Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1[Se]C#N)([O-])=O.[CH2:13]([O:20][C@@H:21]([C@@H:28]([CH2:45][CH2:46]O)[CH:29]=[CH:30][C@@H:31]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.OO>O1CCCC1>[CH2:13]([O:20][C@@H:21]([C@@H:28]([CH:45]=[CH2:46])[CH:29]=[CH:30][C@@H:31]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCC[C@@H](C=C[C@H](CCO)[C@@H](CC(OC)OC)OCc1ccccc1)OCc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: N#C[Se]c1ccccc1[N+](=O)[O-]
Agent: OO
Solvent: C1CCOC1
Product: C=C[C@@H](C=C[C@H](CCCCC)OCc1ccccc1)[C@@H](CC(OC)OC)OCc1ccccc1
Temperature: 0 °C
Yield: 91 %

Procedure:
To a suspension of 997 mg (3.67 mM) of o-nitrophenylselenium cyanide in 12 ml of anhydrous tetrahydrofuran was dropwise added 886 mg (1.83 mM) of (3R,4S,7S) 3,7-dibenzyloxy-4-(2'-hydroxyethyl)-1,1-dimethoxydodeca-5-ene [7] described above. The mixture was stirred for several minutes and 0.91 ml (3.67 mM) of tri-n-butylphosphine was dropwise added to the mixture. The reaction solution was stirred for ten minutes then, cooled to 0° C. and 35% hydrogen peroxide aqueous solution was dropwise added thereto at the same temperature while stirring. After stirring for 3 hours, the aqueous phase was extracted with a solvent mixture of diethyl ether:hexane=7:3. The extracts were combined and washed sequentially with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The precipitated crystals were taken from the residue by filtration to give 776 mg (1.67 mM) of (3R,4 S,7S) 3,7-dibenzyloxy-4-vinyl-1,1-dimethoxydodeca-5-ene [8]. Yield, 91%.
Reaction SMILES: [CH:1]([N:5]1[CH:13]=[N:12][C:11]2[C:6]1=[N:7][C:8]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:9][C:10]=2[C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)([CH2:3][CH3:4])[CH3:2].C1C(=O)N([Br:34])C(=O)C1>C(Cl)(Cl)Cl>[Br:34][C:13]1[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[C:6]2[C:11]([N:12]=1)=[C:10]([C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)[N:9]=[C:8]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)[N:7]=2
Reactant: CCC(C)n1cnc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCC(C)n1c(Br)nc2c(-c3cnc(N)nc3)nc(N3CCOCC3)nc21
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of 5-(9-sec-Butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine, (200 mg, 0.57 mmol) in 15 ml of chloroform, was added slowly NBS, (120 mg, 0.68 mmol) at a temperature of 5° C. The reaction was continued for 2 hours at this temperature. After simple work-up, the product 5-(8-Bromo-9-sec-butyl-2-morpholin-4-yl-9H-purin-6-yl)-pyrimidin-2-ylamine was purified by flash column (solvent system: 50% ethyl acetate in hexane) to deliver the desired compound in a yield of 49% (120 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.Cl.[Br-:15].[K+].OO>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:15][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [Br-]
Reactant: CCOC(=O)C(C)c1nc(C)cs1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(Br)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of ethyl 2-(4-methyl-1,3-thiazol-2-yl)propanoate (3.91 g, 19.62 mmol) in toluene (95 mL) was added hydrochloric acid (1.77 mL, 21.58 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and then potassium bromide (MERCK, 2.57 g, 21.58 mmol) and hydrogen peroxide (2.37 mL, 25.5 mmol) were added. Reaction mixture was stirred at 0° C. for 5 hours, at which point TLC (1:1 EtOAc-Hex) showed reaction had gone to completion. Reaction mixture was quenched with 1N Na2S2O3 (60 mL) and saturated NaHCO3 (60 mL). Organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×60 mL). Combined organics were washed with brine, dried over sodium sulfate and concentrated to give the title compound (5.02 g, 18.05 mmol, 92% yield) as a red oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 7.41 (s, 1H), 4.23 (q, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (t, 3H). [ES+MS] m/z 278 (MH+).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1>O1CCOCC1>[Cl-:1].[CH3:2][O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([NH3+:19])=[CH:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: Cl
Reactant: COC(=O)COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Solvent: C1COCCO1
Product: COC(=O)COc1ccc(-c2ccc([NH3+])cc2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
4 N HCl in dioxane (6.2 mL, 10 equiv) was added to a solution of (4′-tert-butoxycarbonylamino-biphenyl-4-yloxy)-acetic acid methyl ester (220 mg, 0.62 mmol), prepared in the previous step, in dioxane and the reaction stirred at room temperature for 2 h. The solid that formed was collected by filtration, rinsed with ethyl acetate and dried under reduced pressure to give 4′-(2-methoxy-2-oxoethoxy)-1,1′-biphenyl-4-aminium chloride (135 mg, 85%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][SiH:4]([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2].CN(C)[C:13](=[O:15])[O-].[CH3:17][NH2+]C>>[CH2:1]([O:3][Si:4]([O:15][CH2:13][CH3:17])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCO[SiH](OCC)OCC
Reactant: C[NH2+]C
Reactant: CN(C)C(=O)[O-]
Product: CCO[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 22 %

Procedure:
A round bottomed, three necked, 50 ml flask equipped with a magnetic stirring unit, thermometer and constant pressure addition funnel was flushed with argon. The flask was then charged with 7.8 gm (48 mmole) of triethoxysilane and 6.3 gm (48 mmole) of dimethylammonium dimethylcarbamate. The flask an its contents were heated with stirring under argon by means of a heating mantle to 50° C. As determined by glpc the triethoxysilane was consumed after three hours at 50° C. As determined by normalized area percent and retention times, the reaction produced 22% tetraethoxysilane, and 78% N,N-dimethylcarbamatotriethoxysilane. The reaction at room temperature produced the same two products in 31% and 69% yields respectively.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)[CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:34]5[CH:33]=[N:32][C:31]([NH:30][CH:27]6[CH2:28][CH2:29][O:24][CH2:25][CH2:26]6)=[CH:36][CH:35]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(NC3CCOCC3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(NC5CCOCC5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and (tetrahydro-pyran-4-yl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine (stage 214.1.1) to give the title compound as a white solid. (HPLC: tR 2.13 min (Method A); M+H=470 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.89 (s, 1H), 8.15-8.10 (m, 2H), 8.04-8.00 (m, 1H), 7.84-7.79 (m, 1H), 7.47-7.42 (m, 1H), 7.41-7.38 (m, 1H), 6.78-6.73 (m, 1H), 6.57-6.53 (m, 1H), 4.00-3.82 (m, 3H), 3.91 (s, 3H), 3.56 (s, 3H), 3.45-3.37 (m, 2H), 1.96 (s, 3H), 1.91-1.83 (m, 2H), 1.49-1.37 (m, 2H))
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCN1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1cc(N)ccc1OCCN1CCCC1
Reaction time: 3 h
Yield: 98.4 %

Procedure:
To a solution of N-(5-nitro-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (430 mg) in EtOH (10 mL) was added Pd/C (200 mg) and was charged with H2 (1 atm). After stirring for 3 h, Pd/C was removed by filtration and the filtrate was concentrated to give N-(5-amino-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acetamide (380 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:12][C:13]([F:14])([F:15])[F:16])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1OCC(F)(F)F
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)cc1OCC(F)(F)F

Procedure:
4-Nitro-2-(2,2,2-trifluoroethoxy)toluene (2.0 g, 9.0 mmol) from Step 1 above was dissolved in MeOH (20 mL) and shaken with palladium black (100 mg) under 50 psig of hydrogen on a Parr apparatus for 2 h. The catalyst was removed by filtration and the solvent was removed under reduced pressure to give 4-amino-2-(2,2,2-trifluoroethoxy)toluene as a gum.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]2[CH3:44])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: Cc1cn(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c(C)n1
Product: Cc1cn(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccc(F)cc4)ccc3NC(=O)OC(C)(C)C)c2)c(C)n1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (227 mg, 0.75 mmol) and 3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (127 mg).
Reaction SMILES: COC([C@]12C(C)(C)[C@H](CC1)C=C2OS(C(F)(F)F)(=O)=O)=O.[CH3:22][O:23][C:24]([C@@:26]12[C:32]([CH3:34])([CH3:33])[C@@H:29]([CH2:30][CH2:31]1)[CH:28]=[C:27]2[C:35]1[C:40]([O:41][CH3:42])=[CH:39][C:38]([C:43]([CH3:51])([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH3:44])=[CH:37][C:36]=1[O:52][CH3:53])=[O:25]>>[CH3:22][O:23][C:24]([C@:26]12[C:32]([CH3:33])([CH3:34])[C@H:29]([CH2:30][CH2:31]1)[CH:28]=[C:27]2[C:35]1[C:36]([O:52][CH3:53])=[CH:37][C:38]([C:43]([CH3:51])([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[CH3:44])=[CH:39][C:40]=1[O:41][CH3:42])=[O:25]
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Agent: COC(=O)[C@]12CC[C@H](C=C1OS(=O)(=O)C(F)(F)F)C2(C)C
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@H]3CC[C@]2(C(=O)OC)C3(C)C)c(OC)c1

Procedure:
The title compound was prepared from 9b by the general procedure described for compound 11a. Yellowish oil (69%). 1H NMR (300 MHz, CDCl3) δ ppm 6.45 (s, 2H), 6.28 (d, J=3.42 Hz, 1H), 3.72 (s, 6H), 3.45 (s, 3H), 2.43 (m, 2H), 1.80-2.03 (m, 1H), 1.53-1.58 (m, 2H), 1.26 (s, 6H), 1.13-1.22 (m, 7H), 1.11 (s, 3H), 0.98-1.08 (m, 3H), 0.97 (s, 3H), 0.84 (t, J=6.79 Hz, 3H). Exact mass calculated for C28H42O4 m/e 442.31. found 442.91. Anal. calcd. for C28H42O4: C, 75.98; H, 9.56. Found: C, 75.58; H, 9.70.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.[CH3:22][C:23]1([O:26][CH2:25]1)[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(O)CN1c2nc(N3CCOCC3)cc(=O)n2C[C@@]1(C)C(F)(F)F
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To 0.500 g (1.643 mmol) of (S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one, in solution in 15 cm3 of acetonitrile, are added at a temperature close to 20° C., 1.185 g (16.43 mmol) of isobutylene oxide and 0.535 g (16.43 mmol) of cesium carbonate. After 1 hour of stirring at 120° C. and 1 hour 30 mins at 130° C. in a microwave appliance, the reaction medium is dry concentrated under reduced pressure (2.7 kPa) and then diluted in 30 cm3 of ethyl acetate and then washed with twice 20 cm3 of distilled water and 30 cm3 of solution saturated with sodium chloride. The organic phase is dried on anhydrous magnesium sulfate, filtered and dry concentrated under reduced pressure (2.7 kPa) in order to obtain a pale yellow oil which is purified by flash chromatography on silica [eluent: dichloromethane/methanol/acetonitrile (94/3/3 by volume)]. After concentration of the fractions under reduced pressure (2.7 kPa), 500 mg of (S)-1-(2-hydroxy-2-methyl-propyl)-2-methyl-7-(morpholin-4-yl)-2-(trifluoro-methyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained as a white solid melting at 72° C. and including the following characteristics:
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:18][C:7]1[N:8]=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:10]2[S:11][C:3]([CH2:2][N:26]3[CH2:27][CH2:28][C:23]4([O:22][CH2:21][CH2:20][O:19]4)[CH2:24][CH2:25]3)=[CH:4][C:5]=2[N:6]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC4(CC3)OCCO4)cc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.00 g, 2.87 mmol) in DMF (20 mL) were added 1,4-dioxa-8-aza-spiro[4.5]decane (1.06 mL, 8.62 mmol) and cesium carbonate (1.8 g, 5.75 mmol). The resulting mixture was stirred at RT for 90 min. The reaction mixture was diluted with water then extracted with EtOAc. The organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as an orange solid (0.97 g, 82%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:37])=[C:24]([C@:26]2([CH:34]([F:36])[F:35])[C@@H:32]3[C@@H:30]([CH2:31]3)[O:29][C:28]([NH2:33])=[N:27]2)[CH:25]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[NH2:33][C:28]1[O:29][C@H:30]2[C@@H:32]([C@:26]([C:24]3[CH:25]=[C:20]([NH:19][C:4](=[O:6])[C:3]4[C:7]([F:12])=[CH:8][C:9]([F:11])=[CH:10][C:2]=4[F:1])[CH:21]=[CH:22][C:23]=3[F:37])([CH:34]([F:35])[F:36])[N:27]=1)[CH2:31]2
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1=N[C@@](c2cc(NC(=O)c3c(F)cc(F)cc3F)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a solution of 2,4,6-trifluorobenzoic acid (120 mg, 0.681 mmol, Aldrich) in dichloromethane (2 mL) was added oxalyl chloride (0.242 mL, 2.73 mmol, Aldrich), followed by catalytic amounts of DMF (20 μL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (2 mL). This solution was added dropwise to a separate solution of (1R,5S,6R)-5-(5-amino-2-fluorophenyl)-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine (185 mg, 0.682 mmol) and diisopropylethylamine (0.12 mL, 0.682 mmol) in dichloromethane (2.5 mL) cooled to 0° C. After completed addition, the reaction mixture was stirred for 20 min at 0° C. The reaction mixture was quenched with aqueous saturated sodium bicarbonate solution and extracted with DCM (2×3 mL). The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and cooled to 0° C. H2O (4 mL) was added to the solution and the mixture was stirred at 0° C. for 1 h. The white solid was filtered off, washed with H2O and dried in under reduced pressure to give 203 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20](O)=[O:21])[C:14]1=[O:23].Cl>O1CCCC1.C(OCC)(=O)C>[OH:21][CH2:20][CH2:19][C:15]1[C:14](=[O:23])[N:13]([C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[CH2:3][O:2][CH3:1])[CH:18]=[CH:17][CH:16]=1
Reactant: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
Under argon, 37.7 g (109 mmol) of {1-[2-(methoxymethyl)-4-nitrophenyl]-2-oxo-1,2-dihydropyridin-3-yl}acetic acid in 310 ml of tetrahydrofuran were introduced as initial charge at RT, and 53.3 g (327 mmol) of borane-diethylaniline complex were added, at first carefully then, after the considerable foaming has abated, rapidly. The reaction mixture was stirred overnight at RT, diluted with 500 ml of ethyl acetate and admixed with 1N hydrochloric acid (1.55 l), at first carefully (considerable foam formation), then rapidly. The reaction mixture was after-stirred for 30 min, the organic phase was separated off and the aqueous phase was extracted again with 500 ml of ethyl acetate. The combined organic phases were washed twice with in each case 500 ml of 1N hydrochloric acid, washed once with 200 ml of 1N sodium hydroxide solution, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was chromatographically purified firstly over 500 g of silica gel (0.04-0.06 mm) with methanol:dichloromethane 5:95 then 1:9 and again over 500 g of silica gel (0.04-0.06 mm) with acetone:dichloromethane 3:7. 14.2 g (43%) of the desired product were obtained here.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][CH3:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:7][CH:3]([CH2:4][CH2:5][CH3:6])[CH2:2][CH3:1])=[O:15]
Reactant: CCCC(O)CC
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCCC(CC)OC(=O)CCC(=O)CN
Reaction time: 48 h

Procedure:
From 3-hexanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 100° C. The reaction was complete after 2 days. The yield was 0.87 g (58%) of amber oil.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:30])[CH:27](Br)[CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26](=[O:30])[CH:27]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH3:28])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC(Br)C(=O)OCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(O)cc1)C(=O)OCCOCc1ccccc1
Temperature: 60 °C

Procedure:
12.1 g of hydroquinone were dissolved in 60 ml of dry dimethylformamide, 31.7 g of potassium carbonate were added thereto in a slow stream of nitrogen, and then the mixture was heated to 90° to 95° C. for one hour with stirring. The mixture was cooled to 60° C., and to it were added dropwise 28.7 g of 2-benzyloxyethyl-2-bromopropionate. The reaction mixture was heated at 90° C. for two hours. After cooling the reaction solution to room temperature, it was poured into ice-water and adjusted to pH7, then extracted with 100 ml of toluene. The toluene layer was dried and filtered, and then toluene was removed under reduced pressure. The colorless oily product of 2-benzyloxyethyl-2-(4-hydroxyphenoxy)propionate was obtained in a yield of 24.6 g. (nD21.5 1.5390)
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH:13]([F:15])[F:14])[CH:10]=[C:9]([C:16]3[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[N:8]=2)[CH:6]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[F:14][CH:13]([F:15])[C:11]1[CH:10]=[C:9]([C:16]2[CH:17]=[N:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-n2cnc(I)c2)n1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-iodo-imidazol-1-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.8) (0.47 g, 1.0 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.264 g, 1.2 mmol) according to the general procedure III. Obtained as a yellow solid (0.066 g, 15%). MS (ISP) 434.2 [(M+H)+]; mp 258° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>CC(N(C)C)=O>[S:14]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5])(=[O:17])(=[O:16])[NH2:15]
Reactant: CCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Solvent: CC(=O)N(C)C
Product: CCCOc1cccc(NS(N)(=O)=O)c1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
To a solution of 2-amino-6-propoxybenzonitrile (Example 111b) (4.23 g, 24.01 mmol) in dimethylacetamide (20 mL) under N2 was added sulfamoyl chloride (5.56 g, 48.02 mmol). The reaction mixture was then stirred at room temperature under nitrogen for 4 hours. Upon completion, the reaction was quenched by addition of ice/water (250 mL). The resulting precipitate was collected by filtration, rinsed with water and dried to yield 2-sulfamoylamino-6-propoxybenzonitrile (4.73 g, 77%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.01 (d, J=7.2 Hz, 3H), 1.76 (sext, J=7.2 Hz, 2H), 4.08 (t, J=6.8 Hz, 2H), 6.96 (d, J=8.5 Hz, 1H), 7.15 (t, J=8.5 Hz, 1H), 7.28 (br s, 2H), 7.57 (d, J=8.5 Hz, 1H), 9.46 (s, 1H). MS 256 (MH+).