Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]([CH3:19])([CH3:18])[CH2:10]2)[C:5]([F:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]2)=[C:24]([C:42]([F:45])([F:44])[F:43])[CH:23]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CC(O)C.CCOC(C)=O>[CH3:18][C:11]1([CH3:19])[CH2:10][C@H:9]([NH:8][C:6]2[C:5]([F:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:41]=[CH:40][C:25]([O:26][CH:27]4[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]4)=[C:24]([C:42]([F:45])([F:43])[F:44])[CH:23]=3)[N:7]=2)[CH2:17][C@H:16]2[N:12]1[CH2:13][CH2:14][CH2:15]2
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2C(F)(F)F)CC1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCNCC4)c(C(F)(F)F)c3)ncc2F)C[C@@H]2CCCN21
Temperature: 110 °C
Yield: 36 %

Procedure:
A mixture of (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-5,5-dimethyloctahydroindolizin-7-amine (0.2 g, 0.95 eq, 0.7 mmol), tert-butyl 4-(4-amino-2-(trifluoromethyl)phenoxy)piperidine-1-carboxylate (0.25 g, 1.0 eq, 0.7 mmol) and PTSA (0.24 g, 1.8 eq, 1.3 mmol) was taken in iPrOH (50 mL) and heated at 110° C. overnight. After 18 hours of heating, reaction mixture was cooled to room temperature and PTSA (1.0 eq) was added to complete the deprotection of the Boc group. Next, the reaction mixture was heated at 110° C. for 2 hours while stifling and cooled to room temperature. The volatiles were removed under vacuum to leave a crude solid. The crude mixture was dissolved in EtOAc (100 mL) and partitioned with 1N aqueous NaOH solution (50 mL). Organic layers were separated and the aqueous layer was washed with EtOAc (50 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to leave a crude solid. The solid was purified by column chromatography on silica gel (ISCO System) using 2M NH3 in MeOH/CH2Cl2 (gradient system from 0:1 to 2:8) as eluent to give the product as a solid in 36% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1.[Mg].Br[CH2:15][CH3:16].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[C:7]([CH:8]([OH:9])[CH2:15][CH3:16])=[CH:6][C:5]2[O:10][CH2:11][O:12][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C=O)OCO2
Reactant: CCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1cc2c(cc1C)OCO2
Reaction time: 2 h
Yield: 95.9 %

Procedure:
A solution of 2.0 g of (6-methyl-1,3-benzodioxol-5-yl)-carboxaldehyde in 15 ml of anhydrous tetrahydrofuran was dropwise added at a room temperature to a Grignard reagent prepared from 0.32 g of magnesium ribbon, 20 ml of anhydrous tetrahydrofuran and 1.4 g of bromoethane, followed by stirring for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and the obtained mixture was distilled to remove the solvent. The residue was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate and concentrated in a vacuum. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2:8) to obtain 2.27 g of the title compound as a colorless crystal.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][C@H:7]\1[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[ClH:27].O1CCOCC1>C(Cl)Cl>[ClH:27].[OH:1]/[N:2]=[C:3]1/[C@H:7]([CH2:8][NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][NH:5][CH2:4]/1
Reactant: CC(C)(C)OC(=O)N1C/C(=N\O)[C@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(NC[C@@H]1CNC/C1=N\O)OCc1ccccc1

Procedure:
Dissolve 1,1-dimethylethyl(3Z,4R)-3-(hydroxyimino)-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.90 g, 2.53 mmol) in methylene chloride (10 mL). Add HCl/dioxane (excess) and stir at ambient temperature for 3 hours. Concentrate solution under reduced pressure. (0.66 g, quant). LCMS: m/z 254.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[C:18]([CH3:19])[C:13]=2[O:12][C:11](=[O:27])[CH:10]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][CH2:4][C:5]([C:10]1[C:11](=[O:27])[O:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=[CH:15][C:14]=2[C:9]=1[OH:8])=[O:7])[CH3:2]
Reactant: CCOCC(=O)O
Reactant: Cc1c(OC2CCCCO2)ccc2c(O)cc(=O)oc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOCC(=O)c1c(O)c2ccc(OC3CCCCO3)c(C)c2oc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.21 ml of ethoxy acetic acid is added to a solution containing 5.00 g of 4-hydroxy-8-methyl-7-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-1-benzopyran-2-one, 7.30 g of 4-dimethylaminopyridine and 3.816 g of N-(3-dimethylaminopropyl)- N′-ethylcarbodiimide hydrochloride. This mixture is agitated for 16 hours at ambient temperature. After diluting with dichloromethane, washing is carried out with an aqueous solution of sodium dihydrogen phosphate then with brine. After drying over magnesium sulphate, filtering and evaporating to dryness, the product obtained is triturated in a hexane-ethyl acetate mixture (4-1). The product obtained is separated and dried. In this way 5.40 g of sought product is obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1.O.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1>CCO.[Pd]>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([OH:35])(=[O:34])=[O:33].[F:1][C:2]1[C:7]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1ccc(OC[C@@H]2CCN2C(=O)OCc2ccccc2)c(F)n1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(OC[C@@H]2CCN2)c(F)n1
Reaction time: 16 h
Yield: 60.3 %

Procedure:
2-Fluoro-6-methyl-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine from Example 117d (714 mg, 2.16 mmol) was combined with 10% Pd/C (50 mg) and p-toluenesulfonic acid monohydrate (830 mg, 4.36 mmole) in 30 mL of EtOH, and the mixture was stirred under an H2 atmosphere for 16 hours. The mixture was filtered, concentrated, the residue was triturated with ether, and the product was recrystallized from ethyl acetate/ether to yield 480 mg (60%) of the title compound. mp 141-143° C. 1H NMR (D2O 300 MHz) δ: 2.40 (s, 6H), 2.65-2.71 (m, 2H), 4.07-4.16 (m, 2H), 4.43(d, J=4.5, 2H), 4.81-95 (m, 1H), 7.16 (d, J=8.0, 1H), 7.37 (d,J=8.0, 2H), 7.55 (dd, J=8.0, 2.5, 1H), 7.70 (d,J=8.0, 2H). MS (DCI/NH3) m/e 197 (M+H)+ 214 (M+NH4)+. Anal. calcd. for C10H13FN2O.C7H8S: C, 55.42; H, 5.75; N, 7.60. Found: C, 55.27; H, 5.69; N, 7.44. [α]D −3.2 (c 1, MeOH).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([CH2:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][CH2:16]/[C:17](=[CH:19]/[CH2:20][OH:21])/[CH3:18])[CH3:13])[CH3:8])[CH3:3].CN(C)C=O.[C:27](Cl)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C1(C)C=CC=CC=1>[CH2:20]([O:21][C:27](=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])/[CH:19]=[C:17](/[CH2:16][CH2:15][CH2:14][C@@H:12]([CH2:11][CH2:10][CH2:9][C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[CH3:13])\[CH3:18]
Reactant: C/C(=C\CO)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Reactant: CCCCCCCC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCC(=O)OC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C

Procedure:
To a solution of 3 g phytol (3,7,11,15-Tetramethyl-2-hexadecen-1-ol), 1,5 g dimethyl formamide in 50 ml toluene is being added dropwise during one half hour a solution consisting of 2 g caprylic acid chloride (excess) in 25 ml toluene at 20° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[C:13]([CH3:25])[CH:12]=1>ClCCl>[CH3:8][O:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[C:13]([CH3:25])[CH:12]=1
Reactant: COC(=O)c1ccc(CC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Trifluoroacetic acid (15 ml) was added to a solution of 4-tert-butoxycarbonylmethyl-3-methyl-benzoic acid methyl ester from Example E32.1 (2.84 g, 10.7 mmol) in dichloromethane (15 ml). The mixture was stirred for 90 min at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was recrystallised from EtOAc and hexane to yield the title compound (1.81 g, 81%).
Reaction SMILES: C(O[CH:5]([CH2:11][CH3:12])[CH:6]([N+]([O-])=O)[CH3:7])(=O)C.[N+:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[C-:14]>>[CH2:11]([C:5]1[C:6]([CH3:7])=[CH:14][NH:13][C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:12]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CCC(OC(C)=O)C(C)[N+](=O)[O-]
Product: CCOC(=O)c1[nH]cc(C)c1CC

Procedure:
reacting 3-acetoxy-2-nitropentane with ethyl isocyanoacetate in the presence of a nonnucleophilic base to form ethyl 3-ethyl-4-methylpyrrole-2-carboxylate;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]3)=[O:9])=[CH:6][CH:7]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(Br)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
To a solution of (4-amino-phenyl)-(4-methyl-piperazine-1-yl)-methanone (10.0 g, 0.0456 mol) and TEA (4.7 g, 0.0456 mol) in DCM (150 mL) was added 4-bromophenyl isocyanate (10.9 g, 0.0547 mol). The reaction mixture was stirred at room temperature for 12 h. The white solid was obtained and was filtered and dried to afford the title compound [15.0 g, 79%]; LC-MS (ESI): Calculated mass: 416.1; Observed mass: 417.1 [M+H]+ (RT: 0.23 min).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:22])[S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1>C(Cl)CCl>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[N:6]([CH3:22])[C:5]=1[C:3]([NH:23][C:24]1[S:28][N:27]=[C:26]([CH3:29])[CH:25]=1)=[O:4])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: Cc1cc(N)sn1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1C
Solvent: ClCCCl
Product: Cc1cc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2C)sn1
Yield: 44 %

Procedure:
4-Hydroxy-2-methyl-N-(3-methyl-5-isothiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 22 from 4-hydroxy-2-methyl-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methylester-1,1-dioxide and 5-amino-3-methyl-isothiazole. Yield: 44% of theory; m.p. 268° C (decomp.; from ethylene chloride).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[NH2:17][C:18]1[C:19]([Cl:36])=[C:20]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:29])([F:28])[F:27])[CH3:25]>O.O1CCOCC1>[Cl:36][C:19]1[C:18]([N:17]=[C:1]=[S:2])=[C:34]([Cl:35])[CH:33]=[CH:32][C:20]=1[CH2:21][NH:22][C:23](=[O:31])[C:24]([CH3:30])([C:26]([F:27])([F:28])[F:29])[CH3:25]
Reactant: CC(C)(C(=O)NCc1ccc(Cl)c(N)c1Cl)C(F)(F)F
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl)C(F)(F)F

Procedure:
1,1′-Thiocarbonyldi-2-pyridone (3.12 g, 13 mmol) is added to a mixture of N-(3-amino-2,4-dichloro-benzyl)-2-methyl-2-trifluoromethyl-propionamide (3.90 g, 11.8 mmol) and dioxane (135 mL) and stirred at reflux overnight. The mixture is diluted with water, most of the dioxane is removed under reduced pressure and the resulting precipitate is filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][N:18]1[C:22]([CH2:23]O)=[CH:21][C:20]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)=[N:19]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:32]([F:34])([F:33])[F:35])=[CH:29][CH:30]=4)[CH:21]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2cc(O)ccc21
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2cc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)ccc21

Procedure:
In analogy to the procedure described for example 3 c], (5-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {5-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH2:22].[Br:23][C:24]1[N:32]2[C:27]([CH:28]=[N:29][C:30](S(C)=O)=[N:31]2)=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>COCCO>[Br:23][C:24]1[N:32]2[C:27]([CH:28]=[N:29][C:30]([NH:22][C:4]3[CH:5]=[CH:6][C:7]([N:9]4[CH2:14][CH2:13][CH:12]([N:15]5[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]5)[CH2:11][CH2:10]4)=[CH:8][C:3]=3[O:2][CH3:1])=[N:31]2)=[CH:26][CH:25]=1
Reactant: CS(=O)c1ncc2ccc(Br)n2n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Temperature: 170 °C
Yield: 34.5 %

Procedure:
A mixture of 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine (1.25 g, 0.00411 mol) (for preparation see: Ahmed, et al. WO2008051547), 7-Bromo-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (0.75 g, 0.0029 mol) and N,N-Diisopropylethylamine (2.02 mL, 0.0116 mol) in 2-Methoxyethanol (10 mL) was heated in the microwave at 170° C. for 90 minutes. Purification by Isco chromatography gave (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine as a tan solid (0.50 g, 35%). MP: 171-173° C.; LCMS (m/e) 500 (M); 1H-NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1H), 8.02-8.00 (d, 1H, J=8.76 Hz), 7.74 (s, 1H), 6.93-6.85 (q, 2H, J=4.76 Hz), 6.67-6.66 (s, 1H), 6.52-6.49 (d, 1H, J=6.40 Hz), 3.85 (s, 3H), 3.71-3.68 (d, 2H, J=12.20 Hz), 2.67-2.62 (t, 2H, J=11.80 Hz), 2.31-2.28 (br, 4H), 1.83 (s3H), 1.86-1.83 (d, 2H), 1.55-1.50 (2, 2H).
Reaction SMILES: O=[C:2]([CH2:7][C:8](=[O:20])[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[NH2:21]O.Cl>CO>[F:17][C:16]([F:19])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:20][N:21]=[C:2]([C:3]([O:5][CH3:6])=[O:4])[CH:7]=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: COC(=O)C(=O)CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)on1
Yield: 95.9 %

Procedure:
A mixture of methyl 2,4-dioxo-4-(4-(trifluoromethoxy)phenyl)butanoate (6.85 g, 23.6 mmol) and NH2OH.HCl (4.92 g, 70.8 mmol) in MeOH (120 mL) was refluxed for 4 h. The volatiles were removed under reduced pressure, the residue was taken up in CHCl3 (200 mL) and washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.50 g, 95.6%), which was used in the next step without further purification. MS (ES+) C12H8F3NO4 requires: 287. found: 288 [M+H]+.
Reaction SMILES: O.[CH3:2][C:3]([CH3:23])([CH3:22])[CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19]CC)=[O:18])[C:11]=2[N:12]=1)=[O:6].[OH-].[Na+]>CO>[CH3:2][C:3]([CH3:23])([CH3:22])[CH2:4][C:5]([NH:7][C:8]1[S:9][C:10]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=[O:18])[C:11]=2[N:12]=1)=[O:6]
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)CC(C)(C)C)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)CC(=O)Nc1nc2c(s1)CCCC2C(=O)O
Reaction time: 24 h

Procedure:
Water (2 mL) and methanol (8 mL) were added to ethyl 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (185 mg, 0.57 mmol) and NaOH (27 mg, 0.675 mmol), and the resultant mixture was stirred at room temperature under a blanket of nitrogen as inert gas. To complete the reaction, NaOH (200 mg, 5 mmol) was again added, and stirring was continued for a further 24 hours at room temperature. Following removal of MeOH, 2M HCl (10 mL) was added, and the resultant mixture was extracted with CH2Cl2 (3×20 mL). Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(3,3-dimethylbutyrylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid in a yield of 144 mg (corresponding to 85% of theory).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:38])[CH2:33][S:34]([CH3:37])(=[O:36])=[O:35]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:24])([F:26])[F:25])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:29][N:38]=[C:32]([CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Reactant: CS(=O)(=O)CC(N)=NO
Product: Cc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 55 mg (0.36 mmol) of N′-hydroxy -2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 72 mg (56% of theory)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:8]1.C[O:23][C:24](=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:31][C:27]3[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=3)[C:24]([OH:33])=[O:23])[CH2:18][CH2:17]2)=[CH:8]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1coc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4ccco4)c4ccccc34)CC2)c1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 2.8 g (10 mmol) of 1-furan-2-ylmethyl-3-piperidin-4-yl-1H-indole and 2.5 g (11 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 1.5 g (36% of yield) of the expected acid were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH:23]=O)=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]>>[CH2:12]([O:14][C:15]([C:17]1[NH:18][C:19]([CH:23]=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)[NH:7][C:6]2=[O:11])=[C:20]([CH3:22])[CH:21]=1)=[O:16])[CH3:13]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCOC(=O)c1cc(C)c(C=O)[nH]1
Product: CCOC(=O)c1cc(C)c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]1
Yield: 93.9 %

Procedure:
5-Chloro-1,3-dihydroindol-2-one (2.22 g, 13.2 mmol) was condensed with 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (2.43 g) using method E to give 4.1 g (94%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(OCC)C>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([CH3:19])=[CH:21][CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: Cc1ccc(NC(=O)C(=O)N2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 4-methyl-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 115-117° C. (diethylether)
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH2:20])[CH3:16].[CH:24](=O)[C:25]([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][NH:20][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:16]
Reactant: CCOC(CN)OCC
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(CNCC(C)(C)C)OCC
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (5.30 g) was added to a cooled at 0° C. solution of aminoacetaldehyde diethyl acetal (2.91 mL) and pivalaldehyde (2.21 mL) in dichloromethane (50 mL). The reaction was stirred for 16 h, allowing the temperature to warm to ambient conditions. Water (50 mL) was added, followed by portionwise addition of sodium bicarbonate (8.40 g), causing effervescence. The mixture was stirred vigorously for 1 h, then allowed to partition. The phases were then separated and the aqueous phase extracted with further dichloromethane (20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford N-(2,2-diethoxyethyl)-2,2-dimethylpropan-1-amine (3.79 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.63 (t, J=5.6 Hz, 1H), 3.71 (dq, J=9.5, 7.1 Hz, 2H), 3.55 (dq, J=9.4, 7.1 Hz, 2H), 2.73 (d, J=5.6 Hz, 2H), 2.37 (s, 2H), 1.22 (t, J=7.1 Hz, 6H), 0.91 (s, 9H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.[CH:28]([O:31][CH2:32][CH:33]1[O:35][CH2:34]1)([CH3:30])[CH3:29]>CC(O)C>[OH:35][CH:33]([CH2:32][O:31][CH:28]([CH3:30])[CH3:29])[CH2:34][N:8]1[C:7]([C:14]#[N:15])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: CC(C)OCC1CO1
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: COc1ccc2c(=O)n(CC(O)COC(C)C)c(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
To a suspension of 97 (52 mg, 0.19 mmol) in iPrOH (3 mL) were added pyridine (0.03 mL, 0.38 mmol) and glycidyl isopropyl ether (0.047 mL, 0.38 mmol). The resulting mixture was heated to reflux overnight then cooled to room temperature. It was partitioned between EtOAc and NaHCO3. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The product 98 was purified by automated flash chromatography (20-50% EA/Hex).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([N+:9]#[C-:10])[CH2:7][CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20]Cl)=[CH:14][CH:13]=1>>[CH2:7]([C:6]([N+:9]#[C-:10])([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:20][CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)[CH3:8]
Reactant: [C-]#[N+]C(CC)c1cccs1
Reactant: ClCCCc1ccc(Cl)cc1
Product: [C-]#[N+]C(CC)(CCCc1ccc(Cl)cc1)c1cccs1
Yield: 56.7 %

Procedure:
5.44 g of 1-(2-thienyl)propyl isocyanide and 6.81 g of 3-(4-chlorophenyl)propyl chloride are treated in the same manner as described in Example 1-(1) to give 6.2 g of 1-ethyl-4-(4-chlorophenyl)-1-(2-thienyl)butyl isocyanide as a colorless oil. yield; 56.7%