Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:6]([O:14][C@@H:15]1[C@@H:38]([O:39][C:40](=[O:47])[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:48][C:49](=[O:56])[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C@@H:36]([CH2:57][O:58][C:59](=[O:66])[C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:35][C@H:16]1[O:17][C:18]1[C:22]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](/[CH:4]=[CH:3]/[CH2:2][CH2:1][OH:5])=[CH:26][C:25]=2[CH3:31])=[C:21]([CH:32]([CH3:34])[CH3:33])[NH:20][N:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1cc(Br)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Reactant: C=CCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(/C=C/CCO)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n[nH]c1C(C)C
Temperature: 90 °C
Yield: 70.6 %

Procedure:
Add 3-buten-1-ol (0.58 mL, 6.8 mmol) to a solution of 4-(4-bromo-2-methylbenzyl)-5-(propan-2-yl)-1H-pyrazol-3-yl 2,3,4,6-tetra-O-benzoyl-beta-D-glucopyranoside (3 g, 3.4 mmol) in acetonitrile (30 mL) and triethylamine (20 mL). Degas the solution with nitrogen over 10 minutes. Add tri-o-tolylphosphine (205 mg, 0.67 mmol) and palladium acetate (76 mg, 0.34 mmol). Reflux at 90° C. for 2 hours. Cool to room temperature and concentrate to remove the solvent under the reduced pressure. Purify the residue by flash chromatography to yield the title compound (2.1 g, 2.4 mmol). MS (m/z): 878.4 (M+1).
Reaction SMILES: O1C2C=CC(N)=CC=2NCC1.FC(F)(F)C(=O)CC(OCC)=O.[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][C:35](=[O:43])[CH2:36][C:37](=O)[C:38]([F:41])([F:40])[F:39])=[CH:33][C:28]=2[NH:27][CH2:26][CH2:25]1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[F:39][C:38]([F:41])([F:40])[C:37]1[C:31]2[CH:30]=[C:29]3[C:28]([NH:27][CH2:26][CH2:25][O:24]3)=[CH:33][C:32]=2[NH:34][C:35](=[O:43])[CH:36]=1
Reactant: O=C(CC(=O)C(F)(F)F)Nc1ccc2c(c1)NCCO2
Agent: CCOC(=O)CC(=O)C(F)(F)F
Agent: Nc1ccc2c(c1)NCCO2
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=c1cc(C(F)(F)F)c2cc3c(cc2[nH]1)NCCO3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,4-dihydro-2H-benzo[1,4]oxazin-6-yl amine (0.56 g, 3.73 mmol) in toluene (20 mL) was added ethyl 4,4,4-trifluoroacetoacetate (0.55 mL, 3.73 mmol) and 4 drops of pyridine. The solution was heated to reflux for 6 hours, then allowed to stir overnight at room temperature. The solvent was removed under vacuum and the residue triturated with diethyl ether. The solid was filtered off and washed with diethyl ether to yield a gray solid which was determined by 1HNMR to contain crude N-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4,4,4-trifluoro-3-oxo-butyramide. The rest of the material in the filtrate was also determined by 1HNMR to be crude N-(3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-4,4,4-trifluoro-3-oxo-butyramide, but much less pure than the gray solid filtered off. The mixture was recovered by evaporating the ether. This mixture (0.8 g) was stirred in of concentrated sulfuric acid (8 mL) overnight at room temperature. The reaction mixture was then poured onto ice and neutralized by adding 1N sodium carbonate. The resulting solution was extracted three times with ethyl acetate, the extracts dried over magnesium sulfate, filtered and evaporated under vacuum to yield a brown oil. The brown oil (crude material) was purified by column chromatography on a Biotage system eluting with 4% methanol/ethyl acetate to yield 8-trifluoromethyl-3,4-dihydro-2H,5H-1-oxa-4,5diaza-anthracen-6-one as the main product.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O[C@@H:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]2[C:20]2[CH:25]=[CH:24][C:23]([O:26][C@H:28]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:22][CH:21]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1ccc(CCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Yield: 33 %

Procedure:
A solution of 4-{1-[3-(4-butylphenyl)propan-1-yl]-5-methyl-1H-pyrrol-2-yl}phenol (880 mg, 2.53 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (492 mg, 2.53 mmol), triphenylphosphine (665 mg, 2.54 mmol) and diethyl azodicarboxylate (442 mg, 2.54 mmol) in toluene (30 ml) was refluxed for 20 hours under heating. The residue was poured into water, extracted with ethyl acetate, washed with saturated brine and dried over magnesium sulfate anhydride. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give the object compound as an oily substance. 440 mg (yield: 33%)
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH:41]=O)=[CH:33][CH:32]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:41][C:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:31]=[CH:32][CH:33]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:30])[C:16]1[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reactant: O=Cc1ccnc2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
3.35 g (7.78 mmol) of (2R,4S)-2-benzyl-1-(3,5-bis-(trifluoromethyl)benzoyl)-4-piperidinamine are reacted in analogy to Example 2g with 1.34 g (8.56 mmol) of quinoline-4-carboxaldehyde and 1.3 g of magnesium sulfate in 30 ml of toluene, and subsequently reduced with 324 mg (8.56 mmol) of sodium borohydride in 25 ml of methanol. The title compound ##STR64## is obtained (3.5 g, 79% ) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.21, FD-MS: M+ =571, [α]D =+0.7 (c=1, MeOH), IR: 1635 cm-1.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:30][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCCN
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCNCC1CCn2c(nc3ccccc32)S1
Yield: 43.3 %

Procedure:
To a solution of 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (30 ml) was added 4 ml of n-butylamine. A catalytic amount of sodium hydride was thereafter added under ice-cooling, stirring conditions. After stirring for 15 minutes at room temperature, the mixturewas refluxed for 24 hours. The reaction mixture was cooled and then condensed under reduced pressure. The residue was added with water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.71 g (yield: 43.3%) of the intended product, m.p. 122°-124° C.; IR νmaxKBr cm-1 : 3320, 3100-2700, 1430; Anal. Calcd. for C15H21N3S: C, 65.42; N, 7.68; N, 15.26; S, 11.64; Found: C, 65.63; H, 7.61; N, 15.46; S, 11.30.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[C:12](=O)([O-])[O-].[K+].[K+].COP(C(=[N+]=[N-])C(=O)C)(=O)OC>CO>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([I:1])=[C:3]([O:10][CH3:11])[CH:4]=1)#[CH:12]
Reactant: COc1cc(C=O)ccc1I
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(I)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.6 %

Procedure:
4-Iodo-3-methoxy-benzaldehyde (27.26 g, 104 mmol) and potassium carbonate (28.8 g, 208 mmol) were placed in a 2000-mL flask under nitrogen and methanol (1317 ml) was added. To the yellowish suspension was added (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (23.98 g, 125 mmol) in 20 mL MeOH via syringe. The reaction mixture was stirred at room temperature for 16 h giving a yellow solution. LCMS showed complete conversion to product. The yellow suspension was concentrated down to approximately 200-300 mL, then aqueous sodium hydrogen carbonate (saturated, 100 mL) was added and the mixture was diluted with diethyl ether (450 mL). The combined organic fractions were washed with brine (saturated, 2×10 mL), dried (MgSO), filtered and the solvent was evaporated under reduced pressure. The residue was dried on high vacuum over night to give a yellow solid. The crude material was purified on silica gel (330 g column; gradient to 30% EtOAc/heptane) and the resulting oil was dried under high vacuum to afford 4-ethynyl-1-iodo-2-methoxy-benzene (22.7 g) a semi-solid yellow material which was pure by NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([N:18](CC2C=CC(OC)=CC=2)[CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]([CH3:46])[CH3:45])[CH:37]=2)=[O:34])=[C:4]([F:47])[CH:3]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:31])[N:10]([CH2:29][CH3:30])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:6][C:5]([NH:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([CH2:43][N:44]([CH3:45])[CH3:46])[CH:37]=2)=[O:34])=[C:4]([F:47])[CH:3]=1
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN(C)C)c3)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN(C)C)c3)c(F)cc2Cl)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78 %

Procedure:
A mixture of 1-(4-chloro-5-(1-ethyl-7-((4-methoxybenzyl)(methyl)amino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea (174 mg, 0.263 mmol) in TFA (2.0 mL) was stirred at RT for 2.5 h. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3, stirred for 0.5 h and the resulting solid collected via filtration and dried to afford 1-(4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(3-((dimethylamino)methyl)-4-fluorophenyl)urea (111 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.63 (s, 1H), 8.41 (s, 1H), 8.15 (d, J=8.7 Hz, 1H), 7.74 (s, 1H), 7.54-7.50 (m, 2H), 7.23 (m, 1H), 7.09-7.01 (m, 2H), 6.23 (s, 1H), 4.13 (q, J=6.8 Hz, 2H), 3.37 (s, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.13 (s, 6H), 1.20 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 541.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:49])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH2:48])[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]4[CH:34]=[N:35][CH:36]=[C:37]([C:39](=[O:47])[C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:27])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:50]([O:54][C:55]([N:57]([CH3:63])[C@@H:58]([CH3:62])[C:59](O)=[O:60])=[O:56])([CH3:53])([CH3:52])[CH3:51].C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:49])[NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C@H:25]([NH:48][C:59](=[O:60])[C@@H:58]([N:57]([C:55]([O:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[CH3:63])[CH3:62])[C:26]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[C:33]4[CH:34]=[N:35][CH:36]=[C:37]([C:39](=[O:47])[C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH:38]=4)=[O:27])=[CH:22][CH:23]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H](Cc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1)N(C)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
To a solution of [4-((S)-2-amino-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (I-2b: 2.4 g, 3.7 mmol), (S)-2-(tert-butoxycarbonyl-methyl-amino)-propionic acid (0.89 g, 4.4 mmol) and ethyldiisopropylamine (7 mL) in DMF (20 mL) was added a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (1.67 g, 4.4 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol (0.6 g, 4.4 mmol) in DMF (10 mL) and the reaction mixture was shaken for 16 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed sequentially with brine (2×) (300 mL), saturated aqueous bicarbonate solution (300 mL), brine (300 mL), water (300 mL), and brine (300 mL), then dried over Na2SO4/MgSO4, and concentrated in vacuo to provide crude [4-((S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-3-oxo-propyl)-phenyl]-carbamic acid 9H-fluoren-9-ylmethyl ester as a yellow foam.
Reaction SMILES: [C:1]([C:9]1C=[CH:15][CH:14]=[C:11]2[CH2:12][CH2:13][C:10]=12)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:19]([OH:21])C>>[CH:12]1[C:11]2[CH:14]=[CH:15][C:1]([C:2]3([CH:3]=[CH:4][CH:5]=[CH:6][CH2:7]3)[CH2:19][OH:21])=[CH:9][C:10]=2[CH:13]=1
Reactant: O=C(c1ccccc1)c1cccc2c1CC2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: OCC1(c2ccc3c(c2)C=C3)C=CC=CC1

Procedure:
4-Benzoylbenzocyclobutene is reduced with sodium borohydride in 2 mL ethanol. 1-(4-Benzocyclobutenyl)benzyl alcohol is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[C:14](OCC)=[O:15])[CH2:8]1.O1CCCC1.[BH4-].[Li+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][CH:7]1[O:11][C:10](=[O:12])[N:9]([CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][OH:15])[CH2:8]1
Reactant: CCCC(C(=O)OCC)N1CC(COc2cccc(Cl)c2)OC1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCC(CO)N1CC(COc2cccc(Cl)c2)OC1=O
Yield: 53.4 %

Procedure:
A procedure similar to that described in Preparation 5 was repeated, except that 4.31 g of ethyl 2-[5-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]pentanoate (polar isomer), obtained as described in Preparation 96, 40 ml of anhydrous tetrahydrofuran, 0.42 g of lithium borohydride and 0.31 g of anhydrous methanol were used, to give 2.03 g of the title compound, melting at 98° C. to 102° C., from the polar diastereomer.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([C:9]([CH:11]=O)=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH2:15][CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=2[O:25][CH3:26])[CH2:17]1>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]([OH:10])[CH2:11][NH:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[C:22]=3[O:25][CH3:26])[CH2:17]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1OC)CC(N)C2
Reactant: O=CC(=O)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1OC)CC(NCC(O)c1cccc(C(F)(F)F)c1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of m-trifluoromethylphenylglyoxal and 2-amino-4,5-dimethyoxyindane in toluene is refluxed for 2 hours, using a Dean-Stark trap to remove the formed water. The solution is concentrated in vacuo and the residue is dissolved in methyl alcohol. The resulting solution is cooled in ice, sodium borohydride is added in portions and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo, the residue is partitioned between water and methylene chloride and the layers are separated. The organic layer is dried over sodium sulfate and concentrated in vacuo to give 1-(3-trifluoromethylphenyl)-2-(4,5-dimethoxyindan-2-yl)aminoethanol. Under anhydrous conditions, tetrahydrofuran, triethylamine and carbonyldiimidazole are added to the above compound and the mixture is stirred at room temperature for 20 hours. The reaction mixture is quenched with water and extracted with diethyl ether. The diethyl ether extracts are combined, washed with 2N hydrochloric acid, saturated sodium chloride, dried over magnesium sulfate. The solution is evaporated in vacuo to give a mixture of (R*,R*) and (R*,S*)-5-(3-trifluoromethylphenyl)-3-(2,3-dihydro-4,5-dimethoxy-1H-inden-2-yl)-2-oxazolidinone. This mixture is separated into the individual (R*,R*) and (R*,S*) racemates by chromatographic techniques described in Example 1. Each racemate is treated with boron tribromide and the individual products are reacted with diethyl dibromomalonate, as described in Example 1, to give (R*,R*) and (R*,S*)-7- 2-(3-trifluoromethylphenyl)-2-hydroxyethyl!amino!-7,8-dihydro-6H-indeno 4,5-d!-1,3-dioxole-2,2-dicarboxylic acid diethyl esters. These products are then hydrolyzed with 2.5N sodium hydroxide, as described in Example 3, to give the desired products.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8].Cl.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([NH:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH3:31])[C:14]([NH:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([O:26][C:27]([F:28])([F:29])[F:30])[CH:23]=[CH:22][C:20]=4[N:21]=3)=[N:15][C:11]=2[CH:10]=1)=[O:8])=[O:39]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCN)ccc21
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)NCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 101 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-dimethylamino-acetylamino)-ethyl]-amide (62 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-amino-ethyl)-amide dihydrochloride (60 mg), N,N-dimethylglycine hydrochloride (18 mg), HBTU (57 mg), and DIEA (33 uL). LC/MS: m/z 536.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.48 (s, 1H), 8.08 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.80-7.65 (m, 2H), 7.49 (d, 1H), 7.37 (d, 1H), 3.76-3.46 (m, 5H), 2.97 (s, 2H), 2.89 (s, 2H), 2.25 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[NH:6][C:7](=[O:15])[C:8]([C:13]#[N:14])=[C:9](SC)[N:10]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21]1>C(#N)C>[OH:28][CH2:27][CH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:9]2[N:10]=[C:5]([CH2:4][C:3]3[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=3[CH3:1])[NH:6][C:7](=[O:15])[C:8]=2[C:13]#[N:14])[CH2:21][CH2:22]1
Reactant: CSc1nc(Cc2ccccc2C)[nH]c(=O)c1C#N
Reactant: OCCC1CCNCC1
Solvent: CC#N
Product: Cc1ccccc1Cc1nc(N2CCC(CCO)CC2)c(C#N)c(=O)[nH]1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(2-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.14 g (1.1 mmol) of 2-(4-piperidinyl)ethan-1-ol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 13 mg (10% of theory) of the title compound are obtained as a colourless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].O[CH2:36][C:37]1[O:38][C:39](=[O:43])[O:40][C:41]=1[CH3:42].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O.CC(C)=O>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([O:34][CH2:36][C:37]3[O:38][C:39](=[O:43])[O:40][C:41]=3[CH3:42])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: Cc1oc(=O)oc1CO
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CC(C)=O
Product: CCOc1nc2cccc(C(=O)OCc3oc(=O)oc3C)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 10 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (9.0 g) and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (3.08 g) in N,N-dimethylacetamide (100 mL) were added p-toluenesulfonyl chloride (4.13 g), N,N-dimethylaminopyridine (0.48 g) and potassium carbonate (3.54 g) under ice-cooling and the mixture was stirred at about 10° C. for 3 hrs. After adjusting the pH of the mixture to about 5, the mixture was crystallized by adding water (72 mL) to give crystals as a solvate. The isolated crystals were suspended in a mixture of water (63 mL) and acetone (27 mL) and the suspension was stirred at about 35° C. for 2 hrs. After stirring under ice-cooling for 2 hrs, the crystals were collected by filtration and the crystals were washed with water (18 mL) and dried under reduced pressure at 40° C. to give the title compound (10.6 g, 95%).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH:15]=[C:16]([Br:18])[Br:17])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:17][C:16]([Br:18])=[CH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:7][CH3:6])[CH2:10][CH2:11]1
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C=C(Br)Br)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H]1CC[C@H](C=C(Br)Br)CC1
Reaction time: 2 h

Procedure:
A solution of 975 mg (3.28 mmol) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 20 ml CH2Cl2 was treated at 0° C. with 10 ml TFA (for 20 min). After 2 h at RT, the reaction was evaporated, treated with aqueous saturated NaHCO3(+Na2CO3)/Et2O (3×), dried over Na2SO4 and evaporated to yield 981 mg (87%) of trans-[4-(2,2-Dibromo-vinyl)-cyclohexyl]-methyl-amine, MS: 295 (M, 2Br).