Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)[Cl:2].C([Li])CCC.[C:9]12([OH:20])[CH2:17][CH:13]([C:14]1([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]2([OH:19])[CH3:18].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][B:27]([O-:29])[O-:28]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[C:9]12([OH:20])[CH2:17][CH:13]([C:14]1([CH3:16])[CH3:15])[CH2:12][CH2:11][C:10]2([OH:19])[CH3:18].[Cl:2][C@@H:26]([B:27]([O-:29])[O-:28])[CH2:25][CH2:24][CH2:23][CH2:22][Br:21]
Reactant: ClCCl
Reactant: [O-]B([O-])CCCCCBr
Agent: CC1(O)CCC2CC1(O)C2(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: [O-]B([O-])[C@H](Cl)CCCCBr
Temperature: -100 °C
Reaction time: 0.25 h

Procedure:
The desired (+)-pinanediol-(S)-1-chloro-5-bromo-pentane-1-boronate is prepared according to the procedure given in Organometallics 3, 1284 (1984). Therefore methylenechloride (9.8 ml) in THF is cooled to -100° C. and n-butyllithium (71.6 ml 1.6M solution, 114.5 mMol) is added over 20 min. After 15 min at -100° C., a cold (-78° C.) solution of (+)-pinanediol-5-bromo-pentane-1-boronate (32,8 g, 104.1 mMol) in THF is added. After additional 1 hr at -100° C. anhydrous ZnCl2 (7.1 g, 52,0 mMol) in THF is added. After additional 15 min at -100° C. the reaction mixture is warmed to room temperature and stirred for 2 hr at this temperature. The solvent is removed in vacuo, the residue is diluted with hexane/water and is extracted several times with hexane. After drying over Na2SO4 and removal of the solvent in vacuo, (+ )-pinanediol-(S)-1-chloro-5-bromo-pentane-1-boronate is obtained as a yellow oil which is used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([CH3:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:16])[CH3:15]>C(O)C.[Pd]>[Cl:1][C:2]1[CH:20]=[C:19]([CH:18]=[C:17]([CH3:24])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH:14]([CH3:15])[CH3:16])[NH2:21]
Reactant: Cc1cc([N+](=O)[O-])cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)cc(Cl)c1Oc1ccc2[nH]cc(C(C)C)c2c1
Yield: 59.4 %

Procedure:
500 mg of 5-(2-chloro-6-methyl-4-nitrophenoxy)-3-isopropyl-1H-indole (Example II) are suspended in 10 ml of ethanol and hydrogenated with 50 mg of palladium on active carbon (10%) at atmospheric pressure for 2 hours. The mixture is filtered through kieselguhr, the solvent is removed in vacuo and the product is purified by chromatography (cyclohexane/ethyl acetate). 271 mg of 3-chloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]-5-methylaniline are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]2[N:6]=[C:7]([O:9][C:10]3[C:15]([Cl:16])=[CH:14][C:13]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=4[Cl:31])(=[O:20])=[O:19])=[CH:12][C:11]=3[Cl:32])[S:8][C:4]=2[CH:3]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>>[Cl:31][C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:13]1[CH:14]=[C:15]([Cl:16])[C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:34]=[CH:33][C:5]=3[N:6]=2)=[C:11]([Cl:32])[CH:12]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1
Product: CS(=O)(=O)Nc1ccc2nc(Oc3c(Cl)cc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3Cl)sc2c1

Procedure:
2-Chloro-N-[3,5-dichloro-4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(6-Amino-benzothiazol-2-yloxy)-3,5-dichloro-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (439) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 9.87 (s, 1H), 8.38 (d, J=8.3 Hz, 1H), 8.22 (s, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.31 (s, 2H), 7.23 (dd, J=8.8, 1.5 Hz, 1H). MS (EI): m/z 644 (M−H).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[C:14]([F:15])=[C:13]([N:16]2[CH2:21][C@H:20]([CH3:22])[CH2:19][C@H:18]([CH3:23])[CH2:17]2)[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[C:14]([F:15])=[C:13]([N:16]2[CH2:21][C@H:20]([CH3:22])[CH2:19][C@H:18]([CH3:23])[CH2:17]2)[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: C[C@@H]1C[C@H](C)CN(c2ncnc(Cl)c2F)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1ncnc(N2C[C@H](C)C[C@H](C)C2)c1F
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
0.10 g of sodium hydride (60% oil suspension) was suspended in 3 ml of tetrahydrofuran. 1 ml of tetrahydrofuran solution of 0.16 g of 2-butyn-1-ol was added dropwise therein, and the mixture was stirred for 10 minutes. Into the mixture was added dropwise 1 ml of tetrahydrofuran solution of 0.31 g of 4-chloro-6-(cis-3,5-dimethylpiperidino)-5-fluoropyrimidine and stirred for 6 hours at 60° C. Into the reaction mixture was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.32 g of 4-(2-butynyloxy)-5-fluoro-6-(cis-3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (29)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][NH:6][C@@:7]([C@H:16]1[CH2:20][O:19][CH2:18][C@H:17]1[OH:21])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])[CH3:8].N1C=CC=CC=1.[S:34](Cl)(Cl)=[O:35]>ClCCl>[CH3:1][O:2][C:3]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:4]=1[CH2:5][N:6]1[C@@:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])([CH3:8])[C@@H:16]2[C@@H:17]([CH2:18][O:19][CH2:20]2)[O:21][S:34]1=[O:35]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(CN[C@](C)(c2ccccc2F)[C@H]2COC[C@H]2O)c(OC)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CN2S(=O)O[C@@H]3COC[C@@H]3[C@@]2(C)c2ccccc2F)c(OC)c1
Yield: 94.9 %

Procedure:
Under a dry atmosphere of argon, a solution of rel-(3S,4S)-4-[(S)-1-(2,4-dimethoxy-benzylamino)-1-(2-fluoro-phenyl)-ethyl]-tetrahydro-furan-3-ol (6.8 g, 18.1 mmol) in pyridine (7.32 ml, 90.5 mmol) and dichloromethane (120 ml) was cooled to −77° C. The colorless solution was treated dropwise with thionyl chloride (2.15 g, 18.1 mmol) over about 10 minutes while the temperature rose to −73° C. After removal of the cooling bath the reaction mixture was allowed to reach room temperature. For the workup, the reaction mixture was diluted with dichloromethane (150 ml) and washed consecutively with hydrochloric acid (1N) and a saturated solution of sodium hydrogencarbonate. The organic layer was dried over sodium sulphate and evaporated. The (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5-oxide (7.24 g, 95% yield) was obtained as a white solid. MS (ISP): m/z=422.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[C:15]([O:21][CH3:22])(=[O:20])[CH2:16][C:17]([CH3:19])=O>>[CH3:19][C:17]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=2)=[CH:2][C:16]=1[C:15]([O:21][CH3:22])=[O:20]
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CC(C)=O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C
Yield: 39.4 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-(trifluoromethyl)acetophenone (13.4 g) and methyl acetoacetate (5.8 g) to give the title compound (5.6 g, 39%) as a yellow crystal.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH2:26])[C@H:15]1[OH:16].[C:37]([O:41][C:42]([NH:44][C@@H:45]([C:53](O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:26][C:53](=[O:54])[C@@H:45]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:43])[C@H:15]1[OH:16]
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 89.6 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-(N-tert-butoxycarbonyl-β-phenyl-D-alanyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (488 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate (424 mg) prepared in Example 4 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-β-phenyl-D-alanine (290 mg) according to a similar manner to that of Example 5, mp. 164°-168° C. (dec.).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:15]([N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)(=O)=[O:21])COC)=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O.O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[C:15]([NH:16][S:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=3)=[O:21])=[CH:14][C:13]([Cl:34])=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCN(c1cc(Cl)cnc1C(=O)Nc1ccccc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1ncc(Cl)cc1NS(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid phenylamide (120 mg, 0.224 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) at 85° C. (oil bath) for 4 h. Upon consumption of the reactant, the reaction mixture was concentrated, the residue neutralized (pH 7) with aqueous sodium bicarbonate, and the aqueous layer was extracted with EtOAc (3×80 mL). The combined organic extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide pure final product. MS m/z 490.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CCO>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([C@@H:20]2[CH2:24][CH2:23][CH2:22][N:21]2[CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[O:19])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(C)(CO)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 75 °C
Reaction time: 28 h
Yield: 74.9 %

Procedure:
To 400 mg (0.95 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid (3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amide in EtOH (6.00 mL) are added 119 mg (0.47 mmol) pyridinium-p-toluenesulfonate. The reaction is stirred at 75° C. for 28 h. The reaction mixture is purified by HPLC-MS to afford 240 mg of (S)-1-(tetrahydro-pyran-4-yl)pyrrolidine-2-carboxylic acid [3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]amide. Yield: 75%; ESI-MS: 338 [M+H]+; HPLC (Rt): 0.82 min (method D)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:6]=1)=[O:4].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O>>[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=[C:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=[CH:13][C:12]=2[C:11]1=[O:15]
Reactant: O=Cc1ccco1
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Product: COC(=O)c1ccc2c(c1)CCC(=Cc1ccco1)C2=O
Yield: 80 %

Procedure:
The title compound was prepared from 5-oxo-5,6,7,8-tetrahydronaphtalene-2-carboxylic acid methyl ester (396 mg, 1.9 mmol) and 2-furaldehyde (192 mg, 2.0 mmol) according to Method A3 in 80% yield. ES-MS m/z 283 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1ccsc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccsc2)CCN(C)C1
Yield: 4.4 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.4 g, 2 mmol), 3-bromothiophene (0.347 mL, 4 mmol), K3PO4 (0.848 g, 4 mmol), CuI (38 mg, 0.2 mmol) and L-Proline (46 mg, 0.39 mmol) in dry DMF (6 mL) was stirred at 150° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-thiophen-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (25 mg). 1H NMR (HCl salt, CD3OD) d (ppm): 7.65 (m, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 7.21 (d, 1H), 7.19 (d, 1H), 7.02 (d, 1H), 4.76 (d, 1H), 4.40 (d, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.2-3.0 (m, 5H), 2.42 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.O1CCOCC1.CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC.Cl[C:53]1[N:58]=[C:57]([NH2:59])[C:56]([N+:60]([O-:62])=[O:61])=[C:55]([NH2:63])[N:54]=1>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.O>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:53]3[N:54]=[C:55]([NH2:63])[C:56]([N+:60]([O-:62])=[O:61])=[C:57]([NH2:59])[N:58]=3)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: Nc1nc(Cl)nc(N)c1[N+](=O)[O-]
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)CCCC
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under argon, 860 mg (2.32 mmol) of the compound from Example 6A were introduced into 1,4-dioxane (86 ml), and the reaction mixture was flushed with argon for 10 min. Then 3.51 ml (6.95 mmol) of hexabutylditin and 483 mg (2.55 mmol) of 2-chloro-5-nitropyrimidine-4,6-diamine (prepared by the method of Helvetica Chimica Acta (1951), 34, 835-40) were added. Subsequently 860 mg (0.744 mmol) of tetrakis(triphenylphosphine)palladium(0) were added and the reaction mixture was heated at reflux overnight. The mixture was then cooled to RT, water was added and the mixture was extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulphate, filtered and concentrated. The residue was subjected to extractive stirring in ethyl acetate, and the solid was isolated by filtration and dried under high vacuum. This gave 355 mg (62% purity, 24% of theory) of the desired compound. The crude product was reacted without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([O:16]C)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl-].[Na+].O.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:13]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(F)cc1OCCNC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.8 %

Procedure:
A mixture of methyl 2-(2-tert-butoxycarbonylaminoethoxy)-4-fluorobenzoate (4.2 g, 13.4 mmol), THF (100 mL), and MeOH (50 mL) was treated with 1 M lithium hydroxide (16 mL) and stirred for 48 hours at ambient temperature. The reaction was acidified with 10% aqueous citric acid (50 mL), diluted with brine (100 mL), and extracted with EtOAc (3×100 mL). The combined organic layers were dried over MgSO4 and concentrated to give 3.93 g (13.1 mmol, 98%) of a white solid.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:26](=[O:27])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Combine (S)-4-benzyl-2-oxazolidinone (22.9 g, 129 mmol) and tetrahydrofuran (120 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of n-butyl lithium (52 mL, 2.5 M, 130 mmol). After 15 minutes, slowly add a solution of phenylacetyl chloride (20 g, 129.4 mmol) in tetrahydrofuran (50 mL). After 20 minutes, warm to ambient temperature. After 2 hours, quench the reaction mixture by the addition of a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the aqueous layer with diethyl ether. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 15% ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from diethyl ether/hexane to give (S)-4-benzyl-3-phenylacetyl-2-oxazolidinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36](OS(C(F)(F)F)(=O)=O)=[CH:35][CH:34]=1.[C:47]([C:49]1[CH:53]=[CH:52][S:51][CH:50]=1)#[CH:48]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:48]#[C:47][C:49]2[CH:53]=[CH:52][S:51][CH:50]=2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(OS(=O)(=O)C(F)(F)F)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C#Cc1ccsc1
Product: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#Cc4ccsc4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The compound was obtained starting from 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-(4-trifluoromethylsulfonyloxy-benzyl)-benzene and 3-ethynyl-thiophene.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:41][CH2:40]1
Reactant: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)O
Reactant: Fc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2cccc(C(F)(F)F)c2)c1C(=O)N1CCN(c2ccccc2F)CC1
Yield: 67.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), methyl-3-(3-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol), a white solid required compound (536 mg, 1.24 mmol, 67%) was obtained.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(CCCCn2cc([N+](=O)[O-])cn2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(CCCCn2cc(N)cn2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-4-nitro-1H-pyrazole (1.80 g, 7.05 mmol), iron powder (1.20 g, 21.26 mmol) and NH4Cl (1.90 g, 35.25 mmol) in a mixture of EtOH (46.0 mL) and water (23.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (400 mL) was added followed by 1M NaOH (100 mL). The aq. layer was extracted with CH2Cl2 (2×100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a deep red oil. LC-MS-conditions 02: tR=0.56 min; [M+H]+=226.53. 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 3H), 1.34-1.46 (m, 2H), 1.61-1.70 (m, 2H), 1.77-1.88 (m, 2H), 2.85 (s, 2H), 3.86-3.92 (m, 2H), 3.92-3.96 (m, 2H), 3.99 (t, J=7.3 Hz, 2H), 7.00 (s, 1H), 7.14 (s, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([O:48][CH2:49][C@@H:50]([OH:54])[CH2:51][O:52][CH3:53])[CH2:9]1)=O)(C)(C)C.Cl>CO>[CH3:53][O:52][CH2:51][C@H:50]([OH:54])[CH2:49][O:48][C@H:10]1[C@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH2:13][NH:8][CH2:9]1
Reactant: COC[C@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COC[C@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1) (l) the (3S,4R,5R)-3-[(2S)-2-hydroxy-3-methoxy-propoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl in methanol to yield the (2S)-1-methoxy-3-[(3S,4R,5R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-propan-2-ol as colorless oil; MS: 646.3 (M+H)+.