Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([Cl:32])=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=2)[CH2:4][C@H:3]1[O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35].C1N=CN([C:46](N2C=NC=C2)=[O:47])C=1.[CH3:53][N:54]([CH3:58])[CH2:55][CH2:56][OH:57].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Si:34]([O:33][C@H:3]1[C@H:2]([NH:1][C:46](=[O:47])[O:57][CH2:56][CH2:55][N:54]([CH3:58])[CH3:53])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:20]4=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:19]4[N:18]=3)[C:9]=2[Cl:32])[CH2:4]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)CC[C@H]1N
Reactant: CN(C)CCO
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(NC4CC4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A solution of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (32 mg, 0.055 mmol) in THF (1 mL) was added to CDI (35.8 mg, 0.221 mmol) in THF (1 mL) at 0° C. and the reaction mixture was stirred at room temperature overnight. In a 1-dram vial charged with 2-(dimethylamino)ethanol (44.6 mg, 0.500 mmol) in THF (1 mL) was added lithium bis(trimethylsilyl)amide (1M in THF, 0.884 mL, 0.884 mmol) at 0° C. and the resulting reaction solution was stirred at room temperature for 10 min before added to the above intermediate. The reaction mixture was stirred at room temperature for 1 h Solvent was evaporated and the residue was partitioned between dichloromethane and saturated sodium bicarbonate. The layers were separated and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 1-8% methanol/dichloromethane). (+/−)-2-(dimethylamino)ethyl ((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)carbamate (34 mg) was obtained as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[NH:32][C:33](=[O:47])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=O)=[CH:37][C:36]=1[O:45][CH3:46].CCN=C=NCCCN(C)C.[ClH:59].O>CN(C=O)C>[Cl:59][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=1[NH:32][C:33](=[O:47])[NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:44])=[CH:37][C:36]=1[O:45][CH3:46]
Reactant: Cl
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3c(Cl)cccc3Cl)c(OC)c2)cc1
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (109 mg, 0.35 mmol), 4-[N′-(2,4-dichlorophenyl)ureido]-3-methoxyphenylacetic acid (129 mg, 0.35 mmol) and N,N-dimethylaminopyridine (42.8 mg, 0.35 mmol) in DMF (10 ml) was added EDC.HCl (73.4 mg, 0.39 mmol) at rt, and the resulting mixture was stirred for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[1-[4-[N′-(2,6-dichlorophenyl)ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (208 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 2.00–2.21 (m, 3 H), 2.33–2.39 (m, 1 H), 3.31 (s, 2 H), 3.69 (s, 3 H), 3.88 (s, 3 H), 4.34–4.45 (m, 2 H), 4.59 (br s, 1 H), 4.93 (t, J=6.8 Hz, 1 H), 6.47 (d, J=8.0 Hz, 1 H), 6.63 (s, 1 H), 6.68 (s, 1 H), 6.92–6.95 (m, 2 H), 7.12–7.41 (series of m, 9 H), 7.96–8.01 (m, 4 H); MS (FAB) m/z, 662 (M++H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:18]2[CH:39]=[CH:38][C:21]([C:22]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])=[CH:20][CH:19]=2)=[N:6][C:7]=1[C:8]1[NH:12][C:11]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2nc(-c3nc(-c4ccc(C(=O)N5CCCNCC5)cc4)cnc3N)[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 125.5 %

Procedure:
tert-butyl 4-[4-[5-amino-6-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-yl]benzoyl]-1,4-diazepane-1-carboxylate (117 mg, 0.2218 mmol) was dissolved in DCM (3 mL) and the mixture was cooled to 0° C. TFA (3 mL, 38.94 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for a further 2 hours. Solvents were evaporated and the residue was dissolved in a mixture of MeCN and water (5 mL/5 mL) and submitted to Genevac evaporation to yield the product (119 mg, 99% Yield). 1H NMR (400.0 MHz, CD3OD) δ 2.18-2.04 (2H, m), 2.45 (3H, s), 3.33 (3H, m), 3.44 (2H, m), 3.63 (2H, m), 3.82 (1H, m), 3.96 (2H, m), 7.15 (1H, d), 7.45 (1H, s), 7.55 (2H, d), 7.58 (1H, s), 8.59 (2H, d), 8.59 (1H, s) ppm; MS (ES+) 428
Reaction SMILES: [CH3:1][N:2]([CH3:20])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.N1C=CC=CC=1.[ClH:33]>O>[ClH:33].[CH3:20][N:2]([CH3:1])[N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1
Reactant: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Reactant: C1CNCCN1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(C)n1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21

Procedure:
A mixture of 2.86 g of 1-dimethylamino-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 4.3 g of anhydrous piperazine and 30 ml of dry pyridine is heated at the boiling point under reflux for 6 hours. The pyridine is then stripped off in vacuo and 10 ml of water are added to the residue. The pH of the solution is brought to about 1 with concentrated hydrochloric acid and the precipitate is filtered off with suction in the cold and washed with a little ice-cold 10% strength hydrochloric acid and ethanol. After drying in vacuo at 100° C., 1.5 g of 1-dimethylamino-6,8-difluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride of decomposition point 284°-286° C. are obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CO>[CH3:1][O:2][CH2:5][C:6]1[C:16]2[O:15][CH2:14][CH2:13][C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: COC(=O)C1=Cc2cccc(CCl)c2OCC1
Agent: [Na+]
Solvent: CO
Product: COCc1cccc2c1OCCC(C(=O)OC)=C2
Reaction time: 2 h

Procedure:
28% Sodium methoxide in methanol (1.2ml) was added to a solution of methyl 2,3-dihydro-9-chloromethyl-1-benzoxepin-4-carboxylate (0.8 g) in methanol (8 ml) under ice-cooling and the mixture was stirred at the same temperature for 2 hours. The solvent was removed by concentration and to the residue was added a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give methyl 2,3-dihydro-9-methoxymethyl-1-benzoxepin-4-carboxylate (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](C)[CH:5]=[CH:4][N:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:12]([O-:14])=[O:13])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-3-nitro-4-methylpyridine (25.6 g, 167 mmol) in conc. H2SO4 (100 mL) at 0° C. was added HNO3 (7.77 mL, d=1.49) dropwise over 30 min. The mixture was warmed to r.t. for 20 min then heated to 45° C. for 90 min. The reaction mixture was cooled and poured into 500 g of ice. The resulting percipitate was filtered and air dried to give 2-amino-3,5-dinitropyridine as a yellow solid.
Reaction SMILES: C(C1C=C2C(=CC=1)/C(=[N:12]/[OH:13])/CC2)=C.[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=O)[CH2:20][CH2:19][CH2:18]2>>[I:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)/[C:21](=[N:12]/[OH:13])/[CH2:20][CH2:19][CH2:18]2
Reactant: O=C1CCCc2cc(I)ccc21
Reactant: C=Cc1ccc2c(c1)CC/C2=N\O
Product: O/N=C1\CCCc2cc(I)ccc21

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 87B employing 6-iodo-3,4-dihydronaphthalen-1(2H)-one as a starting material. The compound had an HPLC retention time=3.28 min. (condition C); LC/MS M+1=288.1.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[C:11]([C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1.COC(=O)CC(=O)C1C=CC=C(OCCC)C=1.C1OC2C(=CC=C(C=2)C=O)O1>C1C=CC=CC=1.C(O)(=O)C.N1CCCCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:10]=[C:11](/[C:16](=[O:27])[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][CH2:25][CH3:26])[CH:18]=3)\[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=2[O:2]1
Reactant: CCCOc1cccc(C(=O)C(=Cc2ccc3c(c2)OCO3)C(=O)OC)c1
Agent: CCCOc1cccc(C(=O)CC(=O)OC)c1
Agent: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCCOc1cccc(C(=O)/C(=C/c2ccc3c(c2)OCO3)C(=O)OC)c1
Yield: 48 %

Procedure:
Methyl 3-(3,4 -methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate. To a solution of methyl-3-(Prop-1-yloxy)benzoylacetate (10 g, 4.2 mmol) in benzene (50 mL) was added 3, 4-methylenedioxybenzaldehyde (6.36 g, 4.2 mmol) followed by piperidine (0.42 mL, 0.42 mmol) and glacial acetic acid (8 drops approx.). The mixture was refluxed for 2 h. and the volatiles removed in vacuo to give methyl (Z)-3-(3,4-methylenedioxyphenyl)-2-[3-(prop-1-yloxy)-benzoyl]propenoate (7.4 g, 48%) as an off white solid after trituration with methanol (m. p. 122-123° C.). Anal. Calc. for C21 H20O6: C, 68.47; H, 5.47. Found: C, 68.81; H, 5.49.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH3:16])=[CH:10][CH:9]=1.N1C=CC=CC=1>ClCCl>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:3])=[CH:10][CH:9]=1.[CH3:1][S:2]([O-:4])(=[O:7])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)c1ccc(OC)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCCO)cc1
Product: CS(=O)(=O)[O-]
Temperature: 0 °C
Yield: 421.2 %

Procedure:
Methyl sulphonyl chloride (12.5 g, 0.11M) was added dropwise to a stirred solution of p-methoxyphenylpropanol (16.6 g, 0.10M) in dichloromethane (60 ml)/pyridine (20 ml) at 0° C. The reaction mixture was maintained at 0° C. for 12 hours, then diluted with dichloromethane (250 ml) and washed with hydrochlorid acid (5×50 ml of 5 M.l-1). The solution was washed with water, dried (MgSO4) and the solvent was evaporated off under reduced pressure to give 3-(4-methoxyphenyl)propan-1-ol, methane sulphonate (20 g), as a colourless crystalline solid, m.p. 41°-42° C. (pentane).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH2:55])=[CH:50][CH:49]=1>CN(C=O)C>[CH3:47][C:48]1[S:52][C:51]([CH2:53][CH2:54][NH:55][C:9](=[O:11])[CH2:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[CH:50][CH:49]=1
Reactant: Cc1ccc(CCN)s1
Reactant: O=C(O)CCc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3 g (13 mmol) 4-(trifluoromethyl)hydrocinnamic acid (commercially available) in 30 mL DMF under argon were added 4.7 g (14.37 mmol) TBTU and 11.2 mL (65.3 mmol) N-ethyldiisopropylamine. A solution of 1.85 g (13 mmol) 2-(5-methyl-thiophen-2-yl)-ethylamine in 5 mL DMF was added drop wise over a period of 2 minutes. The mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with water and with a sat. NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The solid was stirred in 30 mL ether, filtered and dried. The mother liquor was concentrated in vacuo and purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated. 3.75 g (84%) of the title compound was yielded as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.Cl.[C@H:13]12[CH2:19][C@H:16]([NH:17][CH2:18]1)[CH2:15][N:14]2[C:20]([C@@:22]1([CH2:36][CH:37]([F:39])[F:38])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1)=[O:21].C(N(CC)CC)C>CS(C)=O>[F:39][CH:37]([F:38])[CH2:36][C@:22]1([C:20]([N:14]2[CH2:15][C@@H:16]3[CH2:19][C@H:13]2[CH2:18][N:17]3[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=2)=[O:21])[CH2:26][CH2:25][C@@H:24]([NH:27][C@@H:28]2[C@H:33]([O:34][CH3:35])[CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2cccc(C(F)(F)F)n2)C1
Temperature: 25 °C
Reaction time: 14.5 h

Procedure:
Prepared as described in example 24 using 2-chloro-6-(trifluoromethyl)pyridine in place of 4-chloro-6-(trifluoromethyl)pyrimidine and modifying step 9 as follows. To a solution of HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (183 mg, 0.43 mmol) in DMSO (2 ml) was added triethylamine (0.2 ml, 1.43 mmol) and 2-chloro-6-(trifluoromethyl)pyridine (179 mg, 1.05 mmol). The reaction was healed to 120° C. for 14.5 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[6-(trifluoromethyl)pyridin-2-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a brown foam (58 mg 28%). LC/MS (M+H)=533.2551 exp, 533.2546 obs; 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.51 (1H), 6.91-6.89 (1H), 6.51-6.38 (1H), 5.94-5.54 (1H), 5.11-4.70 (2H), 4.06-4.01 (1H), 3.93-3.87 (1H), 3.70-3.53 (2H), 3.51-3.31 (6H), 3.27-3.20 (3H), 2.78-2.61 (1H), 2.53-2.36 (1H), 2.20-1.80 (7H), 1.68-1.38 (5H)
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:32])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]=2[O:4]1.C([Li])CCC.[CH2:38]1[O:48][C:41]2([CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[O:40][CH2:39]1>O1CCCC1>[CH3:32][C:3]1([CH3:2])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]=[C:44]3[CH2:45][CH2:46][C:41]4([O:48][CH2:38][CH2:39][O:40]4)[CH2:42][CH2:43]3)[C:5]=2[O:4]1
Reactant: CC1(C)Cc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(C=C3CCC4(CC3)OCCO4)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 18.4 grams (0.039 mole) of (2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)triphenylphosphonium bromide, 15.4 mL (0.039 mole) of n-butyllithium (2.5M in hexanes), and 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 55 mL of dry tetrahydrofuran, yielding 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[O:9].[CH2:10]([C:12](=[CH2:15])[CH:13]=[O:14])[CH3:11].[CH3:16][OH:17]>>[CH3:8][O:9][CH2:15][C:12]([CH2:13][OH:14])([CH2:10][CH3:11])[CH:16]=[O:17]
Reactant: CO
Reactant: C=O
Reactant: C=C(C=O)CC
Solvent: CCN(CC)CC
Product: CCC(C=O)(CO)COC
Reaction time: 7 h

Procedure:
41 g of triethylamine are added to a mixture of 1600 ml of methanol, 500 g of 30% strength formaldehyde solution and 328 g of 2-ethylacrolein in the course of 10 minutes, and the solution is then kept at 78° C. for 7 hours. Low-boiling components are distilled off, after which 390 g (67%, based on 2-ethylacrolein) of the title compound of boiling point 95°-100° C./3 mbar are isolated by distillation under reduced pressure.
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[BH4-].[Na+]>CO>[OH:13][CH2:12][C:11]1[C:2]([I:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1cc2ccccc2nc1I
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cc2ccccc2nc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a stirred solution of 2-iodo-3-quinolinecarboxaldehyde (595 mg, 2.10 mmol) in 40 mL of CH3OH at 0° C. was added NaBH4 (86 mg, 2.31 mmol), and the mixture was stirred at 0° C. for 30 min. After concentrating the mixture to approximately one-half of its original volume, water (30 mL) was added and the mixture was allowed to stand at 5° C. overnight. The solids were filtered and the crude product (570 mg, 95%) was recrystallized from methanol to give 3-hydroxymethyl-2-iodoquinoline (505 mg, 84%) as colorless needles: mp 189°-190° C. 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1 H), 7.99 (d, 1H, J=9 Hz), 7.87 (d, 1H, J=9 Hz), 7.68 (m, 1H), 7.58 (t, 1H, J= 9 Hz), 5.45 (t, 1H, J=6 Hz), 4.66 (d, 2H, J=6 Hz); IR (nujol) 3350, 1580, 1320, 1125, 1060, 995, 755, 720, cm-1.
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([C:12]12[O:19][CH2:18][C:15]([CH2:20][CH2:21][CH3:22])([CH2:16][O:17]1)[CH2:14][O:13]2)[CH2:7][CH2:8][CH2:9][C:10]#[CH:11].CI>O1CCCC1>[CH2:6]([C:12]12[O:17][CH2:16][C:15]([CH2:20][CH2:21][CH3:22])([CH2:14][O:13]1)[CH2:18][O:19]2)[CH2:7][CH2:8][CH2:9][C:10]#[C:11][CH3:1]
Reactant: [Li]CCCC
Reactant: C#CCCCCC12OCC(CCC)(CO1)CO2
Solvent: CI
Solvent: C1CCOC1
Product: CC#CCCCCC12OCC(CCC)(CO1)CO2
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.7 ml, 1.6M solution in hexane) was added dropwise to a stirred solution of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane (0.65 g) in dry tetrahydrofuran (25 ml) at 0°, under a current of nitrogen. The mixture was stirred at 0° for 15 minutes and then methyl iodide (0.18 ml) was added. The reaction mixture was stirred at 0° for 1 hour and then evaporated in vacuo. The residue was partitioned between diethyl ether and water. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. The residue was purified by chromatography on alumina, eluting with 1:10 dichloromethane:hexane, saturated with ammonia. 1-(Hept-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane was obtained as a colourless crystalline solid (0.23 g) {contained 15% of 1-(hex-5-ynyl)-4-n-propyl-2,6,7-trioxabicyclo[2.2.2]octane}.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].C(O)C>CO.ClCCl.[Cl-].[NH4+]>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:31][C:30]([CH:32]=[C:6]3[S:5][C:4](=[S:7])[N:3]([CH:8]4[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]4)[C:2]3=[O:1])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(-c2ccc(C=O)o2)cc1
Reactant: O=C(O)C1CCCC(N2C(=O)CSC2=S)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1ccc(-c2ccc(C=C3SC(=S)N(C4CCCC(C(=O)O)C4)C3=O)o2)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 68.7 %

Procedure:
3-(4-oxo-2-thioxo-thiazolidin-3-yl)-cyclohexanecarboxylic acid (80 mg, 0.31 mmol), 5-(4-tert-butyl-phenyl)-furan-2-carbaldehyde (75 mg, 0.33 mmol), and diethylenediamine diacetate (59 mg, 0.33 mmol) were combined in a 20 mL vial with ethanol (5 mL) and stirred at room temperature for 65 h. The reaction mixture was diluted with 10% methanol in dichloromethane (200 mL) and aqueous ammonium chloride (20 mL) and stirred at room temperature for 15 minutes. The layers were separated and the aqueous layer was extracted with 10% methanol in dichloromethane (2×100 mL). The combined organic extracts were washed with 0.6N sodium hydrogensulfite (1×20 mL) and then brine (1×20 mL), dried (sodium sulfate) and concentrated under vacuum. The residue was triturated with dichloromethane/hexanes (1:5:30 mL), filtered and dried overnight in a vacuum oven at 55° C. to afford 3-{5-[1-[5-(4-tert-butyl-phenyl)-furan-2-yl]-methylidene]-4-oxo-2-thioxo-thiazolidin-3-yl}-cyclohexanecarboxylic acid (100 mg, 69%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.32 (9H, s), 1.25-1.41 (2H, m), 1.67 (1H, m), 1.87-1.92 (3H, m), 2.29-2.45 (3H, m), 4.98 (1H, m), 7.26 (1H, d, J=3.6 Hz), 7.36 (1H, d, J=3.6 Hz), 7.59-7.61 (3H, m), 7.77-7.70 (2H, m), 12.20 (1H, s); APCI-MS: 469.52; HPLC: 95%.
Reaction SMILES: F[C:2]12[CH2:12][C:6]3(F)[CH2:7][C:8](F)([CH2:10][C:4]([CH2:14][OH:15])([CH2:5]3)[CH2:3]1)[CH2:9]2.C12(CO)CC3CC(CC(C3)C1)C2.ClC1C(F)=CC(F)=C(C=1)C(O)=O.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[C:48]([Cl:51])[C:49]=1F)[C:44]([OH:46])=[O:45]>>[C:4]12([CH2:14][O:15][C:49]3[C:48]([Cl:51])=[CH:47][C:43]([C:44]([OH:46])=[O:45])=[CH:42][C:41]=3[Cl:40])[CH2:10][CH:8]3[CH2:7][CH:6]([CH2:12][CH:2]([CH2:9]3)[CH2:3]1)[CH2:5]2
Reactant: OCC12CC3(F)CC(F)(CC(F)(C3)C1)C2
Reactant: O=C(O)c1cc(Cl)c(F)c(Cl)c1
Agent: O=C(O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)c(Cl)c1

Procedure:
Following the procedure as described in Example 274 step 1 and making variations as required to replace (3,5,7-trifluoroadamantan-1-yl)methanol with adamantan-1-ylmethanol and to replace 5-chloro-2,4-difluorobenzoic acid with 3,5-dichloro-4-fluorobenzoic acid, the title compound was obtained as a colorless solid (1.73 g, quant.): 1H NMR (300 MHz, DMSO-d6) δ 13.44 (br s, 1H), 7.86 (s, 2H), 3.53 (s, 2H), 1.99-1.90 (m, 3H), 1.73-1.57 (m, 12H); MS (ES−) m/z 353.2, 355.2 (M−1).