Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(S(N)(=O)=O)=CC=1)(=O)C.C(Cl)(=O)CCCCC.Cl.C([NH:27][C:28]1[CH:44]=[CH:43][C:31]([S:32]([NH:35][C:36](=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:34])=[O:33])=[CH:30][CH:29]=1)(=O)C>O.N1C=CC=CC=1>[C:36]([NH:35][S:32](=[O:33])([C:31]1[CH:30]=[CH:29][C:28]([NH2:27])=[CH:44][CH:43]=1)=[O:34])(=[O:42])[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCC(=O)NS(=O)(=O)c1ccc(NC(C)=O)cc1
Agent: CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Agent: CCCCCC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C

Procedure:
N1 -hexanoylsulfanilamide was prepared as follows. To a mixture of N4 -acetylsulfanilamide (55.0 g) and pyridine (54 mL) at 95° C. was added hexanoyl chloride (28.8 g) over a period of 20 min. After an additional hour the reaction mixture was cooled to room temperature and the reaction was worked up by diluting with 600 mL D.I. water and acidifying with aqueous HCl. The product of this reaction, N4 -acetyl-N1 -hexanoylsulfanilamide, was isolated by filtration and washed with D.I. water (700 mL) to afford an off-white solid. This material was carried directly to the next step.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1.CCOC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C@H:20]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Agent: [Mg]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (170 g, 2365 mmol) in THF (1.35 L), was added 4-bromobenzotrifluoride (532 g, 2365 mmol). Stirring was continued for 4 h (cautious: slightly exothermic, cooled with a water bath if needed). The solution was cannulated to a stirred solution of (S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (270 g, 1182 mmol) in THF (1.3 L) at −78° C. dropwise. Stirring was continued for 1 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (2.5 L), and the solution extracted with Et2O (5×500 mL). The organic layers were combined, dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 25-30% EtOAc in petroleum ether as eluent to give (S)—N—((S)-(3-fluoropyridin-2-yl)(4(trifluoro-methyl)phenyl)methyl)-2-methylpropane-2-sulfinamide as a brown oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.45 (d, J=3.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H), 7.43-7.48 (m, 1H), 6.23 (d, J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H), 1.36 (s, 9H). MS (ESI pos. ion) m/z: 375.1 (M−O and t-Bu).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(OCC)(=O)C>[Cl:9][C:4]1[N:3]=[C:2]([NH:16][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([I:8])[CH:5]=1
Reactant: Clc1cc(I)cc(Cl)n1
Reactant: NC1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cc(I)cc(NC2CCCCC2)n1
Temperature: 150 °C

Procedure:
To a solution of 2,6-dichloro-4-iodopyridine (0.1 g, 0.36 mmol) was added excess (1 mL) cyclohexylamine. The reaction mixture was heated at 150° C. in a microwave for 20 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, at which time a white solid precipitated from the solution. The solid was filtered off and the organics were washed with sodium bicarbonate, water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel by flash chromatography (gradient elution: 0% to 50% ethyl acetate/hexane) to afford the title compound as an oil. m/z 337.0 (DCI, M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1.[C:13]([O-:16])(=[S:15])[CH3:14].[K+].O>CN(C=O)C>[C:13]([S:15][CH2:2][CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:7]2=[CH:6][N:5]=1)(=[O:16])[CH3:14]
Reactant: ClCCc1ncc2cnccn12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCCc1ncc2cnccn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
To a solution of 3-(2-chloroethyl)imidazo[1,5-a]pyrazine (1.51 g) in DMF (10 ml) was added potassium thioacetate (1.23 g). The mixture was stirred for 4 hours at room temperature. To the reaction mixture was added water. The mixture was subjected to extraction with ethyl acetate (50 ml×4). The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (carrier: silica gel, 60 g, developing solvent: ethyl acetate) to give the title compound (1.65 g) as colorless solid product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:8]=1)[NH2:7].[C:10](=[S:15])(OCC)[S-:11].[K+].Cl>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]([SH:15])=[N:7][C:6]=2[CH:8]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2cc(Cl)ccc2s1

Procedure:
A solution of 5-chloro-2-fluoroaniline (2.0 g, 13.7 mmol, 1 eq.) and potassium O-ethyl dithiocarbonate (4.8 g, 30.3 mmol, 2.2 eq) in anhydrous DMF (20 mL) was heated at 100° C. under nitrogen for 4 h. The reaction mixture was cooled to room temp., diluted with water (50 mL), and acidified with 2N HCl with constant stirring at low temperature. Yellowish solid was collected by filtration, and washed with cold water. The wet filter cake was dissolved in ethyl acetate (50 mL), and the solution was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound as yellowish solid. 1H-NMR (CDCl3, 300 MHz): δ=7.71 (d, J=8.1 Hz, 1H), 7.34 (d, J=8.1 Hz, 1H), 7.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:1].[ClH:43].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28]([CH3:31])[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:30])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc31)CNCC2
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: CN1CCc2c(c3ccc(-n4ccc(OCc5ccc(Cl)cn5)cc4=O)cc3n2C)C1
Yield: 64 %

Procedure:
4-((5-Chloropyridin-2-yl)methoxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (50 mg, 0.12 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (39 mg, 64%) as a white solid: mp 278-282° C.; 1H NMR (300 MHz, CD3OD) δ 8.60 (d, J=2.0 Hz, 1H), 7.96-7.92 (m, 1H), 7.61 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.3 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 7.06 (dd, J=8.4, 1.7 Hz, 1H), 6.34 (dd, J=7.6, 2.6 Hz, 1H), 6.12 (d, J=2.6 Hz, 1H), 5.27 (s, 2H), 4.75 (d, J=14.2 Hz, 1H), 4.38 (d, J=14.1 Hz, 1H), 3.95-3.85 (m, 1H), 3.73 (s, 3H), 3.63 (m, 1H), 3.31 (m overlapping with solvent, 2H), 3.13 (s, 3H); ESI MS m/z 435 [M+H]+; HPLC (Method B) 98.9% (AUC), tR=12.1 min.
Reaction SMILES: [CH3:1][NH2:2].[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]=[CH:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]>C1C=CC=CC=1.C(O)C>[N+:3]([C:6]1[CH:17]=[CH:16][C:9]2[CH2:10][CH2:11][CH:12]([NH:2][CH3:1])[CH2:13][C:14](=[O:15])[C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: O=C1C=CCCc2ccc([N+](=O)[O-])cc21
Reactant: CN
Solvent: c1ccccc1
Solvent: CCO
Product: CNC1CCc2ccc([N+](=O)[O-])cc2C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 101.5 g of extemporaneously prepared monomethylamine in 700 ml of benzene was added at 20° C. with stirring to a mixture of 101.6 g of the product of Step B in 1 liter of ethanol and the mixture was stirred for 2 1/2 hours at room temperature and was allowed to stand for 12 hours. The mixture was evaporated to dryness under reduced pressure to obtain 125 g of 3-nitro-7-methylamino-6,7,8,9-tetrahydro [5H] benzocycloheptene-5-one in the form of a brown oil.
Reaction SMILES: [O:1]=[C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])[CH3:3].[CH3:8][C:9](=[CH:11][CH2:12][CH2:13]/[C:14](=[CH:16]/[CH2:17]O)/[CH3:15])[CH3:10].C(O)(=O)C(O)=O>>[CH3:6][C:5]([CH2:7][CH2:17][CH:16]=[C:14]([CH3:15])[CH2:13][CH2:12][CH:11]=[C:9]([CH3:10])[CH3:8])=[CH:4][C:2](=[O:1])[CH3:3]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: O=C(O)C(=O)O
Product: CC(=O)C=C(C)CCC=C(C)CCC=C(C)C
Yield: 81 %

Procedure:
800 parts of mesityl oxide and 200 parts of geraniol have 1 part of oxalic acid added to them and the mixture is heated for three hours at a pressure of 50 atmospheres in the vibrated autoclave described in Example 1 at a temperature of 230°C. The reaction mixture is worked up by distillation. 141 parts of 4,8,12-trimethyl-3,7,11-tridecatrien-2-one is obtained with a boiling point of 92° to 94°C at 10-4 mm. The yield is 81% of theory at a conversion of 57% based on geraniol.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.[OH:15][CH:16]=[C:17]([CH3:23])[C:18](OCC)=O>O>[CH2:8]([S:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:17]([CH3:23])[C:16](=[O:15])[N:6]2[N:5]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nnc(SCc2ccccc2)s1
Reactant: CCOC(=O)C(C)=CO
Solvent: O
Product: Cc1cnc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 0.75 h
Yield: 61 %

Procedure:
Five point six (5.6) grams of the thus obtained 2-amino-5-benzylthio-1,3,4-thiadiazole and 3.6 g of ethyl 3-hydroxy-2-methyl-2-propenoate were mixed with 7.5 g of polyphosphoric acid, and the mixture was stirred at 130°-150° C. for 45 minutes. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous sodium hydrogen carbonate solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was recrystallized from ethanol. Thus 4.4 g of 2-benzylthio-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. m.p. 130°-132° C. Yield 61%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=O.[NH3:28].CO>C1COCC1>[CH3:7][N:8]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:9]([N:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[NH:28]
Reactant: CC(C)CN(C)C(=O)N(C1CCCCC1)C1CCCCC1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)CN(C)C(=N)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (3.6 mL, 18 mmol) and triethylamine (5.6 mL, 40 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.98 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of N-methylisobutylamine (2.2 mL, 18 mmol) and triethylamine (5.5 mL, 40 mmol) in THF (35 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding N-methyl-N-isobutyl-N′,N′-dicyclohexylurea as a dark yellow oil. Yield: 4.8 g (90%). Oxalyl chloride (8 mL, 16 mmol, 2 M solution in dichloromethane) was added to a stirred solution of the urea (4.8 g, 16 mmol) in THF (65 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. Ammonia in methanol (7 mL, 49 mmol, 7 M solution in methanol) was added to a suspension of the formed solid in THF. The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and purified by treatment with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Evaporation to dryness yielded the desired guanidine as a brown oil. Yield: 2.95 g (75%). 1H NMR (CDCl3, 300 MHz): δ 0.80 (d, 6 H), 1.20 (d, 12 H), 1.8 (sept, 1 H), 2.7 (s, 3 H), 2.83 (d, 2 H), 3.52 (sept, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ 19.1, 20.7, 25.6, 36.8, 46.4, 57.2, 164.7 ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.Cl.Cl.[NH2:17][C@@H:18]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:39][C:37]1[CH:38]=[C:33]([CH:34]=[C:35]([F:40])[CH:36]=1)[CH2:32][C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1)[C@H:19]([OH:31])[CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][CH3:30])[CH:24]=1
Reactant: O=C(O)c1ccc(-c2nccs2)cc1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2ccc(-c3nccs3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(1,3-thiazol-2-yl)benzoic acid (110 mg, 0.6 mmol), (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride (220 mg, 0.6 mmol), and HATU (210 mg, 0.6 mmol) stirring in methylene chloride (5 mL) is added N,N-diisopropylethylamine (340 μL, 1.9 mmol). The reaction mixture is stirred at room temperature for 18 h. The reaction mixture is partitioned between methylene chloride and water. The organic layer is washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, gradient 95:5 to 92:8 methylene chloride/methanol) provides the title compound. ESI MS m/z 522.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CO.C(O[C:20]1(O[Si](C)(C)C)[CH2:22][CH2:21]1)C.[BH3-]C#N.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:20]2[CH2:22][CH2:21]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(C2CC2)CC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution of 14.0 g (0.0699 mol) piperidin-4-yl-carbamic acid tert-butyl ester in 500 mL abs. MeOH 250 g of dried molecular sieves 3 Å were added. Under argon 39.9 mL (0.699 mol) acetic acid and 52.5 mL (0.262 mol) (1-ethoxy-cyclopropoxy)-trimethyl-silane were added. Finally 314.5 mL (0.3145 mol) of a 1 M NaCNBH3-solution in THF were added dropwise. After 20 min at room temperature the reaction mixture was stirred for 6 h at 60° C. The mixture was filtered over “Celite”. The filtrate was concentrated under reduced pressure. The resulting residue was taken up in 700 mL ethyl acetate and washed with 250 mL of a 1 M NaOH-solution. The aqueous layer was extracted with 300 mL ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under vacuo to give crude (1-cyclopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester as a colorless solid.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH:2]3[C:14]4[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=4[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=4)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCN(C(c3ccccc3)c3ccccc3)CC1)c1ccccc1-2
Reaction time: 20 h
Yield: 23.4 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.0 g, 4.26 mmol) was suspended in 10 ml of dry tetrahydrofuran, while cooling in an ice bath. 1-(Diphenylmethyl)piperazine (1.1 g, 4.26 mmol) dissolved in 10 ml of dry tetrahydrofuran was added over 10 min., thereafter triethylamine (0.59 ml, 4.26 mmol) in 3 ml tetrahydrofuran was added. The ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran to give 1.36 g of the crude product which was recrystallized two times from acetic acid to yield 0.45 g (20%) of the title compound as a hydrochloride. M.p. 212°14 216° C. 1H-NMR (DMSO-d6, δ): 2.5-3.3 (m, 8H), 4.64 (s, 1H), 5.62 (d, 1H), 7.1-7.9 (m, 14H), 11.25 (s, 1H), 11.74 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].[CH:23]1(C2N=C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)C(C)=NC=2)CC1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH:8]1[CH2:23][CH2:9]1
Reactant: Cc1ncc(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Product: Cc1nc(Br)c(C2CC2)nc1N[C@@H]1c2ccccc2C[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(6-cyclopropyl-3-methylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.99, 2.08, 2.38, 3.04, 3.25, 4.72, 4.97, 5.45, 7.24–7.31; MS (ESI+) for C17H18BrN3O m/z 362 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.ON1C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:19]1[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]1)=[O:7]
Reactant: COc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN1CCNCC1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(=O)N2CCN(C)CC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
2-Methoxy-3-nitro-benzoic acid (1.20 g, 6.09 mmol), 1-Methylpiperazine (1.01 mL, 9.13 mmol) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1750 mg, 9.13 mmol, 1-hydroxybenzotriazole hydrate (1.45 g, 9.13 mmole) and N,N-Dimethylformamide (40.4 mL) were combined into a vial and stirred at room temperature for 1 hour. LCMS showed complete conversion to product. Diluted reaction mixture with saturated NaHCO3 and filtered off resulting ppt. The solid was filtered and washed with water. The solid was dried under vacuum overnight to give (2-Methoxy-3-nitro-phenyl)-(4-methyl-piperazin-1-yl)-methanone as a white solid (0.70 g, 44%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([C:10]1[S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23]
Reactant: COc1ccc(-c2csc3ccccc23)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: COc1ccc(-c2c(C(=O)c3cc(C)cc(C)c3)sc3ccccc23)cc1

Procedure:
3-p-Methoxyphenylbenzothiophene is acylated with 3,5-dimethylbenzoyl chloride as previously described to give 2-(3',5'-dimethylbenzoyl)-3-p-methoxyphenylbenzothiophene. Demethylation with pyridine hydrochloride followed by reaction of the hydroxy compound thus formed with diethylaminoethyl chloride as described above gives the title compound.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]([CH2:14][C:15]2[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:19][CH:20]=2)[CH3:13])=[CH:8][C:7]=1[CH3:34].[Li+].[OH-]>C1COCC1.CCOCC>[CH:31]1([C:16]2[C:15]([CH2:14][N:12]([CH3:13])[C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=3)=[CH:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][CH:22]=3)[N:17]=2)[CH2:33][CH2:32]1
Reactant: COC(=O)COc1ccc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(N(C)Cc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)ccc1OCC(=O)O
Yield: 28.2 %

Procedure:
A solution of 351 mg (0.72 mmol) (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid methyl ester and 1.45 ml 1N LiOH in 4 ml of THF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. The crude product was suspended in AcOEt/heptane 1:19 to give 95.64 mg of pure (4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:15][C:16]1[CH:17]=[C:18]([CH:26]=[C:27]([CH3:29])[CH:28]=1)[O:19][CH:20]([CH2:24][CH3:25])[C:21](Cl)=[O:22]>C1C=CC=CC=1>[CH2:1]([NH:8][C:21](=[O:22])[CH:20]([O:19][C:18]1[CH:17]=[C:16]([CH3:15])[CH:28]=[C:27]([CH3:29])[CH:26]=1)[CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1cc(C)cc(C)c1)C(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCC(Oc1cc(C)cc(C)c1)C(=O)NCc1ccccc1
Reaction time: 5 h
Yield: 62.1 %

Procedure:
In 30 ml of benzene were dissolved 1.8 g (0.017 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise 3.0 g (0.013 mole) of 2-(3,5-dimethylphenoxy)-butyroyl chloride at room temperature with stirring. After the reaction was carried out for 5 hours, the reaction mixture was washed with water, dilute hydrochloric acid, dilute aqueous sodium hydroxide and then water successively. After the benzene layer was dried, the benzene was removed by distillation. The resultant crude crystals were recrystallized from n-hexane to give 2.4 g of N-benzyl-2-(3,5-dimethylphenoxy)-butyramide melting at 93°-94° C. as colorless needles.