Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]2[C:14]=1[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH:17]2[CH2:23][C:24](OCC)=[O:25]>>[F:12][C:13]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]2[C:14]=1[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:31])[CH3:32])[CH:17]2[CH2:23][C:24]([NH:10][C:9]([NH2:11])=[NH:8])=[O:25]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2c(F)ccc(F)c2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2c(F)ccc(F)c2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h

Procedure:
N-[(4,7-Difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 2.68 g of potassium tert-butoxide, 2.74 g of guanidinium chloride and 1.49 g of ethyl (4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then filtered. The filtrate is taken up in 80 cm3 of water and 120 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted twice with 120 cm3 of ethyl acetate. The organic extracts are combined, dried over magnesium 5 sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 40° C. The evaporation residue is purified by chromatography under argon pressure (50 kPa) on a column of silica gel (particle size 15-40 μm), eluting with successive mixtures of dichloromethane/methanol (95/5 and then 90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 35° C. The residue is taken up in diethyl ether, triturated, filtered and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.16 g of N-[(4,7-difluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]-quanidine is thus obtained in the form of a pale yellow solid melting at 212° C. Mass spectrum: DCI: m/e 325 (M+H)+, m/e 263 (base peak).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH:10]([CH3:12])[CH3:11])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:3]1=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl:37][C:38]1[CH:39]=[C:40]([CH2:45][C:46](O)=[O:47])[CH:41]=[C:42]([Cl:44])[CH:43]=1>CN(C)C=O.C(OCC)(=O)C>[O:9]=[C:8]1[N:7]([CH:10]([CH3:11])[CH3:12])[C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]([CH2:17][C:18]([F:19])([F:21])[F:20])[C:3](=[O:22])[CH:2]1[NH:1][C:46](=[O:47])[CH2:45][C:40]1[CH:39]=[C:38]([Cl:37])[CH:43]=[C:42]([Cl:44])[CH:41]=1
Reactant: CC(C)N1C(=O)C(N)C(=O)N(CC(F)(F)F)c2ccccc21
Reactant: O=C(O)Cc1cc(Cl)cc(Cl)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NC(=O)Cc2cc(Cl)cc(Cl)c2)C(=O)N(CC(F)(F)F)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.9 %

Procedure:
To a stirring solution of 3-amino-1-(2-propyl)-5-(2,2,2-trifluoroethyl)-1,5-benzodiazepine-2,4-dione (180 mg, 0.57 mmol) in N,N-dimethylformamide (2 mL) was added EDC (131 mg, 0.69 mmol), HOBT (46 mg, 0.34 mmol) and 3,5-dichlorophenylacetic acid (140 mg, 0.69 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was diluted with ethyl acetate (50 mL), then washed with 10% aqueous potassium hydrogen sulfate (25 mL) then saturated aqueous sodium hydrogen carbonate (25 mL) and finally, brine (25 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 25-40% ethyl acetate:hexane to give 100 mg of product which was crystallized from ethyl acetate/hexane to give colorless crystals (70 mg). m.p.=185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C@H:25]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH3:26])=[O:8]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2N2CC(Oc3cccc(F)c3)C2)cc1
Yield: 80.2 %

Procedure:
The title compound (D147) (90 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (75 mg, 0.232 mmol) and (S)-methyl 4-(1-aminoethyl)benzoate (D3) (50 mg, 0.232 mmol).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].Cl.[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH2:14][NH:13][CH2:12][CH2:11]2.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O>[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[CH2:14][N:13]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:12][CH2:11]2
Reactant: CCC(=O)Cl
Reactant: COc1cc2c(cc1O)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCC(=O)N1CCc2cc(O)c(OC)cc2C1
Reaction time: 18 h
Yield: 69.9 %

Procedure:
55.5 g of propionyl chloride are added dropwise at room temperature over a period of one hour to a mixture of 86.3 g of 1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-isoquinoline-hydrochloride, 138,2 g of potassium carbonate, 600 ml of methylene chloride, and 480 ml of water. The mixture is stirred for an additional 18 hours, the organic phase is separated, and the aqueous phase is extracted twice with methylene chloride. The methylene chloride extracts are dried and evaporated. 65.8 g of 1,2,3,4-tetrahydro-6-hydroxy-7-methoxy-2-propionyl-isoquinoline are obtained. m.p. = 116° - 118° C. (ethyl acetate - diisopropyl ether).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:47])C(=O)C1>CC#N>[NH2:1][C:2]1[C:11]([Cl:47])=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 40 °C
Yield: 75.6 %

Procedure:
A solution of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.60 g, 2.91 mmol) and NCS (0.39 g, 2.91 mmol) in 80 mL CH3CN was stirred at 40° C. for 30 mins. Additional NCS (0.39 g, 2.91 mmol) was added, the reaction mixture was heated at 40° C. for another 30 mins, evaporated onto silica gel, and purified by silica gel chromatography (0-70% EtOAc/hexanes) to afford the title compound (1.29 g, 76%) as a light pink solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (d, J=2.54 Hz, 1H), 7.85-7.92 (m, 2H), 7.71 (s, 1H), 7.65 (d, J=2.63 Hz, 1H), 7.43 (s, 1H), 7.15-7.22 (m, 2H), 6.36 (br. s., 2H), 5.85 (d, J=4.78 Hz, 1H), 3.87 (s, 3H), 3.19 (s, 3H), 2.98 (d, J=4.88 Hz, 3H), 2.15-2.30 (m, 1H), 0.31-1.11 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](#[N:17])[CH2:14][C:15]#[N:16].C([O-])(=O)C.[NH4+].C(O)(=O)C>C1C=CC=CC=1.O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[C:14]([C:13]#[N:17])[C:15]#[N:16])[CH3:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC#N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CC(=C(C#N)C#N)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 1-(4-nitrophenyl)ethanone (15 g, 90.8 mmol), malononitrile (6 g, 90.8 mmol), ammonium acetate (7 g, 90.8 mmol) and acetic acid (10 mL) in benzene (200 mL) was stirred at reflux overnight in a flask equipped with a Dean-Stark trap. The reaction mixture was cooled to room temperature, poured into water, and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 25% ethyl acetate/hexanes to provide 9.42 g of the desired product. Rf=0.33 (25% ethyl acetate/hexanes).
Reaction SMILES: [NH2:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)[C:3]1=[O:21].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][N:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]1=[O:21]
Reactant: COc1ccc(-n2c(=O)cc(C(F)(F)F)n(N)c2=O)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2ccc(O)cc2)c1=O
Yield: 100.2 %

Procedure:
By the method of Example 12, Step B, 1.0 gram (0.0033 mole) of 1-amino-3-(4-methoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 2.5 grams (0.01 mole) of boron tribromide were reacted in 30 mL of methylene chloride, yielding 0.95 gram of 1-amino-3-(4-hydroxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 150°-155° C. The NMR spectrum was consistent with the proposed spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.O=[C:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10](OC)=[O:11]>C1(C)C=CC=CC=1>[CH2:14]([C:8]1[CH:9]=[C:10]([OH:11])[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCC(=O)CC(=O)OC
Reactant: Nc1cc[nH]n1
Solvent: Cc1ccccc1
Product: CCCCc1cc(O)n2nccc2n1
Temperature: 100 °C
Yield: 80.1 %

Procedure:
A solution of 100 g of 3-aminopyrazole and 190 g of methyl 3-oxoheptanoate in 120 ml of toluene was refluxed with heating at 100° C. for 3 hours and then cooled. Toluene was distilled off under reduced pressure and diethyl ether was added to the residue. The crystals precipitated were collected and washed with diethyl ether and acetonitrile to provide 184 g of 5-n-butyl-7-hydroxypyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Br:1][C:2]1[N:3]=[N:4][C:5]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[F:9])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: Brc1ccc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Fc1ccccc1-c1ccc(Br)nn1

Procedure:
300 mg (1.26 mmol) of 3,6-dibromopyridazine, 176.5 mg (1.26 mmol) 2-fluoro-phenylboronic acid, 34.7 mg (0.038 mmol) of tetrakis(triphenylphosphine)palladium and 1.26 ml of an aqueous 1 M sodium carbonate solution in 15 ml of DME were heated under reflux for 3 h. After cooling, the reaction mixture was poured onto water and extracted with ethyl acetate. The combined organic phases were dried, evaporated, and the product purified by RP18 chromatography. Yield: 62 mg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][CH:3]1[OH:14].C(N(CC)CC)C.Cl[CH2:23][C:24](Cl)=[O:25].[H-].[Na+]>C(Cl)Cl.CCOC(C)=O.C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:2]1[NH:1][C:24](=[O:25])[CH2:23][O:14][CH:3]1[CH2:4]2
Reactant: COc1cccc2c1CC(N)C(O)C2
Reactant: O=C(Cl)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CC1NC(=O)COC1C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 68.2 %

Procedure:
To a solution of 3-amino-5-methoxy-1,2,3,4-tetrahydronaphthalen-2-ol (1.7 g, 8.8 mmol) and triethylamine (1.5 ml, 11 mmol) in 100 ml of CH2Cl2 was added chloroacetyl chloride (1.0 g, 8.9 mmol) in 10 ml of CH2Cl2 dropwise at 0° C. The resulting solution was stirred for 1.5 h at 25° C. The reaction mixture was then diluted with EtOAc and washed with 1N aqueous HCl. Organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oil which corresponds to the amide. The oily residue was redissolved in 20 ml of THF, and NaH (0.35 g, 8.8 mmol) and tetrabutylammonium iodide (0.25 g, 0.67 mmol) were added into the solution at 0° C. The reaction mixture was stirred for 12 h at 25 ° C. It was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding an oily residue which was purified by column chromatography (50% CH2Cl2 -EtOAc) to provide 1.4 g (68%) of the desired product. 1H NMR (300 MHz, CDCl3): δ 2.45 (dd, 1H, J=10.5, 16.7 Hz), 2.85 (m, 1H), 3.11-3.34 (m, 2H), 3.65(m, 2H), 3.79 (s, 3H), 4.28 (AB q, 2H, 16.7 Hz), 6.68 (m, 2H), 7.07 (t, 1H, J=7.9 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CCO>C(OCC)(=O)C>[Cl:8][C:7]1[C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: NCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)CCO
Product: NCC1CCN(c2ncccc2Cl)CC1
Temperature: 95 °C
Yield: 72.8 %

Procedure:
A stirred mixture of 2,3-dichloropyridine (20 g), 1-(piperid-4-yl)methylamine (30 g), sodium carbonate (30 g) and 3-methyl-1-butanol (100 ml) was heated at 95° C. for 16 hours, then cooled to ambient temperature, diluted with ethyl acetate (200 ml), and filtered. The solvents were removed in vacua, and the residual oil distilled to give 1-[1-(3-chloropyrid-2-yl)piperid-4-yl]methylamine as a colourless oil (22.2 g), b.p. 115°-140° C. at 0.13 mbar.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([N:32]3[CH2:36][CH2:35][C:34](=[O:37])[CH2:33]3)=[O:31])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>CCCCC.CCOCC>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:34]1([OH:37])[CH2:35][CH2:36][N:32]([C:30]([C:27]2([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:29][CH2:28]2)=[O:31])[CH2:33]1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1C1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-(tert-butyl)benzenesulfonamide (569 mg, 0.00267 mol) in ether (10 mL, 0.1 mol) was added 1.7 M of tert-butyllithium in pentane (4.7 mL) under nitrogen at −78° C. The mixture was stirred at −78° C. for 15 minutes, then at 0° C. for 1 hour. The reaction mixture then was cooled down to −78° C. again and a solution of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-one (640 mg, 0.0024 mol) in ether was added. After stirring for 2 hours, the reaction mixture was quenched with saturated NH4Cl aqueous solution and then extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated. The crude product was purified using Combiflash eluting with 30% AcOEt in hexanes to afford the desired product. LC/MS (M+H+) 478.0.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>C1COCC1.C(Cl)Cl.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.[Cu]I>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[N:3][C:2]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(-c2cnc(I)cn2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc(-c2cnc(C#C[Si](C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2.30 g (7.37 mmol) 2-iodo-5-(4-methoxyphenyl)pyrazine and 1.56 mL (11.1 mmol) ethynyltrimethylsilane in 30 mL THF is charged with 0.12 g (0.15 mmol) bis(triphenylphosphine)dichloropalladium, 0.03 g (15.0 mmol) CuI and 3.01 mL (22.1 mmol) TEA. After stirring at r.t. for 4 h the reaction mixture is diluted with DCM and washed with 50 mL aq. 5% ammonia solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with PE/EtOAc (8/2), filtered through a plug of silica gel and the solvent is again removed in vacuo. The product is used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:25].C(OCC)C>C(OCC)(=O)C>[ClH:25].[ClH:25].[C:1]1([C:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of tert-butyl 4-(4-phenyl-1,3-thiazol-2-yl)piperazine-1-carboxylate (1.25 g, 3.62 mmol) in ethyl acetate (20 ml) was added a solution of 4 N hydrogen chloride in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added diethyl ether (30 ml), and the desired product as a solid was separated by filtration, which was washed with diethyl ether to yield 1.06 g (92.2%) of the desired product.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[S:17][C@H:13]2[CH2:12][C@H:11]([CH2:23][O:24]CC2C=CC=CC=2)[C@H:10]1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1.[B-](Cl)(Cl)(Cl)[S+](C)C>>[OH:24][CH2:23][C@@H:11]1[C@@H:10]([OH:32])[C@H:9]([OH:8])[C@H:14]2[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[S:17][C@H:13]2[CH2:12]1
Reactant: c1ccc(COC[C@H]2C[C@@H]3SC(N4CCCC4)=N[C@@H]3[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: C[S+](C)[B-](Cl)(Cl)Cl
Product: OC[C@H]1C[C@@H]2SC(N3CCCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of (3aR,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(pyrrolidin-1-yl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole (0.200 g, 0.369 mmol) was added excess boron trichloride-methyl sulfide complex (1.70 g, 9.48 mmol). The mixture was stirred at room temperature for 4 days, and then quenched with MeOH at 0° C. The quenched solution was stirred for 10 min, and then concentrated under reduced pressure to dryness. The residue was purified on silica gel by flash column chromatography (1.0 M NH3 in MeOH/CH2Cl2, 1:4), affording (3aR,4R,5R,6R,7aS)-6-(hydroxymethyl)-2-(pyrrolidin-1-yl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole-4,5-diol an off-white solid (0.058 g, 58%). 1H NMR (400 MHz, CD3OD) 4.35-4.33 (m, 1H), 3.79 (dd, J=4.1, 10.4 Hz, 1H), 4.74 (dd, J=6.1, 8.6 Hz, 1H), 3.63 (dd, J=6.1, 10.4 Hz, 1H), 3.50-3.46 (m, 2H), 3.44-3.30 (m, 3H), 3.22 (t, J=10.4, 1H), 2.23-2.18 (m, 1H), 1.98-1.91 (m, 5H), 1.78-1.61 (m, 1H); 13C NMR (100 MHz, CD3OD) δ 164.62, 78.45, 76.43, 74.37, 64.12, 54.72, 50.27, 40.73, 26.90, 26.44; MS, m/z=273 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9](O)=[O:10])([O-:3])=[O:2].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[N+:1]([C:4]1[C:5]([F:15])=[C:6]([Cl:14])[C:7]([F:13])=[C:8]([CH:12]=1)[C:9]([Cl:19])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reaction time: 14 h

Procedure:
An amount of 3.47 g (0.015 mole) of 5-nitro-3-chloro-2,4-difluorobenzoic acid and 2.03 g (0.016 mole) of oxalyl chloride are dissolved in 15 ml of dichloromethane then two drops of DMF are added. The reaction is stirred for 14 hours then the solvent is evaporated under vacuum to afford the desired product.
Reaction SMILES: [C:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([F:14])[C:4]=1C(O)=O)#[N:2].CC[N:17](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[NH2:17][C:4]1[C:8]([F:14])=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[C:1]#[N:2]
Reactant: CCN(CC)CC
Reactant: COc1ccc(F)c(C(=O)O)c1C#N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(N)c1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.6 %

Procedure:
To a stirred solution of 2-cyano-6-fluoro-3-methoxy-benzoic acid (2 g, 10.3 mmol, 1.0 eq) in THF (40 mL) were added Et3N (3.6 mL, 25.8 mmol, 2.5 eq) and DPPA (2.97 g, 10.8 mmol, 1.05 eq). The reaction was stirred at room temperature 3 h then water (10 mL) was added and the mixture was heated at reflux for 2 h. The THF was removed in vacuo and the aqueous solution diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 5:1) to give the title compound as an off-white solid (900 mg, 53%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([O:11][CH3:12])[CH:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]2.[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH:7]([O:11][CH3:12])[CH:6]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:5]3)=[CH:29][CH:28]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCOc1ccc(CCl)cc1
Reactant: CCOC(=O)CC1Cc2cc(O)ccc2C1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(COc2ccc3c(c2)CC(CC(=O)OCC)C3OC)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
In 2 ml of dimethylformamide were dissolved 190 mg of ethyl 5-hydroxy-1-methoxyindane-2-acetate and 220 mg of p-heptyloxybenzyl chloride. To the solution was added 180 mg of potassium carbonate. The mixture was stirred at 60° C. overnight. After allowing to cool, water and ethyl acetate were added to the mixture. By thoroughly shaking the mixture, the organic layer was separated. After washing with water, drying and concentrating the organic layer, the residue obtained was purified by flash chromatography (eluant: toluene/ethyl acetate (25/1)) to obtain 220 mg of ethyl 5-(p-heptyloxybenzyloxy)-1-methoxy-2-indaneacetate as a colorless oily product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16].[Cl:17][CH:18]([Cl:22])[C:19]([OH:21])=[O:20]>>[Br:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:18]([Cl:22])([Cl:17])[C:19]([OH:21])=[O:20]
Reactant: O=C(O)C(Cl)Cl
Reactant: BrCCCCCCCCCCCCCCBr
Product: O=C(O)C(Cl)(Cl)CCCCCCCCCCCCCCBr

Procedure:
Analogously to example 1 from 2.0 g (5.6 mmol) 1,14-dibromotetradecane and 2.3 g (22.5 mmol) dichloroacetic acid. Yield 0.58 g (23%), melting point 61-63° C.