Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[C:12](=O)[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8].CC([O-])=O.[Na+].[NH2:21]O.Cl.[BH4-].[Na+]>CO.Cl[Ni]Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]23[CH2:14][CH:13]2[CH:12]([NH2:21])[CH2:11][CH2:10]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NO
Reactant: O=C1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Agent: Cl[Ni]Cl
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Product: NC1CCC2(c3ccc(Cl)c(Cl)c3)CC12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(3,4-dichlorophenyl)bicyclo[3.1.0]hexan-2-one (100 mg, 0.41 mmol) and anhydrous NaOAc (84 mg, 1.03 mmol) in anhydrous MeOH (5 mL) was added with stirring NH2OH.HCl (152.9 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue, dioxime [IS THIS CORRECT?] was reconstituted in anhydrous MeOH (5 ml) and added to a suspension of anhydrous NiCl2 (116.94 mg, 0.9 mmol) in 5 ml of anhydrous MeOH with stirring. The reaction mixture was cooled to −30° C. and NaBH4 (340.5 mg, 9 mmol) was added in small portions. After completion of the addition the mixture was allowed to warm to room temperature and concentrated in vacuo. This was then basified with aqueous solution of NaOH and extracted with CH2Cl2 (3×). Organic phases were concentrated and the crude was purified by prep. HPLC. The oily product (mixture of isomers) was converted to HCl salt (50 mg, 50.4%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.95 (m, 2 H) 1.18-1.34 (m, 2 H) 1.38-1.45 (m, 1 H) 1.65-1.81 (m, 1 H) 1.83-1.92 (m, 1 H) 1.95-2.05 (m, 1 H) 6.32 (s, 2 H) 7.11-7.22 (m, 1 H) 7.23-7.38 (m, 2 H) 8.50 (broad, 1 H). 13C NMR (500 MHz, DMSO-d6) δ ppm 13.85 (s, 1 C) 14.52 (s, 1 C) 16.03 (s, 1 C) 18.45 (s, 1 C) 22.38 (s, 1 C) 23.24 (s, 1 C) 25.02 (s, 1 C) 26.22 (s, 1 C) 26.22 (s, 1 C) 27.48 (s, 1 C) 28.31 (s, 1 C) 28.51 (s, 1 C) 29.79 (s, 1 C) 29.89 (s, 1 C) 31.39 (s, 1 C) 31.99 (s, 1 C) 51.62 (s, 1 C) 52.72 (s, 1 C) 55.87 (s, 1 C) 127.88 (s, 1 C) 127.95 (s, 1 C) 128.06 (s, 1 C) 128.38 (s, 1 C) 128.60 (s, 1C) 130.15 (s, 1 C) 130.24 (s, 1 C) 131.54 (s, 1 C) 131.70 (s, 1 C) 142.26 (s, 1 C) 142.44 (s, 1 C). MS (M+1) 242.1.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[OH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:12][CH2:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: OCC12CC3CC(CC(C3)C1)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: O=C(Cc1ccc(O)cc1)OCC12CC3CC(CC(C3)C1)C2
Reaction time: 8 h

Procedure:
1-Adamantanemethanol (8.31 g, 0.05 mol), 4-hydroxyphenylacetic acid (7.6 g, 0.05 mol) and p-toluenesulfonic acid (1 g, 0.006 mol) were refluxed in benzene (100 mL) with continuous water separation for 8 hours. The reaction mixture was allowed to cool with stirring overnight, then was washed, first with water (100 mL), then with aqueous 5% NaHCO3 solution (100 mL), then twice more with water (100 mL). Drying over anhydrous MgSO4, filtering and concentrating in vacuo afforded (adamant-1-yl)methyl 4-hydroxyphenylacetate, which was then combined with epichlorohydrin (50 mL) and refluxed for 2 hours in the presence of DBU (1 mL, 0.007 mol). Excess epichlorohydrin was removed in vacuo. The oily residue was dissolved in acetonitrile (100 mL) and combined with isopropylamine (20 mL, 0.23 mol). The resultant reaction mixture was refluxed for 4 hours. The oily brown residue was partitioned between ethyl ether (100 mL) and 1M aqueous KOH solution (100 mL). The ether layer was separated and to it was added 1N HCl (30 mL). The resultant acid layer was separated adn to it were added ethyl ether (100 mL) and 1M aqeuous KOH solution (30 mL). The resultant ether layer was separated, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give the free amine base as a crude product. The crude product (5.16 g, 7.25% yield) was dissolved in acetone (25 mL), and oxalic acid (1.8 g) in acetone (25 mL) was added dropwise, with stirring. The mixture was allowed to stir for 24 hours with additional acetone. The acetone solution was evaporated and the oily residue was partitioned between ether (100 mL) and 1M aqueous KOH solution (100 mL). The ether solution was dried over anhydrous MgSO4, filtered and concentrated. The oily residue was dissolved in acetone ad an equivalent amount of oxalic acid in acetone was added dropwise. The oxalate salt of (adamant-1-yl)methyl 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate which separated was removed and dried. It melted at 55°-57° C. NMR and elemental analysis were consistent with structure. The free base has the formula: ##STR298##
Reaction SMILES: [CH:1]1[C:14]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([O:38][CH2:39][CH3:40])[C:26](NC(C4C=CC=CC=4)CO)=[O:27])=[CH:20][CH:19]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:42].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH:11]1[C:12]2[N:13]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@@H:25]([O:38][CH2:39][CH3:40])[C:26]([OH:42])=[O:27])=[CH:20][CH:19]=3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: CCOC(Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)NC(CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@H](Cc1ccc(OCCN2c3ccccc3Oc3ccccc32)cc1)C(=O)O
Temperature: 100 °C
Yield: 57 %

Procedure:
A solution of [2R diastereomer, N(1S)]-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy-N-(2-hydroxy-1-phenylethyl)propanamide (0.45 g, 0.84 mmol) obtained in example 21a in mixture of 1M sulphuric acid (17 mL) and dioxane/water (1:1, 39 mL) was heated in an oil bath at 100° C. for 60-68 h. The pH of the mixture was adjusted to 3.0 by addition of an aqueous sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate (2×25 mL) and the organic extract was washed with water (50 mL), brine (25 mL), dried (Na2SO4) and evaporated. The residue was chromatographed over silica gel using a gradient of 50-75% ethyl acetate in pet. ether to afford the title compound (0.2 g, 57%) as a white solid. mp: 77-78° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH:13]1[CH:17]=[C:16]([CH2:18][NH2:19])[O:15][CH:14]=1.O>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:19][CH2:18][C:16]2[O:15][CH:14]=[CH:13][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: NCc1ccco1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
4-Cyanobenzenesulfonyl chloride (1.77 g, 8.78 mmol) was dissolved in 8 mL of anhydrous pyridine and 2-furfurylamine (1.04 g, 9.66 mmol, 0.98 mL) was added. After 2 h, the reaction solutions were added to 100 mL cold water and stirred for 10 min. Filtration and washing with water provided the title compound as a yellow solid (2.04 g, 7.78 mmol, 89%). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.18 (s, 1H), 6.19 (m, 1H), 6.10 (m, 1H), 4.95 (m, 1H), 4.28 (d, J=6.0 Hz, 2H) ppm.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:21][C:22]1[CH:23]=[C:24]([F:31])[C:25]([O:29][CH3:30])=[C:26]([F:28])[CH:27]=1.CN([CH:35]=[O:36])C>C1COCC1>[Br:21][C:22]1[C:27]([CH:35]=[O:36])=[C:26]([F:28])[C:25]([O:29][CH3:30])=[C:24]([F:31])[CH:23]=1
Reactant: COc1c(F)cc(Br)cc1F
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1c(F)cc(Br)c(C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add n-butyl lithium 1.6N (22 ml, 35.2 mmol) to diisopropylamine (4.8 ml, 34.2 mmol) in anhydrous THF (7 ml) at 0° C. Stir the resulting yellow solution for 30 min at 0° C. Add this LDA solution dropwise via canula to a solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.83 g, 26.17 mmol) in anhydrous THF (40 ml) at −78° C. over 40 min. Stir the resulting bright yellow solution for 50 min at −78° C. Add anhydrous DMF (2.7 ml, 34.8 mmol) and stir the mixture for 1.5 h at −78° C. Quench the mixture with dilute sulfuric acid and extract the product with EtOAc (×3). Wash the combined organic layers with water (×3), saturated aq. sodium chloride and dry over anhydrous sodium sulfate. Filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Li+].CC([N-]C(C)C)C.[C:21]([O:25]C(C)=O)(C)(C)[CH3:22].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]([C:49]([C:51]4[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=4)=O)[C:44]([NH:47][CH3:48])=[N:45][CH:46]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1>C1COCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([C:41]3[CH:42]=[C:43]4[C:44](=[N:45][CH:46]=3)[N:47]([CH3:48])[C:21](=[O:25])[CH:22]=[C:49]4[C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([O:57][CH3:58])[CH:52]=3)[O:40][CH2:39][CH2:38][O:37]2)=[CH:32][CH:31]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: CNc1ncc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(=O)n(C)c3ncc(C4(c5ccc(Cl)cc5)OCCO4)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
To a solution of diisopropylamine (1.32 mL, 9.43 mmol) in THF, a solution of BuLi (7.86 mL, 7.08 mmol, 0.9 M solution in hexane) was added at −20° C. and the resulting mixture was stirred for 30 min. To this solution of LDA was added tBuOAc (0.95 mL, 7.08 mmol) at −78° C. The mixture was stirred for 30 min and a solution compound G (500 mg, 1.18 mmol) was added to it. The reaction mixture was allowed to warm to RT and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with EtOAc (50 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified by column chromatography to obtain 0.3 g (57%) of compound H off-white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:4][C:5]([C:22](F)([F:24])[F:23])=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:7]([CH:14]([CH3:16])[CH3:15])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C1CCN2C(=NCCC2)CC1.C1COCC1>O>[F:24][CH:22]([F:23])[C:5]1[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([CH:14]([CH3:15])[CH3:16])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:3]([C:2]([F:27])([F:1])[F:26])[N:4]=1
Reactant: CCOC(=O)C1=C(C(F)(F)F)NC(C(F)(F)F)=C(C(=O)OCC)C1C(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C(C)C
Yield: 37.8 %

Procedure:
A mixture of 50.0 g (0.124 mole) of diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-isopropyl-3,5-pyridinedicarboxylate, 18.87 g (0.124 mole) of DBU and 200 ml of THF is held at reflux for 18 hours and poured into water and extracted with ether. The ether extract is washed with diluted hydrochloric acid, dried (MgSO4) and concentrated. The residue is kugelrohr distilled at 1 torr to give 17.97 g (37.8%) of the desired product which is a liquid, nD25 1.4465.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([C:14]3[S:18][C:17]([CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[C:16]([CH3:25])[CH:15]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH2:21]([N:20]([CH2:19][C:17]1[S:18][C:14]([C:12]2[O:11][N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:4][CH:5]=3)[N:13]=2)=[CH:15][C:16]=1[CH3:25])[CH2:23][CH3:24])[CH3:22]
Reactant: CS(=O)(=O)Cl
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CN)cc3)no2)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CNS(C)(=O)=O)cc3)no2)cc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.7 %

Procedure:
To a solution of {5-[3-(4-aminomethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-thiophen-2-ylmethyl}-diethyl-amine (60 mg, 168 μmol) and DIPEA (33 mg, 252 μmol) in DCM (10 mL), methanesulfonyl chloride (23 mg, 202 μmol) is added. The mixture is stirred at rt for 15 h before it is diluted with DCM and washed with sat. aq. NaHCO3 solution. The washing is extracted back three times with DCM, the organic extracts are combined, dried over MgSO4, filtered and concentrated. The crude product is purified by prep. HPLC. The product containing fractions are combined and concentrated. The product is dissolved in methanol and filtered over Amberlyst A21. The filtrate is evaporated and dried to give the title compound (10 mg) as a colourless resin; LC-MS: tR=0.52 min; [M+1]+=435.03; 1H NMR (CDCl3): δ1.14 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 2.68 (q, J=6.8 Hz, 4H), 2.93 (s, 3H), 3.79 (s, 2H), 4.42 (d, J=5.8 Hz, 2H), 5.04-5.10 (m, 1H), 7.51 (d, J=8.3 Hz, 2H), 7.68 (s, 1H), 8.15 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:15])=[C:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[C:16](=[O:27])[C:17]#[C:18][CH2:19][O:20]C1CCCCO1.C(=O)(O)[O-].[Na+]>CO.Cl>[Br:1][C:2]1[N:6]2[C:7]([CH3:15])=[C:8]([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][C:3]=1[C:16](=[O:27])[C:17]#[C:18][CH2:19][OH:20]
Reactant: CCc1c(OC)nc2nc(C(=O)C#CCOC3CCCCO3)c(Br)n2c1C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCc1c(OC)nc2nc(C(=O)C#CCO)c(Br)n2c1C
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A solution of 5.0 g (11.5 mmol) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-(tetrahydropyran-2-yloxy)-2-butyn-1-one in a mixture of 100 ml of methanol and 35 ml of 2N hydrochloric acid stood at room temperature for 30 minutes and then was neutralized with aqueous sodium bicarbonate. Extraction with chloroform gave an oil which was chromatographed over silica (chloroform: ether: methanol 100:0:0 gradually changing to 0:95:5) to obtain 1.3 g (32%) of 1-(3-bromo-6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidin-2-yl)-4-hydroxy-2-butyn-1-one as off-white crystals melting at 212°-3° C. (decomp.).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH:17][N:18]=[CH:19][CH:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:21](OCC)=[O:22])=[N:15][CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([NH:8][C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([OH:22])=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=3)[CH:19]=[N:18]2)=[N:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C=NNc1ccc(C(=O)NCc2ccccc2)cn1)c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)NCc4ccccc4)cn3)c2O)cc1
Yield: 6.2 %

Procedure:
Combined ethyl 3-(2-(5-(benzylcarbamoyl)pyridin-2-yl)hydrazono)-2-(4-cyanophenyl)propanoate (90 mg, 0.204 mmol) and potassium carbonate (42.3 mg, 0.306 mmol) in ethanol (2 mL) and heated for 1 hour at 60° C. The reaction mixture was evaporated to give a residue which was purified by HPLC (ZQ9, Prep-TFA-50-55, Rt 4.54 min) to give the title compound (5 mg, 6%) as an off-white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 4.69 (d, J=5.56 Hz, 2H), 6.37 (br. s., 1H), 7.30-7.42 (m, 5H), 7.62-7.69 (m, 2H), 7.77-7.83 (m, 2H), 7.91 (s, 1H), 8.02 (d, J=8.08 Hz, 1H), 8.32 (dd, J=8.84, 2.27 Hz, 1H), 8.80 (d, J=1.77 Hz, 1H). MS m/z [M+H]+ 396.3.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[Cl:14].[Li+].[BH4-].[NH4+].[Cl-].CCOC(C)=O>C1COCC1.O>[Cl:14][C:6]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:5]=1[CH2:4][CH2:3][OH:2]
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CCO)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
(2-Chloro-4-nitro-phenyl)-acetic acid methyl ester (17 g, 74 mmol) was dissolved in dry THF (85 mL) and cooled to 0° C. A solution of LiBH4 in THF (2M, 75 mL, 148 mmol) was added drop-wise at 0° C. and the reaction mixture was maintained for 5 hours at RT. After completion of reaction, NH4Cl solution (2 mL) was added to the reaction mixture which was then stirred for 15 minutes. EtOAc (170 mL) and water (85 mL) were added and stirred for 10 minutes. The separated aqueous layer was extracted with EtOAc (85 mL), then the combined organic extracts were dried (Na2SO4) and evaporated under reduced pressure to give a yellow oil. The oil was purified by column chromatography on neutral silica gel using 5-10% EtOAc in hexane to give the title compound (10 g, 55%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[N:10][N:11]([CH3:12])[C:7]=2[CH:6]=[C:5]([C:13]2[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[C:15]([C:35]([F:38])([F:37])[F:36])[CH:14]=2)[N:4]=1)#[N:2].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl.C(#N)C>[OH:45][C:39]([C:41]([F:44])([F:43])[F:42])=[O:40].[CH3:12][N:11]1[C:7]2[CH:6]=[C:5]([C:13]3[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)=[C:15]([C:35]([F:38])([F:37])[F:36])[CH:14]=3)[N:4]=[C:3]([C:1]#[N:2])[C:8]=2[N:9]=[N:10]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)cc21
Solvent: CC#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl 4-(2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethyl)piperidine-1-carboxylate (6 g) in DCM (40 ml) and acetonitrile (20 ml) was added TFA (40 ml). The mixture was stirred at room temperature for 10 minutes, then solvent removed under vacuum. To the residue was then dissolved ethyl acetate (40 ml) and product was precipitated by adding ether (50 ml) and collected by filtration (6.05 g as TFA salt).
Reaction SMILES: BrC1C=CC=C[N+]=1C.[CH2:9]([OH:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:19](O)(=[O:21])[CH3:20].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[C:19]([O:18][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: OCC=Cc1ccccc1
Agent: C[n+]1ccccc1Br
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CC(=O)OCC=Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended CH2Cl2 (2 ml) solution of 2-bromo-1-methylpyridinium (720 mg, 2.4 mmol) was added a mixture of cinnamyl alcohol (268 mg, 2.0 mmol), acetic acid (120 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in CH2Cl2 (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and cinnamyl acetate was isolated in 82% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=C1CNCCN1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of 2-piperazinone (0.98 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (Aldrich, 2.0 mL, 14.35 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of 2-thiophenesulfonyl chloride (1.79 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (10 mL). After 30 min, the mixture was diluted with saturated aqueous NaHCO3 (10 mL) and stirred at room temperature for 3 d. The slurry was filtered and washed with water (3×5 mL) to give 4-(2-thiophenylsulfonyl)-2-piperazinone as a white powder (2.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(Cl)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (4.9 mL, 42.8 mmol) followed by LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (31 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.97 g (5.27 mmol, 98%) of (2R)-2-(4-chlorophenyl)propanoic acid; [α]D=−64.8° (C=1.05, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1 H), 7.32–7.23 (m, 4 H), 3.72 (q, 1 H, J=7.3 Hz), 1.50 (d, 3 H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11](C(OC)=O)[NH:12][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].O.NN>C(O)COCCOCCO>[CH2:1]([C:9]1[CH:10]=[CH:11][NH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)c[nH]1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: c1ccc(Cc2cc[nH]c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
12.0 g (52.4 mmole) of methyl 4-benzoyl-2-pyrrolecarboxylate, 8.79 g (157 mmole) of potassium hydroxide and 10.5 g (210 mmole) of hydrazine hydrate are dissolved in 150 ml of triethylene glycol. Reaction is carried out by stirring the solution at 120° C. for 2 hours and then at 160° C. for 3 hours in an atmosphere of nitrogen gas. After reaction is finished, the reaction solution is allowed to cool and poured into ice water, followed by extraction with ether. The extract is washed with water saturated with sodium chloride and concentrated. The residue is distilled under reduced pressure to obtain 5.86 g of 3-benzylpyrrole as a colorless liquid. Yield 71.2%. nD29.5 1.5790. Boiling point 95°-98° C. (0.09 mmHg).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[NH:30][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[CH:14]=2)[CH:8]=1)=[O:4].[CH3:31][NH:32][CH3:33]>O1CCOCC1.C(O)C>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:20]2[C:15]3[CH:14]=[C:13]([C:9]4[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=4)[CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:32]([CH3:33])[CH3:31])[NH:30][C:16]=3[N:17]=[CH:18][N:19]=2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CNC
Reactant: O=C(CCl)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Solvent: C1COCCO1
Solvent: CCO
Product: CN(C)CC(=O)NCc1cccc(-c2cc3c(Nc4ccc(F)c(Cl)c4)ncnc3[nH]2)c1
Temperature: 100 °C

Procedure:
2-Chloro-N-{3-[4-(3-chloro-4-fluoro-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzyl}-acetamide (120 mg, 0.222 mmol) in 2 ml dioxane and 0.145 ml (0.81 mmol) 5.6 N dimethylamine in ethanol (Fluka, Buchs, Switzerland) is stirred and heated to 100° C. for 4.5 h. The mixture is cooled and the solvent evaporated. The residue is shaken with THF (5 ml), dichloromethane (3 ml), methanol (2 ml) and saturated sodium bicarbonate (2 ml). The two clear layers are separated and the organic phase is treated with 1 g silica gel. The solution containing the silica gel is evaporated and the solid put on top of a flash chromatography column containing 33 g of silica gel. The column is eluted using a mixture of dichloromethane/methanol with gradually increasing concentrations of methanol starting with 100:2.5 and ending with 100:5 and then switching to dichloromethane/methanol/conc. ammonia starting with 100:5:0.25 and ending with 100:10:0.5. The title compound is obtained as colorless crystals; m.p. 272-273° C.: MS-ES+: (M+H)+=453.