Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[OH-].[Li+].[C:26](OC(=O)C)(=[O:28])[CH3:27]>O>[C:26]([NH:21][S:20]([C:11]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])(=[O:23])=[O:22])(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1

Procedure:
3-Nitro-4-phenoxy-5-sulphamyl-benzoic acid (10 g) was dissolved in water (250 ml) by adjusting the pH to 8 by addition of 1N lithium hydroxide. Then acetic anhydride (12 g) was added dropwise, while stirring and keeping the pH constant at pH 9 by means of 1N lithium hydroxide, using an automatic titrator. After the acetic anhydride was consumed, the reaction mixture was acidified by addition of 4N hydrochloric acid. The precipitated 5-acetylsulphamyl-3-nitro-4-phenoxy-benzoic acid was isolated by filtration and recrystallized from aqueous ethanol. The compound with a melting point of 270°-271° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:13][O:14][C:15]1[N:20]=[C:19]([CH:21]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C=O)n1
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(C=C2N=C(c3cccs3)OC2=O)n1
Temperature: 90 °C
Yield: 44.2 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 6-methoxy-2-pyridinecarboxaldehyde (46 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 38 mg of the above-captioned compound.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([CH3:34])([CH3:33])[CH3:27])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)CC(=O)O
Agent: Cl
Product: CC(C)(C)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (85 mg, 80%), MS (ISP) m/z=427.5 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 3,3-dimethyl-butyric acid.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+]=[N-]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: [N-]=[N+]=NCCCCCCCCC(=O)O
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: NCCCCCCCCC(=O)O
Reaction time: 4 h

Procedure:
9-Azido-nonanoic acid (2.83 g, 14.2 mmol) was dissolved in ethanol (30 mL) and Lindlar catalyst (300 mg) added. The solution was hydrogenated at 50 psi, 30° C. for 4 hours, after which the catalyst was removed by filtration through Kieselguhr, washing with methanol. The solvent was removed in vacuo to give a pale yellow solid, 1.7 g (70%);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C:29]1([CH3:35])[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:30]3[C:29]([CH3:35])([CH3:28])[CH2:33][O:32][C:31]3=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: CC1(C)COC(=O)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C(=O)OCC4(C)C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 14.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (785 mg) described in Preparation Example 9 and 4,4-dimethyloxazolidin-2-one (200 mg), the title compound (126 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6]CP(=O)OCC)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:17][CH3:18])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: CCO[PH](=O)CCc1ccc(N)c(OC)c1
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC

Procedure:
This material was prepared according to the procedure described above for ethyl (4-amino-3-methoxybenzyl)methylphosphinate using triethylphosphite in the first step. MS (ES+): m/z 274.01 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH:17](C(OCC)=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]>O>[F:12][C:13]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[CH:28][C:14]=1[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Yield: 71.6 %

Procedure:
0.3 g of p-toluenesulphonic acid is added to an emulsion of 284.8 g of crude diethyl 2,3,4,5-tetrafluorobenzoyl-malonate in 300 ml of water. The mixture is heated at the boiling point for 4.5 hours, with thorough stirring, the cooled emulsion is extracted several times with methylene chloride, the combined methylene chloride solutions are washed once with saturated sodium chloride solution and dried with sodium sulphate and the solvent is distilled off in vacuo. Fractionation of the residue under a fine vacuum gives 160.2 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate of boiling point 75°-96° C./0.06-0.09 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:36]=[CH:35][C:18]3[O:19][C:20]([CH3:34])([CH3:33])[C@:21]([OH:32])([CH3:31])[C@H:22]([O:23][C:24]4[N:29]=[N:28][C:27]([OH:30])=[CH:26][CH:25]=4)[C:17]=3[CH:16]=2)=[N:13][N:12]=[N:11]1)=[O:5])[CH3:2].S(OC)(O[CH3:41])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14]([C:15]2[CH:36]=[CH:35][C:18]3[O:19][C:20]([CH3:34])([CH3:33])[C@:21]([OH:32])([CH3:31])[C@H:22]([O:23][C:24]4[CH:25]=[CH:26][C:27](=[O:30])[N:28]([CH3:41])[N:29]=4)[C:17]=3[CH:16]=2)=[N:13][N:12]=[N:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CCCCn1nnnc1-c1ccc2c(c1)[C@@H](Oc1ccc(O)nn1)[C@](C)(O)C(C)(C)O2
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCCn1nnnc1-c1ccc2c(c1)[C@@H](Oc1ccc(=O)n(C)n1)[C@](C)(O)C(C)(C)O2
Temperature: 25 °C

Procedure:
A mixture containing (3S,4R)-3,4-dihydro-6-(1-[4-ethoxycarbonylbut-1-yl]-1H-tetrazol-5-yl)-3-hydroxy-4-(3-hydroxypyridazin-6-yl)oxy-2,2,3-trimethyl-2H-benzo[b]pyran (see Example 11) (0.25 g), dimethyl sulfate (0.34 ml), anhydrous potassium carbonate (0.51 g) and acetone (10 ml) was heated under reflux for 4 hours. On cooling to room temperature the mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.O>CN(C)C=O>[C:13]([C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])=[CH:10][CH:11]=1)([OH:15])=[O:14]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)/C=C\C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
One molar equivalent of maleic anhydride and p-amino benzoic acid are dissolved in N,N-dimethylformamide (DMF), and the mixture stirred at room temperature for five hours under nitrogen atmosphere. The resulting solution is poured into a sufficient water to precipitate crude N-(4-carboxyphenyl)maleamic acid. This is filtered, dried, and recrystallized three times from water to obtain pure N-(4-carboxyphenyl)maleamic acid.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:20]=1>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:22]2[N:23]([CH:2]=[C:3]([C@@H:5]3[CH2:7][C@@H:6]3[C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[N:25]=2)[N:24]=1
Reactant: O=C(CBr)[C@@H]1C[C@@H]1c1ccc2ccccc2n1
Reactant: Nc1nnc(Cl)cc1N1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reaction time: 48 h

Procedure:
Compound 79c (67 mg, 0.23 mmol) was dissolved in DMF (2 mL) and compound 19a (50 mg, 0.23 mmol) was added in one portion. The reaction was allowed to stir for 48 h under an argon atmosphere, at which time it was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate (50 mL). The organic layer was concentrated under reduced pressure and then purified by preparative TLC (5% MeOH/DCM) to afford compound 79d. Mass spectrum (LCMS, ESI pos.) Calcd. For C22H20ClN5O 406.1 (M+H). found 406.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH:18]C(=O)C3C=CC=CC=3)[S:15][C:5]=2[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:7][CH:8]=1
Reactant: COc1cnc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cnc(-c2ccccc2)c2sc(N)nc12
Temperature: 130 °C
Yield: 47.4 %

Procedure:
To a stirred suspension of 360 mg (1.00 mmol) N-(7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-yl)-benzamide in 3 ml methanol was added 1 ml 5 N aq. sodium hydroxide solution and the resulting solution was then heated at 130° C. for 10 min in a microwave oven. The reaction mixture was then cooled to room temperature and concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) afforded 122 mg (48%) 7-methoxy-4-phenyl-thiazolo[5,4-c]pyridin-2-ylamine as a white crystalline solid. ES-MS m/e (%): 258 (M+H+, 100).
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][NH2:43]>>[Cl:33][C:34]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:35]=1[CH2:41][CH2:42][NH:43][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Reactant: NCCc1ccc(Cl)cc1Cl
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccc(Cl)cc2Cl)n1

Procedure:
Followed the same procedure in the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro-pyrido[1,2-a]pyrimidin-6-one, the sulfoxide (0.11 g, 0.3 mmol) was displaced with 2-(2,4-dichlorophenyl)ethylamine (0.14 mL, 0.9 mmol) to give the title compound as a yellow solid. MS m/e 492 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[C:18]1([C:24]#[CH:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]1([C:24]#[C:25][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:11])=[O:9])=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: O=C(C(=O)c1ccc(C#Cc2ccccc2)cc1)c1ccccc1

Procedure:
4-Bromobenzil (10.0 g, 0.0346 mol), phenylacetylene (3.88 g, 0.0380 mol), and (PPh3)2PdCl2 (0.121 g, 0.0002 mol) in diethylamine (950 mL) is stirred at ambient temperature for 72 hours, followed by concentration to dryness. The residue is then taken up in methylene chloride. Standard aqueous workup followed by recrystallization from 2-propanol gives the title compound.
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[C:15]2[N:16]=[C:17](N)[S:18][C:14]=2[CH:13]=[C:12]([F:20])[CH:11]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:17]1[S:18][C:14]2[CH:13]=[C:12]([F:20])[CH:11]=[C:10]([F:9])[C:15]=2[N:16]=1
Reactant: Nc1nc2c(F)cc(F)cc2s1
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2nc(Cl)sc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution containing copper chloride (II) (0.87 g, 6.45 mmol) and tri(ethylene glycol) dimethyl ether (3 mL) in acetonitrile (50 mL) was added isoamyl nitrite (0.94 g, 8.06 mmol), and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 4,6-difluoro-1,3-benzothiazol-2-amine (1.0 g, 5.37 mmol) in tri(ethylene glycol) dimethyl ether (5 mL). The reaction mixture was stirred at rt for 10 minutes, and then heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (200 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered and concentrated down to afford 2-chloro-4,6-difluoro-1,3-benzothiazole (1.1 g, 99%). 1H NMR (400 MHz, DMSO-d6) 7.05 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH2:27])[CH:26]=2)[CH:16]=[N:17][CH:18]=1>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:21]2[CH:22]=[CH:23][C:24]([F:28])=[C:25]([NH:27][S:8]([CH3:7])(=[O:10])=[O:9])[CH:26]=2)[CH:16]=[N:17][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(C#Cc2cncc(Cl)c2)ccc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 91.5 %

Procedure:
Add pyridine (193 mg, 2.44 mmol) followed by methanesulfonyl chloride (127 mg, 1.11 mmol) to a solution of 5-(5-chloropyridin-3-ylethynyl)-2-fluorophenylamine, (prepared as described in EXAMPLE 190), (275 mg, 1.11 mmol) in dichloromethane (10 mL) at 0° C. under nitrogen. Warm to room temperature and stir 20 h. Add additional methanesulfonyl chloride (32 mg, 0.28 mmol). Stir at room temperature for 2 h. Concentrate and purify by silica gel chromatography, eluting with 3:1 ethyl acetate:hexanes, to give the title compound as a white solid (330 mg, 92%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:15][C:16]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>CN1CCCC1=O>[F:15][C:16]1[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccc2c(Nc3ccc(C(F)(F)F)cc3F)nccc12
Yield: 46.7 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-1, step-2 using 1-chloro-5-nitroisoquinoline (Intermediate-1, step-1, 250 mg, 1.19 mmol), and 2-fluoro-4-(trifluoromethyl)aniline (330 mg, 1.84 mmol) in N-methylpyrrolidinone (2 mL) to afford 195 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.69 (s, 1H), 8.84 (d, J=7.8 Hz, 1H), 8.55 (d, J=7.8 Hz, 1H), 8.15 (d, J=5.7 Hz, 1H), 7.86-7.57 (m, 5H); MS (m/z): 352.18 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[S:31][C:30]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:29][N:28]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:35]1[CH2:34][CH2:33][N:32]([C:30]2[S:31][C:27]([C:26]([F:38])([F:25])[F:39])=[N:28][N:29]=2)[CH2:37][CH2:36]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate. The crude material was purified by chromatography (SiO2, dichloromethane/methanol 99:1) to yield the title compound as a colorless solid. MS (m/e): 479.2 (M+H+, 100%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[S:13][C:12]([S:14]([NH:17][C@H:18]([C:24]([OH:26])=[O:25])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])(=[O:16])=[O:15])=[CH:11][CH:10]=1>C1COCC1.CO>[CH3:1][O:25][C:24](=[O:26])[C@H:18]([CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[NH:17][S:14]([C:12]1[S:13][C:9]([Cl:8])=[CH:10][CH:11]=1)(=[O:15])=[O:16]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)[C@H](NS(=O)(=O)c1ccc(Cl)s1)C(=O)OC
Yield: 94.9 %

Procedure:
Trimethylsilyldiazomethane (3.1 mL, 6.1 mmol) was added to a solution of N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline (1.0 g, 3.1 mmol) in THF (20 mL) and MeOH (5 mL). After 2 h the mixture was concentrated to give N-[(5-chloro-2-thienyl)sulfonyl]-3-ethyl-L-norvaline methyl ester as a white solid (1.0 g, 99%). Mass Spectrum (−ESI): 338.00 (M−H)−.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[CH3:26])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl.C(OC(=O)C)C>C1COCC1>[CH3:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[CH2:18][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:12][CH2:13]1)=[O:27]
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)Cc3cc(C)ccc3C)CC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C)c(CC(=O)N2CCC(c3nc(C(=O)O)cs3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
To a solution of 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (10.46 g, 27.06 mmol) in THF (30 mL) is added aqueous solution of sodium hydroxide (2 M, 20.3 mL) at RT. After stirring 3 h at RT, the reaction mixture is acidified with aqueous solution of HCl (2 M) until pH 2-3, and ethylacetate (30 mL) is added to the reaction mixture, and layers are separated. The aqueous layer is extracted with ethyl acetate (20 mL) and the combined organic layers are washed with brine (10 mL), dried over sodium sulafte, filtered, and evaporated under reduced pressure to give 2-{1-[2-(2,5-dimethyl-phenyl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid (5.9 g, 60.8%), which can be used in the next step without further purification. 1H-NMR (400 MHz, d6-DMSO): δ=1.55-1.65 (m, 2H), 2.01-2.12 (m, 2H), 2.15 (s, 3H), 2.22 (s, 3H), 2.77-2.86 (m, 1H), 3.18-3.29 (m, 1H), 3.65 (d, 2H), 3.98-4.07 (m, 1H), 4.45-4.53 (m, 1H), 6.90 (s, 1H), 6.92 (s, 1H), 6.93 (s, 1H), 7.04 (d, 1H), 8.49 (br, 1H), 12.95 (s, 1H). MS: m/z=359 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1.[C:24](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]([CH3:24])[C:11](=[O:22])[C@H:10]([CH3:23])[N:9]=1
Reactant: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: C[C@@H]1N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
57.5 g (0.18 M) of (S)-5-(o-fluorophenyl)-1,3-dihydro-3-methyl-7-nitro-2H-1,4-benzodiazepin-2-one are dissolved in 600 ml of absolute acetone. The solution is treated with 48 g of powdered potassium carbonate and 21 ml of methyl iodide and stirred at room temperature for 5 hours. The mixture is concentrated and the residue is treated with ice-water and extracted several times with methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulphate, filtered and concentrated. The residue is crystallised from ether/petroleum ether and there is obtained (S)-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one which melts at 118°-126° C. with decomposition; [α]25D =+563.1° (in methylene chloride; 1%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:4][N:3]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[CH:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nc2)c1
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(C(F)(F)F)c3)cn12

Procedure:
A mixture of 2 g. of 2-chloro-5-[3-(trifluoromethyl)phenyl]pyridine and two equivalents of acetylhydrazine in n-butanol is heated at reflux for 48 hours to give the product of the Example as crystals, m.p. 185°-187° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[CH:7]=1)(=[O:5])=[O:4]>CO.CCOC(C)=O.[Pd]>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CNS(=O)(=O)c1cccc(N)c1

Procedure:
A solution of N-methyl-3-nitrobenzene sulfonamide (608 mg, 2.8 mmole) in 30 mL of MeOH and 5 mL of EtOAc was treated with 10% Pd/C (100 mg) and hydrogenated at 1 atmosphere H2 pressure for 16 hours. The catalyst was filtered, and the filtrate evaporated. The residue was dissolved in EtOAc, washed with H2O, dried and the solvent removed, and gave the titled product, 498 mg (96%). MS (ESI) 187 (MH+).