Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([O:28]C)=[O:27])[CH:20]=3)[NH:15]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1>[CH:1]1([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]2[C:23]([CH3:25])([CH3:24])[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:26]([OH:28])=[O:27])[CH:20]=3)[NH:15]2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccccc1NC(=O)C1CCC1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccccc1NC(=O)C1CCC1
Yield: 75.5 %

Procedure:
A mixture of methyl 2-(2-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (54 mg, 0.14 mmol, 1.0 eq.) and 1.8 mL aqueous solution of sodium hydroxide (2 M, 3.57 mmol, 25 eq.) in tetrahydrofuran (3 mL) was stirred at reflux for 3 h. Thin layer chromatography indicated that the starting material was consumed completely. The tetrahydrofuran was removed under reduced pressure and the residue was acidified to pH 5-6 with 1 M hydrochloric acid. Then a lot of white precipitates were formed and collected by filtration to afford 40 mg of 2-(2-(cyclobutanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid; yield: 76%. MS (ESI+APCI) M+1=379.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH2:9][OH:10]>[Pt].CC(C)=O>[C@H:3]12[CH2:2][O:1][C:9](=[O:10])[C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8]2
Reactant: OCC1CCCCC1CO
Agent: [Pt]
Solvent: CC(C)=O
Product: O=C1OC[C@@H]2CCCC[C@H]12
Temperature: 0 °C
Yield: 92 %

Procedure:
There were weighed out 1,2-bis(hydroxymethyl)cyclohexane (7, meso compound) (144 mg, 1.00 mmol) and (S)-(−)-3,3,5,5-tetramethyl-4H-dinaphtho[2,1-c:1′,2′-e]-azepin-N-oxyl (3.0 mg, 1.00 mmol). Then, 2 ml of acetone was added to obtain a uniform solution. Two platinum electrodes (1.5×1.0 cm) were applied to the solution which was then subjected to an electrolytic oxidation reaction for 4 hours while being vigorously stirred at 0° C. and maintaining the current at 30 mA (quantity of electricity being 4.5 F/mol). After completion of reaction, silica gel was filtered off from the reaction mixture, extraction was effected with 5 ml of acetone and acetone was distilled off. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=7/1), giving (1R, 6S)-8-oxabicyclo[4.3.0]nonan-7-one (8) (cis lactone) (122 mg, yield 92%, optical purity 85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:21])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(O)ccc2C[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2cc(OCc3ccccc3)ccc2CC1C(=O)O
Yield: 19.2 %

Procedure:
2.0 g, (6.8 mmol) of (3S)-7-hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester was reacted with 2.56 g (15.0 mmol) of benzyl bromide as described in general procedure H. The resulting crude product was subjected to hydrolysis as described in general procedure C. The crude product was purified by column chromatography using 1:1 ethyl acetate and hexane as eluent to afford 0.5 g of 7-benzyloxy-3,4-dihydro-1H-isoq uinoline-2,3-dicarboxylic acid 2-tert-butyl ester.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:24]12([C:31](=O)[CH:30]3[CH2:33][CH:27]1[CH2:28][CH2:29]3)[CH2:26][CH2:25]2.Cl>O1CCCC1.O>[C:24]12([CH:31]([CH:2]=[O:3])[CH:30]3[CH2:33][CH:27]1[CH2:28][CH2:29]3)[CH2:26][CH2:25]2
Reactant: O=C1C2CCC(C2)C12CC2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: O=CC1C2CCC(C2)C12CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 179.4 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (6.41 g) was suspended in tetrahydrofuran (80 mL) and cooled to 0° C. in nitrogen atmosphere. After adding 1.56 M n-butyl lithium-in-hexane solution (36.2 mL) at 0° C., the reaction mixture was stirred for an hour. Into the resulting deep red-colored solution, a spiro[bicyclo[2.2.1]heptane-2,1′-cyclopropane]-3-one (6.41 g) solution in tetrahydrofuran (10 mL) was dropped at 0° C., and thereafter the temperature was raised to room temperature, followed by an overnight's stirring. To the reaction mixture, 5M hydrochloric acid (50 mL) was added at room temperature and stirred for further 3 hours. The reaction mixture was diluted with water and extracted with diethyl ether. The extract washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed by distillation and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=99/1−97/3) to provide 5.04 g of the title compound as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1.[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12]([CH2:13][Br:16])=[CH:11][CH:10]=[CH:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2oc3cc(Cl)ccc3c12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2c(c1)oc1cccc(CBr)c12
Yield: 71.6 %

Procedure:
A mixture of 7-chloro-1-methyl-dibenzofuran (6.27 g, 29.1 mmol), N-bromosuccinimide (5.4 g, 30.3 mmole) and dibenzoyl peroxide (0.82 g, 3.4 mmole) in tetrachlorocarbon (100 mL) was heated at reflux for 3 hours, and then concentrated to about 50 mL. The resulting suspension was filtered, rinsed by CCl4. The solid was dissolved in CH2Cl2, washed by water, dried over Na2SO4, evaporated to give 6.16 g of beige solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])=[CH:20][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccnc2n1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2cccnc2n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a mixture of {(S)-1-[3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethyl}carbamic acid tert-butyl ester (99 mg, 0.27 mmol) in DCM (1 mL) was added TFA (1 mL) and the reaction mixture was stirred at RT for 3 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[3-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridin-2-yl]ethylamine as an orange oil (71 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9]CO1)C.[H-].[Na+].[CH3:14]N(C=O)C.C(Br)CCC>C1COCC1.C1(C)C=CC=CC=1>[CH2:6]([O:5][CH2:3][C@@H:2]([OH:1])[CH3:14])[CH2:11][CH2:10][CH3:9]
Reactant: CN(C)C=O
Reactant: C[C@@H](CO)OC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCBr
Solvent: C1CCOC1
Product: CCCCOC[C@H](C)O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
(S)-1-hydroxy-2-tetrahydropyranyloxypropane (120 g, 0.75 mol) was dropwise added to sodium hydride (44.8 g, 1.87 mol) in THF (400 ml), followed by adding DMF (200 ml), agitating the mixture for 2 hours, dropwise adding to the mixture, butyl bromide (112.4 g, 0.82 mol) at 30° C. or lower, agitating the mixture at room temperature for 6 hours, adding toluene, sufficiently agitating the mixture, washing the resulting organic layer with 2N-NaOH aqueous solution and then with water, drying it over anhydrous magnesium sulfate, distilling off toluene, adding to the resulting oily residue, pyridium p-toluenesulfonate (18 g) and ethanol (500 ml), heating the mixture at 70° C. for one hour, distilling off ethanol, adding toluene to the residue, sufficiently washing the mixture with water, distilling off toluene and distilling the residue to obtain (S)-1-butyloxy-2-hydroxypropane (79.3 g) (b.p. 87° C./35 mmHg) (αD24 =+3.6 (l=1.0 dm neat)).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8]C2C=CC(Cl)=C(NC(=O)C3C=CC=C(Cl)C=3)C=2)=[O:7])=[CH:4][N:3]=1.C([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>>[N:35]1([C:2]2[CH:27]=[CH:26][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(N2CCNCC2)nc1

Procedure:
6-chloro-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.16 mmol) was used in general procedure 3 with Boc-piperazine (0.868 mmol). The product was deprotected by treatment with TFA and purified by RP-HPLC to give N-(4-chloro-3-(3-chlorobenzamido)phenyl))-6-(piperazin-1-yl)nicotinamide. MS (Q1) 470.1 (M)+
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:25][C:24]([OH:27])([CH3:26])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[N:30][CH:29]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.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.CCOC(C)=O>[OH:27][C:24]1([CH3:26])[CH2:25][N:22]([C:3]2[C:2]([C:32]3[CH:33]=[N:28][CH:29]=[N:30][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1
Reactant: OB(O)c1cncnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(O)CN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2-c2cncnc2)C1
Temperature: 95 °C

Procedure:
5-Bromo-6-(3-hydroxy-3-methylazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 128.1, 89 mg, 0.2 mmol) and pyrimidin-5-ylboronic acid (50 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M Na2CO3 (0.300 mL, 0.6 mmol) and EtOH (120 μL) were added, the mixture was flushed with argon, Pd(PPh3)2Cl2 (17 mg, 0.02 mmol) was added and the RM was heated at 95° C. for 3 h in a pressure safe vial. After cooling at RT, the RM was treated with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, first EtOAc/MeOH from 0 to 10% MeOH; then second flash DCM/MeOH, from 2% to 5% MeOH) and treated with Si-Thiol (80 mg) in MeOH to afford the title compound as a white crystalline solid. HPLC (Condition 4) tR=4.74 min, UPLC-MS (Condition 7) m/z=446.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 4H) 3.50-3.64 (m, 3H) 5.49 (s, 1H) 7.34 (d, J=8.60 Hz, 2H) 7.83 (d, J=8.99 Hz, 2H) 8.09 (d, J=1.56 Hz, 1H) 8.78 (d, J=1.95 Hz, 1H) 8.90 (s, 2H) 9.20 (s, 1H) 10.20 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Tert-butyl 4-(4-trifluoromethylphenyl)-piperazine-1-carboxylate (3.8 g, 11.5 mmol) prepared in Reference Example 77 was dissolved in methylene chloride (40 ml), to which trifluoroacetic acid (10 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was neutralized with saturated sodium hydrogencarbonate aqueous solution and the mixture was extracted with methylene chloride. The extract was dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(4-trifluoromethylphenyl)piperazine (2.5 g, yield 96%) as a white powder.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1>O1CCCC1>[CH:25]([O:24][C:22]([CH2:21][O:20][N:19]=[C:15]([C:13]1[N:14]=[CH:10][S:11][CH:12]=1)[C:16]([OH:18])=[O:17])=[O:23])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1nc(C(=NOCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: O=C(CON=C(C(=O)O)c1cscn1)OC(c1ccccc1)c1ccccc1
Yield: 48 %

Procedure:
A solution of isopentyl nitrite (5.9 ml) in tetrahydrofuran (50 ml) was dropwise added to a mixture of 2-(2-aminothiazol-4-yl)-2-(benzhydryloxycarbonyl-methoxyimino)acetic acid (syn isomer) (10.6 g) in tetrahydrofuran (100 ml) at 50° to 55° C. under stirring and the mixture was stirred at 55° to 60° C. for 30 minutes. Tetrahydrofuran was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-(benzhydryloxycarbonylmethoxyimino)-2-(4-thiazolyl)acetic acid (syn isomer) (4.9 g).
Reaction SMILES: CCOCC.[F:6][C:7]1[CH:33]=[C:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:8]=1[O:9][CH2:10][CH2:11][C@@H:12]1[CH2:14][C@@H:13]1[CH:15]1[CH2:20][CH2:19][N:18](CC(C2C=CC=CC=2)=O)[CH2:17][CH2:16]1>C(O)C.[Pd]>[F:6][C:7]1[CH:33]=[C:32]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:31]=[CH:30][C:8]=1[O:9][CH2:10][CH2:11][C@@H:12]1[CH2:14][C@@H:13]1[CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(CC(=O)c3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: CCOCC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Reaction time: 64 h

Procedure:
The ether, 2-[4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl]-1-phenylethanone (740 mg, 1.62 mmol) in ethanol (25 mL) was added Palladium on carbon (10 wt. %, wet, 0.200 g), degassed (3× vacuum/H2) again and stirred under H2 at 1 atm for 64 h. The reaction mixture was filtered through a plug of celite, and the filter cake rinsed with ethanol (150 mL), ethyl acetate (150 mL), and the filtrate was concentrated under reduced pressure to provide the piperidine as a yellow oil. MS (ESI): 342 [M+H]+.
Reaction SMILES: C([CH:4]1[C:12]2[C:7](=[C:8](O)[CH:9]=[CH:10][C:11]=2CC)[C:6](=[O:16])[CH2:5]1)(C)C.CC1CC2C(=CC3OCOC=3C=2)C1=O>C(O)C>[C:6]1(=[O:16])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: CCc1ccc(O)c2c1C(C(C)C)CC2=O
Agent: CC1Cc2cc3c(cc2C1=O)OCO3
Solvent: CCO
Product: O=C1CCc2ccccc21

Procedure:
The above aromatic composition of the present process is added in an amount of 1 ppm to the material milk of yoghurt and the material is fermented to make yoghurt. A 5 % ethanol solution of the mixture (in the ratio 1:1) of 3-isopropyl-4-ethyl-7-hydroxyindan-1-one and 2-methyl-5,6-methylenedioxyindan-1-one is added to the material milk but in an amount to give 10 ppm by weight of said indanone compounds mixture thereto, and yoghurt is prepared therefrom.
Reaction SMILES: [CH:1]([N:4]([CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12]C)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:3])[CH3:2].C1(C)C(S(O)(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([N:4]([CH2:9][CH:10]1[O:11][CH2:12][CH2:16][CH2:15][O:14]1)[C:5](=[O:8])[CH2:6][Cl:7])([CH3:2])[CH3:3]
Reactant: CCOC(CN(C(=O)CCl)C(C)C)OCC
Agent: Cc1ccccc1S(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)N(CC1OCCCO1)C(=O)CCl

Procedure:
N-Isopropyl-N-(2,2-diethoxyethyl)-α-chloroacetamide (10 grams), propandiol-1,3 (2.9 ml) and trace amounts of toluenesulfonic acid were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated until no more ethanol was given off. After this time sodium carbonate (1 gram) was added to the mixture with stirring and the resulting mixture was distilled to yield the desired product N-isopropyl-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide having a boiling point of 165° C. at 1.0 mm of Hg pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH:26]([OH:28])[CH3:27])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:29]([O:28][CH:26]([C:23]1[S:24][CH:25]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[N:22]=1)[CH3:27])(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CC(O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Temperature: 0 °C
Yield: 24.09 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-hydroxy-ethyl)thiazole-4-carboxamide (250 mg, 0.601 mmol), 4-dimethylaminopyridine (7.34 mg, 0.060 mmol) and pyridine (3 ml) were added into a flask and the mixture was cooled to 0° C. Acetic anhydride (0.063 ml, 0.661 mmol) was added dropwise and the mixture was allowed to warm to RT with stirring. The reaction was left to react overnight. Next morning more acetic anhydride (10 μl, 0.106 mmol) was added and the reaction was stirred for another hour in RT. The mixture was evaporated and dried overnight in vacuum at 40° C. The product was purified by recrystallization twice from ethanol/heptanes to yield 24.09% of final product. 1H-NMR (400 MHz; DMSO-d6): δ 1.14 (d, 3H), 1.62 (dd, 3H), 2.11 (s, 3H), 4.29-4.53 (m, 3H), 6.02-6.10 (m, 1H), 6.94-6.98 (m, 1H), 7.84-7.87 (m, 1H), 7.92-8.00 (m, 2H), 8.07 (d, 1H), 8.22 (d, 1H), 8.38-4.49 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-])=O.CC(=O)OCC>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH2:9]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(F)ccc1F
Temperature: 20 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 1,4-difluoro-2-nitrobenzene (500 mg, 3.14 mmol) in MeOH (20 mL) was added Pd/C (66.9 mg, 0.629 mmol) in portions. Then the mixture was stirred under a H2 atmosphere at 20° C. for 1 h. After TLC (PE/EA=3/1) analysis showed the starting material had disappeared, the mixture was filtered. The filtrate was concentrated to give the desired product 2,5-difluoroaniline (338 mg, 2.61 mmol, 83% yield). 1H NMR: (400 MHz, CDCl3) δ 6.94-6.88 (m, 1H), 6.50-6.46 (m, 1H), 6.40-6.31 (m, 1H), 3.82 (br. s., 2H).
Reaction SMILES: NC1[C:3]([Br:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][C:6]=1[Br:7].[H-].[Na+].IC.[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Br:13][C:3]1[C:21]([N:19]([CH3:18])[CH3:20])=[C:6]([Br:7])[S:5][C:4]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1sc(Br)c(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1sc(Br)c(N(C)C)c1Br
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 58.97 %

Procedure:
To a solution of Ethyl 4-amino-3,5-dibromothiophene-2-carboxylate (compound 34b, 5.0 g, 15.19 mmol) in DMF (25 ml) was added NaH (60% suspension in mineral oil) (1.82 g, 45.49 mmol) in portion wise manner at a temperature of about −5° C. The reaction mixture was then stirred at −5° C. for 20 min. To the reaction mixture was then added iodomethane (6.47 g, 2.83 ml, 45.59 mmol) and stirring was continued for 40 min at −5° C. The progress of the reaction was monitored by TLC. The reaction mixture was then quenched by addition of cold water (50 ml). the mixture so obtained was then extracted with ethyl acetate (3×100 ml). The combined organic layer was then dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 2.5% ethyl acetate in hexanes as an eluent to obtain the title compound (3.2 g, 58.97%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][N:5]([Si](C)(C)C)[Si](C)(C)C.[CH3:16][O:17][CH:18]([O:27][CH3:28])[CH2:19][NH:20][C:21]([CH3:26])=[CH:22][C:23](=O)[CH3:24].FC(F)(F)C(F)(F)C(O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH3:1][O:2][CH:3]([O:14][CH3:15])[CH2:4][NH:5][C:23](=[CH:22][C:21](=[N:20][CH2:19][CH:18]([O:17][CH3:16])[O:27][CH3:28])[CH3:26])[CH3:24]
Reactant: COC(CNC(C)=CC(C)=O)OC
Reactant: COC(CN([Si](C)(C)C)[Si](C)(C)C)OC
Agent: CC(C)(C)[O-]
Agent: O=C(O)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CN=C(C)C=C(C)NCC(OC)OC)OC
Temperature: 150 °C
Reaction time: 1 h

Procedure:
8.0 g (0.032 moles) of bis(trimethylsilyl)aminoacetaldehyde dimethylacetal were mixed with 4.0 g (0.021 moles) of 4-(2,2-bis(methoxy)ethylamino)-3-penten-2-one. To this mixture was added 4.37 g (0.0266 moles) of pentafluoropropionic acid dropwise over 5 minutes with rapid stirring. The mixture darkened and became warm, eventually forming two immiscible layers, and was allowed to stir for 1 hour. 2.56 g (0.0266 moles) of sodium t-butoxide dissolved in 5 ml of tetrahydrofuran was then added dropwise over a five minute period. The mixture warmed and became one liquid phase which was yellow. The solvent was then removed by vacuum distillation at room temperature and the product then vacuum distilled out of the resulting residue as a clear liquid by heating>150° C. Yield of MeC(NCH2CH(OMe)2)CHC(HNCH2CH(OMe)2)Me=5.26 g (90% of theoretical).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)([O-:3])=[O:2].[H-].[Na+].[F:17][C:18]([F:28])([F:27])[C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[C:18]([F:17])([F:27])[F:28])[CH:8]=2)([O-:3])=[O:2]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: O=[N+]([O-])c1cnc2cc(O)ccc2c1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
In dimethylformamide (DMF, 9 mL) was dissolved 3-nitro-7-hydroxyquinoline (800 mg, 4.24 mmol.). To the solution were added subsequently sodium hydride (168 mg, 4.24 mmol.) and 2-trifluoromethylbenzyl chloride (816 mg, 4.24 mmol.) under chilling with ice. The resulting mixture was stirred overnight at room temperature. After the completion of reaction was confirmed, ethyl acetate and aqueous sodium sulfate were added. The ethyl acetate portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 790 mg of the desired compound as a white crystalline product, yield 53%.