Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=Cc1cccc(F)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Product: Fc1cccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)c1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(3-fluorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:12])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[OH:4].Br[CH2:14][CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][C:17]=1[Cl:29].C(N(CC)C(C)C)(C)C.O>CN(C)C=O>[Cl:29][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][C:16]=1[CH2:15][CH2:14][NH:1][C@@H:2]([CH3:12])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)cc1
Reactant: CCOC(=O)COc1ccc(CCBr)c(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(CCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(Cl)c1
Yield: 31.7 %

Procedure:
A solution of (1R,2S)-2-amino-1-(4-hydroxyphenyl)propan-1-ol (97 mg), ethyl 2-[4-(2-bromoethyl)-3-chlorophenoxy]acetate (187 mg) and N,N-diisopropylethylamine (203 μl) in N,N-dimethylformamide (3 ml) was stirred for 10 hours at 60° C. After cooling, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After the solvent was removed in vacuo, purification of the residue by medium pressure liquid column chromatography on aminopropyl silica gel (eluent: ethyl acetate/ethanol=30/1) gave ethyl 2-[3-chloro-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methyl-ethyl]amino]ethyl]phenoxy]acetate (75 mg).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]=O)[CH2:17][CH2:16]1)[CH3:14].[CH2:25]([NH:28][C:29]1[CH2:33][S:32][C:31](=[O:34])[N:30]=1)[C:26]#[CH:27].C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C.C(OCC)(=O)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18](/[CH:21]=[C:33]2/[C:29]([NH:28][CH2:25][C:26]#[CH:27])=[N:30][C:31](=[O:34])[S:32]/2)[CH2:19][CH2:20]1)[CH3:14]
Reactant: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(C=O)CC1
Reactant: C#CCNC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(C(C)c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
To a solution of 1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}piperidine-4-carbaldehyde (1.15 g) and 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (1.00 g) in 2-propanol (16.3 mL) was added piperidinium acetate (0.473 g). The reaction mixture was stirred at 60° C. overnight, allowed to cool to room temperature, and diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), further purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (1.13 g).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:18][CH:17]=1.C(N(CC)CC)C>CCOCC>[ClH:1].[ClH:15].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:7])[CH2:29][CH2:30]2)=[CH:18][CH:17]=1
Reactant: CCCCCCNC(=O)NCCCCl
Reactant: Clc1ccc(CCCN2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCNC(=O)NCCCN1CCN(CCCc2ccc(Cl)cc2)CC1
Product: Cl
Yield: 64.5 %

Procedure:
A mixture of 1-(3-chloropropyl)-3-n-hexylurea (2.21 g; 10 mmole), 1-[3-(4-chlorophenyl)propyl]piperazine (2.39 g; 10 mmole), triethylamine (1.01 g; 10 mmole) and alcohol (25 ml) was refluxed for 18 hours. The cooled reaction mixture was diluted with ether and washed with water, dried (sodium sulfate) and concentrated in vacuo. The resulting yellow viscous oil was purified on a silica gel column (methylene chloride/methanol; 93:7) and precipitated with ethereal hydrochloric acid to provide the title compound (1.6 g; 38% yield) as colorless crystals, m.p. 213°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[O:15][N:14]=[C:13]([C:16](O)=O)[CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.ClC(OCC(C)C)=O.[F:34][C:35]([F:45])([F:44])[C:36]1[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=1>C1COCC1.O>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:41]=[CH:40][C:39]2[N:42]=[C:16]([C:13]3[CH:12]=[C:11]([C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[O:15][N:14]=3)[NH:43][C:38]=2[CH:37]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cc(C(=O)O)no1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)c1cc(-c2nc3ccc(C(F)(F)F)cc3[nH]2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of (R)-5-(1-(tert-butoxycarbonylamino)ethyl)-isoxazole-3-carboxylic acid (55 g, 0.215 mol) and Et3N (36 mL, 0.26 mol) in THF (2 L) was added dropwise isobutyl chloroformate (33 mL, 0.26 mol) at −20° C. The reaction mixture was stirred for 1 hr, and a solution of 4-(trifluoromethyl)benzene-1,2-diamine (45.4 g, 0.26 mol) in THF was added. After stirring for 2 h at −20° C., the mixture was allowed to warm up to RT and stirred for another 2 hr. Water was added to quench the reaction and the reaction mixture was evaporated under reduced pressure to remove THF. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated. The residue was re-dissolved in acetic acid (250 mL) and stirred for 2 hr at 90° C. The solution was concentrated under vacuum and partitioned with ethyl acetate and water. The organic layer was separated, washed with water, Na2CO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to afford compound N.7, (R)-tert-butyl 1-(3-(6-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)isoxazol-5-yl)ethylcarbamate (75.7 g, 88.8%). 1H NMR (DMSO-d6) δ 7.8 (m, 4H), 6.9 (s, 1H), 4.91 (m, 1H), 1.46 (d, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(=Nc3ccccc3)CC2)cc1
Yield: 64.8 %

Procedure:
A 1000 ml round bottom flask affixed with a stirring bar, a Dean-Stark trap and a condenser was charged with 101.6 g of benzylpiperidone, 500 ml of toluene, 50 g of aniline and 500 mg of p-toluene sulfonic acid. The mixture was refluxed overnight. After removal of the solvent, the reaction mixture was poured into 600 ml of isopropyl ether. The resulting solution was filtered, and the filtrate concentrated and then vacuum distilled at 185°-190° C., 1.25 torr to obtain 91.9 g (about 65% yield) of product as a light yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][C:45]1=[O:50]>CC(N(C)C)=O>[CH3:43][N:44]1[CH2:49][CH2:48][N:47]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:40])([F:41])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:22][CH:23]=2)[CH2:46][C:45]1=[O:50]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CN1CCNCC1=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1=O
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
DIPEA (15.27 mL, 87.69 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (14.19 g, 29.23 mmol) and 1-methylpiperazin-2-one (CAS 59702-07-7, 3.67 g, 32.15 mmol) in DMA (70 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature, absorbed onto silica, evaporated to dryness and then purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM. Pure fractions were evaporated and the resulting gum was scratched with ether until solid. The solid was stirred in ether (100 mL) for 4 hours then collected by filtration and dried to give 1-methyl-4-[2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl]piperazin-2-one (10.08 g, 68.5%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH2:18]C(O)C3)=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:25])[CH3:24])[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH:28](O)[CH2:27]1.N1(CCCN)CCCC[CH2:34]1>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:34])=[C:11]([C:13]([NH:15][CH2:20][CH2:19][CH2:18][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:14])[N:12]=2)=[C:4]([NH:22][CH:23]([CH3:24])[CH3:25])[CH:3]=1
Reactant: NCCCN1CCCCC1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Reactant: OC1CCCNC1
Product: Cc1sc(-c2cnc(Cl)cc2NC(C)C)nc1C(=O)NCCCN1CCCCC1

Procedure:
Followed the same procedure as mentioned in the synthesis of compound no. 24a, instead of piperidin-3-ol, 3-(piperidin-1-yl)propan-1-amine was used.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].[C:7]1([CH2:13][CH2:14][CH:15](O)C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[C:7]1([CH:13]([OH:2])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:7]1([CH2:13][CH:14]([OH:2])[CH3:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(O)CCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(O)Cc1ccccc1
Product: CC(O)c1ccccc1
Reaction time: 8 h

Procedure:
This half-ester R-3c (250 mg; 1.0 mmol) was dissolved in methanol (2 mL) and treated with potassium carbonate (276 mg; 2.0 mmol; 2 equiv.) and stirred overnight to completely consume 3c (tlc analysis). The reaction mixture was diluted with water (25 mL) and extracted with ether (3×10 mL). The combined extracts were dried (MgSO4) and concentrated to afford 118 mg (79%) of R-1c. All achiral properties of 1c are as reported above. The absolute configuration of 1c was not exhaustively proven, but was presumed to be R-(-) by analogy with the enzymatic results of 1a and 1b. 1H nmr analysis of the MTPA ester using an analogous procedure to that of Dale et al., J. Org. Chem., 1969, 34, 2543, indicated 54% ee for R-1c. [α]D20 -8.2° (c. 1.19, CH3OH).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1>CN(C=O)C.CCOC(C)=O>[N:21]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]#[N:33])[CH:25]=[N:24][CH:23]=[N:22]1.[N:10]1[N:11]=[CH:12][N:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]#[N:9])[CH:14]=1
Reactant: N#Cc1ccccc1F
Reactant: c1nc[nH]n1
Agent: N#Cc1ccccc1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-n1cnnc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-fluorocyanobenzene (5.0 g, 41 mmol) in DMF (75 mL) was added 1,2,4-triazole (3.0 g, 43 mmol) and cesium carbonate (14 g, 43 mmol). The mixture was warmed to 50° C. and stirred under inert atmosphere for 18 h. The mixture was cooled to ambient temperature, diluted with an equal volume of EtOAc, filtered, and the filtrate solvents were removed under reduced pressure. The residue was partitioned between ether (50 mL) and water (100 mL). The undissolved solid was collected by suction filtration and dried under reduced pressure to give 4.6 g of a 10:1 mixture of 2-(1,2,4-triazol-1-yl)cyanobenzene (hplc retention time=2.29 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.6, EtOAc) and 2-(1,2,4-triazol-4-yl)cyanobenzene (hplc retention time=1.91 min, 5% to 100% CH3CN in water containing 0.1% TFA, Zorbax C8, 4.6 mm ID×7.5 cm, 3.5 micron; TLC Rf=0.1, EtOAc). The mixture was separated by flash chromatography using a gradient elution of 0:100 to 5:95 MeOH:EtOAc to give 2-(1,2,4-triazol-1-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.19 (s, 1H), 8.37 (s, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.96–7.87 (m, 2H), 7.71 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)) and 2-(1,2,4-triazol-4-yl)cyanobenzene (1H NMR (DMSO-d6) δ 9.03 (s, 2H), 8.13 (d, J=7.6 Hz, 1H), 7.93(t, J=7.8 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.74 (t, J=7.7 Hz, 1H); mass spec m/z=171 (M++H)), both as white solids.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[NH:39]1[C:43](=[O:44])[CH2:42][CH2:41][CH:40]1[C:45](O)=[O:46].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:45]([CH:40]2[CH2:41][CH2:42][C:43](=[O:44])[NH:39]2)=[O:46])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: O=C1CCC(C(=O)O)N1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CCC(=O)N2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-(2-[(methylsulfonyl)-amino]phenyl)piperidyl)propan-1-one (Example 1, Step g) (118 mg, 0.25 mmol), DIEA (Aldrich) (0.05 mL, 0.25 mmol), DL-pyroglutamic acid (Aldrich) (344 mg, 0.5 mmol), HOAT (Aldrich) (68.2 mg, 0.5 mmol) and EDC (Aldrich) (95.8 mg, 0.5 mmol) in DMF (3 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a colorless film (82 mg). MS (ESI, pos. ion) m/z: 547 (M+1); (ESI, neg. ion) in/z: 545 (M−1). Calc'd for C26H31ClN4O5S: 546.17.
Reaction SMILES: C1C[O:37][C:3]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:4][CH2:5][C@H:6]2[C@H:10]([O:11]C3CCCCO3)[CH2:9][C:8](=[O:18])[C@@H:7]2[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])O1.C(O)(=O)C.[CH2:43]1[CH2:47]OC[CH2:44]1>O>[OH:11][C@@H:10]1[CH2:9][C:8](=[O:18])[C@H:7]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH:43]([CH3:47])[CH3:44])=[O:28])[C@H:6]1[CH2:5][CH2:4][C:3](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: C1CCOC1
Reactant: CCCCCCCC1(CC[C@H]2[C@H](OC3CCCCO3)CC(=O)[C@@H]2C/C=C\CCCCCC(=O)[O-])OCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCC(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OC(C)C
Reaction time: 3 h

Procedure:
The compound (45) (0.311 g) was dissolved in a mixed solvent (5 ml) consisting of acetic acid, THF and water (2:1:1) and kept at 50° C. for 3 hours. The resultant mixture was worked up with the conventional procedure and the residue was subjected to silicagel column chromatography to give the titled compound (46). Yield: 0.156 g (66%). Compound (46) [Q1 =Q2 =H, Rb-Rc=hexyl, P3 =isopropyl]NMR(CDCl3)δ: 0.86 (t,3H,J=6.5 Hz), 1.20 (d,6H,J=6 Hz), 1.23-2.75 (m,33H), 4.20 (m,1H), 4.99 (Hept,1H,J=6 Hz), 5.15-5.50 (m,2H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=2)[NH2:26])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([CH2:22][CH2:21][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:24]=1
Reactant: Nc1cccc(CCN2CCCC2)c1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1cccc(CCN2CCCC2)c1
Yield: 71.1 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (180 mg, 0.635 mmol) was reacted with 3-[2-(pyrrolidin-1-yl)ethyl]aniline (120 mg, 0.635 mmol) to afford the desired product (198 mg, 71%) as a yellow solid: ESI MS m/z 438 [C23H24BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1C=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1CNC.C1N=[CH:18][N:17]([C:20]([N:22]2[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:21])C=1.[NH2:27]C(N)=N>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:7][C:8]([C:11]([F:12])([F:14])[F:13])=[CH:9][C:24]=1[CH2:23][N:22]([C:20]([NH:17][CH3:18])=[O:21])[C:26]([NH2:25])=[NH:27]
Reactant: N=C(N)N
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCc1cc(C(F)(F)F)ccc1Cl
Product: CNC(=O)N(Cc1cc(C(F)(F)F)ccc1Cl)C(=N)N
Product: Cl
Yield: 77.7 %

Procedure:
1.0 g of N-(2-chloro-5-trifluoromethylbenzyl)-N-methylamine was reacted with 0.75 g of CDI and 1.1 g of guanidine analogously to Example 23. 0.6 g of N-(2-chloro-5-trifluoromethylbenzyl)-N-methylaminocarbonylguanidine hydrochloride is obtained;
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:16][C:15]=3[CH2:30][CH3:31])=[CH:11][CH:12]=2)[N:7]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[N:6]=1)=[NH:4].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH2:57])[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C(O)(=O)C>C(O)C>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][C:48]([O:54][CH2:55][CH3:56])([O:51][CH2:52][CH3:53])[CH:47]([NH:57][C:3]([C:5]2[C:13]3[C:8](=[CH:9][C:10]([C:14]4[CH:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:27])[CH3:28])=[CH:16][C:15]=4[CH2:30][CH3:31])=[CH:11][CH:12]=3)[N:7]([CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[N:6]=2)=[NH:4])[CH2:46]1)=[O:44])([CH3:39])([CH3:41])[CH3:40]
Reactant: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1-c1ccc2c(C(=N)OC)nn(C3CCCCO3)c2c1
Reactant: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1N
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC1(OCC)CCN(C(=O)OC(C)(C)C)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Temperature: 50 °C
Yield: 117.3 %

Procedure:
To a solution of 6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboximidic acid methyl ester (Preparation 7, 31.4 g, 59.5 mmol) in ethanol (140 mL) was added a solution of 3-amino-4,4-diethoxy-piperidine-1-carboxylic acid tert-butyl ester (US-2004/0229862, 18.02 g, 62.48 mmol) in ethanol (100 mL). Acetic acid (6.81 mL, 119 mmol) was added and the reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (100 mL) to give the title compound as a foam (54.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].O.[N:19]#[C:20]Br>C(O)C>[NH2:19][C:20]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Reactant: N#CBr
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc2nc(N)[nH]c2c2c1OC(C)(C)C2
Yield: 45.2 %

Procedure:
To a solution of methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 2.00 g, 8.47 mmol) in ethanol:water (50:4 mL) was added cyanogen bromide (1.07 g, 10.16 mmol). The reaction mass was refluxed for 4-5 h. The reaction mass was quenched in water, neutralised with sodium bicarbonate and extracted with solution of (10%) DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 3.03 (s, 2H), 3.71 (s, 3H), 6.67 (bs, 2H), 7.33 (s, 1H), 10-11 (bs, 1H). MS [M+H]+: 237.03.
Reaction SMILES: C[OH:2].Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][C:30]([CH3:32])=[O:31]>>[C:30]([OH:2])(=[O:31])[CH3:32].[CH3:29][C:30]1([CH3:32])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[N:18]1
Reactant: CO
Reactant: CC(C)=O
Reactant: CCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
300 ml of methanol, 250 ml of acetone and 1.2 ml of concentrated hydrochloric acid were added to 18.2 g (46.6 mmol) of N1-benzyl-N5-nonyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. The residue was dissolved in 300 ml of ethanol, and to the solution were added 200 ml of water and 18 ml of 5N aqueous sodium hydroxide. The mixture was refluxed for 1.5 hours, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure to obtain 18.9 g of colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[Cl:12]C1C=CC(C(O)=O)=C(F)C=1>>[Cl:12][C:3]1[CH:2]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([F:11])[CH:4]=1
Reactant: NC(=O)c1cc(Cl)ccc1F
Reactant: O=C(O)c1ccc(Cl)cc1F
Product: NC(=O)c1ccc(Cl)cc1F

Procedure:
A method similar to the preparation of 5-chloro-2-fluorobenzamide (see page 17 above) was followed using 4-chloro-2-fluorobenzoic acid (500 mg, 5.73 mmol). The title compound was isolated as an off-white solid (465 mg, 94%).