Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Br.[NH2:13][CH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]4[CH2:34][CH2:35][C@H:25]4[C:24]=23)[N:16]=1>CN(C)C=O>[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10][C:14]([CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7])([NH2:13])[C:15]1[O:19][N:18]=[C:17]([C:20]2[N:21]=[CH:22][N:23]3[C:29]4[CH:30]=[CH:31][S:32][C:28]=4[C:27](=[O:33])[N:26]4[CH2:34][CH2:35][C@H:25]4[C:24]=23)[N:16]=1
Reactant: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCC(N)(CC=C(C)C)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2sccc2-3)no1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70 %

Procedure:
2.5 g of potassium carbonate and 0.48 ml (4.1 mmol) of dimethylallyl bromide were added to a solution of 660 mg (2 mmol) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one in 20 ml of dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction solution was subsequently filtered and the filtrate was partitioned between methylene chloride and water. The aqueous phase was back-extracted three times with methylene chloride; the combined organic phases were subsequently dried over sodium sulfate, filtered and evaporated. The residue obtained was chromatographed (silica gel, methylene chloride/methanol/aqueous ammonia 300:10:1) and there were obtained 650 mg (70%) of (S)-1-[5-[bis-(3-methyl-but-2-enyl)-aminomethyl]-1,2,4-oxadiazol-3-yl]-11,11a-dihydro-8H,10H-azeto[1,2-a]imidazo[5,1-c]thieno[3,2-e][1,4]diazepin-8-one as a colourless foam, Rf=0.16 (silica gel, methylene chloride/methanol/aqueous ammonia 300:10:1).
Reaction SMILES: C([O-])(=O)/C=C\C([O-])=O.[Ca+2].[O:10]1[CH:15]([C:16]([O-:18])=[O:17])[CH:11]1[C:12]([O-:14])=[O:13].[Ca+2].[Ca].S(=O)(=O)(O)O>CC(C)=O>[O:10]1[CH:15]([C:16]([OH:18])=[O:17])[CH:11]1[C:12]([OH:14])=[O:13]
Reactant: O=C([O-])C1OC1C(=O)[O-]
Agent: O=C([O-])/C=C\C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Solvent: CC(C)=O
Product: O=C(O)C1OC1C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
The epoxidation of acid calcium maleate was effected in accordance with Example 1. 50 g. of the calcium epoxysuccinate attained in this manner (calcium content 11.9% by weight) were suspended, with stirring, in 400 g. of 50% aqueous acetone. 15 g. of concentrated sulphuric acid were then added and the suspension was kept for 2 hours at 20° C. If the suspension is made in acetone alone, a corresponding amount of dilute sulphuric acid may be added instead of concentrated sulphuric acid. The suspension was then heated to 50° C. and, after being kept for 2 hours at this temperature, the calcium sulphate was filtered off and washed with water. The acetone was removed by distillation from the mixture of acetone and water, and the remaining aqueous epoxysuccinic acid solution was subjected directly to hydrolysis. From two moles of acid calcium epoxysuccinate, 512 g. of free epoxysuccinic acid were obtained, corresponding to a yield of 97% of the theoretical.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)[S:8][C:7]=3[C:6]=2[CH:28]=1.[NH:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[NH:29]1[CH:33]=[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[CH:10]=[C:9]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)[S:8][C:7]=4[C:6]=3[CH:28]=2)[CH:31]=[N:30]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(F)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2cc(-c4cn[nH]c4)ccc2OCC3)c(F)c1

Procedure:
5-(9-Bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-1-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole was treated with 4-pyrazoleboronic acid pinacol ester using standard Suzuki condition to yield 400. NMR: (CDCl3): 3.15 (2H, t), 4.31 (2H, t), 6.82 (1H, s), 7.01 (1H, d), 7.08-7.18 (2H, m), 7.31 (1H, d), 7.51-7.55 (1H, m), 7.72 (1H, s), 7.90 (2H, s, br.), 8.18 (1H, s). MS. ESI+489 (MH++MeCN)
Reaction SMILES: CN(C=O)C.F[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>C(OCC)(=O)C.O>[N:25]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][C:8]=2[C:15]([F:18])([F:17])[F:16])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc(-n2ccnc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 2.9 %

Procedure:
To a DMF (2.0 mL) solution of 4-fluoro-3-trifluoromethylbenzaldehyde (400 mg), potassium carbonate (414 mg) and imidazole (136 mg) were added one by one, and the reaction solution was agitated at 80° C. for 6 hours. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent: hexane:ethyl acetate 3:1->ethyl acetate) and 13.7 mg of 4-(1H-imidazol-1-yl)-3-trifluoromethylbenzaldehyde was obtained. Next, malonic acid (11.0 mg) and piperidine (53.0 mg) were added to an ethanol (1.0 mL) solution of the obtained aldehyde compound (13.0 mg), and the reaction solution was refluxed for 5 hours. Pyridine (2.0 mL) and malonic acid (11.0 mg) were added to the reaction solution, and the reaction solution was refluxed for one and a half hour. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and 15.0 mg of crude carboxylic acid was obtained by condensing under reduced pressure. By the same method as in Example 324, 10.7 mg of the title compound was obtained from the obtained carboxylic acid and 1-aminoindan. The physical properties of the compound are as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[Cl-].[Li+].C([Li])CCC.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: BrCCCCCBr
Reactant: O=C1Cc2cccc(F)c2N1
Agent: [Cl-]
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1Nc2c(F)cccc2C12CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
7-Fluoro-1,3-dihydro-indol-2-one (EXAMPLE 99, step 4) (1.16 g, 7.68 mmol) and lithium chloride (0.81 g, 19.2 mmol) were dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. n-Butyllithium (6.14 mL, 15.4 mmol) was added dropwise and the mixture was stirred 15 minutes. 1,5-Dibromopentane (1.05 mL, 7.7 mmol) was added slowly and stirring was continued for 2 hours at o° C. then warmed to 25° C. After 16 hours the reaction was quenched with a saturated aqueous solution of ammonium chloride. The mixture was diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 5% to 40% ethyl acetate in hexane) to afford 0.90 g (54%) of 7′-fluorospiro-[cyclohexane-1,3′-indol]-2′(1′H)-one. HPLC purity 95.9% at 210-370 nm, 19.2 min.; Xterra MSC18, 5u, 150×3.0 mm column, 0.5 mL/minutes, 95/5-5/95 (0.1% formic acid in H2O/MeOH) for 20 minutes, hold 3 min.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:15]=[C:14]([CH3:16])[C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][CH:21]=3)[CH:8]=2)=[C:4]([CH3:17])[CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1cc(Br)cc(C)c1Oc1ccnc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1Oc1ccnc(Nc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
In a flask outfitted with a reflux condensor, 15 (1 g, 3.2 mmol) and 4-bromoaniline (1.1 g, 6.4 mmol, 2 equiv) were melted together at 190° C. for 5 h. The reaction was cooled to room temperature and the resulting black solid was dissolved in 4:1 THF-1N NaOH soln (5 mL) stirring overnight. The reaction was diluted with EtOAc and the organic phase was washed with 1 N NaOH soln, 0.1 M HCl soln. Activated charcoal was added and the organic phase was stirred at room temperature for 0.5 h, filtered through celite and concentrated. The resulting brown solid was recrystallized from CH2Cl2 (˜4 mL) to provide the purified product as a white solid (1.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ8.03 (d, J=5.9 Hz, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.23 (m, 3H), 6.42 (s, NH), 6.19 (m, 2H), 6.14 (d, J=1.9 Hz, 1H), 2.10 (s, 6H).
Reaction SMILES: Cl.CN1C2=CCC(=O)C=C2[O:5][CH:4]1[CH2:13]CN.Cl.[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH2:30]>>[CH3:17][N:18]1[C:22]2=[CH:23][CH2:24][C:25](=[O:27])[CH:26]=[C:21]2[S:20][CH:19]1[CH2:28][CH2:29][NH:30][C:4](=[O:5])[CH3:13]
Reactant: CN1C2=CCC(=O)C=C2OC1CCN
Reactant: CN1C2=CCC(=O)C=C2SC1CCN
Agent: Cl
Product: CC(=O)NCCC1SC2=CC(=O)CC=C2N1C

Procedure:
By replacing 2-(3-methyl-6-benzoxazolinonyl)-ethylamine hydrochloride in Example 61 by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, described in French Patent Application 90/11,866, the product of the title is obtained
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[C:16](OCC)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.CCCCCCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:23]=[CH:22][C:13]([O:14][CH:15]([CH3:21])[CH:16]=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: CC(C=O)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: -55 °C
Reaction time: 5 h
Yield: 91.5 %

Procedure:
A solution of ethyl 2-{p-[(3,5-dichloro-2-pyridyl)oxy]phenoxy]propionate (1,455 g, 4.06 mol) in toluene (12 L) is cooled to -55° C. under a nitrogen atmosphere and diisobutylaluminum hydride (5.42 L of a 1.0M solution) is added over 2 hours. The reaction mixture is then stirred for 5 hours at -55° C. and glacial acetic acid (1.8 L) is added dropwise, while allowing the mixture to exotherm to 15° C. Heptane 2 L) is added and the mixture is washed sequentially with 5% hydrochloric acid solution, water, saturated sodium bicarbonate solution and water and concentrated in vacuo to obtain the title product as a yellow-orange liquid (1,159 g) which is identified by 1H NMR spectral analysis.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][CH:15]=[C:14]([C:21](N(C)OC)=[O:22])[CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][Mg]Br.O1CCCC1.O>O1CCCC1>[C:21]([C:14]1[CH:13]=[C:12]2[C:17]([NH:18][C:19](=[O:20])[C:10]3[N:11]2[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[N:8][CH:9]=3)=[CH:16][CH:15]=1)(=[O:22])[CH3:27]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2[nH]c(=O)c3cnc(C4CCCCC4)n3c2c1
Reaction time: 3.7 h

Procedure:
To a suspension of 354 mg of 1-cyclohexyl-N,O-dimethyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-8-hydroxamic acid as synthesized in above Example 142 in 10 mL of tetrahydrofuran, 1.33 mL of 3M methylmagnesium bromide/tetrahydrofuran solution was added, followed by 3.7 hours' stirring under nitrogen atmosphere and addition of 30 mL of water. The organic layer extracted with ethyl acetate-tetrahydrofuran mixed solvent was washed with water, dried over magnesium sulfate and the solvent therein was distilled off. The crude product was heat-suspended in 10 mL of methanol and purified, to provide 106 mg of the title compound.
Reaction SMILES: Cl.[CH:2]([C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])[CH3:3].C[Al](C)C.C1(C)C=CC=CC=1.C[O:25][C:26](=O)[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1>ClCCCl>[NH2:12][C:7]1[CH:6]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:10]=[CH:9][C:8]=1[NH:11][C:26](=[O:25])[CH2:27][N:28]1[CH:32]=[CH:31][N:30]=[C:29]1[C:33]1[S:34][CH:35]=[CH:36][N:37]=1
Reactant: CC(C)c1cc(N)c(N)cn1
Reactant: COC(=O)Cn1ccnc1-c1nccs1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CC(C)c1cc(N)c(NC(=O)Cn2ccnc2-c2nccs2)cn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a mixture of 6-isopropyl-pyridine-3,4-diamine hydrochloride (265 mg, 1.41 mmol) in 1,2-dichloroethane (10 mL) at room temperature under N2 is added 2.0 M AlMe3 in toluene (2.12 mL, 4.24 mmol). The mixture is stirred at room temperature for 45 min and then treated with a solution of (2-thiazol-2-yl-imidazol-1-yl)-acetic acid methyl ester (252 mg, 1.13 mmol) in 1,2-dichloroethane (2 mL) via cannula, followed by a 1 mL rinse. The reaction mixture is then stirred at reflux for 20 h. After cooling, the reaction mixture is diluted with some MeOH (˜2 mL), followed by some water and then saturated aq NaHCO3. The resulting mixture is stirred vigorously for 15 min. The mixture is then extracted thrice with CHCl3 containing some (˜5) MeOH. The combined extracts are dried over Na2SO4 and concentrated. The crude residue is then triturated with CHCl3, and the resulting mixture filtered. The solid is washed with a small amount of CHCl3 and dried, affording N-(4-amino-6-isopropyl-pyridin-3-yl)-2-(2-thiazol-2-yl-imidazol-1-yl)-acetamide as an off-white solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.52 (s, 1H), 7.86 (s, 1H), 7.85 (d, J=3.3 Hz, 1H), 7.75 (d, J=3.6 Hz, 1H)/, 7.39 (s, 1H), 7.04 (d, J=0.9 Hz, 1H), 6.45 (s, 1H), 5.65 (s, 2H), 5.38 (s, 2H), 2.74 (sept, J=6.9 Hz, 1H), 1.13 (d, J=6.9 Hz, 6H) ppm. The filtrate is concentrated and further purified by flash chromatography on silica gel. Elution with 20:1 CHCl3-MeOH followed by 15:1 CHCl3-MeOH affords 6-isopropyl-2-(2-thiazol-2-yl-imidazol-1-ylmethyl)-1H-imidazo[4,5-c]pyridine (160 mg, 44%). 1H NMR (CDCl3, 300 MHz) δ 12.23 (br, 1H), 8.97 (br, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.43 (d, J=3.3 Hz, 1H), 7.23 (br, 1H), 7.20 (d, J=0.9 Hz, 1H), 7.04 (s, 1H), 5.82 (s, 2H), 3.14 (sept, J=6.9 Hz, 1H), 1.30 (d, J=6.9 Hz, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]#[CH:21])[C:6]([N:8]1[CH:14]2[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:7].[Cl-:22].[NH4+]>[Cl-].[Zn+2].[Cl-].C(Cl)(Cl)Cl>[Cl:22][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][C:20]#[CH:21])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: [Cl-]
Reactant: C#CCOc1ccc(C(=O)N2C3CCCCC32)cc1OC
Agent: [NH4+]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: C#CCOc1ccc(C(=O)NC2CCCCC2Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2 ml of chloroform and 224 mg of zinc (II) chloride was stirred at room temperature for 5 minutes. Then, a mixture of 235 mg of 7-[3-methoxy-4-(2-propynyloxy)benzoyl]-7-azabicyclo[4.1.0]heptane and 2 ml of chloroform was added dropwise thereto at room temperature, and the resulting mixture was stirred at room temperature for 5 hours. Then, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and this was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to obtain 0.25 g of N-(2-chlorocyclohexyl)-3-methoxy-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 108 of the present invention) represented by the formula:
Reaction SMILES: N1C=CC=CC=1.[ClH:7].[O:8]1[CH2:13][CH2:12][N:11]([NH:14][N:15]=[CH:16][NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1.Cl.[C:28]([C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[C:37]([CH2:41][C:42](=[O:44])[NH2:43])=[C:36](O)[CH:35]=[CH:34]2)(=[NH:30])[NH2:29].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)(=O)C>[ClH:7].[ClH:7].[O:8]1[CH2:13][CH2:12][N:11]([NH:14][N:15]=[CH:16][NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([O:24][C:36]3[CH:35]=[CH:34][C:33]4[C:38](=[CH:39][CH:40]=[C:31]([C:28](=[NH:29])[NH2:30])[CH:32]=4)[C:37]=3[CH2:41][C:42](=[O:44])[NH2:43])=[O:23])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNN2CCOCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCC(C)=O
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 101.2 %

Procedure:
55 Milliliters of 10% hydrous pyridine was added to 1.5 g of 4-morpholinoaminoiminomethylamino-benzoic acid.hydrochloride, 1.12 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.55 g of DCC and 61 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 24 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of methanol, and the solution was added dropwise to 400 ml of ether, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 20 ml of methanol and 2.07 ml of concentrated hydrochloric acid, and the solution was added dropwise to a mixed liquid of 200 ml of ether and 200 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 1.42 g of the desired product.
Reaction SMILES: O.NN.[CH3:4][N:5]([CH:25]1[CH2:28][O:27][CH2:26]1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=2)[CH2:7]1>C(O)C.[Pd]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([N:5]([CH3:4])[CH:25]3[CH2:28][O:27][CH2:26]3)[CH2:7]2)=[CH:13][C:14]=1[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(N2CCC[C@@H](N(C)C3COC3)C2)ccc1N
Temperature: 90 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
24 mg of palladium-on-carbon (10%) and then 0.269 ml of hydrazine hydrate are added to a solution of 161 mg of (3R)—N-methyl-1-[4-nitro-3-(propan-2-yloxy)phenyl]-N-(oxetan-3-yl)piperidin-3-amine in 4 ml of ethanol. This mixture is heated at between 85° C./90° C. with magnetic stirring for 1 h 30, then 24 mg of palladium-on-carbon (10%) are added while continuing the refluxing for 2 h. 24 mg of palladium-on-carbon (10%) and 0.269 ml of hydrazine hydrate are again added. The mixture is heated for 1 h at 85° C./90° C., and then allowed to return to ambient temperature and the mixture is filtered through a Whatman AutoCup sintered glass funnel. The filtrate is concentrated under vacuum so as to obtain 136 mg of (3R)-1-[4-amino-3-(propan-2-yloxy)phenyl]-N-methyl-N-(oxetan-3-yl)piperidin-3-amine in the form of an orangey-yellow solid which is used for the subsequent step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([CH2:17][CH2:18][CH2:19]Br)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>O>[C:11]1([CH2:17][CH2:18][CH2:19][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(OCCCc2ccccc2)cc1
Reaction time: 8 h
Yield: 58.1 %

Procedure:
A mixture of 68.1 g (0.5 mole) of 4'-hydroxyacetophenone, 100.3 g (0.5 mole) of a 3-phenylpropyl bromide, 69.0 g (0.5 mole) of potassium carbonate and 500 ml of anhydrous acetone is refluxed with stirring for 8 hours. After adding 1 liter of water the product is extracted into ether, the extract is washed with water and 2 N sodium carbonate solution and dried over anhydrous sodium sulfate and the solvent is evaporated. The resulting oil (125.8 g) begins to crystallize and yields after two recrystallizations from ether-hexane and ether, respectively, 73.9 g (58% yield) of the desired product, M.P. 80°-81°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[N:14]([CH2:18][CH2:19][CH3:20])[CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[Ca+2].[Cl-].C(OCC)(=O)C>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[N:14]([CH2:18][CH2:19][CH3:20])[CH:15]=[CH:16][N:17]=2)=[O:12])=[CH:6][CH:5]=1
Reactant: CCCn1ccnc1C(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCn1ccnc1C(=O)Cc1ccc(N)cc1
Yield: 80.8 %

Procedure:
An aqueous solution (20 ml) of (2-(4-nitrophenyl)-1-(1-propylimidazol-2-yl)ethanone (1.2 g), reduced iron (1.2 g) and anhydrous calcium chloride (244 mg) in 85% ethanol was stirred for 4 hours under nitrogen atmosphere at 105° C. The mixture was allowed to be at room temperature, ethyl acetate was added to the mixture, the insolubles were filtered off, and water was added to separate the layers. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=0.4:1) to give 2-(4-aminophenyl)-1-(1-propylimidazol-2-yl)ethanone (863 mg) as red oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 82 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Preparation 2, was reacted with 3,4-dichlorophenylisocyanate (7.6 mmol) as described in Preparation 2 to obtain 2.4 g of the title product as a solid.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][NH:8][S:9]([CH2:12][CH:13]1[CH2:18][CH2:17][C:16]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:15][CH2:14]1)(=[O:11])=[O:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([S:27]([C:16]2([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])[CH2:15][CH2:14][CH:13]([CH2:12][S:9]([NH:8][CH2:7][C:6]([OH:37])=[O:5])(=[O:10])=[O:11])[CH2:18][CH2:17]2)(=[O:29])=[O:28])=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNS(=O)(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of [4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl) -cyclohexylmethanesulfonylamino]-acetic acid tert-butyl ester (Example 20) (80 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL) and the reaction stirred for 3 hours then evaporated. Purification by column chromatography on silica, eluting with ethyl acetate:dichloromethane:acetic acid (75:25:1), afforded the desired product. MS (ES+) 522 ([MH]+).