Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH:14]1(COS(C2C=CC(C)=CC=2)(=O)=O)[CH2:18]C[CH2:16][CH2:15]1.Cl.C(=O)([O-])O.[Na+]>CN(C)C=O.C(OC(C)C)(C)C.O>[CH:2]1([CH2:3][O:4][CH:5]2[CH2:6][CH2:7][C:8](=[O:11])[CH2:9][CH2:10]2)[CH2:16][CH2:15][CH2:14][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: OC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CC(C)OC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(OCC2CCCC2)CC1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
23.7 g (150 mmole) 1,4-dioxa-spiro[4.5]decan-8-ol were dissolved in 120 ml dimethylformamide and stirred for 1 hour in a nitrogen atmosphere at room temperature with 7.2 g (159 mmole) of 50% sodium hydride in mineral oil. 38 g (150 mmole) toluene-4-sulphonic acid cyclopentylmethyl ester were then added (Krapcho, Johnson, J. Org. Chem., 36, 146, (1971). The mixture was stirred at room temperature and cooled to a temperature between 5° C. and 10° C. 125 ml water were then added dropwise. The product was extracted with ether and dried over sodium sulphate, and the solvent was removed by distillation. The product obtained (32 g) was dissolved in diisopropyl ether and stirred for 20 hours with 65 ml water and 95 ml concentrated hydrochloric acid. It was then neutralised with sodium hydrogen carbonate, extracted with ether and dried over sodium sulphate. The oil obtained (23.4 g) was purified with 1:1 diisopropyl ether/n-hexane via a silica gel column. 17.5 g of compound (61) were obtained (60% theoretical).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:24])[NH:4][N:5]=[C:6]([NH2:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=1.Br[C:26]1C(=O)NN=C([N+]([O-])=O)[C:31]=1NCC1C=CC(OC)=C(OCCCC)C=1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.CO.C(C(C)=O)C>[CH2:26]([N:4]1[C:3](=[O:24])[C:2]([Br:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:11]=2)[C:6]([NH2:23])=[N:5]1)[CH3:31]
Reactant: CCCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Br)ccc1OC
Reactant: CCCCOc1cc(CNc2c(N)n[nH]c(=O)c2Br)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCI
Solvent: ClC(Cl)Cl
Product: CCCCOc1cc(CNc2c(N)nn(CC)c(=O)c2Br)ccc1OC
Reaction time: 2 h

Procedure:
A mixture comprising 280 mg of 4-bromo-5-(3-n-butoxy-4-methoxybenzylamino)-6-amino-3(2H)pyridazinone (Compound No. 30) prepared according to the process of Example 3 from 4-bromo-5-(3-n-butoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 29) as the starting material, 0.29 ml of ethyl iodide, 487 mg of anhydrous potassium carbonate and 15 ml of methyl ethyl ketone, was refluxed under stirring for 2 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with chloroform. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off, the residue thereby obtained was subjected to silica gel thin layer chromatography by using a solvent mixture of chloroform:methanol (9:1 v/v) as the developer, the oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 180 mg of the above identified compound having a melting point of from 108° to 110.5° C. as light yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:14][C:13]=3[C:24]([F:27])([F:26])[F:25])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.OC1CCNC1.[NH:34]1[CH2:42][CH2:41][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35]1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:19]=[CH:20][N:21]=[C:22]([N:34]5[CH2:42][CH2:41][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35]5)[CH:23]=4)=[CH:14][C:13]=3[C:24]([F:25])([F:26])[F:27])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1cc(-c2ccncc2)ccc1Sc1ccc2c(c1)OCCO2
Reactant: O=C(O)C1CCNCC1
Agent: OC1CCNC1
Product: O=C(O)C1CCN(c2cc(-c3ccc(Sc4ccc5c(c4)OCCO5)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with isonipecotic acid. A yellow solid 127 was obtained (0.014 g, 28%). 1H-NMR (CDCl3, 400 MHz) δ 1.89-1.98 (m, 2H), 2.08-2.15 (m, 2H), 2.68-2.76 (m, 1H), 3.40-3.48 (m, 2H), 4.13-4.20 (m, 2H), 4.28-4.34 (m, 4H), 6.91-6.98 (m, 3H), 7.04 (dd, J=1.9 Hz, 8.4 Hz, 1H), 7.09 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 7.82 (s, 1H), 8.20 (d, J=6.2 Hz, 1H); MS (APCI) m/z 517 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][C:25](Cl)=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH:7][C:25](=[O:26])[CH2:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([O:15][CH3:14])[CH:17]=1
Reactant: COc1cccc(CCN)c1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Product: COc1ccc(CC(=O)NCCc2cccc(OC)c2OC)cc1OC

Procedure:
prepared from 2,3-dimethoxyphenethylamine (Lindemann, Helv. Chim. Acta. 1949, 32, 69-75) and 3,4-dimethoxyphenylacetyl chloride; mp 80° C. (lit.29 79-80° C.); IR 3315, 2962, 2838, 1636, 1593, 1548; 1H NMR δ 2.61 (t, 2H), 3.22-3.30 (m, 4H), 3.58 (s, 3H), 3.64 (s, 6H), 3.67 (s, 3H), 6.22 (brs, 1H), 6.44-6.79 (m, 6H); 13C NMR δ 30.0, 41.0, 43.7, 55.9, 56.2, 56.3, 60.9, 111.2, 111.9, 112.9, 122.0, 122.6, 124.4, 127.9, 133.1, 147.5, 148.5, 149.5, 153.1, 171.9.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1.[N+:16]([O-])([OH:18])=[O:17].C(O)(=O)C.CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=[N+]([O-])O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
50 g (250 mmoles) of 2-methyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene are dissolved in 200 ml of acetic anhydride. The solution is cooled to 0° C. and there is slowly added a solution of 10.5 ml (250 mmoles) of nitric acid, 20 ml of acetic acid and 20 ml of acetic andydride, while maintaining the temperature between 0 and 5° C. The reaction mixture is then stirred for 1 hour at ambient temperature, poured into ice water and filtered. The resulting solid is washed with water. The solid is dissolved in methylene chloride, washed with water and then with a saturated solution of sodium bicarbonate, dried on MgSO4 and evaporated. 45.8 g (74%) of 2-methyl-3-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl naphthalene which melts at 143-144° C. are obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.Cl.[OH:20][CH2:21][C:22]1([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(OCCO)C.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:25]2[CH2:26][CH2:27][C:22]([CH2:21][OH:20])([OH:28])[CH2:23][CH2:24]2)[CH:7]=1
Reactant: OCC1(O)CCNCC1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: Cl
Solvent: CCOCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](Nc1nc(Cl)cc(N2CCC(O)(CO)CC2)n1)c1ccc(F)cc1
Temperature: 135 °C
Reaction time: 20 h
Yield: 97.2 %

Procedure:
150 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 97 mg of 4-(hydroxymethyl)piperidin-4-ol hydrochloride were dissolved in 3 ml of 2-ethoxyethanol, and 274 μl of N,N-diisopropylethylamine was added thereto, and the mixture was stirred at 135° C. for 20 hours. The reaction solution was air-cooled to room temperature, and then diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 194 mg of the objective compound as brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:57]1[CH2:62][CH2:61][NH:60][CH2:59][C:58]1=[O:63].ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:60]1[CH2:61][CH2:62][NH:57][C:58](=[O:63])[CH2:59]1)=[O:6])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCNC(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 58 %

Procedure:
Prepared analogously to Example 1g from 2-chloro-4-{N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine, and piperazin-2-one in tetrahydrofuran. Yield: 58%; Rf value: 0.22 (silica gel; dichloromethane/ethanol=9:1); C21H19Cl2N5O3 (460.32); mass spectrum: (M+H)+=460/462/464 (chlorine isotope) and (M−H)−=458/460/462 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@H:30]1[CH2:32][O:31]1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1.[F:28][C:29]([F:34])([F:33])[C@H:30]([OH:31])[CH2:32][NH:20][C@@:12]([C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=1)([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)[C@H]1CO1
Agent: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Solvent: CC#N
Product: O[C@H](CN[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1)C(F)(F)F
Temperature: 160 °C
Yield: 92.2 %

Procedure:
(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine was prepared as described in Procedures 4, 5 and 6. (R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (50 mg, 0.133 mmol) was dissolved in anhydrous acetonitrile (0.26 mL). (R)-2-(trifluoromethyl)oxirane (0.07 mL, 0.625 mmol), (approximate 85:15 ratio of R to 5) was added to the solution in a microwave vial followed by Yb(OSO2CF3)3 (0.005 g, 0.008 mmol). The sealed vial was heated to 160° C. for 30 minutes under microwave irradiation. The crude product was purified by preparative HPLC using 30-100% acetonitrile in H2O with 0.1% TFA as mobile phase to give (R)-1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)propan-2-ol as a colorless oil (30 mg, 46% yield). LC-MS (ESI): 361.15 (M+H), retention time=4.10 min (0-100% MeOH in H2O with 0.1% TFA); Analytical HPLC: 3.49 min (CH3CN in H2O with 0.1% TFA in 4 min run, purity 100%); 1H NMR (400 MHz, CD3OD) δ ppm 2.59-2.73 (m, 1H), 2.72-2.84 (m, 1H), 3.69 (m, 2H), 4.09 (m, 1H), 6.61-6.82 (m, 2H), 7.00-7.19 (m, 5H), 7.20-7.48 (m, 5H).
Reaction SMILES: [CH2:1]([C@H:8]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19])[C:9]([O:11]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[CH2:1]([C@H:8]([N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19])[C:9]([OH:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccccc1)n1c(C)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C)n1[C@@H](Cc1ccccc1)C(=O)O

Procedure:
L-phenylalanyl methyl ester hydrochloride was converted into the corresponding free base by shaking with a sodium bicarbonate solution in ether and heated to 100° for 2.5 hours in glacial acetic acid with acetonylacetone. Thereafter, the solvent was evaporated and the residue was filtered with toluene over silica gel, to obtain methyl (S)-α-benzyl-2,5-dimethylpyrrole-1-acetate, MS: 258 (M+H)+. The ester so obtained was allowed to stand at room temperature for 1.5 hours with 1N sodium hydroxide solution in a 9:1 mixture of methanol and water. After extracting the aqueous solution with ether and washing the organic phase, there was obtained (S)-α-benzyl-2,5-dimethylpyrrole-1-acetic acid, MS: 244 (M+H)+, which was used directly in the next step.
Reaction SMILES: FC(F)(F)C1C=CC(NC2N=C3C=CC=C([C:18]4[CH:19]=[CH:20][C:21]5[N:25]=[C:24]([C:26]([NH2:28])=[O:27])[NH:23][C:22]=5[CH:29]=4)N3N=2)=CC=1.OO.[OH-].[Na+].FC(F)(F)C(O)=O>CS(C)=O.O>[NH:23]1[C:22]2[CH:29]=[CH:18][CH:19]=[CH:20][C:21]=2[N:25]=[C:24]1[C:26]([NH2:28])=[O:27]
Reactant: NC(=O)c1nc2ccc(-c3cccc4nc(Nc5ccc(C(F)(F)F)cc5)nn34)cc2[nH]1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: NC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
6-(2-(4-(Trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide. A mixture of 6-(2-(4-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)-1H-benzo[d]imidazole-2-carbonitrile (300 mg, 0.5 mmol), hydrogen peroxide (30%, 1.0 mL) and sodium hydroxide (40 mg, 1.0 mmol) in dimethylsulfoxide (5 mL) was stirred at room temperature for 3 h. The reaction mixture was poured into water (15 mL), and the mixture was extracted with ethyl acetate (15 mL×3). The combined organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by reverse-phase preparatory HPLC (35-65% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give 64244-(trifluoromethyl)phenylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)-1H-benzo[d]imidazole-2-carboxamide (65 mg, 29.7% yield) as a trifluoroacetic acid salt, which was converted to the hydrochloride salt with methanolic hydrochloride solution. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 10.19 (s, 1H), 8.37 (s, 1H), 7.95 (m, 5H), 7.73 (m, 4H), 7.29 (d, J=7.2 Hz, 1H); MS (ESI): m/z 438.1 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].C([O-])(O)=O.[Na+].Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH3:29])[CH2:27][CH:26]2[NH2:28])=[CH:21][CH:20]=1.CCOC(C)=O>ClCCl>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C@@:25]2([CH3:29])[CH2:27][C@H:26]2[NH:28][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])=[CH:23][CH:24]=1
Reactant: CC1(c2ccc(Cl)cc2)CC1N
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@]1(c2ccc(Cl)cc2)C[C@H]1NC(=O)c1c(F)cccc1F

Procedure:
2,6-difluorobenzoyl chloride (156 mg, 0.881 mmol) was added to a rapidly stirred mixture of NaHCO3 (1 M aq., 4 ml) and a solution of racemic (1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropanamine hydrochloride (172 mg, 0.735 mmol) in dichloromethane (4.5 ml). After stirring for 30 minutes EtOAc was added, the organic phase was separated, washed with brine, dried over MgSO4, and the solvent evaporated to give 241 mg, 100%) of racemic N-[(1R,2R)-2-(4-chlorophenyl)-2-methyl-cyclopropyl]-2,6-difluoro-benzamide. M.p. 140-142° C.
Reaction SMILES: [CH3:1][N:2](C)/C=N/[H].[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH3:21])[C:15]([C:18]([OH:20])=O)=[N:16][CH:17]=1.CC([O-])(C)C.[K+].Cl>C1COCC1>[CH3:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[N:16][C:15]2[C:18](=[O:20])[NH:2][CH:1]=[CH:21][C:14]=2[CH:13]=1
Reactant: COCCOc1cnc(C(=O)O)c(C)c1
Reactant: [H]/N=C/N(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COCCOc1cnc2c(=O)[nH]ccc2c1
Temperature: 25 °C

Procedure:
5-(2-Methoxy-ethoxy)-3-methyl-pyridine-2-carboxylic acid 1-dimethylamino-meth-(E)-ylideneamine (500 mg, 1.885 mmol) was dissolved in THF (15 ml) and heated to gentle reflux. KOtBu (317 mg, 2.83 mmol) in THF (30 ml) was added dropwise and the reaction mixture was heated to reflux for 2.5 h and then cooled to rt. The pH was adjusted to 7 with concentrated HCl. The reaction mixture was concentrated.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:13][S:14](O)(=[O:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:11][CH:12]=1
Reactant: Cc1ncoc1-c1ccccc1
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: Cc1ncoc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 4 °C
Reaction time: 0.5 h

Procedure:
To a chilled solution (ice-bath) of 4-methyl-5-phenyl-oxazole (0.2 g, 1.3 mmol) in CHCl3 (1 ml) was added drop-wise chlorosulfonic acid (0.5 ml, 7.7 mmol). The dark-brown reaction mixture was stirred at 4° C. for 30 min and slowly warmed to reflux. After 2 h the reaction mixture was poured into ice-water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried (MgSO4.2H2O), filtered and evaporated to yield a light-brown solid: 0.19 g, (56%), MS: m/e 257.1.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:30][C:31]2[NH:32][CH:33]=[CH:34][N:35]=2)=[CH:25][CH:24]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:29]([C:26]2[CH:25]=[CH:24][C:23]([C:22]([F:37])([F:36])[F:21])=[CH:28][CH:27]=2)[CH2:30][C:31]2[NH:35][CH:34]=[CH:33][N:32]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: FC(F)(F)c1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(C(F)(F)F)cc2)[C@@H]1O
Yield: 22.2 %

Procedure:
The title compound (146 mg, 22%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (356 mg, 1.26 mmol) and 4-trifluoromethylphenyl-1H-imidazol-2-ylmethylamine (305 mg, 1.26 mmol), according to the same procedure used for the preparation of example 0.1 above.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[NH2:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36].NC1C=C2OCOC2=CC=1C(=O)C>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:32][C:33]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:34]=1[C:35]#[N:36])=[O:17])(=[O:9])=[O:10]
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Agent: CC(=O)c1cc2c(cc1N)OCO2
Product: COc1cc(C#N)c(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)cc1OC

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that 2-amino-4,5-dimethoxybenzonitrile was used in stead of 2'-amino-4',5'-(methylenedioxy)acetophenone. N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamide was obtained via HPLC purification as a light brown powder (36% yield, m.p. 53-56° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:34][C:35]1([CH3:39])[CH2:38][NH:37][CH2:36]1>>[NH2:34][C:35]1([CH3:39])[CH2:38][N:37]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([CH:14]=2)=[N:12][C:13]2[N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[C:7](=[O:20])[C:8]=2[CH:9]=3)[CH2:36]1
Reactant: CC1(N)CNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Product: CC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 89 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 16, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethanesulphonate. 1.7 g of 8-(3-amino-3-methyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 298° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH2:24])[CH3:20]>>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][NH:24][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][N:17]=[CH:18][C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])[CH3:20]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: CCOC(CN)OCC
Product: CCOC(CNC(=O)c1ccncc1Nc1ccc(I)cc1F)OCC

Procedure:
N-(2,2-diethoxyethyl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.33 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.5 mmol of 2,2-diethoxy-ethylamine. LC/MS [5.51 min; 474 (M+1)]
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:8][CH:7]=1.Cl>CO.O>[O:17]=[C:13]1[CH2:14][CH2:15][CH2:16][N:12]1[C:9]1[CH:10]=[CH:11][C:6]([C:5]([OH:18])=[O:4])=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(N2CCCC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(N2CCCC2=O)cc1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A mixture of pyrrolidin-2-one (500 mg, 5.9 mmol), 4-bromo benzoic acid methyl ester (1.5 g, 6.97 mmol), Pd2(dba)3 (135 mg, 0.14 mmol), xantphos (256 mg, 0.44 mmol) and cesium carbonate (2.7 g, 8.28 mmol) in dioxane (2 mL) in a sealed tube was subjected to reaction in a microwave reactor (time: 20 min, temp: 105° C., power: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. The residue obtained was purified by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 485 mg (37.89% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester. NaOH (295 mg, 7.4 mmol) was added to a stirred mixture of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (485 mg, 2.2 mmol) in a mixture of MeOH (5 mL) and H2O (5 mL), stirring was continued at 60° C. for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to get the residue, which was acidified with 10% aqueous HCl solution, the precipitate was collected to afford 300 mg (66% Yield) of 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid.