Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28](=[O:43])[C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1.[OH-].[Na+].O>C(O)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:32]=1)[C:28]([NH:27][C:5]1[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:19][CH:18]=2)[CH:8]=[CH:9][C:4]=1[C:3]([OH:44])=[O:2])=[O:43]
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cc1
Temperature: 25 °C
Yield: 44.4 %

Procedure:
To a solution 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.30 g, 0.48 mmol) in ethanol (20 mL) was added 1.0 N, sodium hydroxide solution (4 mL). This mixture was heated to reflux for 20 minutes and then allowed to cool back to room temperature. Water (5 mL) was added to the mixture, it was concentrated to approximately ¼ volume and then partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 3 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with two additional portions of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (10/90 with 1% formic acid gradient to 20/80 with 1% formic acid) and then recrystallized one time from chloroform/hexanes (1/20) to give 2-{[3,5-bis(trifluoromethyl)benzoyl]amino}-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.13 g, 45%) as a white powder. mp=157.5-158.5° C. 1H NMR (500 MHz, DMSO-d6); δ 13.54 (bs, 1H), 12.54 (s, 1H), 8.51 (s, 2H), 8.45 (s, 1H), 8.32 (d, 1H), 8.21 (s, 1H), 8.00 (d, 1H), 7.50-7.37 (AA′BB′, 4H), 6.83 (dd, 1H), 4.27 (t, 2H), 4.21 (t, 2H), 2.16 (m, 2H), 1.23 (s, 9H). Mass spec (MW 610.55); (ES−) m/z 609.2. Elemental analysis; Calculated for C30H28F6N2O5: C, 59.02; H, 4.62; N, 4.59. Found: C, 58.78; H, 4.52; N, 4.46.
Reaction SMILES: [CH:1]1([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:17][C:18]#[N:19]>>[CH:1]1([N:10]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]#[N:19])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N#CCBr
Reactant: c1ccc2c(c1)CCC2N1CCNCC1
Product: N#CCN1CCN(C2CCc3ccccc32)CC1

Procedure:
The title compound is synthesized by coupling of 1-Indan-1-yl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=242.2: CtRet=4.25.
Reaction SMILES: Br[CH2:2][C:3](=[O:26])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C@@H:11]([CH2:12][C@:13]([C:24]#[CH:25])([OH:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[SH:27][CH2:28][CH2:29][OH:30].C(N(CC)CC)C>CCCCCC.CC(C)=O>[C:24]([C@@:13]1([OH:23])[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:26])[CH2:2][S:27][CH2:28][CH2:29][OH:30])[CH2:12]1)#[CH:25]
Reactant: OCCS
Reactant: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]32)C1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: C#C[C@@]1(O)CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(=O)CSCCO)CC[C@@H]32)C1

Procedure:
A solution of 21-bromo-3β-ethynyl-3α-hydroxy-5β-pregnan-20-one (150 mg, 0.356 mmol), 2-mercaptoethanol (31 μL, 0.445 mmol), and triethylamine (62 μL, 0.445 mmol) in 5 mL of TBF was stirred at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic layer was washed with sat. aq. NaCl, dried with Na2SO4 and concentrated in vacuo resulting in 3β-ethynyl-3α-hydroxy-21-hydroxyethylthio-5β-pregnan-20-one (141 mg) as a white solid; mp 122-126° C.; TLC Rf (hexane:acetone 3:1)=0.11.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:22])([O-:21])[CH3:20].[Na+].C1(C)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:19]([O:21][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1)([CH3:22])([CH3:20])[CH3:18]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ccc2cc(NC(=O)C3CC3)ncc2c1
Yield: 5.2 %

Procedure:
A mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (70.6 mg, 0.242 mmol), sodium tert-butoxide (36.0 mg, 0.374 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (13.0 mg, 0.0126 mmol), and Q-Phos (19.3 mg, 0.0272 mmol) in toluene (1.0 mL, 9.4 mmol) was subjected to microwave irradiation at 120° C. for 30 minutes. The reaction mixture was neutralized with 10% aqueous citric acid and extracted with dichloromethane. The organic extract was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 3.6 mg (5.2%) of N-(7-tert-butoxyisoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=4.371, M+H=285.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 9.06 (s, 1H), 8.40 (s, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.35 (dd, J=8.9, 2.4 Hz, 1H), 2.12-1.97 (m, 1H), 1.39 (s, 9H), 0.91-0.75 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:17]1([C:23]2[N:24]=[CH:25][C:26]3[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=3[N:28]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(Cl)Cl>[C:8]([CH:18]1[CH2:19][NH:20][CH2:21][CH2:22][N:17]1[C:23]1[N:24]=[CH:25][C:26]2[CH2:31][C:30](=[O:32])[N:29]([CH3:33])[C:27]=2[N:28]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)Cc2cnc(N3CCNCC3)nc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)Cc2cnc(N3CCNCC3C(=O)c3ccccc3)nc21
Yield: 75.8 %

Procedure:
One gram of triethylamine, 50 ml of methylene chloride and 0.6 g (4.3 mmoles) of benzoyl chloride were added to 1.0 g (4.3 mmoles) of 2-piperazino-5,6-dihydro-7-methyl-6-oxo(7H) pyrrolo[2,3-d]pyrimidine, and the mixture was reacted overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and after adding an aqueous solution of sodium hydrogen carbonate, extracted with chloroform. The chloroform layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.1 g (yield 76%) of the desired compound.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([O:36]C)=[O:35])=[CH:28][CH:27]=1>>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:28][CH:27]=2)=[CH:11][CH:12]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(S(C)(=O)=O)cc1
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)cc2)cc1)c1ccc(S(C)(=O)=O)cc1
Yield: 39.91 %

Procedure:
Compound 92 was synthesized from [4-({(2Z)-2-(methoxyimino)-2-[4-(methylsulfonyl)phenyl]ethyl}oxy)phenyl]methanol (0.57 g, 1.63 mmol) and methyl 3-(4-hydroxyphenyl)propanoate (0.293 g, 1.63 mmol) by following the procedure described in scheme 5 (0.2 g, yield: 39.91%); Purity: 96.52%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51].[F-].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[C:4]([CH:8]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]4[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]4)[CH2:18]3)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[N:6][CH:7]=2)=[CH:43][C:42]=1[N+:50]([O-:52])=[O:51]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Reactant: O=[N+]([O-])c1cc(B(O)O)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(-c2ccc(Cl)c([N+](=O)[O-])c2)c1
Temperature: 100 °C
Reaction time: 60 h
Yield: 52 %

Procedure:
To 171.5 mg (0.28 mmol) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 8c) in 7 ml toluene were added 6.5 mg (0.01 mmol) tetrakis(triphenylphosphine)palladium(0), 68.0 mg (0.34 mmol) (4-chloro-3-nitro-phenyl)boronic acid in 1.7 ml ethanol and 50.7 mg (0.87 mmol) potassium fluoride in 1.7 ml water. The mixture was stirred at 100° C. for 60 hours, diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated in vacuum. Chromatography over 10 g silica gel (dichloromethane/ethanol 100/0-95/5-90/10) gave 100 mg (47%) tert-butyl 4-{3-[(3R)-3-({1-[5-(4-chloro-3-nitrophenyl)pyridin-3-yl]-3-methoxy-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([N:16]([CH2:28][CH3:29])[C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH2:19][CH2:20][NH:21][CH:22]2[CH3:27])[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][CH:25]=[CH:26][C:17]=4[N:16]([CH2:28][CH3:29])[CH2:14][CH3:15])[CH:22]3[CH3:27])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCN(CC)c1cccc2c1CCNC2C
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CCN(CC)c1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with Diethyl-(1-methyl-1,2,3,4-tetrahydro-isoquinolin-5-yl)-amine to provide the title compound in moderate yield.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:22])[CH2:18][N:19]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]([OH:22])[CH2:18][NH2:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCC(O)COCCCCCCCCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC(O)COCCCCCCCCc1ccccc1
Yield: 88.7 %

Procedure:
A procedure similar to that described in Preparation 13 was repeated, except that 2.6 g of 3-(8-phenyloctyloxy)-2-hydroxypropylazide (Prepared as described in Preparation 65), 0.65 g of lithium aluminum hydride and 80 ml of anhydrous tetrahydrofuran were used, to give 2.11 g of the title compound, melting at 50° C. to 54° C.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([O:11][CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:13]([N:16]1[CH2:24][CH2:23][CH:19]([C:20](Cl)=[O:21])[CH2:18][CH2:17]1)(=[O:15])[CH3:14]>C(=S)=S>[C:13]([N:16]1[CH2:17][CH2:18][CH:19]([C:20](=[O:21])[C:8]2[CH:9]=[CH:10][C:5]([O:11][CH3:12])=[CH:6][CH:7]=2)[CH2:23][CH2:24]1)(=[O:15])[CH3:14]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Yield: 58.9 %

Procedure:
To a suspension of aluminum trichloride (3.40 g, 25.7 mmol) in CS2 (15 mL) were added anisole (1.90 mL, 17.6 mmol) and, portionwise, N-acetylisonipecotoyl chloride (2.40 g, 11.7 mmol). After the addition was complete, the mixture was refluxed for 1 h. The solvent was decanted and the red residue was dissolved in 5% HCl (50 mL) and was extracted with EtOAc (4×30 mL). The combined organic phase was dried and was concentrated under reduced pressure to afford the title compound as a colorless solid (1.8 g, 60%): mp 102-105° C.; 1H NMR (CDCl3) d 1.50-1.75 (m, 1H), 1.70-2.00 (m, 3H), 2.10 (s, 3H), 2.70-2.90 (m, 1H), 3.15-3.30 (m, 1H), 3.40-3.53 (m, 1H), 3.86 (s, 3H), 3.85-4.00 (m, 1H), 4.56 (d, J=13.2 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H).
Reaction SMILES: [Na].[Cl:2][CH2:3][C:4]#[N:5].[NH2:6][C:7]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[CH:12][C:8]=1[C:9](O)=[O:10]>CO>[Cl:16][C:14]1[CH:15]=[C:7]2[C:8]([C:9](=[O:10])[NH:5][C:4]([CH2:3][Cl:2])=[N:6]2)=[CH:12][C:13]=1[CH3:17]
Reactant: Cc1cc(C(=O)O)c(N)cc1Cl
Reactant: N#CCCl
Agent: [Na]
Solvent: CO
Product: Cc1cc2c(=O)[nH]c(CCl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
To a flask containing sodium (36 mg) was added anhydrous MeOH (5 ml). Chloroacetonitrile (0.520 g, 6.9 mmol) was then added and the clear solution was stirred at room temperature for 30 min under argon. A solution of 2-amino-4-chloro-5-methylbenzoic acid (1.13 g, 6.0 mmol) in anhydrous methanol (25 ml) was then added with a syringe via a rubber septum. The reaction mixture was stirred at room temperature for 2 hours under argon, then it was fitted with a condenser and placed in an oil bath preheated to 80° C. Stirring was continued at this temperature for 2 hours under argon, then the reaction mixture was allowed to cool to room temperature. The precipitate was collected by filtration, washed with methanol (10 ml), and water (10 ml), and dried in vacuo over P2O5 to afford a grey solid (1.0 g, 69%), mp 287-290° C.; 1H-NMR (DMSO-d6) 2.47 (s, 3H, 6-CH3), 4.53 (s, 2H, CH2Cl), 7.75, 8.08 (2×s, 2H, 5-H and 8-H); 12.60 (s, 1H, N3—H); MS (FAB, m/z) 243, 244, 245 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:13])=[C:5]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:7]#[N:8].[K].[O-][CH2:16]CCC.CI>O1CCCC1.O.CCOCC>[Br:1][C:2]1[N:3]([CH3:16])[C:4]([Br:13])=[C:5]([C:9]([F:10])([F:11])[F:12])[C:6]=1[C:7]#[N:8]
Reactant: CCCC[O-]
Reactant: N#Cc1c(Br)[nH]c(Br)c1C(F)(F)F
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cn1c(Br)c(C#N)c(C(F)(F)F)c1Br
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 2,5-dibromo-4-(trifluoro-methyl)pyrrole-3-carbonitrile (0.10 g, 0.30 mmo1) in tetrahydrofuran is treated with solid potassium! butoxide (0,053 g, 0.49 mmo1), stirred for I hour at 25° C., treated dropwise with methyl iodide (0 067 g, 0.47 mmol), stirred for 2 hours at 25° C. and for 1 hour at 50° C. and diluted with water and ether. The phases are separated and the organic phase is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to afford the title compound as a white solid, 0.09 g, mp 101° to 104° C.
Reaction SMILES: O=O.[S:3]([N:13]1[CH2:16][C:15]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:14]1)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(=O)(O)[O-:22].[Na+]>O.[Pt]>[S:3]([N:13]1[CH2:14][C:15]([CH2:19][OH:20])([C:17]([OH:22])=[O:18])[CH2:16]1)([C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)N2CC(CO)(CO)C2)cc1
Reactant: O=C([O-])O
Agent: [Pt]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CC(CO)(C(=O)O)C2)cc1
Reaction time: 5 h

Procedure:
Oxygen was bubbled rapidly through a stirred mixture of N-tosyl-3,3-bishydroxymethyl azetidine (0.5 g, 0.0018 mol), sodium bicarbonate (0.155 g, 0.0018 mol) and 5% Pt/C (0.3 g) in distilled water (10 ml) at 60° C. for 15 h. Sodium bicarbonate (0.155 g, 0.0018 mol) was added to maintain pH7-8 and the reaction continued a further 5 h. After cooling, the catalyst was filtered off, washed with water and the filtrate acidified with 4N HCl. Extraction with ether (x3), drying and evaporating left a white solid. The catalyst was washed again with water and the above procedure repeated to yield further solid. The whole was recrystallised from ethanol/water to give the title product as white crystals m.p. 148°-150° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH:11]12[O:20][CH:17]([CH2:18][CH2:19]1)[CH:16]1[CH:12]2[C:13](=[O:22])[CH2:14][C:15]1=[O:21].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[CH3:8][C:7]1[C:2]([CH:14]2[C:13](=[O:22])[CH:12]3[CH:16]([CH:17]4[O:20][CH:11]3[CH2:19][CH2:18]4)[C:15]2=[O:21])=[N:3][C:4]([S:9][CH3:10])=[N:5][CH:6]=1
Reactant: CSc1ncc(C)c(Cl)n1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: CSc1ncc(C)c(C2C(=O)C3C4CCC(O4)C3C2=O)n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 11.2 %

Procedure:
A microwave vial is charged with 4-chloro-5-methyl-2-methylsulfanylpyrimidine (174 mg, 1 mmol), 10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (166 mg, 1 mmol), palladium acetate (12 mg, 0.05 mmol), X-Phos (48 mg, 0.1 mmol) and potassium phosphate (424 mg, 2 mmol). 1,2-dimethoxyethane (3 ml) is added and the reaction heated to 160° C., with stirring, for 30 minutes. Silica gel is added to the crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-10-oxa-tricyclo[5.2.1.0*2,6*]decane-3,5-dione (34 mg).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:13][O:12][C:11]1[C:2]([C:18]2[CH:17]=[N:16][N:15]([CH3:14])[CH:19]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1ccc2ncccc2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2ncccc2c1-c1cnn(C)c1
Temperature: 100 °C
Yield: 139.3 %

Procedure:
A mixture of 5-bromo-6-methoxy-quinoline (6.5 g, 0.021 mol), 1-methyl-4-pyrazoleboronic acid pinacol ester (8.74 g, 0.042 mol), Na2CO3 (6.687 g, 0.063 mol), Pd(dppf)Cl2 (1.7 g, 0.001 mol), H2O (32 mL) and 1,4-dioxane (80 mL) was heated at 100° C. overnight. After cooling down to room temperature, most of the dioxane was removed under vacuo. The mixture was diluted with ethyl acetate (50 mL) and brine (50 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give compound 7 g of 6-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-quinoline.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[N:11]([O-:13])=[O:12].[Na+].C(OC(C)C)(=O)C.II.C(OO)(=O)C.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C>[N+:11]([C:7]1[CH2:8][CH2:9][C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=1)([O-:13])=[O:12]
Reactant: C1=Cc2ccccc2CC1
Reactant: O=N[O-]
Agent: CC(=O)OO
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)O
Product: O=[N+]([O-])C1=Cc2ccccc2CC1
Temperature: 50 °C
Yield: 89.4 %

Procedure:
Into a three-necks flask equipped with a reflux condenser and a mechanic stirrer, at room temperature and under inert gas, 1,2-dihydronaphthalene (3.9 g; 30 mmoles), sodium nitrite (6.2 g; 90 mmoles) and isopropyl acetate (40 ml) were charged. The mixture was kept under stirring and heated at 50° C. Iodine (3:8 g; 15 mmoles) and then, through a rubber separator, a solution of peracetic acid in acetic acid (8.5 ml—solution 39% w/w) were added in 4 hours. At the end of the addition, the mixture was kept under stirring for further 30 minutes, cooled to 20° C., then a freshly prepared 10% sodium metabisulphite solution was slowly (15 minutes) added up to decoloration of iodine (about 30 ml). The phases were separated and the aqueous phase was washed with isopropyl acetate (2×10 ml). The collected organic phases were washed with a saturated sodium chloride aqueous solution (10 ml). After separation of the phases, the organic phase was dried on sodium sulphate, filtered and the solvent was removed under reduced pressure obtaining crude 2-nitro-3,4dihydronaphthalene (4.7 g; 73% yield) as a brown oil.