Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([CH3:12])=[N:5]1)([CH3:3])[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:44]=[CH:45][CH:46]=1)[O:28][C:29]1[CH:30]=[CH:31][C:32]2[N:33]([N:35]=[C:36]([NH:38][C:39]([CH:41]3[CH2:43][CH2:42]3)=[O:40])[N:37]=2)[CH:34]=1>CN(C)C=O.CN(C)C(=O)C>[CH:41]1([C:39]([NH:38][C:36]2[N:37]=[C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:26]=[C:25]([NH:24][C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[C:6]([CH3:12])[CH:7]=5)=[O:11])[CH:46]=[CH:45][CH:44]=4)=[CH:34][N:33]3[N:35]=2)=[O:40])[CH2:42][CH2:43]1
Reactant: Cc1cc(C(=O)O)n(C(C)C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)n(C(C)C)n1
Yield: 88.9 %

Procedure:
In the same manner as in Example 18-4 and using 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylic acid (218 mg, 1.29 mmol), tetrahydrofuran (7 mL), oxalyl chloride (169 μL, 1.94 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (264 mg, 89%) was obtained as a white solid.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@@H:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]1=[O:33])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([N:23]([CH:25]([CH3:27])[CH3:26])[CH3:24])[CH2:19][C@@H:18]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:13]1=[O:33]
Reactant: CCOC(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)[C@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Yield: 100.6 %

Procedure:
A solution of (1S,2S,5R)-ethyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (530 mg, 1.1 mmol) in methanol was treated with 150 mg of 10% Pd/C and hydrogenated at 55 psi of H2 in a Parr shaker overnight. The catalyst was filtered and the filtrate concentrated in vacuo to give 360 mg of (1S,2S,5R)-ethyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)cyclohexanecarboxylate. This was used without further purification. MS found: (M+H)+=326.3.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[C:30]([NH:32][C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[C:29]([N+:39]([O-])=O)=[CH:28][C:27]=2[F:42])=[CH:21][CH:20]=1)C(=O)OC(C)(C)C.C([OH:45])C>[Pd]>[F:35][C:34]([F:37])([F:36])[C:33]([OH:38])=[O:45].[F:42][C:27]1[C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][NH:10][CH:2]3[CH2:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3]3)=[CH:20][CH:21]=2)=[CH:31][C:30]2[NH:32][C:33]([C:34]([F:37])([F:36])[F:35])=[N:39][C:29]=2[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Oc2cc(NC(=O)C(F)(F)F)c([N+](=O)[O-])cc2F)cc1)C1Cc2ccccc2C1
Reactant: CCO
Agent: [Pd]
Product: Fc1cc2nc(C(F)(F)F)[nH]c2cc1Oc1ccc(CNC2Cc3ccccc3C2)cc1
Product: O=C(O)C(F)(F)F
Reaction time: 4 h

Procedure:
To an ethanol (3 mL) solution of the crude 1,1-dimethylethyl 2,3-dihydro-1H-inden-2-yl{[4-({2-fluoro-4-nitro-5-[(trifluoroacetyl)amino]phenyl}oxy)phenyl]methyl}carbamate (0.375 g, 0.636 mmol) was added 10% palladium on carbon (0.076 g) and the reaction mixture was subjected to hydrogenation under an atmosphere of hydrogen. The reaction mixture was stirred for 4 hours and the catalyst removed by filtration through Celite. The filtrate was concentrated and the residue re-dissolved in glacial acetic acid (3 mL) and heated to 60 degrees Centigrade for 1 hour, cooled, concentrated and azeotroped several times with toluene/CH2Cl2. The residue was dissolved in CH2Cl2 and trifluoroacetic acid added. The reaction mixture was stirred for 16 hours and then concentrated. Purification of the final compound was accomplished by preparative HPLC to afford N-[(4-{[5-Fluoro-2-(trifluoromethyl)-1H-benzimidazol-6-yl]oxy}phenyl)methyl]-2,3-dihydro-1H-inden-2-amine trifluoroacetate (Example No. 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:19](CC)CC)C.ClC(OCC)=O.N>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]#[N:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCCC1C#N
Temperature: -20 °C
Yield: 80.4 %

Procedure:
Piperidine-1,2-dicarboxylic acid-1-tert-butyl ester (12.8 g, 55.6 mmol) and THF (170 mL) were added to a 500 mL round bottom flask equipped with stir bar. The solution was cooled to −20° C. and triethylamine (10.1 mL, 72.3 mmol) was added followed by ethyl chloroformate (5.32 mL, 55.6 mmol). The resulting white precipitate was left stirring at −10° C. for 1 h. Aqueous ammonia (22.6 mL, 1168 mmol) was added to the above reaction mixture and the clear reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the isolated residue was dissolved in ethyl acetate (300 mL). The organic phase was successively washed with water (300 mL) and brine (200 mL), dried (sodium sulfate), filtered and concentrated in vacuo to isolate a clear gum. The gum was triturated with hexanes to isolate the title compound (9.4 g, 74%) as a white solid. 1H-NMR (CDCl3), δ(ppm): 6.03 (bs, 1H), 5.55 (bs, 1H), 4.77 (bs, 1H), 4.05 (bs, 1H), 2.81 (t, 1H), 2.27 (bs, 1H), 1.47 (m, 14H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[O:12][C:13]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=1.C(N(CC)CC)C.[CH3:38][N:39]=[C:40]=[O:41]>C(Cl)Cl>[C:16]([C:14]1[N:15]=[C:11]([C:5]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=2[F:3])[O:12][C:13]=1[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:40]([NH:39][CH3:38])=[O:41])[CH2:29][CH2:30]2)=[N:21][CH:20]=1)(=[O:17])[NH2:18]
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide dihydrochloride (0.060 g, 0.13 mmol) in DCM (3 mL) was added triethylamine (40 uL, 0.29 mmol) followed by methyl isocyanate (12 uL, 0.20 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC and then by SPE using a MP-TsOH resin (500 mg) cartridge to afford 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)-N-methylpiperazine-1-carboxamide (0.0057 g, 0.013 mmol, 10%) as a yellow solid. 1H NMR (DMSO) 2.58 (3H, d), 3.40 (4H, m), 3.61 (4H, m), 6.54 (1H, br. q), 6.99 (1H, d), 7.38 (2H, t), 7.65 (1H, br. s), 7.67 (1H, br. s), 7.72 (1H, m), 8.37 (1H, dd), 8.95 (1H, d). LCMS (2) Rt: 2.27 min; m/z (ES+) 443.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].N[C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][C:27]2=[O:30])=[CH:23][CH:22]=1.Cl.[N:32]1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:15][CH2:16][CH3:17])[N:5]=[CH:4][C:3]([C:18]#[N:19])=[C:2]2[NH:32][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:21]=1)[C:27](=[O:30])[CH2:26][CH2:25]2)[CH3:14]
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: c1ccncc1
Reactant: Nc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)CCC4=O)c2cc1OCC
Temperature: 100 °C
Yield: 89.5 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile, 227 mg (1.54 mM) of 6-Amino-1-Indanone and 161 mg (1.44 mM) of pyridine hydrochloride in 12 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 483 mg of 6,7-Diethoxy-4-(1-oxo-indan-5-ylamino)-quinoline-3-carbonitrile as a white solid: mass spectrum (electrospray, m/e): M+H 388.0, mp=Decomposed at 263° C.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]([C:12]([OH:14])=O)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].C1CCC(N=C=NC2CCCCC2)CC1.CN(C=O)C.[NH2:36][C@H:37]([C:44]([N:46]1[CH2:53][CH2:52][CH2:51][C@H:47]1[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]1[N:43]=[CH:42][NH:41][CH:40]=1>C(N(CC)CC)C>[O:15]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:11]([C:12]([NH:36][C@H:37]([C:44]([N:46]2[CH2:53][CH2:52][CH2:51][C@H:47]2[C:48]([NH2:50])=[O:49])=[O:45])[CH2:38][C:39]2[N:43]=[CH:42][NH:41][CH:40]=2)=[O:14])[N:2]1[CH3:1]
Reactant: CN1C(=O)c2ccccc2C[C@@H]1C(=O)O
Reactant: NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)Cc1c[nH]cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)c2ccccc2C[C@H]1C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 48 h
Yield: 47.6 %

Procedure:
A solution of (3R)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (350 mg), DCC (412 mg) and DMF (8 ml) is stirred at 9° C. for 1.5 hours, and L-histidyl-L-prolinamide.2HBr (702 mg) and triethylamine (0.49 ml) are added thereto. The mixture is stirred for 2 days. Insoluble materials are filtered off, and the filtrate is distilled under reduced pressure to remove DMF. The residue is dissolved in an aqueous sodium bicarbonate solution, and the solution is passed through a column (2.4×21 cm) packed with CHP-20P resin. The column is washed with water (one liter), and the product is eluted with 30% methanol. The fractions positive to Pauly reagent are collected, and the collection solution is distilled to remove methanol. The residue is lyophilized, whereby Nα -[(3S)-1-oxo-2-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbonyl]-L-histidyl-L-prolinamide (370 mg) is obtained. Yield: 47.6%
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.[CH3:39][C:40]1[CH:47]=[CH:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>ClC(Cl)C.ClCCCl>[NH2:20][CH2:19][CH2:18][CH2:17][N:16]([CH2:39][C:40]1[CH:47]=[CH:46][C:43]([CH3:44])=[CH:42][CH:41]=1)[C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15]
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (52.6 mg, 0.10 μmol) in dichloroethane (0.5 mL) was treated with respective aldehydes (in this case 4-methyl benzaldehyde, 0.25M solution in DCE, 0.8 mL, 0.2 μmol). The mixture was stirred at room temperature for 16 h. Solvent was removed under reduced pressure. Residue was taken in MeOH (1.0 mL) and treated with hydrazine (0.25 mL). Reaction mixture was stirred at room temperature for 16 h and solvent removed under reduced pressure. The product was purified with reverse phase chromatography to give final product. Yield (14 mg, 24%). LCMS: m/e 500 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:14]3[CH:13]=[C:12]4[C:17](=[CH:16][CH:15]=3)[N:9]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[CH:10]=[CH:11]4)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-4-methylbenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([CH3:12])[CH:3]=1
Reactant: CO
Reactant: Cc1cc(Cl)c(I)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)c(Cl)cc1C
Temperature: 75 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-chloro-5-iodo-2-methylbenzoic acid (compound 177.1, 20.0 g, 67.5 mmol, 1.00 equiv) in methanol (100 mL) was added sulfuric acid (5 mL) dropwise. The resulting mixture was stirred overnight at 75° C. After cooling to ambient temperature, the methanol was removed under reduced pressure. The pH value of the remaining aqueous layer was carefully adjusted to 7 with sodium bicarbonate (aq., 1 M. Note: significant gas evolution). The aqueous phase was extracted with 2×200 mL of ethyl acetate and the combined organic layers were washed with 2×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to furnish 20.0 g (95%) of methyl 4-chloro-5-iodo-2-methylbenzoate as a light yellow liquid.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH2:27]1[O:29][CH2:28]1>>[CH3:1][CH:2]([CH3:26])[CH:3]([NH:15][C:16]([CH:18]1[CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][N:19]1[CH2:27][CH2:28][OH:29])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: C1CO1
Reactant: CCCCC1CNC1C(=O)NC(C(C)C)C1OC(SC)C(O)C(O)C1O
Product: CCCCC1CN(CCO)C1C(=O)NC(C(C)C)C1OC(SC)C(O)C(O)C1O

Procedure:
A sample of 3-Butyl-azetidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared in example 70 was alkylated with ethyleneoxide as depicted in scheme 12 (R6=2-hydroxyethyl) to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:13]([F:14])([F:15])[F:16]
Reactant: CC(C)C(O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=Cc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
1.50 g (5.9 mmol) 1-(4-chloro-3-trifluoromethyl-phenyl)-2-methyl-propan-1-ol and 0.50 g (2.6 mmol) p-toluenesulphonic acid monohydrate in 50 mL toluene are refluxed for 3 hours using the water separator. After working up analogously to Example 1b) a brown oil is obtained. Yield: 1.4 g; mass spectrometry: [M]+=234/6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][Si](C(C)(C)C)(C)C)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>C1COCC1>[C:1]([O:5][C:6](=[O:25])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To an ice cooled solution of 198 mg (0.55 mmol) [4-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid tert-butyl ester in 2 ml of THF was added a 1 M solution of tetrabutylammonium fluoride hydrate in tetrahydrofuran (0.55 ml, 0.55 mmol). The reaction mixture was stirred for 1 h at ambient temperature. Diethyl ether was added and the ether solution was washed with saturated aqueous NH4Cl solution, water and brine. Evaporation of the solvent under reduced pressure gave 49 mg (0.2 mmol, 36%) of (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH2:35][CH3:36])[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:33]([CH2:35][CH3:36])[CH3:34])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC(C)I
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
To a suspension of 500 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 352 mg of potassium carbonate in 1.3 ml of N,N-dimethylformamide, 704 mg of 2-iodobutane was added, and the mixture was stirred at room temperature for 12 hours. After completion the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 522 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH3:5][Si:6]([CH3:21])([CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]1[CH2:14][O:13]1>C(O)C>[CH3:21][Si:6]([CH3:5])([CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:13])[CH2:14][NH:4][CH:1]([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCOCC1CO1
Reactant: CC(C)N
Solvent: CCO
Product: CC(C)NCC(O)COCCC[Si](C)(C)CC[Si](C)(C)C
Temperature: 60 °C

Procedure:
Isopropylamine (2.15 g, 36.4 mMol) and 40 mL of ethanol were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 60° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 60° C. for an additional 8 hours. Ethanol and isopropylamine were stripped off on the rotovap. The mixture was distilled under vacuum distillated to remove impurities.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[N:22]=[CH:21][CH:20]=[CH:19][C:9]=1[C:10]([NH:12][CH2:13][C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:11].Cl[CH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27]>CN(C=O)C>[O:27]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25][CH2:24][S:7][C:8]1[C:9]([C:10]([NH:12][CH2:13][C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[O:11])=[CH:19][CH:20]=[CH:21][N:22]=1
Reactant: O=C(NCc1cccs1)c1cccnc1S
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCSc1ncccc1C(=O)NCc1cccs1)c1ccccc1
Reaction time: 0.5 h
Yield: 13.3 %

Procedure:
227 mg (1.65 mmol) of K2CO3 were added to a solution of 375 mg (1.5 mmol) of 2-mercapto-N-(thiophen-2-ylmethyl)nicotinamide in DMF (3.5 ml), and stirring was carried out for 30 min at RT. 252 mg (1.5 mmol) of 3-chloro-1-phenylpropan-1-one were then added and stirring was carried out for a further 2 d at RT. The mixture was then concentrated in vacuo and the residue was taken up in a mixture of EA and a 1N aq. NaHCO3 sol. The organic phase was separated off and the aqueous phase was extracted again with EA. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 1:1), and subsequent crystallization (EA/hexane) yielded 73 mg (0.2 mmol, 13%) of 2-[(3-oxo-3-phenyl-propyl)sulfanyl]-N-(thiophen-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 383.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[N:9]([CH2:19][CH3:20])[CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1>[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20].[OH2:15].[OH2:15].[OH2:15].[CH2:19]([N:9]1[C:8]2[N:7]=[C:6]3[CH:21]=[C:2]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:3]([F:22])=[CH:4][C:5]3=[CH:14][C:13]=2[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(Cl)cc3nc21
Reactant: C1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CCNCC4)cc3nc21
Product: O

Procedure:
1-Ethyl-7-fluoro-8-(1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Example 5, but starting from 1.6 g of 8-chloro-1-ethyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid and 4.3 g of piperazine in 20 cm3 of pyridine. After recrystallizing 3 times from, in total, 300 cm3 of dimethylformamide, 0.94 g of 1-ethyl-7-fluoro-8-(1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid trihydrate is obtained in the form of a yellow solid melting at 320°-322° C.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@H:17]2[CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH:18]1[CH2:19][CH2:20][C@@H:17]1[CH2:16][O:15][C:14]1[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:13]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][N:7]\1[CH2:36][C@H:37]1[CH2:41][CH2:40][CH2:39][O:38]1)=[O:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H]2CCN2)s1
Yield: 84.1 %

Procedure:
The mixture of Example 1B (472 mg, 0.79 mmol) and 2,2,2-trifluoroacetic acid (608 μL, 7.9 mmol) in CH2Cl2 (10 mL) was stirred at room temperature overnight. Saturated aqueous Na2CO3 (20 mL) and CH2Cl2 (20 mL) were added. The organic layer was washed with brine and concentrated. Purification by gradient flash chromatography (silica gel, 5-30% solvent A in EtOAc, solvent A: MeOH (10):Et3N (1)) afforded 330.5 mg (84%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H), 1.56-2.00 (m, 4 H), 2.03-2.34 (m, 2 H), 3.23-3.35 (m, 2 H), 3.59-3.71 (m, 2 H), 3.74-3.83 (m, 2 H), 4.03-4.34 (m, 5 H), 7.27 (s, 1 H), 7.32 (d, J=8.81 Hz, 1 H), 7.75 (dd, J=8.98, 2.20 Hz, 1 H), 7.98 (d, J=2.37 Hz, 1 H); MS (ESI) m/z 498 (M+H)+.