Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][OH:23])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[C:25](Cl)(=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][O:23][C:25](=[O:41])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Reaction time: 0.75 h
Yield: 34 %

Procedure:
To 3.0 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (8.4 mmol.) suspended in 30 ml. of pyridine at 0° C. was added dropwise 2.5 ml. of hexadecanoyl chloride (10.9 mmol.). After stirring for 45 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature, resulting in the formation of a yellow precipitate. The precipitate was collected, washed with water and air-dried, then purified using flash chromatography on silica gel, using a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined, and the solvent was removed in vacuo. The residue was triturated with diethyl ether to yield 4-(4-chlorophenyl)-2-[(1-oxohexadecyloxy)methyl]-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one as a light yellow solid (1.69 g; 34% yield) having the structural formula, ##STR18## a melting point in the range of 89°-92° C. and the following elemental analysis:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH2:23](O)[CH2:24][OH:25].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH3:19][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:3]([C:2]([F:1])([F:21])[F:22])=[N:4][N:5]=4)[CH:8]=3)=[CH:13][CH:14]=2)[O:25][CH2:24][CH2:23][O:20]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CC1(c2ccc(-c3ccc4nnc(C(F)(F)F)n4c3)cc2)OCCO1
Reaction time: 8 h

Procedure:
In a 50-mL round-bottom flask equipped with a magnetic stir bar 1-(4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)phenyl)ethanone (50 mg) was dissolved in dry toluene (1 mL), ethylene glycol (0.1 mL) and camphorsulfonic acid (a few crystals) were added. The reaction mixture was stirred overnight at reflux temperature. Extracted with concentrated NaHCO3 and EtOAc, organic layer dried over MgSO4, concentrated, and purified by chromatography (1:1 hexanes/EtOAc). The desired 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine was isolated.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C)C=O>[CH2:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(O)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-3-methylphenol (10 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (8.87 g) and benzyl bromide (6.36 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-1-bromo-2-methylbenzene (14.6 g). This material was dissolved in tetrahydrofuran (200 mL). To the solution was added n-butyl lithium (2.66 mol/L n-hexane solution, 21.7 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. To the reaction mixture was added N,N-dimethylformamide (10.1 mL), and the mixture was allowed to warm to 0° C. and stirred for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 4-benzyloxy-2-methylbenzaldehyde. This material was dissolved in ethanol (100 mL). To the solution was added sodium borohydride (1.99 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added methanol, and the resulting mixture was concentrated under reduced pressure. To the residue was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with diethylether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethylacetate=6/1-3/1-1/1) to give the title compound (10.5 g).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:15]([O:16][C:17]2[CH:28]=[CH:27][C:20]([C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])=[CH:19][CH:18]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:32]=1
Reactant: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CON(C)C(=O)c1ccc(Oc2ccc(Cl)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product from Example 128b (192 mg, 0.62 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (50.9 mg, 15%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.72 (s, 3H) 3.19 (s, 3H) 3.42 (s, 3 H) 6.71 (d, J=6.99 Hz, 1 H) 6.94 (d, J=8.82 Hz, 2 H) 7.36 (d, J=8.82 Hz, 1 H) 7.50 (d, J=8.82 Hz, 2 H) 7.63 (dd, J=8.82, 2.57 Hz, 1 H) 7.72 (d, J=8.82 Hz, 1 H) 7.75 (d, J=2.57 Hz, 1 H) 8.53 (d, J=6.99 Hz, 1 H) 8.81 (d, J=8.46 Hz, 1 H) 10.88 (s, 1 H) 14.46 (s, 1 H); MS (ESI+) m/z 449 (M+H−TFA)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([NH2:27])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=S)=[CH:38][C:30]=1[O:31][CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][O:34]1>CC#N.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][C:43]([NH:42][C:39]5[CH:40]=[CH:41][C:29]([Cl:28])=[C:30]([O:31][CH2:32][CH:33]6[CH2:37][CH2:36][CH2:35][O:34]6)[CH:38]=5)=[N:27][C:22]=4[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=Nc1ccc(Cl)c(OCC2CCCO2)c1
Reactant: Nc1cc(Oc2ccnc(C(=O)NCCCCN3CCCC3)c2)ccc1O
Solvent: CN(C)C=O
Solvent: CC#N
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc3oc(Nc4ccc(Cl)c(OCC5CCCO5)c4)nc3c2)ccn1

Procedure:
To a stirring RT solution of 4-(3-amino-4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step E, 162 mg, 0.438 mmol) in CH3CN (20 mL) and DMF (2 mL) was added 2-(2-chloro-5-isothiocyanato-phenoxymethyl)-tetrahydro-furan (112 mg, 0.417 mmol). The following day, the CH3CN was evaporated off, and the crude mix was diluted into 1 N NaOH and EtOAc. The layers were separated. The aqueous layer was extracted 3× with EtOAc, and the combined organic layers were washed once with 1N NaOH and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound as a yellow solid. MS(MH+)=606.3; Calc'd 605.24 for C32H36ClN5O5.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:35][C@@H:31]1[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][NH:63]2)[CH:51]=1>ClCCl.C(N(CC)CC)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][N:63]2[C:32](=[O:33])[C@H:31]2[CH2:35][C@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH:51]=1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
Triethylamine (40 μL), 1-hydroxybenzotriazole (36 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg) were added to a solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylglycylamino)-D-proline (F, 112 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 100 mg) in dichloromethane (10 mL) at 0° C. The mixture was stirred at room temperature for 18 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:chloroform=1:50 to 1:20, v/v) to give the title compound (124 mg) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.34-1.44 (m, 18H), 1.86-1.92 (m, 1H), 2.03-2.14 (m, 1H), 2.21-2.64 (m, 3H), 2.71-2.75 (m, 2H), 3.33-3.75 (m, 4H), 3.94-4.10 (m, 2H), 4.21-4.78 (m, 3H), 7.14-7.27 (m, 5H), 7.51-7.71 (m, 2H), 7.83-7.99 (m, 2H), 8.70-8.72 (m, 1H), and 8.96-9.05 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[C:11]([NH:15][NH2:16])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: NN
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Solvent: CCO
Solvent: O
Product: NNc1nc2cc(Cl)ccc2nc1Cl

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C.
Reaction SMILES: [OH:1][C@H:2]([CH2:6][CH3:7])[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>O1CCCC1>[C:3]([C@H:2]([O:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:6][CH3:7])(=[O:4])[NH2:5]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@@H](O)C(N)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@@H](OS(C)(=O)=O)C(N)=O
Temperature: 20 °C

Procedure:
To a mixture of (R)-2-hydroxybutyramide (4.2 g, 40.7 mmol) and triethylamine (6.2 ml, 44.8 mmol, 1.1 equiv.) in tetrahydrofuran (50 ml) is added drop wise at −40° C. methanesulfonic acid chloride (3.5 ml, 44.8 mmol, 1.1 equiv.). The mixture is allowed to warm to 20° C. and is filtered over magnesium sulfate (8 g). The cake is rinsed twice with tetrahydrofuran (2×20 ml) and combined filtrates are concentrated to dryness under reduced pressure to afford methanesulfonic acid (R)-1-carbamoyl-propyl ester (IIi) as a solid. (7.9 g, 106%, triethylamine hydrochloride salts are present).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([C:12]3[N:16]([C:17]4[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=4)[N:15]=[C:14]([Cl:24])[CH:13]=3)[O:8][C:7](=[O:25])[C:6]=2[CH:5]=[C:4]([C:26]#[N:27])[CH:3]=1.[CH3:28][NH2:29]>O1CCCC1>[Cl:24][C:14]1[CH:13]=[C:12]([C:9]([NH:10][C:11]2[C:6]([C:7]([NH:29][CH3:28])=[O:25])=[CH:5][C:4]([C:26]#[N:27])=[CH:3][C:2]=2[Cl:1])=[O:8])[N:16]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:15]=1
Reactant: N#Cc1cc(Cl)c2nc(-c3cc(Cl)nn3-c3ncccc3Cl)oc(=O)c2c1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(C#N)cc(Cl)c1NC(=O)c1cc(Cl)nn1-c1ncccc1Cl
Reaction time: 0.08 h

Procedure:
To a solution of 8-chloro-2-[3-chloro-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-cyano-4H-3,1-benzoxazin-4-one (i.e. the cyanobenzoxazinone product of Step C) (187 mg, 0.446 mmol) in tetrahydrofuran (5 mL) was added dropwise methylamine (2.0 M solution in THF, 0.5 mL, 1.0 mmol) and the reaction mixture was stirred for 5 minutes, at which point thin layer chromatography on silica gel confirmed completion of the reaction. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was purified by chromatography on silica gel to afford 49 mg of the title compound, a compound of the present invention, as a white solid that melted at 197-200° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[F:23][C:24]1[C:31]([F:32])=[CH:30][CH:29]=[C:28]([F:33])[C:25]=1[CH2:26][NH2:27].CCN(C(C)C)C(C)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:22])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:27][CH2:26][C:25]3[C:28]([F:33])=[CH:29][CH:30]=[C:31]([F:32])[C:24]=3[F:23])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Cl)cc2)c1
Reactant: NCc1c(F)ccc(F)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3c(F)ccc(F)c3F)cc2)c1
Yield: 94 %

Procedure:
4-[3-(3-Cyanophenyl)-ureido]-benzenesulfonyl chloride (1.0 g, 2.98 mmol) was dissolved in 20 ml THF, 2,3,6-trifluoro-benzylamine (0.48 g, 2.98 mmol) and DIEA (0.52 ml, 2.98 mmol) were added and the solution was refluxed for about 3 h. The solvent was removed in vacuo and the residue cristallized with ethanol/water. The solid was filtered and dried in vacuo. Yield 94% of 4-[3-(3-cyano-phenyl)-ureido]-N-(2,3,6-trifluorobenzyl)-benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:39])[CH2:13][N:14]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])=[CH:24][CH:23]=1)[CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[NH:11][C:12](=[O:39])[CH2:13][N:14]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][C:29]([CH3:37])([CH3:38])[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=1)[CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)OC(C)(C)C)cc2)Cc2ccco2)cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C)c(NC(=O)CN(Cc2ccc(SC(C)(C)C(=O)O)cc2)Cc2ccco2)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
190 mg of tert-butyl 2-[[4-[[[2-[(2,5-dimethyl-4-methoxyphenyl)amino]-2-oxoethyl](2-furanyl-methyl)amino]methyl]phenyl]thio]-2-methyl-propanoate are dissolved in 5 ml of dichloromethane and reacted with 1 ml of trifluoroacetic acid. The mixture is stirred at room temperature for 20 h and then concentrated and purified chromatographically (dichloromethane/methanol 50+1). This gives 166 mg of the title compound as a solid foam.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].Cl[CH2:21][C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: ClCc1nc2ccccc2o1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2nc3ccccc3o2)c(=O)[nH]c1=O
Yield: 43.2 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-chloromethyl benzoxazole were reacted by the same way with the example 1 to obtain the titled compound (176 mg, yield: 43.2%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[O:16])(=[O:5])=[O:4].[H-].[Na+].Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CN(C=O)C>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10](=[O:15])[C:9]2=[O:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of N,N-dimethyl-2,3-dioxoindoline-5-sulfonamide (0.639 g, 2.51 mmol) in dry DMF (10 ml), cooled at 0° C. under nitrogen, NaH (60% dispersion in mineral oil, 0.111 g, 2.76 mmol) was added. The mixture turned dark blue. After stirring at 0° C. for 30 minutes, tert-butyl bromoacetate (0.446 ml, 3.02 mmol) was added, and the mixture was stirred at room temperature for 36 hours. The mixture was partitioned between ethyl acetate and brine and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated to dryness affording tert-butyl 2-(5-(N,N-dimethylsulfamoyl)-2,3-dioxoindolin-1-yl)acetate (0.926 g, 2.51 mmol). MS/ESI+ 368.9 [MH]+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: OCCCCBr
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCCCO)CC2)cc2ccccc12
Yield: 8.8 %

Procedure:
By the reaction in the same manner as in Example 21a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (500 mg) and 4-bromo-1-butanol (434 mg), 3-[1-(4-hydroxybutyl)piperidin-4-yl]-2H-isoquinolin-1-one (50 mg) was obtained.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li].[CH3:19]C(NC(C)C)C.IC>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:19])[C:16]#[N:17])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(CC#N)cc1OC1CCCC1
Reactant: CC(C)NC(C)C
Agent: [Li]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(C(C)C#N)cc1OC1CCCC1
Temperature: -78 °C
Yield: 100 %

Procedure:
A mixture of 3-(cylcopentyloxy)-4-methoxybenzeneacetonitrile (20 g) in THF (200 ml) was stirred at -78° C. under a N2 flow. N-(1-methylethyl)-2-propanamine lithium salt (45 ml) was added dropwise and the resulting mixture was stirred for 30 minutes at -78° C. Iodomethane (13.5 g) was added dropwise and the resulting reaction mixture was allowed to warm to RT. The reaction mixture was stirred for 2 hours. The mixture was quenched with a saturated aqueous NH4Cl solution (200 ml) and was extracted with CH2Cl2 (3×φml). The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding 17.7 g (100%) of (±)-3-(cyclopentyloxy)-4-methoxy-α-methylbenzeneacetonitrile (interm. 8).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:5]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2][NH:20][CH:17]2[CH2:19][CH2:18]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC1CC1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(C(CCNC2CC2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-bromo-1,1-diphenylpropane 9 (2.06 g, 7.49 mmol) in DMF (15 mL) at room temperature was added cyclopropylamine (3.26 g, 57.1 mmol, 4.0 mL) and cesium carbonate (3.19 g, 9.79 mmol). The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 1% to 6% MeOH (2 M NH3) in DCM) gave N-(3,3-diphenylpropyl)cyclopropanamine 10 as a colorless oil. Mass spectrum: calculated for C18H21N 251.2; found 252.2 (M++1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[F:26]>>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)c(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (73 mg, 87%), MS (ISP) m/z=338.5 [(M+H)+], mp 243° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,4-difluoro-phenylboronic acid (51.3 mg, 0.325 mmol).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14]N)[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].N([O-])=[O:17].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:1]([C:4]1[C:13]2[C:8](=[C:9]([CH2:14][OH:17])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1nccc2c(CN)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1nccc2c(CO)cccc12
Reaction time: 0.5 h
Yield: 81.2 %

Procedure:
1-iso-Propyl-5-aminomethylisoquinoline (8.7 g) was dissolved in 20 ml of acetic acid and 20 ml of water, and with ice cooling, 9 g of sodium nitrite was added. The mixture was stirred for 30 minutes. Then, 30 ml of a 10 N aqueous solution of sodium hydroxide was added, and the mixture was heated for 1 hour. The product was extracted with ethyl acetate, washed in water, and dried, followed by distilling off the solvent. Recrystallization of the residue from methylene chloride/n-hexane afforded 7.1 g of 1-isopropyl-5-hydroxymethylisoquinoline as colorless needles having a melting point of 119.9° to 120.9° C.