Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([O:28]CC)=[C:15](C(O)=O)[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br.[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH2:42].N1C(C)=CC=CC=1C>O1CCCC1>[Br:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][NH:42][S:2]([C:5]1[CH:6]=[C:7]([N:11]=[N:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][C:21]=3[NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]([OH:28])=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: NCCCCCCBr
Reactant: CCOc1c(C(=O)O)cc(N=Nc2cccc(S(=O)(=O)Cl)c2)c2c(NS(C)(=O)=O)cccc12
Agent: Br
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)Nc1cccc2c(O)ccc(N=Nc3cccc(S(=O)(=O)NCCCCCCBr)c3)c12

Procedure:
A suspension of 4-[3-chlorosulfonylphenylazo]-1-ethoxycarboxy-5-methanesulfonamidonaphthalene (20.4 g), 6-bromohexylamine hydrobromide (14.4 g), 2,6-lutidine (600 ml) and tetrahydrofuran (30 ml) was reacted for one hour at 50°-55° C. The mixture was cooled and filtered; the filtrate was concentrated to an oil which was dissolved in a minimum amount of acetonitrile and chromatographed on silica gel using acetonitrile as the eluant. The orange colored eluate was concentrated and cooled to obtain the product; yield 7.3 g (32%), m.p. 163°-5° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]#[C:25][CH3:26])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]>CO.C1COCC1.[OH-].[Na+]>[CH2:23]([O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:11]([CH3:12])[C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)(=[O:14])=[O:15])=[CH:21][CH:20]=1)[C:24]#[C:25][CH3:26]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)OC)CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C2(C(=O)O)CCCCC2)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of methyl1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)-amino]cyclohexanecarboxylate (4.6 g, 12.1 mmol) in methanol:THF (4:1, 100 ml), 10 N sodium hydroxide (15 ml) was added at room temperature. The reaction was stirred for 16 h and evaporated to dryness in vacuo and the residue was dissolved in 100 mL water. The pH was adjusted to 1 with 5N hydrochloric acid solution and the mixture was extracted with chloroform, washed with water, dried and concentrated to give 1-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]cyclohexanecarboxylic acid as a yellow solid. Yield: 4 g(88%); mp 124-6° C. Electrospray Mass Spec 364(M−H)−.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]([C:14]([N:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][C:38](Cl)=[CH:37][CH:36]=3)[CH:29]=2)[C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:15])[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:42]([OH:44])=[O:43])(=O)C.C([O-])(O)=O.[Na+]>CO.O>[OH:4][C:5]1[CH:13]=[C:12]([C:14]([N:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=2)[C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[O:15])[C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:42]([OH:44])=[O:43]
Reactant: CC(=O)Oc1cc(C(=O)N(Cc2cccc(Oc3ccc(Cl)cc3)c2)[C@H]2CCCc3ccccc32)c(C(=O)O)cc1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Oc3ccccc3)c2)[C@H]2CCCc3ccccc32)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
The products from Example 104B (0.97 g, 1.68 mmol) in methanol (60 mL) were treated with NaHCO3 (3.9 g, 46.4 mmol) in water (30 mL) and the mixture was stirred at room temperature for 24 hours. The methanol was removed under reduced pressure and the remaining aqueous solution was acidified to pH 1 with 1N HCl. The acidified solution was extracted with ethyl acetate (5×15 mL). The organic extracts were combined, washed with brine (10 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 9:1 CH2Cl2:methanol to 8:2 CH2Cl2:methanol) to provide the title compounds as a foamy white solid (208 mg, 23%).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C@@H:7]([NH:12][C:13]1[C:18]([F:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[C@@H](COS(C)(=O)=O)Nc1nc(Cl)ncc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CN=[N+]=[N-])Nc1nc(Cl)ncc1F
Temperature: 70 °C

Procedure:
A mixture of (S)-2-((2-chloro-5-fluoropyrimidin-4-yl)amino)-3,3-dimethylbutyl methanesulfonate, 75a, (2.37 g, 7.26 mmol) and sodium azide (1.89 g, 29.07 mmol) in DMF (50 mL) was heated at 70° C. for 6 hours. The reaction mixture was cooled to room temperature and poured into water. The aqueous phase was extracted with EtOAc (2×25 mL), dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 1.2 g of the desired product as a white crystalline solid: 1H NMR (400 MHz, CDCl3) δ 7.86 (dd, J=2.6, 1.1 Hz, 1H), 5.07 (m, 1H), 4.32-4.09 (m, 1H), 3.60 (dd, J=12.8, 3.9 Hz, 1H), 3.34 (dd, J=12.8, 7.6 Hz, 1H), 0.96 (m, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.28 minutes (M+H) 273.14.
Reaction SMILES: [C:1]1([C@@H:11]([NH2:13])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:14]([NH:13][C@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:12])(=[O:16])[CH3:15]
Reactant: C[C@H](N)c1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)N[C@@H](C)c1cccc2ccccc12
Temperature: 38 °C
Reaction time: 12 h
Yield: 59479.9 %

Procedure:
5 g of (S)-(-)-α-(1-naphthyl)ethylamine (manufactured by Hydras Kagaku) was dissolved in 20 ml of pyridine, and 5.07 mg of acetic anhydride was added thereto under cooling with ice. The mixture was stirred at 38° C. for 12 hours. The reaction solution was diluted with 500 ml of chloroform, and the organic layer was sequentially washed with a dilute hydrochloric acid aqueous solution, a dilute sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The reaction mixture thus obtained was recrystallized from dried ethanol to obtain 6.3 g of N-acetyl-(S)-α-(1-naphthyl)ethylamine. This substance is a known compound, and the measured values of various physical properties agreed to the values disclosed in literatures.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:14]=[C:12]([I:13])[C:11]([O:15][C:16]2[CH:23]=[C:21]([I:22])[C:20]([OH:24])=[C:18]([I:19])[CH:17]=2)=[C:9]([I:10])[CH:8]=1)[NH2:5].[C:26]([NH:36][CH2:37][C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].C1(N=C=NCCN2CCOCC2)CCCCC1.O>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:6][C:7]1[CH:8]=[C:9]([I:10])[C:11]([O:15][C:16]2[CH:17]=[C:18]([I:19])[C:20]([OH:24])=[C:21]([I:22])[CH:23]=2)=[C:12]([I:13])[CH:14]=1)[NH:5][C:42](=[O:43])[CH2:41][NH:40][C:38](=[O:39])[CH2:37][NH:36][C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27]
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reactant: O=C(O)CNC(=O)CNC(=O)OCc1ccccc1
Agent: C(=NCCN1CCOCC1)=NC1CCCCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CNC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Thyroxine methyl ester (5 g), as prepared above, N-carbobenzoxyglycylglycine (1.67 g) and cyclohexylmorpholinoethylcarbodiimide (5.3 g) were combined in 40 ml of dimethylacetamide. The mixture was stirred at room temperature for 24 hours, poured into deionized water, and the resulting residue collected and washed with water. The residue was recrystallized from methanol and water, yielding the product, N-carbobenzoxyglycylglycylthyroxine methyl ester.
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[NH:22][C:21]4=[O:29])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[C:30]([N:22]1[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:20]([CH:17]2[CH2:18][CH2:19][N:14]([C:7]3([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:15][CH2:16]2)[C:21]1=[O:29])(=[O:32])[CH3:31]
Reactant: O=c1[nH]c2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(=O)n1c(=O)n(C2CCN(C3(c4ccccc4)CCCCCC3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.5 %

Procedure:
A mixture of 1-[1-(1-phenylcycloheptyl)-4-piperidyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (60 mg, 0.154 mmol, this was prepared as Example 17), pyridine (1 ml), acetic anhydride (44 μl, 0.462 mmol), and dimethylaminopyridine (6 mg, 0.0462 mmol) was stirred at room temperature for 1 h. After evaporation of the solvent, the residue was purified by preparative TLC (acetone/hexane:1/2) to give 48.2 mg (72.5%) of colorless oil.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: CC(C)N1CCNCC1
Reactant: O=Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.4 %

Procedure:
To a mixture of 4-(bromoethyl)benzaldehyde (0.200 g, 1.0 mmol) and K2CO3 (0.277 g, 2.0 mmol) in DMF (5 mL) was added N-isopropylpiperazine (0.129 g, 1.0 mmol) and the reaction was stirred at room temperature for 5 hours, then concentrated in vacuo. The resulting mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 4-((4-Isopropylpiperazin-1-yl)methyl)benzaldehyde (0.240 g, 97%).
Reaction SMILES: Br[C:2]1[C:3](C2C=CC=CC=2)=[N:4][NH:5][CH:6]=1.C1C=C[C:16](/[CH:19]=[CH:20]/[C:21](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=O)=[CH:17][CH:18]=1.C1C=C[C:34](/[CH:37]=[CH:38]/[C:39](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd:67].[Pd].C.Cl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:2]([C:3]1[N:4]([C:48]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:42]2[CH:34]=[CH:37][CH:38]=[C:39]([OH:40])[CH:41]=2)[N:5]=[C:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:23]=1[C:21]1[CH:18]=[CH:17][CH:16]=[CH:19][CH:20]=1)[CH3:6].[Pd:67]
Reactant: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Reactant: Brc1c[nH]nc1-c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1c(-c2ccccc2)c(-c2ccccc2)nn1-c1ccccc1-c1cccc(O)c1

Procedure:
The reaction of Example 1 (reaction scale: 10 mmol of bromophenyl pyrazole) was conducted with 0.15 mole % of Pd2(dba)3. After the reaction was judged to be essentially complete, THF (10 mL/g of bromophenyl pyrazole starting material) was added to dissolve the precipitates, and the solution was passed through a Darco zeta pad twice. The filtrate was neutralized with 1N aq. HCl to a pH of 7.0 to 7.5. After filtration, the crude solid, whose palladium level was 111 ppm, was dissolved in THF (9 mL/g of bromophenyl pyrazole starting material), and the mixture was stirred in the presence of PS-PPh3 resin (Argonaut Technologies, 1.61 mmol PPh3/g, 5 wt %) at ambient temperature for 21 h, then filtered twice through a Darco zeta pad. The filtrate was concentrated and the product was recrystallized from THF/acetone/water to afford 2′-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)-[1,1′]-biphenyl-3-ol containing less than 2 ppm of palladium.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14]([NH2:15])=[CH:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1.[CH:16]1([C:19](=O)[CH2:20][C:21](=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1.C1C=CC=CC=1>CC(O)=O>[CH:16]1([C:19]2[CH:20]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:13]3[CH:12]=[N:11][N:10]([CH2:9][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[C:14]=3[N:15]=2)[CH2:17][CH2:18]1
Reactant: COc1ccc(Cn2nccc2N)cc1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C2CC2)nc2c1cnn2Cc1ccc(OC)cc1
Temperature: 63 °C
Yield: 71 %

Procedure:
A mixture of 1-{[4-(methyloxy)phenyl]methyl}-1H-pyrazol-5-amine (3 g, 14.76 mmol), ethyl 4-cyclopropyl-2,4-dioxobutanoate (2.72 g, 14.76 mmol) and benzene (50 mL) were heated at 63° C. for 16 h. The solvent was removed under reduced pressure. The crude residue was purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford 2.56 g of the desired cyclized product and 1.71 g of the uncyclized adduct. The uncyclized adduct was dissolved in 25 mL of AcOH and heated to reflux for 16 hours. The solvent was removed under reduced pressure and the residue purified via silica gel chromatography (eluent: 0 to 25% EtOAc:Hex) to afford an additional 1.15 g of the desired cyclized product (combined yield=71%). LCMS E-S (M+H)=352.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.13 (m, 4 H) 1.38 (t, J=7.07 Hz, 3 H) 2.39 (s, 1 H) 3.67 (s, 3 H) 4.41 (q, J=7.07 Hz, 2 H) 5.51 (s, 2 H) 6.84 (d, J=8.84 Hz, 2 H) 7.21 (d, J=8.59 Hz, 2 H) 7.64 (s, 1 H) 8.23 (s, 1 H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](Cl)=[O:6].[CH3:20][C:21]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:30])[CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:30][C:21]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)([CH3:20])[CH:22]([NH:29][C:5](=[O:6])[C:4]1[C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-(methylthio)-4,6-bis(trifluoromethyl)benzoyl chloride D55 (60 mg; 0.19 mmol) in dry DCM (1 ml) was treated with (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (60 mg, 0.27 mmol) followed by triethylamine (5drops) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product as an oil (80 mg, 85%). 1H NMR (CDCl3) δ: 0.94 (3H, s), 1.00 (3H, s), 1.69 (4H, overlapping m), 2.54 (3H, s), 2.62 (2H, m), 2.72 (2H, m), 4.78 (1H, s), 7.25-7.45 (6H, overlapping m), 7.68 (1H, s), 7.72 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 505 (MH+) C24H26F6N2OS requires 504. Ret time 2.24 min.
Reaction SMILES: Cl.[O:2]1CCOCC1.C(OC(NC[C@H]1CC[C@H](C(N[C:26](=[O:36])[C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[NH2:28])=O)CC1)=O)(C)(C)C>CCCCCC>[NH2:28][C@H:27]([C:26]([OH:36])=[O:2])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Agent: Cl
Solvent: CCCCCC
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After evaporation of the solvent, the residue was extracted with ethyl acetate, washed with water, and dried over sodium sulfate. After evaporation of the solvent, a white powder of N-(t-butoxycarbonyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide (I) (0.5 g) was obtained. After confirmation by NMR and IR, 4N hydrogen chloride/1,4-dioxane solution (5 ml) was added to the above compound (I) (0.5 g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added and the solids precipitated were washed several times with diethyl ether to obtain white solids (0.45 g) of L-phenylalanine 4-cis/trans-methylcyclohexylamide hydrochloride (II). This structure was confirmed by NMR spectrum. To the mixture of 4-guanidino benzoic acid hydrochloride, dry pyridine (3 ml) and 1,3-dicyclohexylcarbodiimide (0.36 g), the above compound (II) was added under ice-cooling, and the mixture was left to stand at room temperature for 12 hours. After a conventional post-treatment, pale yellow solids of N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide (III) (0.5 g) were obtained. After confirmation by NMR, the above compound (III) (0.5 g) was added to a saturated sodium hydrogen carbonate solution (10 ml) and the mixture was stirred for 5 minutes, followed by a recovery of the precipitates. After washing several times with water, pale yellow solids of N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/trans-methylcyclohexylamide carbonate (IV) (0.25 g). After confirmation by IR, the above compound (IV) (0.2 g) was added to a 4N hydrogen chloride/1,4-dioxane solution (1 ml) under ice-cooling, and the mixture was stirred for 20 minutes. Diethyl ether was then added, and the precipitated solids were washed several times with diethyl ether to obtain N-(4-guanidinobenzoyl)-L-phenylalanine 4-cis/transmethylcyclohexylamide hydrochloride (0.15 g) as pale yellow solids.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][CH:6]=2.Cl[C:17]1[CH:22]=[C:21]([CH2:23][CH3:24])[N:20]=[CH:19][N:18]=1>CN1CCCC1=O.C(OCC)(=O)C>[CH2:23]([C:21]1[N:20]=[CH:19][N:18]=[C:17]([NH:13][CH2:12][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:11]3)[CH:22]=1)[CH3:24]
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: CCc1cc(Cl)ncn1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1cc(NCc2ccc3[nH]c(C(F)(F)F)cc3c2)ncn1
Temperature: 100 °C
Yield: 34.7 %

Procedure:
A stirred mixture of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 34, 171 mg, 0.8 mmol), 4-chloro-6-ethylpyrimidine (Intermediate 12, 171 mg, 1.200 mmol) and DI PEA (0.279 mL, 1.600 mmol) in N-methyl-2-pyrrolidone (1 mL) was heated at 100° C. for 2 hours. After cooling to room temperature the reaction mixture was diluted with ethyl acetate. The solution was washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 50-100% ethyl acetate in isohexane to give the crude product which was triturated with ether/isohexane and the resulting colourless solid was collected, washed with cold ether and dried to give the title compound (89 mg).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([O:30]C)=[O:29])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[OH-].[Na+]>CO.C1COCC1>[CH3:1][S:2]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:20][CH:21]=3)=[CH:15][C:10]=2[CH:9]=[C:8]([C:28]([OH:30])=[O:29])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: COC(=O)C1=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc2N(S(C)(=O)=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)N1CCC(C(=O)O)=Cc2cc(-c3ccc(N4CCOCC4)cc3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
In methanol (100 ml) and THF (100 ml) was dissolved methyl 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.4 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature overnight. To the mixture was added 1N sodium hydroxide solution (5 ml), and the mixture was stirred at 60° C. for 1.5 hours and concentrated. To the residue was added water, and the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give 1-methanesulfonyl-7-(4-morpholinophenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.36 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(=O)(O)[O-].[Na+].O1[CH2:38][CH2:37]OCC1>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([N:27]3[CH2:38][CH2:37][N:3]([CH3:4])[CH2:2][CH2:7]3)[CH2:23][CH2:22]2)[N:3]=1
Reactant: C1COCCO1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (105 mg, 0.28 mmol, Example 120) and sodium bicarbonate (84 mg, 1 mmol) in 1,4-dioxane (3 mL), bis-2-chloroethyl-methylamine hydrochloride (58 mg, 0.30 mmol, Aldrich) was added and the mixture was stirred at reflux overnight. An additional 20 mg of bis-2-chloroethyl-methylamine hydrochloride (Aldrich) was added and the reaction was refluxed for another 12 hours. The reaction was quenched with water and the mixture was extracted with ethyl acetate (3×10 mL) and the extracts were dried with sodium sulfate. Removal of solvent gave a yellow solid which was chromatographed (8% 9N ammonia in methanol/dichloromethane) to give a pale yellow solid. 16 mg, 12%. MS (ES) MH+=461.
Reaction SMILES: [C:1]([C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8](O)=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C>C1COCC1>[C:1]([C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]2[O:14][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[C:9]=2[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(C)(C)C(=O)O)c(O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OC(=O)C2(C)C
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a solution of compound 18 (7.10 g, 25.2 mmol) in 710 mL of anhydrous THF was added EDCI (14.5 g, 75.6 mmol). The resulting suspension was left stirring at 30° C. overnight. The precipitate was filtered and thoroughly washed with DCM. The filtrate was concentrated to dryness and the residue was dissolved in DCM (100 mL). The solution was washed with water (50 mL×2) and brine (50 mL×1). The DCM layer was then dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified via column chromatography on silica gel (Petroleum ether/EtOAc 200:1→100:1→50:1) to give compound 19 as a white solid. 1H NMR (CDCl3; 400 MHz) δ 7.36 (s), δ 7.10 (s), 81.53 (s), δ 1.41 (s).