Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[C:2]#[CH:3].N1C=CC=CC=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>CCOCC>[CH2:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:25]([CH:22]1[CH2:24][CH2:23]1)=[O:26])[C:2]#[CH:3]
Reactant: O=C(Cl)C1CC1
Reactant: C#CCOCCCCCCCCCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: C#CCOCCCCCCCCCCOC(=O)C1CC1

Procedure:
91 g. of 10-(2-propynyloxy)-1-decanol are dissolved in 500 ml. of ether and treated with 37 g. of pyridine. While cooling with ice and stirring, there are added dropwise 49.5 g. of cyclopropane carboxylic acid chloride and 50 ml. of ether thereto. Subsequently, the mixture is stirred at room temperature for 3 hours. The mixture is poured onto ice-water, exhaustively extracted with ether and the extract is washed with 2 N hydrochloric acid, water, 10% potassium bicarbonate solution, semi-saturated and saturated sodium chloride solution, dried over sodium sulfate and evaporated. By chromatography on silica gel with hexane/ethyl acetate (95:5 parts by volume) there is obtained pure cyclopropane carboxylic acid 10-(2-propynyloxy)decyl ester; nD25 =1.4616.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.C(O)(=O)C>[C:17]([N:11]1[C:12]([CH:13]([CH3:14])[CH3:15])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:16])[NH:10]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.50 g) was dissolved in tetrahydrofuran (6.0 g) at room temperature. Acetic anhydride (0.708 g) and acetic acid (0.0208 g) was added to the solution successively. After the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (The product was eluted with dichloromethane at first, and then n-hexane/ethyl acetate=4/1) to give 1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.38 g).
Reaction SMILES: [CH2:1]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])P(=O)(OCC)OCC.[H-].[Na+].[CH:20]([C:22]1[C:23]([NH:33][C:34](=[O:58])[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]3[N:45]=[C:46]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[O:47][C:48]=3[CH3:49])=[C:38]([O:56][CH3:57])[CH:37]=2)=[N:24][N:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:26]=1)=O.O>CN(C)C=O>[CH3:57][O:56][C:38]1[CH:37]=[C:36]([CH2:35][C:34]([NH:33][C:23]2[C:22](/[CH:20]=[CH:1]/[P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])=[CH:26][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:24]=2)=[O:58])[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][C:44]1[N:45]=[C:46]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:47][C:48]=1[CH3:49]
Reactant: COc1cc(CC(=O)Nc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1NC(=O)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21 %

Procedure:
To a solution of tetraethyl methylenediphosphonate (357 mg) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 54 mg), and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added a solution of N-(4-formyl-1-phenyl-1H-pyrazol-3-yl)-2-{3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetamide (590 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with distilled water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1 to 1:0, v/v) to give diethyl (E)-2-{3-[({3-methoxy-4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl}acetyl)amino]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless amorphous form (159 mg, yield 21%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH2:3][O:4][CH2:5][C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24](Cl)(=[O:26])=[O:25]>>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([CH3:23])[C:17]=1[S:24]([NH:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][O:4][CH2:3][C:2]([F:1])([F:13])[F:14])[N:11]=1)(=[O:26])=[O:25]
Reactant: Nc1cccc(COCC(F)(F)F)n1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1cccc(COCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 1 from 6-(2,2,2-Trifluoro-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 2,4-dichloro-6-methyl-benzenesulfonyl chloride (0.11 g) as a light yellow solid (0.1 g). MS (ESI−): 427.1 ([M−H]−).
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[CH2:26][N:27]=2)[CH:19]=[CH:20][CH:21]=1.C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:15][C:16]1[CH:17]=[C:18]([C:22]2[C:23]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:24]=3[N:25]([CH2:28][CH3:29])[C:26](=[S:2])[N:27]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCN1CN=C(c2cccc(Cl)c2)c2ccc(C)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCn1c(=S)nc(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Yield: 54 %

Procedure:
Diphosphorus pentasulfide (3.00 g, 13.5 mmol) was added to a solution of 2.00 g (6.69 mmol) of 4-(3-chlorophenyl)-1-ethyl-7-methylpyrido[2,3-d]pyrimidine in 100 ml of 1,2-dichloroethane, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, mixed with saturated sodium bicarbonate and extracted with chloroform. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the resulting filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-chloroform) and further recrystallized from ethyl acetate-diisopropyl ether to give 1.14 g of 4-(3-chlorophenyl)-1-ethyl-7-methylpyrido[2,3-d]pyrimidin-2(1H)-thione. The yield was 54%.
Reaction SMILES: [BH4-].[Na+].C(N)CN.[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12][C:13]#[C:14][CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33].[H][H]>C(O)C.[Ni](Cl)Cl>[CH3:7][O:8][C:9](=[O:34])[CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][N:16]1[CH:21](/[CH:22]=[CH:23]/[C:24](=[O:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:20][CH2:19][CH2:18][C:17]1=[O:33]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: NCCN
Product: COC(=O)CCC/C=C\CN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Reaction time: 0.25 h
Yield: 73 %

Procedure:
A round bottom flask was charged with nickel (II) chloride (68 mg, 0.52 mmol) and sodium borohydride (9.9 mg, 0.26 mmol), then 95% ethanol (1.0 mL) was added. The mixture immediately turned black. After 15 min at rt, ethylene diamine (56 μL, 0.84 mmol) was added. After another 15 min at rt, 7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-hept-5-ynoic acid methyl ester (40 mg, 0.10 mmol) in 95% ethanol (1.0 mL) was added via cannula. A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 18 h. The reaction mixture was filtered through celite, washing with ethanol, and the filtrate was concentrated in vacuo. Purification of the resulting residue by flash column chromatography (CH2Cl2→30% EtOAc/CH2Cl2, gradient) afforded 28 mg (70%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:50](O)[CH2:51]CC>>[CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:28])[C:13]3[C:14](=[C:16]([CH2:26][CH3:27])[N:17]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[N:18]=3)[N:15]=2)=[CH:8][C:7]([S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][CH3:39])[CH2:34][CH2:33]2)(=[O:30])=[O:31])=[CH:6][N:5]=1)[CH2:2][CH2:50][CH3:51]
Reactant: CCCCO
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1-c1nc2c(CC)n(Cc3ccccn3)nc2c(=O)[nH]1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis(trimethylsilyl)amide (360 mg, 1.81 mmol) and n-butanol (5 ml) was stirred at 100° C. for 18 hours, then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (5 ml) and dichloromethane (5 ml). The phases were separated and the aqueous layer extracted with dichloromethane (2×10 ml), then the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel, using dichloromethane: methanol (97.5:2.5) as eluant, to yield the title compound (145 mg, 69%) as a white solid. Found: C, 57.43; H, 6.29; N. 18.82. C28H36N8O4S; 0.20 H2O requires C, 57.56; H, 6.28; N, 19.18%. δ (CDCl3): 1.03 (6H, 2×t), 1.30 (3H, t), 1.55 (2H, m), 1.94 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.13 (4H, m), 4.67 (2H, t), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.56 (1H, d), 8.62 (1H, s), 9.01 (1H, s), 10.64 (1H, s). LRMS: m/z 581 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N+:14]([O-:16])=[O:15])=[C:7]([C:11]([OH:13])=O)[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:18][NH:19][O:20][CH3:21].CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N+:14]([O-:16])=[O:15])=[C:7]([C:11]([N:19]([O:20][CH3:21])[CH3:18])=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1[nH]c2cc(Cl)ccc2c1[N+](=O)[O-]
Reaction time: 4 h
Yield: 55.9 %

Procedure:
To a mixture of 6-chloro-3-nitroindole-2-carboxylic acid (step 1, 2.35 g, 9.77 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.81 g, 39.1 mmol) in DMF (50 ml) was added dropwise a dimethylformamide (15 ml) solution of WSC (5.61 g, 29.3 mmol) over 10 min. After stirring for 4 h the mixture was diluted with diethyl ether (200 ml) and washed with water (100 ml×4). The organic extract was dried (MgSO4) and solvent removed by evaporation. The crude product was recystallized from ethyl acetate to afford 1.55 g (56%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:29]=[C:30]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[C:31](=[N:33]O)[NH2:32].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:20][N:33]=[C:31]([C:30]4[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:28]([F:27])[CH:29]=4)[N:32]=3)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: NC(=NO)c1cc(F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2cc(F)cc(C(F)(F)F)c2)no1
Yield: 7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (step-2 of Intermediate-15, 0.100 g, 0.26 mmol), 3-fluoro-N′-hydroxy-5-(trifluoromethyl)benzimidamide (Intermediate-22, 0.088 g, 0.39 mmol), sodium hydride (0.017 g, 0.42 mmol) and dry THF (5.0 mL) at RT to afford 0.010 g of desired product. 1HNMR (DMSO-d6): δ 4.01 (s, 3H), 7.50 (m, 1H), 7.60 (m, 1H), 7.70 (m, 1H), 7.84 (m, 1H), 7.92 (br s, 1H), 8.02 (d, 1H), 8.18 (m, 2H), 8.25 (d, 1H), 12.95 (br s, 1H); MS (m/z): 550.07 [M]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:21].Cl>O1CCOCC1>[NH2:21][C:6]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: O=C(NCCCN1CCOCC1)c1c(Cl)ncnc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ncnc(Cl)c1C(=O)NCCCN1CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 34 %

Procedure:
4,6-Dichloro-N-(3-morpholinopropyl)pyrimidine-5-carboxamide (1.13 g, 3.08 mmol) was dissolved in dioxane (10 ml) and cooled in an ice bath. Ammonia solution (2.2 ml, 7N in MeOH) was added dropwise and the mixture was stirred at 0° C. for 15 min and 4 h at room temperature. After dilution with ethyl acetate, this organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvents evaporated under reduced pressure, to yield an oil which was rejected. The aqueous phase was neutralized with 2N HCl, extracted with DCM, dried over magnesium sulphate, filtered and the solvent evaporated. An oil was obtained (450 mg, 70% purity, 34% yield) which was used in the next synthetic step without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:1][C:2]([Cl:11])=[CH:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(C=C(Cl)Cl)C(=O)O
Solvent: c1ccccc1
Product: CC(C)C(C=C(Cl)Cl)C(=O)Cl

Procedure:
In 15 ml of dry benzene were dissolved 1.8 g of α-(2,2-dichlorovinyl)isovaleric acid, followed by the addition of 3.5 g of thionyl chloride. The mixture was refluxed for 5 hours and, then, distilled to remove the low-boiling fraction. By the above procedure there was obtained α-(2,2-dichlorovinyl)isovaleroyl chloride. This chloride was dissolved in 20 ml of benzene, and 2.0 g of α-ethynyl-3-phenoxybenzyl alcohol were added. This was followed by the addition of 2.9 g of pyridine and the mixture was stirred at room temperature for 8 hours. The resultant reaction mixture was diluted with diethyl ether, washed with water and dilute aqueous hydrogen chloride and dried over anhydrous magnesium sulfate. The low-boiling fraction was then distilled off and the residue was chromatographed on a column of silica gel (benzene/n-hexane=1:1 v/v). By the above procedure there were obtained 2.6 g of α-ethynyl-3-phenoxybenzyl α-(2,2-dichlorovinyl)isovalerate (compound [2]) having the following properties [yield: 71% based on α-(2,2-dichlorovinyl)isovaleric acid].
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[CH:16][C:15]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:13][C:14]1[C:15]([N:29]2[C:9](=[O:10])[NH:8][C:6]([C:5]3[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=3)=[N:30]2)=[CH:16][C:17]([CH2:21][NH:22][C:23](=[O:28])[C:24]([F:26])([F:27])[F:25])=[C:18]([F:20])[CH:19]=1
Reactant: O=C=NC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(-n2nc(-c3ccc(I)cc3)[nH]c2=O)c(Cl)cc1F)C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-iodobenzoyl isocyanate (Intermediate-67, 0.700 g, 1.8 mmol), tert-butyl 2-(2-chloro-4-fluoro-5-{[(trifluoroacetyl)amino]methyl}phenyl)hydrazine carboxylate (Intermediate-89, 0.992 g, 3.63 mmol), DCM (50 mL), trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.47 (s, 2H), 7.61 (d, J=2.1 Hz, 3H), 7.86-7.90 (br d, 3H), 10.05 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:20]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:23])=[N:19][CH:18]=1)=[O:22])([CH3:26])[CH3:25]
Reactant: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)O)s1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cn2)c1/C=C/c1ncc(C(=O)NC(C)C)s1
Yield: 59 %

Procedure:
As described for example 77c, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-thiazole-5-carboxylic acid (83 mg, 0.25 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (55 mg, 59%) which was obtained as an off white solid after recrystallization from heptane/ethyl acetate. MS: m/e=373.1 [M+H]+.
Reaction SMILES: N1C(C2C=CC([C:12]3[C:21](C)=[CH:20][C:19]4[C:14](=[CH:15][CH:16]=[C:17]([O:23]C)[CH:18]=4)[N:13]=3)=CC=2)=NN=N1.B(Br)(Br)Br.C(Cl)[Cl:30]>>[Cl:30][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:23])[CH:18]=2)[N:13]=1
Reactant: ClCCl
Reactant: COc1ccc2nc(-c3ccc(-c4nnn[nH]4)cc3)c(C)cc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2nc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 2-chloro-6-methoxyquinoline (Intermediate 1) (2.00 g, 10.4 mmol) in anhydrous DCM (100 mL) was added BBr3 (6 mL, 62.2 mmol) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 2 hours, then quenched with aqueous saturated NH4Cl (50 mL) and filtered. The filtrate was extracted with CH2Cl2/MeOH (v/v=10/1, mL×2) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-chloroquinolin-6-ol (1.30 g, yield 70%) as yellow solid. 1H NMR (CDCl3 300 MHz): δ 7.95 (t, J=8.1 Hz, 2H), 7.35 (dd, J=6.0, 3.3 Hz, 2H), 7.13 (d, J=2.7 Hz, 1H).
Reaction SMILES: [N+]([O-])(O)=O.[CH3:5][N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8][C:7]1=[O:16].[ClH:17]>C(O)(=O)C>[Cl:17][C:12]1[NH:11][C:10]2[C:9](=[O:15])[NH:8][C:7](=[O:16])[N:6]([CH3:5])[C:14]=2[N:13]=1
Reactant: Cl
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
Nitric acid (9 ml) was slowly added dropwise to a suspension of 3-methylxanthine (10 g) in acetic acid (180 ml) at 100° C., and the resulting white suspension was stirred at 100° C. for 30 minutes followed by 140° C. for 20 minutes. After cooling the reaction solution to room temperature, the solvent was removed by distillation at reduced pressure at 60° C. to give a yellow solid. The resulting yellow solid was washed with water, and recrystallization from 0.5 M hydrochloric acid gave a pale yellow solid. A suspension of the solid in concentrated hydrochloric acid (500 ml) was stirred at 110° C. for 15 minutes, then the reaction solution was cooled to room temperature, and the solvent was removed by distillation at reduced pressure to give a yellow-white solid. Recrystallization of the resulting solid from water gave 6.75 g of the title compound.
Reaction SMILES: Br[C:2]([F:15])([F:14])[C:3]([F:13])([F:12])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CO.[BH4-].[Na+]>O1CCCC1>[F:12][C:3]([F:13])([CH:2]([F:14])[F:15])[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCC(F)(F)C(F)(F)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)CCCC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Under a nitrogen atmosphere, 1 g (3.39 millimoles) of ethyl 6-bromo-5,5,6,6-tetrafluorohexanoate was dissolved in 10 mL of tetrahydrofuran and 1 mL of methanol and then 129 mg (3.39 millimoles) of sodium borohydride was added thereto, followed by stirring at room temperature for 1 hour. A reaction solution was extracted with ethyl acetate after the addition of a sulfuric acid aqueous solution, followed by concentrating a solvent. With this, ethyl 5,5,6,6-tetrafluorohexanoate was obtained at a yield of 50%. There cannot be confirmed production of 6-bromo-5,5,6,6-tetrafluorohexan-1-ol.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[CH3:21][NH:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:4]=[C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:14]4[O:18][CH:17]=[N:16][CH:15]=4)[CH:12]=3)[NH:7][C:6]2=[O:19])=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CNS(=O)(=O)Cc1ccc(N)cc1
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: Cl
Product: CNS(=O)(=O)Cc1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 56 %

Procedure:
The title compound was prepared in 56% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and N-methyl-4-aminophenylmethanesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ 10.72 (d, 1H), 10.67 (s, 1H), 8.71 (d, 1H), 8.37 (s, 1H), 7.43–7.34 (m, 7H), 6.89 (m, 2H), 4.28 (s, 2H), 2.54 (d, 3H); APCI-MS m/z 409 (MH)−.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.C[O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39]4([CH3:44])OCC[O:40]4)=[CH:35][C:29]=3[C:30](=O)[O:31]2)=[CH:26][CH:25]=1.[Li]>C1COCC1.O>[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]3[CH:38]=[CH:37][C:36]([C:39](=[O:40])[CH3:44])=[CH:35][C:29]=3[CH:30]([C:2]3[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)[O:31]2)=[CH:26][CH:25]=1
Reactant: COc1ccc2c(c1)oc(=O)c1cc(C3(C)OCCO3)ccc12
Reactant: Brc1ccc(OCCN2CCCCC2)cc1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)Oc1cc(O)ccc1-2
Temperature: -78 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
1-[2-(4-bromo-phenoxy)-ethyl]-piperidine (0.76 g, 2.7 mmol) from Step F was dissolved in THF (15 ml) under Ar and cooled to −78° C. n-Butyl lithium (10.0 M, 0.26 ml, 2.6 mmol) was added and the mixture was stirred at −78° C. for 1 hour. The compound from Step E (1.11 g, 3.56 mmol) was dissolved in THF (35 ml) under Ar and cooled to −78° C. to which the freshly prepared lithium salt of 1-(2-(4-bromo-phenoxy)-ethyl)-piperidine was transferred via a cannula. The reaction was stirred for 2 h. Water (150 ml) was added and the reaction extracted three times with ethyl acetate (150 ml). After removing the solvent the crude product was chromatographed on silica gel with 7% CH3OH/CH2Cl2 to yield 0.56 g (48%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 1.44 (2H, m, NCH2CH2CH2), 1.59 (4H, m, NCH2CH2CH2) 1.61 (3H, s, CH3), 2.25 (4H, m, NCH2CH2CH2), 2.83 (2H, m, NCH2CH2O), 3.78 (2H, m, OCH2), 3.85 (3H, s, OCH3), 4.01 (2H, m, OCH2), 4.18 (2H, m, NCH2CH2O), 6.69 (1H, s, ArH), 6.73 (1H, d, ArH), 6.96 (2H, d, ArH), 7.17 (1H, s, ArH), 7.56 (1H, m, ArH), 7.60 (2H, d, ArH), 7.76 (2H, m, ArH).