Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1(C)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C

Procedure:
One hundred milligrams of 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-5-heptanolide was dissolved in 0.1 ml of methylene chloride and 0.63 ml of acetic anhydride, 0.56 ml of triethylamine and 1.5 mg of N,N-dimethyl-4-pyridineamine were added thereto under cooling at 0° C. After allowing to stand under ice-cooling for 4 hours, the reaction mixture was poured into ice-water and the crystals thus precipitated were recrystallized from a mixture of ethyl acetate and n-hexane (1:10) affording 68 mg of the desired compound melting at 98°-101° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH3:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=1.[Cl:20][C:21]1[S:25][C:24]([S:26](Cl)(=[O:28])=[O:27])=[CH:23][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:20][C:21]1[S:25][C:24]([S:26]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][C:9]=3[O:11][CH3:12])[N:4]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:3]=2)(=[O:28])=[O:27])=[CH:23][CH:22]=1
Reactant: COc1cccc2c1c(N)nn2C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2C(=O)OC(C)(C)C

Procedure:
To a solution of 1,1-dimethylethyl 3-amino-4-(methyloxy)-1H-indazole-1-carboxylate (for a preparation see Intermediate 5) (6.03 g, 22.9 mmol) and 5-chloro-2-thiophenesulfonyl chloride (3.07 mL, 22.9 mmol) in DCM (30 mL) was added dropwise at 0° C. a solution of pyridine (3.7 mL, 46 mmol) in DCM. The reaction mixture was stirred allowing to warm from 0° C. to room temperature over 2 h, then stirred at room temperature over the weekend. Pyridine (50 mL) were added and resulting mixture was stirred at 50° C. for another 24 h. The reaction mixture was then quenched with 50 mL of a saturated NaHCO3 solution. The organic layer was partitioned and the aqueous layer was further extracted with 50 mL of DCM. The organic solutions were combined, washed with water (50 mL) then brine (50 mL), and dried with an hydrophobic frit. The crude product was purified by chromatography on two 100 g Si cartridges on Flashmaster, eluting with 0 to 25% gradient of EtOAc in DCM, over 60 min to give the desired product as a pale orange solid: (2.21 g, 22%). LCMS (System A) RT=1.35 min, ES+ve m/z 444 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[O:30]1[C:35]2[CH:36]=[CH:37][C:38]([CH:40]=O)=[CH:39][C:34]=2[O:33][CH2:32][CH2:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[Cl:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:40]([C:38]3[CH:37]=[CH:36][C:35]4[O:30][CH2:31][CH2:32][O:33][C:34]=4[CH:39]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc5c(c4)OCCO5)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.024 g, 0.06 mmol) and EtOH (3.0 ml) was added 2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde (0.017 g, 0.10 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was stirred at 80° C. for 22 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with 2% methanol in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.007 g, 23%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 4.31 (s, 4H, OCH2CH2O), 7.01 (d, J=8.2 Hz, 2H, PhH), 7.24 (d, J=3.5 Hz, 1H, thiazole H), 7.48 (d, J=3.5 Hz, 1H, thiazole H), 7.69 (m, 3H, PhH)), 8.08 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.87 (s, 1H, CONH), 13.30 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.[ClH:34]>O1CCOCC1>[ClH:34].[ClH:34].[C:1]([O:5][C:6]([N:8]([C@@H:22]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23]1)[C:9]1[N:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)OCC)cn2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCN1CC[C@@H](N(C(=O)OC(C)(C)C)c2ccc(/C=C/C(=O)O)cn2)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (308 mg) in dioxane (7.4 mL) was added 1N sodium hydroxide (2.21 mL). After stirring at 60° C. for 2 hours, the reaction mixture was added H2O (37 mL) and acidified with 1N hydrochloric acid (to pH 1). A resulting mixture was extracted with CHCl3, and the organic layer was dried over MgSO4, filtered, and evaporated in vacuo to give (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-1-butyl-3-pyrrolidinyl]amino}-3-pyridinyl)acrylic acid dihydrochloride (214 mg).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:16])[CH:7](O)[C:8]1[C:9](=O)[CH2:10][CH:11]([CH3:13])[CH:12]=1)[CH2:2][CH2:3][CH3:4].O.C1(C)C=CC(S(O)(=O)=[O:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:6](=[O:16])[CH:7]=[C:8]1[CH2:12][CH:11]([CH3:13])[C:10](=[O:25])[CH2:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCOC(=O)C(O)C1=CC(C)CC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C=C1CC(=O)C(C)C1
Temperature: 15 °C
Reaction time: 2 h
Yield: 1072.9 %

Procedure:
Step 3 Dehydration (n-Butyl Ester): Into a 5-L, 3-necked, round-bottomed flask equipped with a condenser, thermometer and nitrogen inlet were added 154.8 g (0.68 M) alpha-hydroxy-4-methyl-3-oxo-cyclopentene acetic acid butyl ester (as prepared by Example 4), 2.3 L of toluene, and 12.9 g (0.068 M) of p-toluenesulfonic acid monohydrate. The resulting reaction mixture was stirred at 75°-78° C. for 61/2 hours under nitrogen. When the reaction was complete, the mixture was cooled to 15° C., poured into a separatory funnel, washed with three 1-L portions of a total of 3 L of water, dried (MgSO4) and evaporated to give 153 g of the homogeneous 4-methyl-3-oxo-cyclopentylidene acetic acid butyl ester bp 82°-84° C./0.05 mm Hg, as a red oil for use in Example 8.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:14]([CH:19]=[CH:20][CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[CH2:23]([S:22][C:13]1[C:12]([NH:11][CH:1]=[O:2])=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1cccc(N)c1SCc1ccccc1
Reactant: O=CO
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cccc(NC=O)c1SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
27.0 g (0.586 mol) of formic acid are added dropwise to 48.6 g (0.476 mol) of acetic anhydride at 0° C. After the mixture has been stirred at 50°-60° C. for 2 h it is cooled to 0° C. and a solution of 50.0 g (0.183 mol) of methyl 3-amino-2-benzylmercaptobenzoate in 150 ml of THF is added. The reaction solution is then stirred at room temperature for 4 h. The mixture is concentrated under reduced pressure (60° C., 0.1 torr). The resulting oily residue (61.77 g) is employed in subsequent reactions without further purification (cf. Example e)).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][N:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH:9]([OH:14])[CH2:8][C:7]1([CH3:16])[CH3:15].[OH-].[K+]>C1C=CC=CC=1>[C:1]([CH2:2][CH2:3][O:14][CH:9]1[CH2:8][C:7]([CH3:15])([CH3:16])[N:6]([CH3:5])[C:11]([CH3:13])([CH3:12])[CH2:10]1)#[N:4]
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: CN1C(C)(C)CC(OCCC#N)CC1(C)C
Reaction time: 16 h

Procedure:
2.65 parts of acrylonitrile was added dropwise with stirring to a solution of 8.55 parts of 1,2,2,6,6-pentamethylpiperidin-4-ol and 0.30 parts of 40 % potassium hydroxide solution in 80 parts of benzene. Stirring was continued at room temperature for 16 hours after which time the solution was washed with water, dried and the benzene solvent removed by distillation under reduced pressure. Fractional distillation of the residue, under reduced pressure gave 1.70 parts of 4-(2'-cyanoethoxy)-1,2,2,6,6-pentamethylpiperidine having a boiling point of 105°-6° C. at 0.1 mm of Hg and the following elemental analysis by weight:
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:33][CH:32]([N:34]5[CH2:38][CH2:37][CH2:36][C:35]5=[O:39])[CH2:31]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: O=C1CCCN1C1CNC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCCC4=O)C3)n(C)c2n1
Reaction time: 65 h
Yield: 63.7 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (165 mg, 0.42 mmol), 1-azetidin-3-ylpyrrolidin-2-one (65 mg, 0.46 mmol) and 4 Å powdered molecular sieves in DCE (4 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (180 mg, 0.84 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-15%) affording 588 as an orange foam (138 mg, 64%). LCMS (method I): RT 2.42 min [M+H]+ 516.2 1H NMR (CDCl3, 300 MHz): δ 8.00 (m, 1 H), 7.76 (m, 1 H), 7.27 (m, 2 H), 4.83 (t, J=6.9 Hz, 1 H), 4.35 (m, 4 H), 3.89-3.82 (m, 9 H), 3.67-3.54 (m, 4 H), 3.36 (m, 4 H), 2.42 (t, J=8.1 Hz, 2 H), 2.07 (m, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][C:4]=1[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:4]1[N:5]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[S:7][C:3]=1[CH2:1][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: O=Cc1sc(NC(=O)c2ccncc2)nc1-c1ccco1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(CN2CCOCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Compound 85 (250 mg, 0.836 mmol) was dissolved in 1,2-dichloroethane (4 mL), and morpholine (0.15 mL, 1.67 mmol) and sodium triacetoxyborohydride (531 mg, 2.51 mmol) were added thereto, followed by stirring overnight at room temperature. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=30:1) to afford the entitled Compound 86 (302 mg, 98%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=2)[CH:18]=1.O>O1CCCC1>[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]2[CH:31]=[CH:30][C:27](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:25]=2)[CH:18]=1
Reactant: O=Cc1ccc(Oc2cccnc2)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Oc2cccnc2)cc1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
In 6 ml of anhydrous tetrahydrofuran was suspended 700 mg of sodium hydride (purity: 50%), and into the suspension was dropped a mixture of 3.65 g of ethyl diethylphosphonoacetate and 3 ml of anhydrous tetrahydrofuran at a temperature of 30° to 35° C., after which the resulting mixture was subjected to reaction at room temperature for one hour. To the reaction mixture was added dropwise a mixture of 3.0 g of 4-(pyridin-3-yloxy)benzaldehyde and 3 ml of anhydrous tetrahydrofuran at room temperature, and the temperature thereof was gradually elevated. The mixture was subjected to reaction at 60° C. for 15 minutes. Subsequently, the reaction mixture was cooled to room temperature, and 20 ml of water was added to the mixture, after which the resulting mixture was subjected to extraction with 20 ml of ethyl acetate. The extract was washed with 10 ml of a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform], to obtain 3.64 g (yield 89.8%) of colorless, oily ethyl (E)-3-[4-(pyridin-3-yloxy)phenyl]acrylate.
Reaction SMILES: C(S([C:16]1[CH:32]=CC=C[C:17]=1[O:18][C:19]1C=C[CH:22]=[CH:21][C:20]=1S([O-])(=O)=O)(=O)=O)CCCCCCCCCCC.[Na+].[OH2:34]>>[C:17]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])(=[O:34])[CH:16]=[CH2:32]
Reactant: O
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccccc1Oc1ccccc1S(=O)(=O)[O-]
Agent: [Na+]
Product: C=CC(=O)OCCCC

Procedure:
Emulsifier solution 1: 45% strength by weight solution of sodium (dodecylsulfonylphenoxy)benzenesulfonate (Dowfax® 2 A1 from Dow Chemicals) in water
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH:9](C)[CH3:10])=[O:7].[OH:33]S(O)(=O)=O.O>C(O)CO>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH2:10][OH:33])=[O:7]
Reactant: O=S(=O)(O)O
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Solvent: OCCO
Solvent: O
Product: O=C(COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F)OCCO
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (0.63 g, 1.41 mmol, 1.0 eq) in ethylene glycol (30 mL) at room temperature was added H2SO4 (0.4 mL, 7.5 mmol, 5.3 eq) dropwise. The reaction mixture was stirred overnight at 10° C. then heated at 40° C. for 3 h. The reaction was then cooled to room temperature and poured into water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with 5% Na2CO3, water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (EtOAc:petroleum ether, 1:5 to 1:1) to give the title compound as an oil, which crystallised on standing to give a white solid (0.54 g, 85%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13](Br)=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[CH3:23][C:24]([OH:28])([C:26]#[CH:27])[CH3:25]>C(NC(C)C)(C)C.C([O-])(=O)C.[Cu+]>[OH:28][C:24]([CH3:25])([CH3:23])[C:26]#[C:27][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([C:27]#[C:26][C:24]([CH3:25])([OH:28])[CH3:23])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22]
Reactant: C#CC(C)(C)O
Reactant: Fc1c(F)c(-c2c(F)c(F)c(Br)c(F)c2F)c(F)c(F)c1Br
Agent: [Cu+]
Agent: CC(=O)[O-]
Solvent: CC(C)NC(C)C
Product: CC(C)(O)C#Cc1c(F)c(F)c(-c2c(F)c(F)c(C#CC(C)(C)O)c(F)c2F)c(F)c1F
Temperature: 0 °C

Procedure:
To a solution of 4,4'-dibromooctafluorobiphenyl (10 g, 21.9 mmol) in degassed diisopropylamine (350 mL) was added dichlorobis(triphenylphosphine) palladium (770 mg, 1.05 mmol, 5 mol %) and copper (1) acetate (219 mg, 1.05 mmol, 5 mol %). The solution was cooled to 0° C. and to this solution was added 2-methyl-3-butyn-2-ol (2.2 equivalents, 4.0 g, 4.7 mL). The solution was allowed to warm to room temperature and was subsequently heated at 50° C. for 12 hours. The solution was cooled and filtered to remove the precipitate of diisopropylammonium bromide. The solvent was removed at reduced pressure and the residue was chromatographed on a column of silica gel (200 g) packed with ethyl acetate. An oily yellow solid was removed from the column. The addition of a couple of drops of methanol caused the oil to solidify. The resulting solid was recrystallized from a mixture of ethyl acetate/hexane (1:2) to yield 4,4'-bis(3-hydroxy-3-methyl-1-butynyl) octafluorobiphenyl as white crystals. The yield was 8.6 (92%), mp 119° -121° C. IR (KBr) 3400, 2960, 1475, 1365, 1210, 1170, 990, 962 cm-1. 1H NMR (80 MHz, CDCl3) δ2.7 (s, 2H), 1.53 (s, 12H); Mass Spectrum (E1)(rel. intensity 462 (3.7), 447 (44.0), 432 (1.5); Anal. Calcd for C22H14F8O2 : C, 57.14; H, 3.03. Found: C,60.60; H,4.78.
Reaction SMILES: Cl.[CH3:2]OC(=O)[C@H](N)CCC.[CH2:11]([C@@H:13]1[CH2:18][NH:17][C@@H:16]([CH3:19])[CH2:15][N:14]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:12]>>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:14]2[CH2:15][C@H:16]([CH3:19])[NH:17][CH2:18][C@H:13]2[CH2:11][CH2:12][CH3:2])=[CH:26][CH:25]=1
Reactant: CC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1
Reactant: CCC[C@@H](N)C(=O)OC
Agent: Cl
Product: CCC[C@@H]1CN[C@@H](C)CN1Cc1ccc(OC)cc1

Procedure:
(2R,5S)-1-(4-Methoxy-benzyl)-5-methyl-2-propyl-piperazine was prepared from (R)-2-amino-pentanoic acid methyl ester hydrochloride in analogy to the synthesis of (2R,5S)-2-ethyl-1-(4-methoxy-benzyl)-5-methyl-piperazine.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([Li])[CH2:7][CH2:8][CH3:9].O>C1(C)C=CC=CC=1>[CH3:4][CH:3]=[CH:2][CH:1]([OH:5])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C/C=C/C=O
Reactant: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC=CC(O)CCCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
31.5 g of crotonaldehyde are added dropwise, at -20° C. in the course of 75 minutes, to 32 g of butyllithium, dissolved in 145.8 g of toluene. After the reaction has proceeded for two hours, the temperature increasing slowly to 0° C., 250 ml of water are carefully added dropwise. The aqueous phase is separated off and washed once with 100 ml of toluene. The combined organic phases are washed neutral with water, dried over sodium sulphate and distilled. 46 g of oct-2-en-4-ol of boiling point 68°-72° C./13 mb are obtained. According to the gas chromatogram, the purity is 96%. The NMR spectrum confirms the expected structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C@H:15]2[CH2:19][CH2:18][C@@:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[F:61][CH2:62][CH2:63]O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:63][CH2:62][F:61])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]2[CH2:19][CH2:18][C:17]3([CH2:23][CH2:22][N:21]([CH3:24])[C:20]3=[O:25])[NH:16]2)[CH:10]=1
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4cc(O)ccc4F)ccn3)N2)C1=O
Reactant: OCCF
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CN1CCC2(CCC(c3cc(-c4cc(OCCF)ccc4F)ccn3)N2)C1=O
Temperature: 120 °C

Procedure:
To a Smith microwave vial was added (2R,5S)-2-[4-(2-fluoro-5-hydroxy-phenyl)-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (which may be prepared as described in Description 134) (66.5 mg, 0.1900 mmol), triphenyl phosphine (102.19 mg, 0.3900 mmol), Di-tert-butyl azodicarboxylate ((89.71 mg, 0.3900 mmol) and 2-fluoroethanol (0.02 mL, 0.2900 mmol) in THF (0.5000 mL). Toluene (1 mL) was added. The reaction mixture was heated by microwave at 120° C. for 45 min. The reaction mixture was eluted on an SCX-2 cartrige (0.5 g) and washed with DCM followed MeOH. The desired product was eluted off the cartridge with ammonia in MeOH (0.2M). Evaporation of solvents gave colourless oil. The crude residue was purified by silica gel chromatography (KPNH silica 11 g) eluting with ethyl acetate in iso-hexane (10-100%) followed by methanol in ethyl acetate (0-18%). Evaporation of desired fractions gave colourless oil. It was further purified by a ChiralPak IA column eluting with ethanol/n-heptane (20%:80%) to give 2R,5S)-2-[4-[2-fluoro-5-(2-fluoroethoxyl)phenyl]-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16](O)=[O:17].CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[I:44][C:45]1[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=1>C(Cl)Cl>[I:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])=[CH:47][CH:46]=1
Reactant: COc1cccc(Cn2c(C(=O)O)cc3ccccc32)c1
Reactant: Nc1ccc(I)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(Cn2c(C(=O)Nc3ccc(I)cc3)cc3ccccc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg 1-(3-Methoxy-benzyl)-1H-indole-2-carboxylic acid in 8 ml DCM and 0.9 NEt3 452 mg, BOP-Cl was added at RT and the mixture was stirred for 30 min. After addition of 583 mg 4-Iodo-phenylamine the mixture was stirred for 16 h. Then the solvent was removed under reduced pressure to yield a white precipitate, which was washed with 1 ml MeOH/DCM 1:1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1>C(O)C>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
4-(Thiazolidin-2,4-dione-5-ylidinemethyl)-phenol (38) was synthesized by the condensation of 4-hydroxy benzaldehyde (36) with commercially available 2,4-thiazolidinedione (37) using piperidine as base in refluxing ethanol, according to a known procedure (Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.) (Scheme 2)