Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:27])[N:19]2[CH3:28])=[CH:14][CH:13]=1.C(N(CC)CC)C>CO>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[O:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:27])[N:19]2[CH3:28])=[CH:16][CH:17]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Cn1c(=O)c2cccnc2n1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1c(=O)c2cccnc2n1-c1ccc(Oc2nc3ccccc3[nH]2)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
A mixture of 2-chloro-1H-benzimidazole (0.057 g), 1-(4-hydroxyphenyl)-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (0.060 g) and triethylamine (3.5 ml) was stirred under a nitrogen atmosphere at 160° C. for 16 hr. The reaction mixture was cooled to room temperature, diluted with methanol, and silica gel was added. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.012 g).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6])[CH:2]=[CH2:3].C(=O)(O)[O-]>CC(C)=O.[Cl-].[Na+].O>[C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:8]([NH:7][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[CH:13]=1)(=[O:16])[CH3:15]
Reactant: C=CCOC(=O)Nc1cc(C(C)O)ccc1CC(=O)OCC
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCC
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
Ethyl [2-{[(allyloxy)carbonyl]amino}-4-(1-hydroxyethyl)phenyl]acetate (10.3 g) prepared by step e) was dissolved in acetone (30 mL) and thereto was added at room temperature Jons' reagent (10 mL), followed by stirring for 30 minutes. To the reaction solution were added saturated bicarbonate solution (50 mL) and saturated brine (100 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The organic layer was combined, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to give a crude product. The crude product was combined with the crude product prepared separately prepared in a scale of 1 g and purified with column chromatography (SiO2 300 g, hexane/ethyl acetate 1:1) to give the object compound (10.3 g, 85%) as a yellow oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(OCC)(=O)C>[CH3:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1
Temperature: 140 °C
Reaction time: 14 h

Procedure:
1.3 g of 3-fluoro-4-nitrophenol and 2.7 g of 4-methylaniline were mixed and stirred for 14 hours at 140° C. After cooling, it was dissolved in ethyl acetate and extracted three times with 4N aqueous hydrochloric acid. The organic phase was washed with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was crystallized from diisopropyl ether. 1.70 g was obtained.
Reaction SMILES: [C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[C:16]([O:22]C)[CH:15]=2)[C:11]2[C:6](=[C:7]([O:26]C)[C:8]([O:24]C)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].B(Br)(Br)Br.ClCCl.CO>ClCCl>[C:1]([N:4]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:22])[CH:15]=2)[C:11]2[C:6](=[C:7]([OH:26])[C:8]([OH:24])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc([C@H]2CN(C(C)=O)Cc3c2ccc(OC)c3OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1Cc2c(ccc(O)c2O)[C@@H](c2ccc(O)c(O)c2)C1
Yield: 96.6 %

Procedure:
(i) 1.78 g of (R)-(-)-N-acetyl-7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline was dissolved in 9 ml of dichloromethane; after adding 24 ml of 1M boron tribromide-dichloromethane solution at -30° C., the mixture was reacted at room temperature for 90 minutes. Then 4.4 ml of methanol was added at -30° C. The reaction solution was concentrated and subjected twice to azeotropic distillation with methanol. To the residue was added 17.8 ml of 0.1N hydrochloric acid. The crystals which separated out were collected by filtration, affording 1.46 g of (R)-(-)-N-acetyl-7,8-dihydroxy-4-(3,4-dihyroxyphenyl)-1,2,3,4-tetrahydroisoquinoline.1/4 hydrate, m.p. above 230° C. (decomposition); [α]D20 =-85° (C=1, CH3OH)
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/C=C(\C)/CCC(OC)=O)=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClCCl.N1C=CC=CC=1.[CH3:41][OH:42]>>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:41]=[O:42])=[C:16]([O:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Reaction time: 0.75 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (11.0 g) in methanol 125 ml), dichloromethane (125 ml) and pyridine (2 ml) was cooled to -78° C. and a stream of ozonized oxygen was bubbled through. After 45 minutes a blue color developed indicating the presence of unreacted ozone. Dimethyl sulfide (5 ml) was added and the cooling bath was removed. After 16 hours the solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate and then water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 2:1 hexane:ethyl acetate, so as to produce 2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) acetaldehyde, mp. 88°-92° C. (ether).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:11][CH:12]=1)[C:6]#[N:7].[BH4-].[Na+]>CO.[Co](Cl)Cl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[O:11][CH:12]=[C:8]([CH:5]([CH2:6][NH2:7])[CH2:4][CH2:3][N:2]([CH3:20])[CH3:1])[N:9]=2)=[CH:18][CH:17]=1
Reactant: CN(C)CCC(C#N)c1coc(-c2ccc(F)cc2)n1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCC(CN)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Cobalt (II) chloride (380 mg, 2.9 mmol) was added to a solution of 4-(dimethylamino)-2-(2-(4-fluorophenyl)oxazol-4-yl)butanenitrile (400 mg, 1.46 mmol) in dry methanol (10 mL) at 0° C., followed by sodium borohydride (550 mg, 14.6 mmol) portionwise. The resulting mixture was stirred at room temperature for 1 h, then quenched carefully with ice water, and filtered through a Celite bed. The filtrate was concentrated under reduced pressure to afford crude 3-(2-(4-fluorophenyl)oxazol-4-yl)-N1,N1-dimethylbutane-1,4-diamine (180 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C15H20FN3O: 277.16. found: 278.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1.C(N(C(C)C)CC)(C)C.O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:12][C:13]1([CH3:37])[CH2:22][CH2:21][C:20]2[N:19]=[CH:18][N:17]=[C:16]([N:23]3[CH2:29][C:28]4[CH:30]=[C:31]([C:5]5[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=5)[CH:32]=[CH:33][C:27]=4[O:26][CH2:25][CH2:24]3)[C:15]=2[CH2:14]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A mixture of 2-amino-5-bromo-3-nitropyridine (0.31 g, 1.4 mmol [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (0.50 g, 1.4 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (103 mg, 0.1 mmol), diisopropylethylamine (0.94 g, 7.1 mmol), 1,4-dioxane (20 mL), and water (2 mL) was stirred at 90° C. for 4 hours. The reaction mixture was cooled, diluted with ethyl acetate (100 mL) then filtered through celite. The filtrate was washed with 50 mL portion each of 5% aqueous citric acid, water, then brine solution, dried over sodium sulfate, filtered and concentrated to give a brown solid residue. It was washed with 35% ethyl acetate-hexane to give 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridin-2-amine (0.63 g, 97% yield). MS (EI) for C24H26N6O3: 447 (MH+).
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[C:24]([O:23][C:21]([CH2:20][N:8]1[C:4]2[CH:3]=[C:2]([I:1])[CH:18]=[CH:17][C:5]=2[N:6]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:7]1=[O:9])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)n1c(=O)[nH]c2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2ccc(I)cc21

Procedure:
A mixture of 1.90 g (5.27 mmol) of tert-butyl 5-iodo-2-oxo-2,3-dihydro-benzimidazole-1-carboxylate (VIb), 1.13 g (5.80 mmol) of tert-butyl bromoacetate and 2.23 g (6.86 mmol) of cesium carbonate in acetonitrile (60 ml) was heated under reflux for 3 h. The solvent was removed in vacuo, water was added to the residue, and the aqueous mixture was extracted four times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution and dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by chromatography on silica gel (mobile phase gradient 15-40% ethyl acetate in heptane). Yield: 2.26 g (90%) of white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23].[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([C:25]#[N:26])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(F)c(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(F)c(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 91 %

Procedure:
A degassed suspension of 6-chloro-5-fluoro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (7.8 g, 21.2 mmol), zinc (II) cyanide (1.84 g, 15.6 mmol), and Pd(PPh3)4 (2.43 g, 2.12 mmol) in DMF (40 mL) was subjected to microwave irradiation at 150° C. for 15 minutes. The reaction mixture was filtered through Celite® and the filtrate diluted with ethyl acetate. The organic phase was washed twice with water and once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with diethyl ether and pentane, and then dried under vacuum to afford the title compound as a yellow solid (6.9 g, 91%). LCMS (method B): RT=4.99 min, [M+H]+=362.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=5[O:33][C@H:34]([CH2:36]C=C)[CH3:35])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:50])([O:4][CH2:1][CH:2]=[CH:3][CH2:35][C@H:34]([CH3:36])[O:33][C:27]2[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:49])[CH3:47]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cccc(F)c5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OC/C=C/C[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1

Procedure:
Prepared in 69% from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the same procedure as methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.13 (br. s., 1H), 8.06 (s, 1H), 8.01 (s, 1H), 7.56 (br. s., 1H), 7.38 (d, J=7.3 Hz, 2H), 7.19-7.13 (m, 1H), 7.09 (d, J=7.3 Hz, 2H), 6.19-6.11 (m, 1H), 6.08 (br. s., 1H), 5.83 (dt, J=15.4, 4.5 Hz, 1H), 5.05-4.94 (m, 1H), 4.48-4.36 (m, 1H), 4.06-3.93 (m, 2H), 3.82-3.74 (m, 1H), 3.69 (s, 3H), 3.08-3.01 (m, 1H), 2.77-2.68 (m, 1H), 2.56-2.51 (m, 1H), 2.49 (br. s., 3H), 2.25-2.14 (m, 1H), 2.05-1.95 (m, 2H), 1.77 (br. s., 2H), 1.34 (s, 3H), 1.26 (s, 9H), 0.88 (d, J=6.0 Hz, 3H); LCMS (ESI, M+1): 656.70.
Reaction SMILES: [C:1]([C:5]1([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C.C(OCC)(=O)C>[C:1]([C:5]([OH:6])([CH2:7][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1(COC2CCCCO2)CO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C(O)(COC1CCCCO1)Cn1ccnc1
Yield: 71.2 %

Procedure:
A solution of 59 g (0.28 mol of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxy-methyl)-oxirane in 100 ml of acetonitrile is added dropwise to a mixture of 119 g 1.75 mol of imidazole, 1 g 9 mols) of potassium tert.-butylate and 500 ml of acetonitrile under a nitrogen atmosphere, the reaction mixture being boiled under reflux. When the addition has ended, the mixture is boiled under reflux for a further 10 hours, the solvent is then stripped off under reduced pressure and the residue which remains is taken up in ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The product thus obtained is purified chromatographically over silica gel with chloroform as the mobile phase. 56.3 g (72% of theory) of 2-tert.-butyl-3-(imidazol-1-yl)-1-(tetrahydro-2H-pyran-2-yloxy)-propan-2-ol are obtained in this manner in the form of a solid substance of melting point 107° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47]CC)=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:51])([F:50])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([OH:47])=[O:46])[CH2:44][C@H:17]2[CH2:16][C:15]([F:50])([F:51])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4c4ccccc34)CN2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclo pentadecine-14a-carboxylate (Example 19c, 320 mg, 0.451 mmol) in tetrahydrofuran (1505 μl), water (752 μl), and ethanol (752 μl) was added lithium hydroxide monohydrate (123 mg, 2.93 mmol) at room temperature The mixture was stirred at room temperature for 16 h and then heated at 37° C. for 6h. The mixture was cooled to room temperature and then eluted through a pad of silica gel with 10% methanol/dichloromethane,and evaporated under reduced pressure. The crude materal was purified by flash chromatography on silica gel (10% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(phenanthridin-6-yloxy)octadeca hydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (215 mg, 70.0% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:4]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH:43]([CH3:47])[C:44](Cl)=[O:45].C(=O)(O)[O-].[Na+]>C1COCC1>[C:22]([O:21][C:20](=[O:26])[NH:19][C:15]1([C:12]2[CH:11]=[CH:10][C:9]([C:5]3[C:4]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:3][C:2]4[NH:1][C:44](=[O:45])[CH:43]([CH3:47])[O:8][C:7]=4[N:6]=3)=[CH:14][CH:13]=2)[CH2:18][CH2:17][CH2:16]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3[nH]c(=O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: CC(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of tert-butyl 1-(4-(5-amino-6-oxo-3-phenyl-1,6-dihydropyridin-2-yl)phenyl)cyclobutylcarbamate (0.5 g, 1.159 mmol) in THF (Volume: 20 ml) was added DIPEA (1.01 ml) followed by the addition of 2-chloropropanoyl chloride (0.235 g, 1.854 mmol) in THF (5 ml) in dropwise at 0 degree over 1 h. The resulted mixture was stirred at r.t. over night. Sodium bicarbonate saturated solution (30 ml) was added. The resulted mixture was heated to reflux for 16 h. The reaction mixture was cooled down to room temperature. The organic phase was separated. The aqueous phase was extracted with ethyl acetate (40 ml). The organic phase was combined and washed with water (30 mlX2), brine (25 ml) then concentrated at reduced pressure. The residue was suspended in DCM (10 ml). The precipitate was collected by filtration and washed with DCM (5 ml) to afford product (439 mg). 1H NMR (500 MHz, CD3OD): 7.20-7.29 (m, 8H), 7.13-7.15 (m, 2H), 4.98 (q, 1H), 2.41-2.47 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.64 (d, 3H), 1.21-1.36 (br, 9H).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:13]=[CH:12][C:10](N)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.N([O-])=O.[Na+].[BrH:18]>O>[Br:18][C:10]1[CH:12]=[CH:13][C:7]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:8][CH:9]=1
Reactant: Cc1nccn1-c1ccc(N)cc1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nccn1-c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 51 %

Procedure:
To a solution of 4-(2-methyl-1H-imidazol-1-yl)aniline (10 g, 57.8 mmol) in 100 mL of HBr solution was added a solution of NaNO2 (5.2 g, 75.1 mmol) in H2O (60 mL) at 0° C. Stirred at this temperature for 20 min., then poured the mixture into a solution of CuBr (58 g, 404 mmol) in HBr solution (200 mL) at 0° C., and stirred for 30 min., diluted with water, and stirred at room temperature for 1 hour. The precipitate was separated out, and evaporated in vacuo to give 28 g of crude product, which was purified by Prep-HPLC to obtain 1-(4-bromophenyl)-2-methyl-1H-imidazole (7 g, yield 51%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:12])([F:13])[F:11])[C:5]=1[NH:14][CH2:15][CH2:16][OH:17]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1cccc(C(F)(F)F)c1NCCO
Temperature: 60 °C
Yield: 89.9 %

Procedure:
To a solution of 2-{[2-nitro-6-(trifluoromethyl)phenyl]amino}ethanol (0.72 g, 2.88 mmol) in methanol (30 mL) a suspension of 85% sodium hydrosulfite (2.0 g, 9.8 mmol) in water (6 mL) was added. Additional water (4 mL) was added, and the mixture was heated at 60° C. for 15 min. The reaction mixture was cooled and concentrated in vacuo. The residue was extracted with ethyl acetate, and the organic phase was dried over magnesium sulfate. The solvent was removed in vacuo affording 0.57 g of 2-{[2-amino-6-(trifluoromethyl)phenyl]amino}ethanol: MS (ES) m/z 219 [M−H].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH3:10][N:11]([CH3:15])[C:12](Cl)=[S:13].[OH-].[K+]>>[CH3:10][N:11]([CH3:15])[C:12](=[S:13])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1
Reactant: N#Cc1cccc(O)c1
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Product: CN(C)C(=S)Oc1cccc(C#N)c1

Procedure:
If the procedure described in Preparation XI is followed starting from 15 g (126.10-3 mol) of 3-hydroxybenzonitrile, 17.9 g (145.10-3 mol) of dimethylthiocarbamoyl chloride and 7.4 g (132.10-3 mol) of potassium hydroxide, 29 g (quantitative yield) of the expected product are obtained.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[N:28]=[C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)[CH:26]=[CH:25][N:24]=1>>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:23]3[N:28]=[C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)[CH:26]=[CH:25][N:24]=3)[CH2:8]2)[CH2:1]1)=[O:10]
Reactant: Clc1nccc(-c2cccs2)n1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Product: O=C(c1ccccc1-c1cccs1)N1CC2CN(c3nccc(-c4cccs4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS (ESI) mass calcd. for C25H22N4OS2, 458.60; m/z found, 459.1 [M+H]+.