Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[S:9](=[O:10])[CH:8]=[N:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>CC(C)=O>[C:22]([N:7]1[C:6]2[CH:11]=[C:2]([CH3:1])[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=2[S:9](=[O:10])[CH2:8]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Cc1cc2c(c([N+](=O)[O-])c1)S(=O)C=N2
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)N1CS(=O)c2c1cc(C)cc2[N+](=O)[O-]
Yield: 82.6 %

Procedure:
6.3 g (0.03 mol) of 5-methyl-7-nitro-benzothiazolone and 3.3 g (0.03 mol) of triethylamine are dissolved in 150 ml of acetone. 2.35 g (0.03 mol) of acetyl chloride are allowed to run in slowly dropwise, with stirring, at an internal temperature of 5°-10° C. The reaction mixture is stirred at room temperature for a further 3 hours and then poured onto ice. 6.3 g (83 % of theory) of 3-acetyl-5-methyl-7-nitro-benzothiazolone are obtained in the form of creamcolored flakes of melting point 141° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[F:10]F>O>[F:10][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[CH3:1]
Reactant: FF
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Solvent: O
Product: Cc1[nH]c(=O)[nH]c(=O)c1F
Reaction time: 48 h

Procedure:
The preceding example was substantially repeated but at a lower reaction temperature. A suspension of 6-methyl uracil (4.00g) in water (30 ml) was maintained at 0°-10°C and fluorinated with a stream of fluorine and nitrogen, present in equal volumes, until fluorine was detected at the reactor outlet. The reaction mixture was allowed to stand for two days at room temperature and 1.05g of crystals were collected and found to have a different IR spectrum than the starting material. A DSC analysis showed 2 transitions at 313°C and 318°C followed by apparent decomposition. The structure of the product was identified as 5-fluoro-6-methyl uracil by NMR analysis.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:30])[CH:21]=[CH:22][C:23]=1[C:24]1[S:28][C:27]([CH3:29])=[N:26][CH:25]=1>CCCCCCC.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:30][C:20]2[CH:21]=[CH:22][C:23]([C:24]3[S:28][C:27]([CH3:29])=[N:26][CH:25]=3)=[C:18]([O:17][CH3:16])[CH:19]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc(C)cc(Cc3ccccc3)n2)ccc1-c1cnc(C)s1
Yield: 69.5 %

Procedure:
The title compound was prepared from 4-benzyl-2-chloro-6-methyl-pyrimidine (130 mg, 0.59 mmol) and 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (131 mg, 0.59 mmol) using in analogous manner the procedure described in example 206c). Column chroma-tography (20 g silica, heptane/ethyl acetate 1:1 v/v) afforded the title compound as an off-white solid (165 mg, 69%). MS ISP (m/e): 403.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.90 (s, 1H), 7.82 (s, 1H), 7.45 (d, 1H), 7.29 (m, 5H), 7.14 (s, 1H), 6.98 (dd, 1H), 6.48 (s, 1H), 3.97 (s, 2H), 3.87 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H). Mp 138-141° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:14])[CH3:13]>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:14])[CH3:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: Oc1ccc2ncccc2c1
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
Quinolin-6-ol (135 g, 0.93 mol) was dissolved in pyridine (500 mL) and cooled to 0° C. in an ice-bath under a flow of nitrogen. Acetyl chloride (79 mL, 1.16 mol) was added to the reaction mixture slowly. Then it was stirred at room temperature for 3 hours. The mixture was partitioned between ethyl acetate (400 mL) and saturated aqueous NaHCO3 (200 mL). The organic phase was separated and washed with brine (5*200 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography to afford 120 g of acetic acid quinolin-6-yl ester as white solid (69% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@H:4]([OH:9])[CH2:5][N:6]=[N+:7]=[N-:8].[CH3:17][O:18][C:19]1[C:20](=O)[C:21](=[O:25])[C:22]=1[O:23]C.C(N(CC)CC)C>C(#N)C>[N:6]([CH2:5][C@@H:4]([OH:9])[C@@H:3]([NH:2][C:20]1[C:21](=[O:25])[C:22](=[O:23])[C:19]=1[O:18][CH3:17])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=NC[C@@H](O)[C@@H](N)CC1CCCCC1
Reactant: COc1c(OC)c(=O)c1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N[C@@H](CC2CCCCC2)[C@H](O)CN=[N+]=[N-])c(=O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.1 %

Procedure:
The HCl salt of (2R,3S)-3-amino-1-azido-4-cyclohexylbutan-2-ol (˜74 mg, 0.30 mmol) and 3,4-dimethoxycyclobut-3-ene-1,2-dione (70 mg, 0.49 mmol) were dissolved in acetonitrile (3 mL). Triethylamine (84 μL, 0.60 mmol) was added. The reaction was stirred at rt for 4 h. The solvent was evaporated and the crude material was redissolved in CH2Cl2. The solution was washed with 2% aq HCl, followed by brine, and dried over Na2SO4. The solution was filtered and the solvent removed under reduced pressure. The crude material was purified by flash chromatography on silica gel eluting with hexanes/EtOAc. 3-((2S,3R)-4-Azido-1-cyclohexyl-3-hydroxybutan-2-ylamino)-4-methoxycyclobut-3-ene-1,2-dione (63 mg) was isolated as a solid; MS m/z 323.
Reaction SMILES: [CH:1]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[N:3]([C@@H:9]2[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C:10]2([F:18])[F:17])[CH:2]=1.Cl[Si:20]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:21][Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24]>N1C=CC=CC=1>[NH2:8][C:7]1[CH:1]=[CH:2][N:3]([C@@H:9]2[O:13][C@H:12]3[C@@H:11]([O:16][Si:20]([CH:30]([CH3:32])[CH3:31])([CH:33]([CH3:35])[CH3:34])[O:21][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:24])[CH3:25])[O:15][CH2:14]3)[C:10]2([F:17])[F:18])[C:4](=[O:5])[N:6]=1
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)C2(F)F)c(=O)n1
Reactant: CC(C)[Si](Cl)(O[Si](Cl)(C(C)C)C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)C(F)(F)[C@@H]2O[Si](C(C)C)(C(C)C)O1

Procedure:
As shown above, Gemcitabine (4-amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidin-2(1H)-one) can be treated with 1,3-dichloro-1,1,3,3-tetraisopropyldisiloxane (TIPDSiCl2) in dry pyridine to provide 4-amino-1-((6aR,8R,9aR)-9,9-difluoro-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidin-2(1H)-one. It is contemplated that other 1,3-dihalo-1,1,3,3-tetraalkyldisiloxanes can be used in place of TIPDSiCl2. It is also contemplated that two monofunctional halosiloxane protecting groups can be used in place of the difunctional TIPDSiCl2. Further, it is also contemplated that other hydroxyl protecting groups (e.g., tetrahydropyranyl (THP) or acetyl (Ac)) can be used in place of TIPDSiCl2.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 95.8 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 2,2,2-trifluoroethylamine (74.19 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (110 mg, 95%) which was obtained as a white solid. MS: m/e=499.8 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17](F)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([F:27])[CH2:16][CH:17]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Product: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (4.0 g) and benzylamine (50 ml) was stirred at room temperature for about 30 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was sufficiently washed with water and concentrated under reduced pressure. Triturating the residue with a mixture of ether and n-hexane, there was obtained γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2-benzylamino-4-fluorobutyrophenone. M.P. 113° - 117°C. IR νmaxNujol 3350, 3300, 1639, 1600 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.Cl.[C:11]1(NN)[CH:16]=CC=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:16]=[CH:11][C:12]([CH3:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Product: Cc1ccn(-c2ccc(Cl)cc2)n1

Procedure:
This compound was prepared by the same methodology described for EXAMPLE 8 with 4-chlorophenyl hydrazine.HCl substituted for phenyl hydrazine and 2-amino-5-(2-N-t-butylaminosulfonylphenyl)pyridine was used in the coupling step. There was obtained the title compound; HRMS (M+H)+: calc. 468.089714; found 468.088873.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@:8]2([O:10][CH2:9]2)[C@H:7](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:6][CH2:5][C@@H:4]1[CH3:20].[CH:21]1[N-:25][CH:24]=[N:23][CH:22]=1.[Na+]>CN(C)C=O.O>[N:23]1([CH2:9][C@:8]2([OH:10])[C@@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[CH2:5][O:6][C@H:7]2/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:22]=[CH:21][N:25]=[CH:24]1
Reactant: c1c[n-]cn1
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]12CO2
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]1(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of (3S,4S,7S,8S)-8-methoxy-7-methyl-4-[(E)-1-nonenyl]-1,5-dioxaspiro[2,5]octane (4.2 mg) and imidazole sodium derivative (14.0 mg) in dry N,N-dimethylformamide(0.5 ml) was stirred for 15 hours at room temperature. The reaction mixture was diluted with water. The mixture was extracted with dietyl ether, the combined ethereal extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by preparative thin layer chromatography (ethyl acetate as an eluent) gave (2S,3S,4S,5S)-3-(1H-imidazol-1-ylmethyl)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-ol (4.1 mg, y. 79%) as colorless oil; EI-MS: m/z 351 (M+); 1H-NMR (CDCl3)d: 0.88 (3H,t,J=8 Hz), 1.10 (3H,d,J=7 Hz), 1.2-1.5 (10H,m), 2.1 (3H,m), 2.39 (1H,br.s, --OH), 2.93 (1H,d,J=5 Hz), 3.39 (3H,s), 3.40 (1H, dd, J=3 & 12 Hz), 3.61 (1H,d,J=8 Hz), 3.76 (1H,dd,J=4 & 12 Hz), 3.96 (1H,d,J=14 Hz), 4.13 (1H,d,J=14 Hz), 5.87 (2H,m), 6.91 (1H, s), 7.14 (1H,s), 7.46 (1H,s).
Reaction SMILES: C(Cl)Cl.[C:4]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)=[O:10])([CH3:7])([CH3:6])[CH3:5].[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(=O)([O-])O.[Na+]>[CH2:21]([N:20]([CH3:19])[C@H:15]1[CH2:16][CH2:17][C@H:12]([NH:11][C:9]([O:8][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:10])[CH2:13][CH2:14]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To 160 ml of a methylene chloride solution containing 16.93 g of 4-(tert-butoxycarbonylamino)cyclohexanone and 10.55 ml of N-methylbenzylamine was added 19.08 g of sodium triacetoxyborohydride under ice-cooling, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained residue was suspended in hexane and collected by filtration. This mother liquor was concentrated and the residue was purified by NH-silica gel chromatography (solvent: hexane-ethyl acetate (97:3 to 83:17)). The residue was further suspended in hexane and collected by filtration and combined with the filtered product to obtain 13.55 g of N′-benzyl-N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])(Cl)Cl.Cl.[OH2:16]>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][C:3]=1[C:11]([Cl:14])=[O:16]
Reactant: Fc1cc(C(Cl)(Cl)Cl)c(F)c(F)c1F
Reactant: O
Agent: Cl
Product: O=C(Cl)c1cc(F)c(F)c(F)c1F
Yield: 89.3 %

Procedure:
802 g of 2,3,4,5-tetrafluoro-benzotrichloride are initially introduced into a stirred apparatus, and 8 g of FeCl3 are added. Water is slowly metered in under the surface of the starting material at 120° C. (54 g of water in total). Vigorous evolution of hydrogen chloride immediately starts. The hydrogen chloride is passed to a destruction tower via the condenser. The mixture is stirred until the evolution of gas has ended. The product is then distilled. 569 g of 2,3,4,5-tetrafluoro-benzoyl chloride are obtained (89.4% of theory), boiling point: 80-82° C./18 mbar.
Reaction SMILES: [C:1]([C:9]1[N:10]([CH2:20][C:21]([OH:23])=O)[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:37][C:38]([NH2:40])=[NH:39].C(N(CC)CC)C>CN(C=O)C>[NH2:39][C:38](=[NH:37])[NH:40][C:21](=[O:23])[CH2:20][N:10]1[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=[C:9]1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: O=C(O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)Cn1c(C(=O)c2ccccc2)ccc1-c1ccccc1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A solution of tert-butyl(2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetate (148 mg, 0.41 mmol) in trifluoroacetic acid was stirred for 2 h at room temperature. After removal of trifluoroacetic acid, the residue was treated with CH2Cl2 (10 ml), MeOH (1 ml) and H2O (10 ml). The two layers were separated and the aqueous was extracted with CH2Cl2 (3×10 ml). The combined organic extracts were washed with H2O (10 ml), brine (10 ml), dried (Na2SO4) filtered and concentrated. The crude material was purified by chromatography (silica gel, EtOAc/hexane/HCO2H: 10/40/0.1) to afford (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (125 mg, 100%) as an oil. To a stirred solution of (2-benzoyl-5-phenyl-1H-pyrrol-1-yl)acetic acid (260 mg, 0.85 mmol) in DMF (2.0 ml) was added 1,1′-carbonyldiimidazole (166 mg, 1.02 mmol) at room temperature. After stirring for 1 h, the reaction mixture was treated with a solution of guanidine hydrochloride (244 mg, 2.55 mmol) in DMF (2.5 ml) and triethylamine (0.54 ml, 2.55 mmol). After stirring over night, the reaction mixture was quenched with H2O (30 ml). The aqueous was extracted with Et2O (3×30 ml), EtOAc (10 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The crude material was purified by chromatography (silica gel; EtOAc/hexane/2M NH3 in MeOH: 65/35/1) to give the titled compound (169 mg, 58%) as a white solid: mp 201-203° C.; MS (−) ES, 345 (M−H)−.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[C:6]12(C(=O)C3C[CH:10]1[CH2:11][CH2:12]3)[CH2:9][CH2:8][CH2:7]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:4]=[C:3]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH:10]2[CH2:1][CH:2]1[CH2:12][CH2:11]2
Reactant: O=C1C2CCC(C2)C12CCC2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1C2CCC(C2)C12CCC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a suspension of (methyl)triphenylphosphonium bromide (49.9 mmol, 18.2 g) in dry tetrahydrofuran (THF) (100 mL) at −78° C. was added n-butyllithium (46.5 mmol, 18.6 mL of 2.5 M solution in hexanes). The mixture was stirred for 30 min at −78° C. To this mixture was added spiro[bicyclo[2.2.1]heptane-2,1′-cyclobutan]-3-one (5.00 g, 33.3 mmol). The resulting mixture was stirred at ambient temperature for 20 h. Hexanes (300 mL) were added, and the mixture was filtered. The filtrate was concentrated, and the residue was purified on an 80 g silica gel column, eluting with hexanes, to obtain 3-methylenespiro[bicyclo[2.2.1]heptane-2,1′-cyclobutane] (Compound III in Scheme 1) (3.7 g, 75%) as oil. 1H NMR (CDCl3, 400 MHz); δ 4.82 (s, 2H), 2.63 (bra, 1H), 2.22 (bra, 1H), 2.05-1.78 (m, 6H), 1.63-1.52 (m. 1H), 1.48-1.34 (m, 3H), 1.21-1.12 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:7][CH:8]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:7][CH:8]=1)(=[O:25])=[O:24]
Reactant: CC(C)CC(=O)c1ccc(CO)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(COS(C)(=O)=O)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Dissolve 5-hydroxymethyl-2-(3-methyl-butyryl)-pyridine (210 mg, 1.086 mmol) in dichloromethane (5 mL). Cool to 0° C. and add triethylamine (0.167 mL, 1.195 mmol) and methanesulfonyl chloride (0.093 mL, 1.195 mmol). Allow the mixture to warm to room temperature and stir for 2 h. Dilute the reaction mixture with dichloromethane and wash with saturated aqueous NaHCO3. Dry the organic phase over Na2SO4, filter and concentrate in vacuo to provide the title compound (256 mg, 87%). GC-MS m/z: 271
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])[C:5]([Cl:13])=[CH:4][C:3]=1[O:14][CH3:15].[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[Cl:13][C:5]1[C:6]([C:8]([CH3:12])([CH3:11])[CH:9]=[CH2:10])=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([O:14][CH3:15])[CH:4]=1
Reactant: CN(C)C=O
Reactant: C=CC(C)(C)c1cc(Br)c(OC)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CC(C)(C)c1cc(C=O)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-bromo-4-chloro-5-(1,1-dimethyl-allyl)-2-methoxy-benzene (3.92 g, 0.0135 mol) in dry THF (30 mL) was cooled to −78° C. under argon. n-BuLi (2.5M, 6 mL, 0.0145 mol) was added keeping the temperature below −70° C. The yellow mixture was stirred for another 15 min and quenched with dry DMF (1.2 mL, 0.015 mol). The cooling bath was removed and the mixture was allowed to warm to 25° C. A saturated solution of NaHCO3 (30 mL) was added and then extracted with EtOAc (3×50 mL). The organic phase was dried (Na2SO4) and evaporated to dryness. The crude product was recrystallized from MeOH. Yield: 3.00 g (93%). GCMS: >99%
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]1([C:22]2[O:23][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:25]([C:27](O)=[O:28])[N:26]=2)[CH2:21][CH2:20]1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]4[CH2:20][CH2:21]4)[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(C2CC2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C4CC4)oc3-c3ccccc3)cn2)s1

Procedure:
Following general procedure X followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-cyclopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05c: tR=0.77 min; [M+H]+=433.25.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([CH2:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18](Br)[CH:19]=3)[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:44]([O:48][CH3:49])(=[O:47])[CH:45]=[CH2:46]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:49][O:48][C:44](=[O:47])/[CH:45]=[CH:46]/[C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[O:14][C:11]1([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)[CH2:22][C:21]2=[O:23]
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Temperature: 100 °C
Yield: 56.5 %

Procedure:
A mixture of 6-bromo-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylic acid tert-butyl ester (1.04 g, 2.62 mmol), Pd(OAc)2 (59 mg, 0.262 mmol), PPh3 (137 mg, 0.52 mmol), TEA (0.73 ml, 5.2 mmol), methyl acrylate (0.47 ml, 5.2 mmol) in dry DMF (10 ml) was heated at 100° C. for 8 h. The mixture was cooled down to RT, filtered on a celite pad and washed with AcOEt (100 ml). The filtrate was washed with NH4Cl and saturated NaHCO3 solution and brine. The organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue was purified by column chromatography (eluent:hexane/AcOEt 90:10 to 70:30) to give (E)-3-{1′-tert-butoxycarbonyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (594 mg) as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12](=[O:14])(=[O:13])[CH:11]=[CH:10][C:9]=2[CH:15]=1)=[O:4].Cl.[C@@H:17]12[N:24]([CH2:25][C@@H:26]([C:28]3[C:29]([CH3:38])=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:37])[O:32][CH2:31]4)[OH:27])[C@@H:21](CC1)[CH2:20][NH:19][CH2:18]2.C(N(CC)C(C)C)(C)C>C1COCC1>[O:13]=[S:12]1(=[O:14])[C:8]2[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:19]3[CH2:18][CH2:17][N:24]([CH2:25][C@@H:26]([C:28]4[CH:36]=[CH:35][C:34]5[C:33](=[O:37])[O:32][CH2:31][C:30]=5[C:29]=4[CH3:38])[OH:27])[CH2:21][CH2:20]3)=[CH:15][C:9]=2[CH:10]=[CH:11]1
Reactant: O=C(CBr)c1ccc2c(c1)C=CS2(=O)=O
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)C=CS4(=O)=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-1-(1,1-dioxido-1-benzothiophen-5-yl)ethanone (50 mg, 0.17 mmol) in 1.0 mL THF and 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride (INTERMEDIATE 12) (61 mg, 0.17 mmol) was added N,N-diisopropylethylamine (0.70 mmol, 120 μL) and allowed to stir at ambient temperature for 2 hours. The reaction was quenched by the addition of water and extracted three times with ethyl acetate (10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (10% DCM/MeOH) to afford 5-[(1R)-2-{4-[2-(1,1-dioxido-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one.