CH2:17][C:18]([O:1][C@H:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: COC(=O)[C@@H](C)O
Reactant: C=C1CC(=O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)OC(=O)CC(C)=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Methyl(2R)-2-hydroxypropanoate (5.0 g, 48 mmol) and triethylamine (49 mg, 0.48 mmol) are dissolved in toluene (40 ml). At 90° C., diketene (5.2 g, 62.4 mmol) is added dropwise. The reaction mixture is stirred at 100° C. for one hour. After cooling to room temperature, the mixture is poured into ice-water. The phases are separated and the aqueous phase is extracted with toluene two times. The combined organic phases are dried over sodium sulfate, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:8][CH:7]=[CH:6][N:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[O:13]1[CH2:14][CH2:15][N:10]([C:9]2[C:4]([NH2:1])=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ncccc1N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ncccc1N1CCOCC1
Reaction time: 3 h

Procedure:
To a solution of 4-(2-nitropyridin-3-yl)morpholine (155 mg, 741 μmol) in ethyl acetate was added Pd/C 10% (15.5 mg, 146 μmol) and the reaction was hydrogenated under an atmosphere of hydrogen for 3 hours at room temperature. The catalyst was filtered off, washed with ethyl acetate and the solvent was evaporated under reduced pressure. The title compound was obtained as a purple solid (128 mg, 96%).
Reaction SMILES: [CH2:1]1[CH:7](O)[NH:6][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[O:3][CH2:2]1.[OH:16][NH:17][C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19].ClC(Cl)(Cl)C(O)=O>CC(C)=O>[OH:16][N:17]([CH:7]1[CH2:1][CH2:2][O:3][P:4]([N:9]([CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][Cl:12])(=[O:5])[NH:6]1)[C:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:19]
Reactant: O=C(NO)N1CCOCC1
Reactant: O=P1(N(CCCl)CCCl)NC(O)CCO1
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: CC(C)=O
Product: O=C(N1CCOCC1)N(O)C1CCOP(=O)(N(CCCl)CCCl)N1
Reaction time: 96 h

Procedure:
1.2 g (4.3 mmol) of 4-hydroxycyclophosphamide in 15 ml of acetone were treated with 630 mg (4.3 mmol) of N-hydroxymorpholino-carboxamide and a trace of trichloroacetic acid and stored at -25° C. After 4 days the crystals were drawn off by suction and recrystallized from acetone.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:8][S:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([NH2:20])(=[O:19])=[O:18])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl>C(#N)C>[CH2:1]([NH:5][C:6]([NH:20][S:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[S:9]([CH3:8])=[O:10])(=[O:19])=[O:18])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)c1ccccc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCNC(=O)NS(=O)(=O)c1ccccc1S(C)=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 87.2 %

Procedure:
10.2 g of n-Butyl isocyanate (0.10 mol) were added dropwise at 25° C. to a suspension of 20.1 g of 2-(methylsulfinyl)benzenesulfonamide (0.09 mol) in 250 ml of acetonitrile. 13.9 g of potassium carbonate (0.10 mol) were added, after which the refluxing mixture was stirred for 4 hours. After cooling to 0° C., the mixture was poured onto 400 ml ice/water, brought to a pH of 1 by adding concentrated hydrochloric acid and extracted with methylene chloride. The organic extracts were washed neutral with water and dried. After removal of the solvent, 25 g of the title compound (85% of theory) were obtained as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([OH:14])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(=N)NO)C=C(C)C=1O[CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])C>>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([O:14][CH2:23][C@@H:24]([OH:31])[CH2:25][NH:26][C:27](=[O:30])[CH2:28][OH:29])=[C:9]([CH2:15][CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: CCc1cc(C(=O)OC(C)(C)C)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxy-acetylamino)-propoxy]-5-methyl-benzoic acid tert-butyl ester (5.94 g) is prepared starting from the above 3-ethyl-4-hydroxy-5-methyl-benzoic acid tert-butyl ester (6.53 g, 27.6 mmol) following the procedures given for N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide. LC-MS: tR=0.87 min; [M+H]+=368.11; 1H NMR (CDCl3): δ1.17 (t, J=7.5 Hz, 3H), 1.53 (s, 9H), 2.28 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.17-3.26 (m, 1H), 3.38-3.46 (m, 1H), 3.65-3.75 (m, 2H), 3.83 (d, J=5.5 Hz, 2H), 3.91-3.97 (m, 1H), 5.28 (d, J=5.3 Hz, 1H), 5.54 (t, J=5.5 Hz, 1H), 7.59 (s, 1H), 7.60 (s, 1H), 7.68 (t, J=5.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:20]2[CH:21]=[CH:22][O:23][C:19]=2[CH2:18][CH2:17][NH:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[O:23][CH:22]=[CH:21][C:20]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2occc21
Product: CC1c2ccoc2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 49 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-Methyl-4,5,6,7-tetrahydro-furo[3,2-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH:12]=O.[Br:14]CC1C2C(=CC=CC=2)C=CC=1>>[Br:14][CH2:12][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: BrCc1cccc2ccccc12
Reactant: O=Cc1ccnc2ccc(Cl)cc12
Product: Clc1ccc2nccc(CBr)c2c1

Procedure:
4-(Bromomethyl)-6-chloroquinoline was prepared from 6-chloroquinoline-4-carbaldehyde following the procedure described in the preparation of 1-(bromomethyl)naphthalene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.F[B-](F)(F)F.[CH3:18][O+](C)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:18])[CH:6]=[CH:5]2
Reactant: C[O+](C)C
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: F[B-](F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2n1

Procedure:
A mixture of 6-bromo-2-[1H]-quinolone (2.90 g) and trimethyloxoniumtetrafluoroborate (2.10 g) was stirred in dichloromethane (50 cm3) for 48 hours under nitrogen. Aqueous 10% sodium hydroxide (20 cm3) was added and the aqueous phase was extracted with dichloromethane (2×40 cm3). The dried (MgSO4) extracts were evaporated and the residue was crystallised from petroleum ether (b.p. 60°-80°) to yield the title compound, m.p. 90°-94°, (2.16 g).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S([O:40][C:41]1[CH2:46][CH2:45][CH2:44][C:43](=O)[C:42]=1[CH3:48])(=O)=O>>[Cl:23][C:21]1[CH:22]=[C:17]([C:15]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:16])[C:18]([O:33][CH3:34])=[CH:19][C:20]=1[C:43]1[CH2:44][CH2:45][CH2:46][C:41](=[O:40])[C:42]=1[CH3:48]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1=O
Product: COc1cc(C2=C(C)C(=O)CCC2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Yield: 40.1 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Example 1, Step E (0.700 g, 1.46 mmol) and 2-methyl-3-oxo-cyclohex-1-en-1-yl trifluoromethanesulfonate (0.416 g, 1.61 mmol) were reacted by the procedure described in Example 1, Step F. Purification by flash column chromatography on silica gel, eluting with 50% ethyl acetate in hexane followed by precipitation from diethyl ether with pentane afforded the title compound (0.270 g) as an amorphous yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14])[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: COCC(=O)Cl
Reactant: CCOc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: CCOc1ccc2nc(NC(=O)COC)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-ethoxybenzothiazole (5.8 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25](O)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.F[P-](F)(F)(F)(F)F.[N:42]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:46]2C=CC=CC=2N=N1.CN.C1COCC1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([NH:42][CH3:46])=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{2-[2-Amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylic acid (12.0 mg, 0.0260 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.0192 g, 0.0433 mmol) in DMF (0.5 mL) was stirred at r.t. for 3 min. and then methylamine in THF (2.0M, 0.2 mL, 0.4 mmol) was added. To this mixture, triethylamine (15.4 uL, 0.110 mmol) was slowly added and the mixture was stirred for 1 h at r.t. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=475.3.
Reaction SMILES: [O:1]=[C:2]([NH:32][C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]CC3C=CC=CC=3)=[O:23])=[CH:17][CH:16]=2)[CH:6]=1)=[O:4]>CN(C=O)C.[Pd].O.C(O)C>[O:1]=[C:2]([NH:32][C:33]1[CH2:34][O:35][C:36](=[O:38])[CH:37]=1)[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:19][CH:20]=2)[CH:6]=1)=[O:4]
Reactant: O=C1C=C(NC(=O)C(=O)c2cn(Cc3ccc(CC(=O)OCc4ccccc4)cc3)c3ccccc23)CO1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccc(Cn2cc(C(=O)C(=O)NC3=CC(=O)OC3)c3ccccc32)cc1
Yield: 64.8 %

Procedure:
A solution of benzyl {4-[(3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-1-yl)methyl]phenyl}acetate (300 mg) in DMF (10 ml) is hydrogenated at room temperature and pressure in the presence of 10% palladium on charcoal (60 mg of a 50% wt/wt suspension in water). After 3 h30′ the catalyst is removed by filtration and the filtrate is concentrated to dryness. The residue obtained is suspended in absolute ethanol and recovered by filtration, to give {4-[(3-{oxo[(5-oxo-2,5-dihydro-3-furanyl)amino]acetyl}-1H-indol-1-yl)methyl]phenyl}acetic acid (160 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.[Cl-].[Na+].O>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: COC(C=O)OC
Reactant: Nc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(CNc1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.7 %

Procedure:
To a solution of 4-fluoroaniline (2.00 mL, 21.1 mmol) and dimethoxyacetaldehyde (60% solution in water, 3.30 mL, 21.9 mmol) in tetrahydrofuran (100 mL) was added sodium triacetoxyborohydride (6.70 g, 30.0 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 12 hours, followed by the addition of brine (50 mL) then extraction with ethyl acetate (3×100 mL). The combined organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography to afford N-(2,2-dimethoxyethyl)-4-fluoroaniline (2.30 g, 57%): MS (ES+) m/z 200.6 (M+1).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][C:6]3[C:11]([CH:2]12)=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:12]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C(#N)C>[OH:1][C@@H:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C@H:2]1[N:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: c1ccc2c(c1)CCC1OC21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCN([C@@H]2c3ccccc3CC[C@H]2O)CC1

Procedure:
At ambient temperature, 3.0 g (20.5 mmol) of the compound obtained in Step B of Example 15 and 4.1 g (20.5 mmol) of N-tert-butyloxycarbonyl-homopiperazine in 41 ml of acetonitrile are mixed together and then heated at reflux for 48 hours. After evaporation and flash chromatography on 300 g of silica (eluant: dichloromethane/ethanol 98/2), the expected compound is collected.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH:10]2[CH2:12][CH2:11]2)[C:7]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:5]=1.O1CCCC1.[OH-].[Li+].Cl>O>[CH:10]1([C:8]2[C:7]([O:13][CH2:14][C:15]([F:18])([F:16])[F:17])=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([OH:19])=[O:2])[CH2:12][CH2:11]1
Reactant: COC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.1 %

Procedure:
In a 25 mL round-bottomed flask, the above prepared 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid methyl ester (830 mg, 3.02 mmol, Eq: 1.00) was combined with tetrahydrofuran (7 ml) and water (3.5 ml) to give a light yellow bi-phasic system. Lithium hydroxide (86.7 mg, 3.62 mmol, Eq: 1.2) was added and the reaction mixture was stirred vigorously at rt. TLC after ˜20 h showed the reaction to be incomplete with some remaining starting material. More lithium hydroxide (43.3 mg, 1.81 mmol, Eq: 0.6) was added and the reaction mixture was stirred at 40° C. TLC after 1 additional h indicated that the reaction was complete. Work up: 10 ml H2O and 7 ml 1N HCl were added and the reaction mixture was extracted with AcOEt (2×50 ml). The organic layers were washed with H2O/NaCl sol, combined, dried over Na2SO4 and concentrated in vacuo. The residue was triturated with heptane to afford 766 mg of the title compound as white powder; MS (EI) 260.0 (M−H)−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C1COCC1.[CH2:12]([N:19]1[C@H:24]([CH3:25])[C:23](=O)[NH:22][C@@H:21]([CH3:27])[C:20]1=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O>[CH2:12]([N:19]1[CH2:20][C@H:21]([CH3:27])[NH:22][CH2:23][C@H:24]1[CH3:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1NC(=O)[C@@H](C)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CN[C@@H](C)CN1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
In an atmosphere of argon, 0.57 g of lithium aluminum hydride was added at 0° C. to 30 ml of THF solution containing 1.0 g of (3S,6R)-1-benzyl-3,6-dimethylpiperazine-2,5-dione, and the mixture was stirred overnight with heating under reflux. The reaction mixture was cooled to 0° C., 1.0 ml of water was added dropwise thereto and 1.0 ml of 10% aqueous sodium hydroxide was added dropwise thereto, and then the mixture was further mixed with 1.0 ml of water and stirred for 30 minutes. The precipitate was separated by filtration and washed with ethyl acetate, and the filtrate was washed with 10% aqueous potassium carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered and then concentrated. The residue was subjected to a silica gel column chromatography and eluted with chloroform-methanol-28% aqueous ammonia (25:1:0.1, v/v/v) to obtain 0.75 g of the title compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([N:23]=[N+:24]=[N-:25])[CH3:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)[C@H]1CC[C@H](COCc2ccccc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(N=[N+]=[N-])[C@H]1CC[C@H](COCc2ccccc2)CC1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
In 50 ml of dry dimethylformamide were suspended 1.70 g of trans-4-benzyloxymethyl-1-(1-methanesulfonyloxyethyl)cyclohexane and 1.69 g of sodium azide, and the mixture was stirred at 110° C. for 30 minutes. To the reaction mixture were added 200 ml of ethyl acetate, and the mixture was washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.48 g of the desired compound as a pale yellow oil. This compound was used for the subsequent reaction without purification.