Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[C@H:7]([CH2:19][CH2:20][CH2:21][NH2:22])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(C)(C)C.[C:24]([O:31]C([O-])=O)(=O)[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([O:25][C:24](=[O:31])[C@H:21]([CH2:20][CH2:19][CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[NH:22][C:24]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:31])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@H](CCCN)NC(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nδ -(Benzyloxycarbonyl-L-ornithine tert-butyl ester (7.50 g, 23.3 mmol) was dissolved in 27 ml of methylene chloride, and the solution was cooled to 0° C. To that solution was added dropwise tert-butyl pyrocarbonate (5.87 g, 26.9 mmol) in 10 ml of methylene chloride. The reaction mixture was stirred at 0° C. for 1 hour, and stirring was continued for 3 additional hours at room temperature. The solvent was evaporated at reduced pressure and the oily residue was chromatographed on a column of silica gel (25 cm×30 mm) using hexane:ethyl acetate (3:1) as solvent. Fractions of approximately 5 ml were collected, and those containing product were identified by thin layer chromatography (see below). Chromatographic fractions containing product were pooled and evaporated to a thick oil by rotary evaporation at reduced pressure. The yield was 8.63 gm (93.5%). 1H NMR (DCCl3) δ1.44 (s,9H), 1.46 (s,9H), 1.5-1.9 (m,4H), 3.23 (t,2H), 4.17 (t,1H), 4.88 (s,1H broad), 5.09 (s,2H and s,1H broad) 7.35 (s,5H).
Reaction SMILES: N1C=CC=C(CNC(C2C=CC3NC(C4C(C(=O)NC(C)C)=CNN=4)=NC=3C=2)=O)C=1.[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[CH:34][C:35]2[N:39]=[C:38]([C:40]3[C:44]([NH2:45])=[CH:43][NH:42][N:41]=3)[NH:37][C:36]=2[CH:46]=1.C(N(C(C)C)CC)(C)C.[N:58]1([C:64](Cl)=[O:65])[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>O1CCCC1>[Cl:31][C:32]1[C:33]([O:47][CH3:48])=[CH:34][C:35]2[N:39]=[C:38]([C:40]3[C:44]([NH:45][C:64]([N:58]4[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]4)=[O:65])=[CH:43][NH:42][N:41]=3)[NH:37][C:36]=2[CH:46]=1
Reactant: COc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1Cl
Reactant: O=C(Cl)N1CCCCC1
Agent: CC(C)NC(=O)c1c[nH]nc1-c1nc2cc(C(=O)NCc3cccnc3)ccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2nc(-c3n[nH]cc3NC(=O)N3CCCCC3)[nH]c2cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
By proceeding in a manner similar to Example 248(a) above but (i) treating a solution of 3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [0.2 g, Example 233(e)] and diisopropylethylamine (392 mg, 4 eq) in tetrahydrofuran (25 mL) with piperidinecarbonyl chloride (450 mg, 4 eq), stirring overnight at ambient temperature, and evaporating the reaction mixture, (ii) triturating the reaction product with water (30 mL) and ethyl acetate (50 mL) and extracting with aqueous layer with ethyl acetate, (iii) combining the organic phases, drying over magnesium sulfate, then evaporating (iv) chromatographing the residue on silica gel (ethyl acetate), (v) triturating the partially purified material with ethyl acetate (15 mL) for 1.5 hours and filtering, and (vi) evaporating the filtrate and chromatographing the residue on silica gel (ethyl acetate/heptane gradient of 20-0%) there was prepared piperidine-1-carboxylic acid[3-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-amide (50 mg) as a yellow solid, mp>310° C. LC-MS (Method E) RT=3.25 minutes, 374 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=O)[CH2:9][CH2:8]1.[F:18][C:19]([F:29])([F:28])[O:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1.[Mg]>O1CCCC1.CC(C)=O.C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:19]([F:18])([F:28])[F:29])=[CH:26][CH:25]=2)([C:24]2[CH:25]=[CH:26][C:21]([O:20][C:19]([F:29])([F:28])[F:18])=[CH:22][CH:23]=2)[OH:15])[CH2:11][CH2:12]1
Reactant: CCOC(=O)C1CCN(Cc2cccs2)CC1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: [Mg]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2cccs2)CC1
Yield: 4.7 %

Procedure:
This compound was prepared in a manner analogous to that of Step B of Example 3, with 2.0 grams (0.008 mole) of ethyl N-(thien-2-ylmethyl)piperidin-4-ylcarboxylate, 3.5 mL (0.024 mole) of 4-trifluoromethoxyphenyl bromide, and 0.6 gram (0.025 gram-atom) of magnesium turnings in about 69 mL of tetrahydrofuran as reagents. The crude reaction product was subjected to column chromatography on silica gel, with pure methylene chloride, 9:1 methylene chloride: acetone, pure acetone, and then 8:2 methylene chloride:acetone as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.2 gram of N-(thien-2-ylmethyl)-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:9]#[N:10])([C:7]#[N:8])[CH2:3][CH2:2]1.[BH4-].[Na+]>CCO>[NH2:10][CH2:9][C:4]1([C:7]#[N:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: N#CC1(C#N)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1(CN)CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A mixture of dihydro-2H-pyran-4,4(3H)-dicarbonitrile (450 mg, 3.31 mmol) and Sodium borohydride (375 mg, 9.92 mmol) in EtOH (15 ml) was stirred at ambient temperature for about 4 hours. The mixture was concentrated and the resulting residue was diluted with ethyl acetate, washed with water and dried. Concentration in vacuo afforded 388 mg of the crude product which was used directly in the next step. LCMS (m/z): 141.0 [M+H]+; Retention time=0.18 min.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][C:12]=1[C:13]#[N:14]>CN(C=O)C.CCOC(C)=O>[CH:19]([C:16]1[CH:17]=[CH:18][C:11]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[C:12]([CH:15]=1)[C:13]#[N:14])=[O:20]
Reactant: CC(O)C(F)(F)F
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C=O)cc1C#N)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.3 %

Procedure:
To a solution of 0.50 g (4.38 mmol) of 1,1,1-trifluoro-2-propanol in 15 mL of DMF at 0° C. was added 0.13 g (5.26 mmol) of sodium hydride (60% dispersion in mineral oil). After stirring for 10 min, 0.65 g (4.38 mmol) of 2-fluoro-5-formylbenzonitrile was added. The reaction mixture was gradually warmed up to rt and stirred overnight. The mixture was diluted with 20 mL of EtOAc and washed with brine (10 mL), H2O (3×10 mL), and brine (10 mL L). The organic layer was dried over MgSO4 and concentrated. Chromatography on a Biotage 40M cartridge using 4:1 v/v hexanes/EtOAc as the eluant gave 0.44 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.67 (d, J=6.4, 3H), 4.95 (m, 1H), 7.22 (d, J=8.9, 1H), 8.12 (dd, J=2.0, 6.7, 1H), 8.16 (s, 1H), 9.96 (s, 1H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:17]=[CH:16][C:14](N)=[CH:13][CH:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.OS(O)(=O)=O.N([O-])=O.[Na+].[I-:27].[Na+]>COCCOC.O.CCOC(C)=O>[I:27][C:14]1[CH:16]=[CH:17][C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[CH:12][CH:13]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2ccc3c(c2)OCO3)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Ic1ccc(Oc2ccc3c(c2)OCO3)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
In a 300 mL round bottom flask, 5.28 g (22.96 mmol) 4-(benzo[d][1,3]dioxol-5-yloxy)aniline was dissolved in 40 mL DME and cooled to 0° C. in a brine/ice bath. Using a dropping funnel, 10 equivalents aqueous H2SO4 (10N aqueous) were slowly added to the DME solution, immediately creating a salt suspension. The suspension was stirred at 0° C. for 10 minutes. Then, a solution of 1.5 equivalents sodium nitrite (2.38 g, 34.45 mmol) in 20 mL water was dropped slowly into the suspension while keeping the temperature below 5° C. After adding the sodium nitrite, the mixture was stirred at 0° C. for 30 minutes. Then, a 30 mL aqueous solution of sodium iodide (10.32 g, 68.88 mmol) was dropped slowly into the mixture. LC/MS showed the reaction was complete. The mixture was diluted with 400 mL EtOAc and washed with 700 mL water and then 700 mL 1M sodium bisulfite. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was then chromatographed by combiflash using a 330 gram silica column and a gradient of EtOAc (15% max) in hexane to provide 6 g of 5-(4-iodophenoxy)benzo[d][1,3]dioxole (77%, light brown oil). m/z 340, 1H NMR (CHCl3): 7.61-7.54 (m, 2H), 6.79-6.68 (m, 3H), 6.58-6.53 (m, 1H), 6.51-6.45 (m, 1H), 6.00-5.96 (s, 2H).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:57])([F:56])[CH:49]1[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:55][C@H:52]2[CH2:53][CH2:54][C@@H:49]([C:48]([F:47])([F:56])[F:57])[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: OC1CCC(C(F)(F)F)CC1
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the title compound was obtained as a colorless solid (0.02 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.35 (d, J=12.5 Hz, 1H), 4.94 (s, 1H), 2.87 (s, 6H), 2.46-2.35 (m, 1H), 2.03-1.93 (m, 2H), 1.72-1.53 (m, 6H); MS (ES−) m/z 445.2, 447.2 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[C:22]([CH2:26][CH2:27]OS(C)(=O)=O)[CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:18][C:13]=3[CH:12]([CH3:33])[N:11]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:10]2=[O:42])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:43][NH:44][CH3:45]>>[CH3:43][N:44]([CH3:45])[CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([NH:19][C:16]2[N:15]=[C:14]3[N:9]([C:5]4[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=4)[C:1]#[N:2])[C:10](=[O:42])[N:11]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=4)[CH:12]([CH3:33])[C:13]3=[CH:18][N:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CNC
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCOS(C)(=O)=O)c4)ncc3C2C)cc1
Product: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4cccc(CCN(C)C)c4)ncc3C2C)cc1
Temperature: 100 °C

Procedure:
A mixture of (±)-methanesulfonic acid (2-{3-[8-(3-cyano-phenyl)-6-(4-methoxy-phenyl)-5-methyl-7-oxo-5,6,7,8-tetrahydro-pyrimido[4,5-d]pyrimidin-2-ylamino]-phenyl}-ethyl)-ester (0.19 g; 0.32 mmol) (from Example 5a supra) and dimethylamine (2.0 M in tetrahydrofuran; 2.00 mL; 4.00 mmol) (Aldrich) in a bomb bottle and heated at 100° C. overnight. Upon cooling, the mixture was concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate and concentrated. At this point, the crude material was combined with material from an earlier run and purified by flash chromatography (Biotage, 12S; 100:0 to 50:50 ethyl acetate-methanol). This material was then crystallized from ethyl acetate and ether to give (±)-3-[7-[3-(2-dimethylamino-ethyl)-phenylamino]-3-(4-methoxy-phenyl)-4-methyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile as a solid. (Yield 0.12 g; 26.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]1([NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:7][N:5]1[CH:6]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[C:25]3[C:20]=2[N:19]=[C:18]([NH:17][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:27]=[CH:26]3)[CH:3]=[C:4]1[C:8]([NH2:10])=[O:9]
Reactant: OB(O)c1cccc2ccc(Nc3ccccc3)nc12
Reactant: Cn1cc(Br)cc1C(N)=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc3ccc(Nc4ccccc4)nc23)cc1C(N)=O
Temperature: 130 °C
Yield: 27.7 %

Procedure:
A mixture of 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (164a; 40 mg, 0.20 mmol), (2-(phenylamino)quinolin-8-yl)boronic acid (Example 165d; 68 mg, 0.26 mmol), XPhos (10 mg) and Pd2(dba)3 (10 mg) in 2 mL of dioxane and 0.5 mL of 2 N Na2CO3 was heated in a microwave at 130° C. for 20 min. The mixture was partitioned between 20 mL of EtOAc and 5 mL of 0.5 N NaOH. The organic layer was concentrated, and purified on silica gel column (25-85% EtOAc in hexanes) to give 1-methyl-4-(2-(phenylamino)quinolin-8-yl)-1H-pyrrole-2-carboxamide (19 mg, 27% yield) as an off-white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.35 (1H, s), 8.06 (1H, d, J=8.8 Hz), 7.90 (2H, m), 7.84 (1H, d, J=1.8 Hz), 7.68 (1H, dd, J=7.3, 1.5 Hz), 7.56 (1H, dd, J=7.8, 1.4 Hz), 7.48 (1H, br.), 7.37 (1H, d, J=2.0 Hz), 7.35-7.24 (3H, m), 7.06 (1H, d, J=8.8 Hz), 7.00 (1H, t, J=7.3 Hz), 6.82 (1H, br.), 3.87 (3H, s). m/z (ESI, +ve) 343.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[Br:19][CH2:20][CH2:21][NH2:22]>C(O)C>[Br:19][CH2:20][CH2:21][NH:22][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: NCCBr
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1NCCBr

Procedure:
The compound was prepared by reacting 2,4-dichloro-3,5-dinitrobenzotrifluoride with 2-bromoethylamine in an ethanol solution. The resultant product melted at 88°-92° C.
Reaction SMILES: CO[C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:24][NH:25][C:26]([NH2:28])=[O:27].C[O-].[Mg+2].C[O-].CO>>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:28][C:26]([NH:25][CH3:24])=[O:27])=[O:23])=[CH:12][CH:13]=1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 13.6 %

Procedure:
A mixture of 2-biphenyl-4-yl-3-cyclopentylpropionic acid methyl ester (987.4 mg, 3.20 mmol) and methyl urea (948.7 mg, 12.80 mmol) was treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 18 mL, 12.80 mmol). The resulting reaction mixture was then heated under reflux for 19 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 1-(2-biphenyl-4-yl-3-cyclopentyl-propionyl)-3-methyl urea (152.5 mg, 14%) as a white solid: mp 195-197° C.; EI-HRMS m/e calcd for C22H26N2O2 (M+) 350.1994, found 350.2004.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(=O)([O-])[O-].[Na+].[Na+]>[OH:8][CH:1]([C:9]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][S:15](=[O:16])[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc2c(c1)S(=O)C=N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Product: O=S1C=Nc2ccc(C(O)c3ccccc3)cc21
Temperature: 25 °C

Procedure:
0.02 mol of 6-benzoylbenzothiazolinone obtained in Example 1 are dissolved in 80 cm3 of 30% aqueous sodium carbonate solution in a 250 cm3 flask 0.015 mol of sodium borohydride are added slowly, with agitation. The agitation is maintained for 16 hours at ambient temperature, followed by acidification with hydrochloric acid diluted 1:1. The precipitate formed is drained, washed with water and dried.
Reaction SMILES: [C:1]([Li])([CH3:4])([CH3:3])C.CN(P(N(C)C)N(C)C)C.I[CH2:17][C:18]1[C:27]([CH3:28])=[C:26]([O:29][C:30](=[O:32])[CH3:31])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.Cl>[Cu](I)I.O.O1CCCC1.CCOCC.CCCCC>[CH2:17]([C:18]1[C:27]([CH3:28])=[C:26]([O:29][C:30](=[O:32])[CH3:31])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)/[CH:17]=[CH:18]/[CH2:27][CH2:26][CH2:25][CH2:3][CH2:1][CH3:4]
Reactant: [Li]C(C)(C)C
Reactant: CC(=O)Oc1c(C)c(CI)nc2ccccc12
Agent: I[Cu]I
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCC/C=C/Cc1nc2ccccc2c(OC(C)=O)c1C
Temperature: -35 °C
Reaction time: 2 h
Yield: 45.3 %

Procedure:
10 ml of a pentane solution of 15.6 mmols of t-butyl lithium was added to 15 ml of 1.86 g (7.8 mmols) of trans-1 -iodo-1-octene ether solution in an atmosphere of argon at -78° C. and stirred at the same temperature for 2 hours. The reaction solution was added to 15 ml of an ether solution of 590 mg (3.10 mmols) of copper iodide at -78° C., after which it was heated up to -35° C. and stirred at the same temperature for 45 minutes. 1.79 g (10 mmols) of hexamethylphosphorus triamide was added to the solution and stirred at -35° C. for 10 minutes, to which 10 ml of a tetrahydrofuran solution of 1.02 g (3.00 mmols) of 2-iodomethyl-3-methyl-4-acetoxyquinoline was added, followed by stirring at the same temperature for 30 minutes. The reaction solution was added to a solution of 3 ml of 1N hydrochloric acid and 100 ml of water, followed by filtration through Celite. The resultant filtrate was extracted with chloroform, washed with water and dried with sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Wako Gel C-200) (solvent: n-hexane : ethyl acetate=15:1) to obtain 221 mg (yield 23%) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxyquinoline
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([C@:8]2([CH3:27])[CH2:13][C@@H:12]([C:14]([F:16])([F:15])[F:17])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(NC(=O)c2ccccc2)=N1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@]1(c2cc(Br)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Temperature: 65 °C
Yield: 95.9 %

Procedure:
A solution of N-((4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4 g, 789 mg, 1.718 mmol) in anhydrous MeOH (20 mL) was treated with 1,8-diazabicyclo-[5.4.0]undec-7-ene (Aldrich; 311 μL, 2.063 mmol) and heated to 65° C. for 16 h. The reaction mixture was concentrated and extracted into EtOAc from saturated aqueous NH4Cl. The organic extract was dried over MgSO4, concentrated, and purified by flash chromatography on silica gel (Gradient: 0%→50% EtOAc/hexane) to give (4S,6S)-4-(5-bromo-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (585 mg, 1.647 mmol) as a white foam. MS m/z=355 M+. Calculated for C12H11BrF4N2O: 355.1
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:48])[CH2:11][NH:12][CH2:13][C@@H:14]1[C@H:17]([NH:18][C:19](=[O:46])/[C:20](=[N:34]\[O:35][C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])/[C:21]2[N:22]=[C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[S:24][CH:25]=2)[C:16](=[O:47])[NH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN([C:54](N2C=NC=C2)=[O:55])C=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[O:48][C:54](=[O:55])[N:12]([CH2:13][C@@H:14]2[C@H:17]([NH:18][C:19](=[O:46])/[C:20](=[N:34]\[O:35][C:36]([CH3:45])([CH3:44])[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])/[C:21]3[N:22]=[C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[S:24][CH:25]=3)[C:16](=[O:47])[NH:15]2)[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CNC[C@@H](O)COCc2ccccc2)cs1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N[C@@H]2CN2C[C@H](COCc3ccccc3)OC2=O)cs1
Yield: 58.3 %

Procedure:
Prepared in analogous manner to example 63 step 2, using tert-butyl 2-(((Z)-(2-(((2R,3S)-2-((((R)-3-(benzyloxy)-2-hydroxypropyl)amino)methyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoate (126 mg, 0.182 mmol), CDI (53 mg, 0.33 mmol), DCM (5 mL). The crude residue was purified via silica gel chromatography (MeOH-DCM, 3-5%) to afford the title compound (76 mg, 58%). LCMS: m/z=715.3 (M−1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].P(Br)(Br)[Br:11]>O>[CH3:2][CH2:1][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][Br:11]
Reactant: BrP(Br)Br
Reactant: CCOCCOCCO
Solvent: O
Product: CCOCCOCCBr

Procedure:
215 g (1.6 mole) of diethylene glycol monoethyl ether was introduced into a 1 l three-necked flask and slightly warmed by a mantle heater. Then, 135.4 g (0.5 mole) of phosphorus tribromide was slowly added dropwise over a period of 2 hours. The reaction mixture was cooled and poured into 500 cc of water. The desired oily product accumulated at the bottom was extracted with ether and the extract was washed with 100 cc of 10% sulfuric acid two times and with 10% sodium carbonate two times. After further washing with water two times, the extract was dried with potassium carbonate to remove ether, followed by distillation of the residue oil under reduced pressure. After removing the inital fraction of low boiling point, fractions having boiling point of 96° - 98° C/30 mmHg were collected. The yield of (I) was about 40%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][NH:27][C:28]1[CH:44]=[CH:43][C:31]([CH2:32][N:33]2[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=3[N:35]=[C:34]2[CH3:42])=[CH:30][C:29]=1[NH2:45].N>O1CCCC1.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11]2[N:27]([CH3:26])[C:28]3[CH:44]=[CH:43][C:31]([CH2:32][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[C:34]4[CH3:42])=[CH:30][C:29]=3[N:45]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(Cn2c(C)nc3ccccc32)cc1N
Agent: N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1Cc1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C

Procedure:
A mixture of 1.94 g (11.0 mmol) of N-(4-cyanophenyl)-glycine and 1.78 g (11.0 mmol) of carbonyldiimidazole is refluxed in 80 ml of absolute tetrahydrofuran for 15 minutes. After the addition of 2.7 g (10.46 mmol) of 1-(4-methylamino-3-aminobenzyl)-2-methyl-benzimidazole the mixture is refluxed for a further 16 hours. Then the solution is evaporated to dryness, the residue is mixed with 80 ml glacial acetic acid and refluxed for 1 hour. It is then evaporated to dryness once more, the residue thus obtained is mixed with 50 ml of water and made alkaline with conc. ammonia (about pH 10). The product which crystallises out is suction filtered, washed with a little water and dried.