Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1Cl.[CH2:24]1[CH:31]2[C:27]3([NH2:33])[CH2:28][CH:29]([CH2:32][CH:25]1[CH2:26]3)[CH2:30]2.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:1][C:2]1[C:3](=[O:23])[N:4]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][CH:13]=2)=[O:11])[N:5]=[CH:6][C:7]=1[NH:33][C:27]12[CH2:28][CH:29]3[CH2:32][CH:25]([CH2:24][CH:31]1[CH2:30]3)[CH2:26]2
Reactant: NC12CC3CC(CC1C3)C2
Reactant: CCN(CC)c1ccc(C(=O)Cn2ncc(Cl)c(Cl)c2=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc(C(=O)Cn2ncc(NC34CC5CC(CC3C5)C4)c(Cl)c2=O)cc1
Yield: 18.2 %

Procedure:
4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one (30 mg, 0.0846 mmol), hexahydro-2,5-methanopentalen-3a(1H)-amine (22 mg, 0.126 mmol) and triethylamine (59 μL, 0.423 mmol) were stirred in N,N-dimethylacetamide (1 mL) at 90° C. for 3 days. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the desired product (7 mg, 17% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].C(OCC)(=O)C>C(O)C.[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH:5]([C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])=[O:7])[C:4]([N:3]([CH2:1][CH3:2])[CH2:33][CH3:34])=[O:32])=[CH:24][CH:25]=1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CC)C(=O)C(Cc1ccc(N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
To a mixed suspension of the compound (2.53 g) obtained in Example 6 in ethanol (200 mL)/ethyl acetate (100 mL) was added 10% palladium/carbon (500 mg), and the mixture was heated under reflux under hydrogen atmosphere for 6 hr. After allowing to cool to room temperature, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.37 g) as a white powder. In some cases, the compound was further converted to a hydrochloride salt with 4 mol/L hydrochloric acid/ethyl acetate and used.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:53][CH:47]4[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:43])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: NC1CCCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NC2CCCCC2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with cyclohexylamine (Aldrich) to give the title product. LC-MS (ES+) 746 [(M+H)+].
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]>C(N(CC)CC)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: NCC(O)CO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1cc(NCC(O)CO)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 9.6 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.41 g of 3-amino-1,2-propanediol, and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was poured into a water/ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 0.28 g of 3-(4-nitro-3-methylphenylamino)propane-1,2-diol (9) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:6]2=[CH:7][C:8]([Cl:30])=[C:9]3[C:14]([C:13](=[O:15])[O:12][C:11]([C:16]4[N:17]([C:23]5[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=5)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=4)=[N:10]3)=[C:5]2[NH:4][N:3]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>CN(C)C=O>[C:32]1([NH:38][C:13]([C:14]2[C:9]([NH:10][C:11]([C:16]3[N:17]([C:23]4[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=4)[N:18]=[C:19]([O:21][CH3:22])[CH:20]=3)=[O:12])=[C:8]([Cl:30])[CH:7]=[C:6]3[C:5]=2[NH:4][N:3]=[C:2]3[Br:1])=[O:15])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: COc1cc(-c2nc3c(Cl)cc4c(Br)n[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(Cl)cc3c(Br)n[nH]c3c2C(=O)NC2(C3CC3)CC2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
To a solution of 120 mg (0.24 mmol) of the above 3-bromo-5-chloro-7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 2.4 mL of N,N-dimethylformamide is added 95 mg (0.71 mmol) of bicyclopropyl-1-ylamine hydrochloride and 99 μL (0.71 mmol) of triethylamine. The reaction is stirred at 50° C. for 24 hours and then concentrated in vacuo. The residue is taken-up with acetone and after filtration the filtrate is evaporated. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 1:1) affords 80 mg (56%) of a solid; LC/MS:606/608 (M+H)+, m.p.: 190-194° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3](=[O:21])[CH:4]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:15][C:14]([NH:13][CH:4]([C:3]([N:2]([CH3:1])[CH3:22])=[O:21])[CH2:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[O:12][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: CN(C)C(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(Oc2cccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)c2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
tert-Butyl 1-(dimethylamino)-3-(3-hydroxyphenyl)-1-oxopropan-2-ylcarbamate (0.025 g, 0.081 mmol) and methyl 4-fluorobenzoate (Aldrich, Cat. #120707) (0.025 g, 0.16 mmol) were combined in acetonitrile (1.0 mL) with cesium carbonate (0.053 g, 0.16 mmol) in a sealed tube and heated to 100° C. After 4 h., the reaction was allowed to cool, diluted with ethyl acetate and washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure to give crude methyl 4-(3-(2-(tert-butoxycarbonylamino)-3-(dimethylamino)-3-oxopropyl)phenoxy)benzoate as a semi-solid. Analytical LCMS (M+H-Boc)+: m/z=342.9.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCOCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3.1 g), morpholine (2 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 4-[(2-phenylquinazolin-4-yl)-carbonyl]-morpholine (3 g), melting at 148° C., is obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](I)=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:27][C:28]1[C:33]([C:34]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][CH:37]=2)=[O:35])=[CH:32][CH:31]=[C:30]([CH3:42])[N:29]=1>O1CCCC1>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([O:23][CH3:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:34]([C:33]3[C:28]([CH3:27])=[N:29][C:30]([CH3:42])=[CH:31][CH:32]=3)([C:36]3[N:40]([CH3:41])[N:39]=[N:38][CH:37]=3)[OH:35])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(I)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Reactant: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
A solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofuran (1.3 M, 0.79 mL, 1.0 mmol) was added dropwise to an ice-water cooled, stirring solution of 3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-4-chloro-6-iodo-2-methoxyquinoline (325 mg, 0.682 mmol, Intermediate 20: step c) in dry tetrahydrofuran (5 mL). After 15 minutes, a solution of (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone (177 mg, 0.818 mmol, Intermediate 19: step b) in tetrahydrofuran (1.5 mL) was added dropwise. After 10 minutes, the flask was removed from the cooling bath and allowed to warm to 23° C. After 4 hours, water (5 mL) was added. The mixture was partitioned between saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated. The organic layer was dried with sodium sulfate and the dried solution was filtered. Silica gel (5 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as a white solid. MS (ESI): mass calcd. for C30H27ClN8O2, 566.2. m/z found, 567.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH3:17][NH2:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:18][CH3:17])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Product: CNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 61 %

Procedure:
According to general procedure A, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and methylamine (10 mL, 33% in ethanol) were stirred in sealed tube for 16 hours. 4-bromo-N-methyl-2-(trifluoromethoxy)benzenesulfonamide (0.21 g, 61%) was provided after purification. MS (ESI) m/z 334. HPLC purity 98.0% at 210-370 nm, 8.8 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)=O.CC(C)=O.[CH2:23]([Mg]Cl)[CH2:24][CH2:25][CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([OH:15])[CH2:23][CH2:24][CH2:25][CH3:26])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: CCCC[Mg]Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4′-chloro-4-biphenylcarbaldehyde (200 mg, 0.92 mmol) in anhydrous THF (10 mL) under nitrogen at −78° C. (dry ice/acetone) was added nBuMgCl (550 μL of a 2M solution in THF, 1.10 mmol). The reaction mixture was stirred at −78° C. for 1 hour and then at rt for 18 hours. The reaction was quenched by cautious addition of water (15 mL) and extracted with EtOAc (3×20 mL). The combined organic extract was then dried (MgSO4) and reduced under vacuum. Purification by flash chromatography (silica), eluting with cyclohexane:EtOAc (9:1) afforded the title compound as a colourless gum (140 mg).
Reaction SMILES: [OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([O-:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4].FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[OH:1][CH:2]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:3]([NH:5][CH:6]1[C:17](=[O:18])[N:8]2[C:9]([C:14]([OH:16])=[O:15])=[C:10]([CH3:13])[CH2:11][S:12][C@H:7]12)=[O:4]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3cccs3)[C@H]2SC1
Yield: 90.6 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2'-hydroxy-2'-[thien-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (543mg, 1.05mmole) was dissolved in anisole (4ml) and stirred with trifluoroacetic acid (4 ml) at +20° to +25° for 7 mins. The anisole and trifluoroacetic acid were evaporated and the residue partitioned between 3%-aqueous sodium bicarbonate solution (ca 50ml) and ethyl acetate (ca 50ml). The aqueous layer was washed with ethyl acetate (3xca 50ml), layered with ethyl acetate and adjusted to pH 2.5. The ethyl acetate layer was combined with the ethyl acetate backwash of the aqueous layer, dried, and evaporated to give (6R,7R,2'R and S)-7-(2'-hydroxy-2'-[thien-2-yl] -acetamido)- 3-methylceph-3-em-4-carboxylic acid as a foam (337mg, 91%). This foam was dissolved in acetone (3ml) and stirred with a solution of sodium 2-ethylhexanoate (186mg, 1.05mmole) in acetone (2ml) and ether (2ml). The precipitated material was filtered off, washed with ether, and dried to give the title compound containing 2mole-equivalents of water (i.r., microanalysis) and one-sixth mole-equivalents of ether (n.m.r., microanalysis) as a pale-brown solid (183mg, 0.486 mmole, 46.4%); λmax (pH6-buffer) 237.5nm, inflexion at 255nm (ε12,640 and 9,250 respectively); νmax (nujol) 3380 (NH,H2O), 1760 (azetidin-2-one), 1680 and 1528 (CONH), and 1600 cm-1 (CO2 -); τ (Me2SO-D6) 1.48 and 1.63 (total 1H, 2d,J9Hz,NH), 2.54 to 3.10 (3H, m, thiophene protons), 4.46 (ca 1H, m, C7 -H), 4.60 and 4.62 (total ca 1H, 2S, CHOH), 5.00 (1H,d,J4.5Hz, C7 -H), 6.49 and 6.87 (2H, ABq, J18Hz, C2 -H2), 8.01 (3H,s, C3 -CH3). A signal at τ 8.89 revealed the presence of one-sixth mole-equivalent of diethyl ether. (Found: C,41.1, 41.4; H,3.6,3.8; N,6.6, 7.0; S,14.5. C14H13N2NaO5S2. One-sixth C2H5OC2H5. 2H2O (424.7) requires C,41.5; H,4.4; N,6.5; S,15.1%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[C:5]([O:19][CH3:20])[CH:4]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].C(N(CC)C(C)C)(C)C>ClCCl>[Si:21]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:14]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(-c2ccc(CO)cc2OC)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(-c2ccc(CO[Si](C)(C)C(C)(C)C)cc2OC)cc1

Procedure:
A solution of Example 417A (136 mg, 0.50 mmol), tert-butyldimethylsilyl chloride (91 mg, 0.60 mmol), and N,N-diisopropylethylamine (129 mg, 1.0 mmol) in dichloromethane (5 mL) at room temperature was stirred for 3 hours, and filtered through a pad of silica gel. The pad was rinsed with ether and the combined solutions were concentrated to provide the desired product.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH:6]([NH2:8])=[NH:7].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22](=O)[C:23]([F:26])([F:25])[F:24])[C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19]2[C:22]([C:23]([F:26])([F:24])[F:25])=[N:8][CH:6]=[N:7][C:18]=2[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C(F)(F)F)C(=O)C1
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(ncnc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.6 %

Procedure:
0.52 mL of sodium ethoxide (21% wt. ethanol solution) was added at room temperature to a solution in which 95 mg (1.18 mmol) of formamidine hydrochloric acid salt was dissolved in 2 mL of anhydrous ethanol at room temperature. After stirring at room temperature for 10 minutes, to the resulting solution, was added a solution in which 232 mg (0.786 mmol) of tert-butyl-3-oxo-4-(trifluoroacetyl)-piperidine-1-carboxylate (product of PREPARATION 47) was diluted with 2 mL of anhydrous ethanol. Thereafter, the temperature of the solution was raised to 80° C., followed by stirring for about 18 hours. After cooling to room temperature, ethanol was removed under reduced pressure, and the reaction solution was diluted with ethylacetate, then washed in sequence aqueous NaCl. An organic layer was dried over anhydrous magnesium sulfate and filtered off. The filtrated solution was distilled off under reduced pressure and then, the residue was isolated and purified by prep-TLC (ethylacetate 20% normal hexane in solvent) to give 30 mg of the title compound in a yield of 13%
Reaction SMILES: CO.[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O.Cl.C(=O)([O-])O.[Na+]>O>[CH3:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13]
Reactant: CC(C)CCc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)CCc1ccccc1N
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture composed of 10 ml of methanol, 1.3 g (6.4 mmol) of the above 2-(3-methylbutyl)nitrobenzene, and 6.4 ml of concentrated aqueous hydrochloric acid solution, 1.4 g (25.1 mmol) of reduced iron was added in portions and heated to 60° C. with stirring for 1 hour. The reaction mass was poured into water, neutralized with a saturated aqueous sodium hydrogen carbonate solution and filtered to remove precipitated iron hydroxide. The filtrate was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 0.95 g of the desired product as oil. Yield was 85%.
Reaction SMILES: [CH3:1][C:2]1[C:13]([O:14]C2CCCCO2)=[CH:12][C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[C:3]=1[CH3:21].[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][C:6]1[C:5]2[CH:12]=[C:13]([OH:14])[C:2]([CH3:1])=[C:3]([CH3:21])[C:4]=2[O:8][C:7]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1cc2cc(OC3CCCCO3)c(C)c(C)c2o1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(=O)c1oc2c(C)c(C)c(O)cc2c1Br
Reaction time: 1 h

Procedure:
To a solution of 1-[6,7-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzofuran-2-yl]-ethanone (200 mg) in chloroform (20 mL) was added bromine (120 mg). After 1 h, the solution was washed with water and dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with 10% hexane in DCM to give 1-(3-Bromo-5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone, as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ: 7.38(s, 1H), 5.55 (s, 1H, OH), 2.60, 2.50, 2.31 (3 s, 9H) ppm. MS (m/z): 283, 285 (M+H+).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.C([NH:48][S:49](Cl)(=[O:51])=[O:50])(OC(C)(C)C)=O>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:49]([NH2:48])(=[O:51])=[O:50])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NS(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Temperature: 25 °C
Reaction time: 45 h
Yield: 55.7 %

Procedure:
To a stirred solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.46 g, 1.0 mmol) in dichloromethane (10 mL) was added triethylamine (0.42 mL) and N-Boc-sulfamoyl chloride (0.8M, 3.75 mL, 3.0 mmol), the reaction mixture was allowed to stir at room temperature for 45 h, poured into ice-water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded a white solid (0.3 g), which was dissolved in TFA (10 mL) and allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (10 mL) was added. The mixture was stirred at room temperature for 30 min, the precipitate was collected by filtration and washed with water. The crude product was further purified by crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.21 g, 39%). MS (ISP) 539.3 [(M+H)+]; mp 174° C.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:4]3[CH:3]=[C:2]([F:1])[N:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)=[O:26])=[CH:20][CH:19]=1)[CH3:17]
Reactant: Nc1ccc(Oc2cc(F)ncn2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Product: CCc1ccc(NC(=O)Nc2ccc(Oc3cc(F)ncn3)cc2)cc1
Reaction time: 4 h

Procedure:
The title compound is prepared as described in Example 102 but using 4-(6-fluoro-pyrimidin-4-yloxy)-phenylamine (Example 111) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 4 h. The title compound is obtained as a white solid: ES-MS: 353.0 [M+H]+; single peak at tR=8.61 min (System 2); Rf=0.14 (CH2Cl2/Et2O, 90/10).