Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl-].[Na+]>CC(N(C)C)=O>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=3[N:7]=2)[CH2:18][CH2:17]1)=[O:20])[CH3:23]
Reactant: Sc1nc2cc(Cl)ccc2o1
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCC(Nc2nc3cc(Cl)ccc3o2)CC1
Yield: 39 %

Procedure:
A mixture of 5-chloro-benzooxazole-2-thiol (4.00 g, 21.5 mmol, 1.0 equiv; commercially available from Aldrich) and ethyl 4-amino-1-piperidine carboxylate (4.9 g, 28.0 mmol, 1.3 equiv) in anhydrous DMAc (5 mL) was heated to 200° C. under microwave irradiation for 20 min. To the crude reaction mixture was added a conc. solution of sodium chloride (100 mL), the solution extracted with ethyl acetate (3×100 mL) and the combined organic phases dried over MgSO4. Purification of the crude material with column chromatography on silica eluting with hexane/ethyl acetate (2:1→1:1) yielded 2.7 g (39%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.19 (t, J=7.1 Hz, 3H), 1.39-1.45 (m, 2H), 1.93-1.97 (m, 2H), 2.98 (br s, 2H), 3.77-3.78 (m, 1H), 3.91-3.95 (m, 2H), 4.04 (q, J=7.1 Hz, 2H), 7.00 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.29 (d, J=2.1 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.19 (d, J=7.6 Hz, 1H). 13C NMR (100 MHz, DMSO): δ 14.53, 31.11, 42.07, 49.60, 60.63, 109.45, 115.10, 119.65, 127.78, 144.86, 146.71, 154.56, 162.50. MS (ISP): 324.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=O)[O:16][C:17]=1[CH3:18]>C(O)(=O)C.CCO>[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[O:16][C:17]=1[CH3:18]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: Cc1cc(C=O)oc1C
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C=NNC(=O)c2ccc(O)cc2)oc1C
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 4,5-dimethyl-2-furaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give red solid 0.47 g, in 90% yield, mp: 251.4° C. 1H NMR (DMSO-d6) δ 11.46 (s, 1H), 10.09 (s, 1H), 8.18 (s, 1H), 7.79 (d, 2H), 6.86 (d, 2H), 6.69 (s, 1H), 2.27 (s, 3H), 1.96 (s, 3H). 13C NMR (DMSO-d6) δ163.1, 161.0, 150.3, 147.2, 137.0, 130.0, 124.4, 117.4, 116.9, 115.4, 11.8, 9.9. Anal. Calcd for C14H14N2O3H2O: C, 60.82; H, 5.11; N, 10.13. Found: C, 60.80; H, 5.03; N, 9.48.
Reaction SMILES: C(=O)([O-])O.[Na+].Br[CH2:7][C:8]([NH:10][C:11]1[C:12]([S:22][CH:23]([CH3:25])[CH3:24])=[N:13][C:14]([CH3:21])=[CH:15][C:16]=1[S:17][CH:18]([CH3:20])[CH3:19])=[O:9].[SH:26][C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>C(#N)C>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[S:26][CH2:7][C:8]([NH:10][C:11]1[C:12]([S:22][CH:23]([CH3:25])[CH3:24])=[N:13][C:14]([CH3:21])=[CH:15][C:16]=1[S:17][CH:18]([CH3:20])[CH3:19])=[O:9]
Reactant: Sc1nc2ccccc2o1
Reactant: Cc1cc(SC(C)C)c(NC(=O)CBr)c(SC(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(SC(C)C)c(NC(=O)CSc2nc3ccccc3o2)c(SC(C)C)n1
Temperature: 25 °C
Reaction time: 28 h
Yield: 44 %

Procedure:
This nitropyridine (1.08 g, 3.77 mmol) was dissolved in a mixed solvent of acetic acid (35 ml) and conc. hydrochloric acid (1.6 ml), and zinc (2.96 g, 45.25 mmol) was added thereto in small portions while being cooled with ice. After the mixture was stirred for 1 hour, the reaction mixture was filtered, and the filtrate was neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted with chloroform. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting residue was purified through silica gel column chromatography (eluent—hexane:ethyl acetate=30:1→10:1) to obtain 774 mg (yield 80%) of 3-amino-2,4-bis(isopropylthio)-6-methylpyridine as a yellow oil. Triethylamine (336 mg, 3.32 mmol) was added to a THF (10 ml) solution of this aminopyridine (774 mg, 3.02 mmol), and bromoacetyl bromide (732 mg, 3.62 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred for 17 hours. The reaction mixture was filtered, and the filtrate was concentrated. Then, the residue was purified through silica gel chromatography (eluent—hexane:ethyl acetate=10:1) to obtain 595 mg (yield 52%) of 2-bromo-N-[2,4-bis(isopropylthio)-6-methyl-3-pyridyl]acetamide as a colorless powdery crystal. sodium hydrogencarbonate (29 mg, 0.35 mmol) was added to an acetonitrile (5 ml) solution of this amide (132 mg, 0.35 mmol) and 2-mercaptobenzoxazole (53 mg, 0.35 mmol), and the mixture was stirred at room temperature for 28 hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through preparative thin-layer chromatography (eluent—hexane:benzen=6:1) to obtain 69 mg (yield 44%) of the desired compound as a colorless powdery crystal.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.Cl.[CH3:37][N:38]([C@H:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1)[C:39]([C:41]1[N:42]=[C:43]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[S:44][CH:45]=1)=[O:40].C(N(CC)CC)C>C(OCC)(=O)C>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[N:5]([CH2:12][C:13]([N:49]2[CH2:50][CH2:51][CH:46]([C:43]3[S:44][CH:45]=[C:41]([C:39]([N:38]([CH3:37])[C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)=[O:40])[N:42]=3)[CH2:47][CH2:48]2)=[O:15])[N:4]=1
Reactant: O=C(O)Cn1nc(C(F)(F)F)cc1C(F)(F)F
Reactant: CN(C(=O)c1csc(C2CCNCC2)n1)[C@@H]1CCCc2ccccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C(F)(F)F)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3,5-bis-(trifluoromethyl)-1H-pyrazole-1-acetic acid (190 mg, 0.73 mmol) (i.e. the product of Example 14, Step A) in ethyl acetate (5.0 mL) was treated with 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.0 mL, 1.6 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to a stirred suspension of N-methyl-2-(4-piperidinyl)-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide monohydrochloride (i.e. the product of Example 6, Step C) (210 mg, 0.53 mmol), triethylamine (0.5 mL, 3.75 mmol) in ethyl acetate (5 mL). The reaction mixture was then stirred at room temperature for 12 h. The resulting suspension was concentrated in vacuo and purified by MPLC on silica gel using ethyl acetate/hexanes as eluant to give 110 mg of the title product, a compound of the present invention as an oil.
Reaction SMILES: [CH:1]([C:3]1[N:34]([S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:37])=[O:36])[C:6]2=[N:7][CH:8]=[CH:9][C:10]([C:11]3[C:12]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[O:26])=[CH:20][CH:19]=4)=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=3)=[C:5]2[CH:4]=1)=O.[NH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:16]([N:14]1[CH:15]=[C:11]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]3[N:34]([S:35]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)(=[O:36])=[O:37])[C:3]([CH2:1][NH:44][CH2:45][CH2:46][N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[CH:4][C:5]=23)[C:12]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:26])=[CH:20][CH:19]=2)=[N:13]1)[CH3:17]
Reactant: NCCN1CCOCC1
Reactant: CCn1cc(-c2ccnc3c2cc(C=O)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCn1cc(-c2ccnc3c2cc(CNCCN2CCOCC2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1

Procedure:
A solution of N-(4-{4-[2-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1-ethyl-1H-pyrazol-3-yl}phenyl)-N′-phenylurea (0.1 mmol), 4-(2-aminoethyl)-morpholine (0.2 mmol), and sodium triacetoxyborohydride (0.2 mmol) in dichloromethane (1 mL) and acetic acid (0.25 mL) under nitrogen was stirred at room temperature for 30 minutes. The reaction was quenched with 1N sodium hydroxide solution (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound as the crude product. ESMS [M+H]+: 705.6
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](SC)[N:5]2[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)=[N:11][N:12]=[C:4]2[CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:34][NH2:35]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:35][CH2:34][C:33]2[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=2)[N:12]2[N:11]=[C:10]([C:13]3[O:14][CH:15]=[CH:16][CH:17]=3)[N:5]=[C:4]2[CH:3]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: CSc1nc(Cl)cc2nnc(-c3ccco3)n12
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(Cl)cc3nc(-c4ccco4)nn23)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
Into 600 mL of THF, 50.0 g (188 mmol) of Compound B was dissolved, and 42.0 mL (280 mmol) of DBU was added thereto, followed by stirring at room temperature for about 30 minutes. During the period, crystals were precipitated from the reaction solution. Next, 94 g (563 mmol) of 3,4-dimethoxybenzylamine was added thereto, followed by stirring at 60° C. for about 2 hours. After completion of the reaction, the solvent was evaporated, the residue was diluted with chloroform and washed with water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was triturated with ethyl acetate to obtain 53.2 g of Compound D as a white solid (yield: 74%). The residue obtained by concentrating the solution part present after trituration was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to additionally recover Compound D in about 10% yield.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[N:12]=[C:11]([CH2:13][CH2:14][OH:15])[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:15][CH2:14][CH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: Cc1cccc(CCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cccc(CCOS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
MsCl (6.7 mmol, 0.52 mL) was added to a solution of 6-methyl-2-pyridineethanol (6.7 mmol, 0.92 g) and triethyl amine (13.4 mmol, 1.88 mL) in toluene (6 mL) at 0° C. dropwise. The resulting mixture was stirred at 0° C. for 30 min. The precipitate generated from reaction was filtered off. The filtrate was concentrated in vacuo to give crude 2-(6-methylpyridin-2-yl)ethyl methanesulfonate which was used for next step without further purification. A mixture of above described 2-(6-methylpyridin-2-yl)ethyl methanesulfonate, PhOH (13.4 mmol, 1.26 g) and NaOH (13.4 mmol, 0.54 g) in isopropanol (20 mL) was refluxed at 90° C. for 3 h. The reaction mixture was concentrated in vacuo and dissolved in EtOAc which was washed with water. The organic layer was separated, dried with MgSO4 and concentrated in vacuo. The crude product was purified by chromatography to give desired 2-methyl-6-(2-phenoxyethyl)pyridine as a colorless oil in 26% yield.
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Temperature: 120 °C
Yield: 123.2 %

Procedure:
A mixture of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide (1.68 g, 4.54 mmol), Pd(OAc)2 (20 mg, 0.091 mmol), tri-o-tolylphosphine (55 mg, 0.18 mmol), triethylamine (1.25 mL), acetonitrile (2.5 mL) and methyl acrylate (0.83 mL, 9.08 mmol) were placed in a stainless steel bomb and heated to about 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the solid reaction mixture was collected, washed with ether and dried to afford 2.1 g of crude product which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:22])=[C:4]([C:9]2[C:20]([NH2:21])=[N:19][C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=2)[C:5]([Cl:8])=[CH:6][CH:7]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>ClCCl>[NH2:21][C:20]1[C:9]([C:4]2[C:3]([Cl:22])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=3)[CH:7]=[CH:6][C:5]=2[Cl:8])=[CH:10][C:11]2[CH:16]=[N:15][C:14]([S:17][CH3:18])=[N:13][C:12]=2[N:19]=1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(N)c3Cl)c(N)nc2n1
Solvent: ClCCl
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 6-(3-amino-2,6-dichloro-phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-ylamine (600 mg, 1.7 mmol) in dichloromethane (60 ml) is added 3-trifluoromethyl-benzoyl chloride (1.76 g, 8.5 mmol) slowly at 0° C. on an ice bath. The reaction is then raised to room temperature and stirred at room temperature for 18 hours. The reaction mixture is washed with 10% NaHCO3 and brine. The organic phase is dried over MgSO4. The crude product is purified by flash silica gel column eluting with CH2Cl2/MeOH (7N NH3) (v/v: 98/2) to give the title compound as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1)=[O:8].[OH-].[Na+].Cl>C(OCC)(=O)C>[NH2:11][C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(=O)oc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
3.9 g (17.6 mmol) of the above 5-methyl-3-nitroisatoic anhydride in ethyl acetate (50 mL) was treated with NaOH at r.t. for 2 h. The mixture was neutralized with dilute HCl solution and the resulting solid was filtered and washed with water and dried to give 2.5 g (72%) of 2-amino-5-methyl-3-nitrobenzoic acid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.06 g), 2-fluoro-5-hexylbenzonitrile (1.23 g), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.60 g of desired compound (refractive index: 1.5779).
Reaction SMILES: C[O:2][C:3](=[O:8])[C@@H:4]([NH2:7])[CH2:5][NH2:6].[F:9][C:10]([F:27])([F:26])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[F:26][C:10]([F:9])([F:27])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:7][C@@H:4]([CH2:5][NH:6][C:23]([C:20]3[CH:19]=[CH:18][C:17]([C:14]4[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:26])[F:27])=[CH:12][CH:13]=4)=[CH:22][CH:21]=3)=[O:24])[C:3]([OH:2])=[O:8])=[O:24])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)[C@@H](N)CN
Product: O=C(NC[C@H](NC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 59.4 %

Procedure:
(2S)-2,3-Diamino-propionic acid methyl ester (0.080 g, 0.421 mmol) was reacted with 4′-trifluoromethyl-biphenyl-4-carboxylic acid (0.224 g, 0.841 mmol) as described in general procedure A yielding the corresponding (2S)-3-bis-[(4′-trifluoromethyl-biphenyl-4-carbonyl)-amino]-propionic acid methyl ester which was then hydrolyzed as per general procedure C to yield the title compound (0.150 g, 60%). 1H-NMR(400 MHz, DMSOd6): 4.16 (m, 2H), 5.0 (m, 1H), 8.17 (m, 8H), 8.28 (m, 8H), 9.18 (m, 1H), 9.21 (d, 1H); LC/MS (m/z): 601.2 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
100 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (76 mg, 0.275 mmol), 1-phenylpiperazine (0.038 mL, 0.250 mmol), DIPEA (44 mL, 0.250 mmol) and NaBH(OAc)3 (185 mg, 0.875 mmol).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[C:27]([C:30]1[S:34][C:33]2=[CH:35][N:36]=[CH:37][N:32]2[CH:31]=1)(=[O:29])[NH2:28]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:36]3[CH:35]=[C:33]4[S:34][C:30]([C:27](=[O:29])[NH2:28])=[CH:31][N+:32]4=[CH:37]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: NC(=O)c1cn2cncc2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4sc(C(N)=O)c[n+]4c3)[C@H](C)[C@H]12
Yield: 6.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 107 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 74 mg of 2-carbamoylimidazo[5,1-b]thiazole were used, thereby obtaining 7.4 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][C:8]1[C:9]([C:18]2[C:19]([Cl:28])=[CH:20][C:21]([Cl:27])=C([CH:26]=2)C(O)=O)=[N:10][N:11]([CH3:17])[C:12]=1[O:13][CH:14]([F:16])[F:15]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:18]2[C:19]([Cl:28])=[CH:20][C:21]([Cl:27])=[C:1]([CH:26]=2)[C:2]([Cl:4])=[O:3])=[N:10][N:11]([CH3:17])[C:12]=1[O:13][CH:14]([F:16])[F:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reaction time: 6 h

Procedure:
20.5 g (160 mmol) of oxalyl chloride were added dropwise to a solution of 7.7 g (20 mmol) of 5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-2,4-dichlorobenzoic acid in 300 ml of toluene. After 6 hours stirring at reflux temperature, the reaction mixture was concentrated. Yield: quantitative.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:17])[N:9]3[CH2:16][CH2:15][CH2:14][C:10]3=[N:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+]>CO>[CH:18](=[C:14]1[C:10]2=[N:11][C:12]3[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=3[C:8](=[O:17])[N:9]2[CH2:16][CH2:15]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c2ccc([N+](=O)[O-])cc2nc2n1CCC2
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1c2ccc([N+](=O)[O-])cc2nc2n1CCC2=Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-nitro-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 196°-197° C. (3.7 g), prepared according to the Example 2, was reacted with benzaldehyde (2 g) in methanol (100 ml) in the presence of sodium methoxide (1.74 g) under stirring at room temperature for 16 hours and then at 60° C. for 4 hours. After concentration in vacuo of the suspension, the precipitate was filtered and washed with water until neutral: crystallization from CH2Cl2 -methanol gave 3-benzylidene-6-nitro-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 255°-257° C. (3.5 g), which was reacted with SnCl2.2H2O (25 g) in 37% HCl (15 ml) and acetic acid (45 ml) under stirring at 60° C. for 3 hours. After cooling the precipitate was filtered and washed with water and then suspended under stirring in 2.5% aqueous NaHCO3 : the product was filtered, washed with water until neutral and then crystallized from ethanol to give 1.6 g of 6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one, m.p. 268°-270° C., NMR (DMSO-d6) δppm: 3.23 (bt) (2H, C-2 protons), 4.11 (t) (2H, C-1 protons), 6.07 (bs) (2H, --NH2), 6.73 (m), (2H, C-5 and C-7 protons), 7.33-7.76 (m) (5H, phenyl protons), 7.68 (bs) (1H, =CH--), 7.83 (d) (1H, C-8 proton).
Reaction SMILES: Cl.Cl[S:3]([C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])(=O)=O>C(O)(=O)C.O>[SH:3][C:6]1[CH:7]=[C:8]([CH2:14][C:15](=[O:17])[CH3:16])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: COc1ccc(CC(C)=O)cc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CC(C)=O)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
While ice-cooling a suspension of 84 g of stannous chloride --2H2O in 320 ml of glacial acetic acid with stirring until a transparent solution was obtained, hyrochloric acid gas was introduced into the solution and then 14.3 g of 3-chlorosulfonyl-4-methoxyphenylacetone was added to the solution at 25°-30° C. After further stirring the mixture at room temperature for 30 minutes, the reaction mixture obtained was poured into 320 ml of concentrated hydrochloric acid and after diluting the mixture with 640 ml of water, the product was extracted with 400 ml of chloroform. The chloroform layer formed was washed with water and then chloroform was distilled off to provide 10 g of oily 3-mercapto-4-methoxyphenylacetone.