Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([C:18](OC)=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.[OH-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN(Cc2ccccc2)CC1c1ccsc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCC1CN(Cc2ccccc2)CC1c1ccsc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
To a solution of 0.55 g (1.84 mmol) of 1-benzyl-3-(SR)-carbomethoxy-4-(RS)-(3-thienyl)pyrrolidine in 30 mL of THF at 0° C. was added 1.84 mL (1.84 mmol) of a 1M solution of lithium aluminum hydride in THF and the reaction was stirred at rt for 12 h. To the reaction mixture was then added 5 mL of EtOAc and 2 mL of 2N NaOH. The reaction mixture was extracted with ether and the combined organic fractions were washed with 2N NaOH solution and sat'd NaCl. The organic fractions were dried over Na2SO4, filtered and the filtrate was concentrated to give 0.49 g of the title compound which was used without further purification. 1H NMR (CDCl3) δ7.28-7.36 (m, 7H), 7.03 (d, 1H, J=4.1 Hz), 3.66-3.78 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[O:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:14])[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: O=CNc1ccc(Br)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of N-(4-bromophenyl)-formamide 50 (250 mg, 1.25 mmol) in DMF (3 mL) is added dropwise to a suspension of sodium hydride (65 mg, 1.63 mmol, 60% dispersion in mineral oil) in DMF (3 mL) at 0° C. After stirring 1 h, iodomethane (113 μl, 1.63 mmol) is added, the reaction mixture warmed to RT and stirred 16 h. The reaction is then quenched with water (10 mL) and extracted into EtOAc (3×10 mL). The combined organic phases are dried over Na2SO4 and reduced in vacuo to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.Cl.[NH2:12][OH:13].C(N(CC)CC)C>CO>[NH2:1][C:2]1[C:3]([C:9](=[N:12][OH:13])[NH2:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=NO)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A solution of 3-amino-6-bromo-pyrazine-2-carbonitrile (1 g, 5.025 mmol) in MeOH (20 mL) was cooled to 0° C. and treated with hydroxylamine hydrochloride (349.2 mg, 5.025 mmol) and triethylamine (508.5 mg, 700.4 μL, 5.025 mmol) and the reaction allowed to warm to ambient temperature. After a period of 2 hours a precipitate was observed which was filtered off. The resultant filtrate was evaporated to dryness and triturated with MeOH to furnish further product as a beige solid (771 mg, 78% Yield).
Reaction SMILES: NC1C2N=C(COCC)N(CC(C)(O)C)C=2C2N=CC(Br)=CC=2N=1.[Br:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([NH:43][CH2:44][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:47])[CH3:46])=[C:31]([NH:36][C:37](=O)[CH2:38][O:39][CH2:40][CH3:41])[CH:32]=[N:33]2)=[N:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[Br:25][C:26]1[CH:27]=[N:28][C:29]2[C:30]3[N:43]([CH2:44][C:45]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:52])([CH3:53])[CH3:54])([CH3:46])[CH3:47])[C:37]([CH2:38][O:39][CH2:40][CH3:41])=[N:36][C:31]=3[CH:32]=[N:33][C:34]=2[CH:35]=1
Reactant: CCOCC(=O)Nc1cnc2cc(Br)cnc2c1NCC(C)(C)NC(=O)OC(C)(C)C
Agent: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Yield: 102.5 %

Procedure:
A modification of the method described in Part D of the preparation of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-2-methylpropan-2-ol was used to treat tert-butyl 2-({7-bromo-3-[(ethoxyacetyl)amino][1,5]naphthyridin-4-yl}amino)-1,1-dimethylethylcarbamate (55.6 g, 0.104 mol) with potassium carbonate (55.6 g). After the ethanol was removed under reduced pressure, and the resulting mixture was extracted with dichloromethane (4×300 mL). The combined extracts were concentrated under reduced pressure to provide 51 g of tert-butyl {2-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-1,1-dimethylethyl}carbamate as a yellowish brown solid.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[F:17])[CH2:29][CH2:28]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(C(C)(C)C)n1

Procedure:
171 mg (90%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 1-(2-fluorophenyl)piperazine (81 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[N:12]=[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:14][C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:10]>C1COCC1.CO.O>[C:20]1([C:13]2[O:14][C:15]([C:16]([F:19])([F:18])[F:17])=[C:11]([C:9]([NH:8][CH2:7][CH2:6][C:5]([OH:26])=[O:4])=[O:10])[N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCNC(=O)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
NaOH (309.7 mg, 7.7 mmol) was added to 3-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)amino]propionic acid methyl ester (265 mg, 0.77 mmol) dissolved in THF/MeOH/water (25 mL, 4:2:1). The reaction mixture was stirred at 25° C. for 12 hours and concentrated under vacuum. The residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum to obtain the desired compound (250 mg, 98%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][C:3]=1/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20].[Br:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28](I)=[CH:27][C:26]=1[Cl:34].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>CCOC(C)=O.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:10]([S:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([NH:1][C:28]2[CH:27]=[C:26]([Cl:34])[C:25]([Br:24])=[CH:30][C:29]=2[O:31][CH3:32])=[C:3](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)c(F)cc1N
Reactant: COc1cc(Br)c(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)c(F)cc1Nc1cc(Cl)c(Br)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (1.60 g, 4.83 mmol), 1-bromo-2-chloro-4-iodo-5-methoxybenzene (2.013 g, 5.79 mmol), xantphos (0.140 g, 0.241 mmol), Pd2(dba)3 (0.111 g, 0.121 mmol), cesium carbonate (2.360 g, 7.24 mmol) and toluene (7.98 ml). The flask was kept under Argon, a reflux condenser was attached and the flask was lowered into a 110° C. heating bath and heated for 4 hours. The mixture was cooled to RT, diluted with EtOAc, and filtered through celite with the aid of EtOAc. The filtrate was concentrated. The oily residue was taken up in 2-PrOH (it remained an oil). The mixture was then concentrated to give a yellow solid with some oily solid present. The mixture was taken up in 2-PrOH to give a suspension, and the suspension was stirred overnight, which broke up the darker, oily solid. The mixture was filtered, and the filtered solid was washed with 2-PrOH (3×). The collected solid was dried on the filter under a flow of N2 (g) for 15 min to give ((E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate (1.8 g, 3.27 mmol, 67.7% yield)as a bright-yellow solid. m/z (ESI) 548.1
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:22])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[C:7]2[C:16]1[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=1.C1C(=O)N([Br:30])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:22][C:3]1[C:2]([F:1])=[C:11]2[C:6]([C:7]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(C)c(F)c2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(-c2cnn(C)c2)c2ccc(CBr)c(F)c2n1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
After degassing with N2, a mixture of methyl 8-fluoro-7-methyl-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate (7-17, 169.2 mg, 0.57 mmol), NBS (106 mg, 0.59 mmol) and benzoyl peroxide (13.7 mg, 0.057 mmol) in CCl4 (2.8 ml) was stirred at 80° C. After 5 h, the solvent was removed and the residue was partitioned between EtOAC and sat. NaHCO3. The organic layer was washed with water, dried over Na2SO4 and filtered. Concentration afforded the crude methyl 7-(bromomethyl)-8-fluoro-4-(1-methyl-1H-pyrazol-4-yl)quinoline-2-carboxylate, which was used without further purification (7-18). LRMS m/z (M+H)+ 378.2 found, 378.0 required.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5].[BH4-].[Na+].CC(C)=O>CO>[F:1][C:2]1[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[C:6]([I:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(I)ccc(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: N#Cc1c(I)ccc(CO)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 mL) at 0° C. was treated with NaBH4 (822 mg, 22 mmol) and the mixture was stirred for 1 h at 0° C. Acetone was added and the mixture was stirred for 5 min, then concentrated to dryness. The residue was partitioned between H2O and EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 3:2 hexanes/EtOAc to give the desired product (3.14 g). Rf=0.38 (3:2 hexane:EtOAc).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:4]=1[NH2:5])[CH3:2].[Br:11]Br.[OH-].[Na+].O>C(Cl)Cl>[Br:11][C:8]1[CH:7]=[C:6]([CH3:10])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(C)c1N
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCc1cc(Br)cc(C)c1N
Temperature: 7.5 °C
Yield: 98.2 %

Procedure:
In a 2.5 L three-necked round-bottom flask 2-ethyl-6-methyl aniline (250 g, 1.85 mol) is dissolved in DCM (900 mL) and cooled to 5-10° C. Bromine (310.3 g, 1.94 mol) is added over a period of 105 min such as to keep the temperature at 5-15° C. An aq. 32% NaOH solution (275 mL) is added over a period of 10 min to the greenish-grey suspension while keeping the temperature of the reaction mixture below 25° C. DCM (70 mL) and water (100 mL) are added and the phases are separated. The aq. phase is extracted with DCM (250 mL). The combined org. phases are washed with water (300 mL) and concentrated at 50° C. to afford the 4-bromo-2-ethyl-6-methyl-aniline (389 g) as a brown oil; 1H NMR (CDCl3): δ 1.27 (t, J=7.3 Hz, 3H), 2.18 (s, 3H), 2.51 (q, J=7.3 Hz, 2H), 3.61 (s br, 1H), 7.09 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=CC(C2CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=[CH:5][CH:4]=1.C(C1C=C[C:35]([C:38]2([Cl:55])[CH2:41][N:40]([CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:39]2)=[CH:34]C=1)(C)(C)C>>[Cl:55][C:38]1([C:35]2[CH:34]=[CH:5][CH:4]=[C:3]([C:2]([F:27])([F:26])[F:1])[CH:8]=2)[CH2:41][N:40]([CH:42]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:39]1
Reactant: FC(F)(F)c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: CC(C)(C)c1ccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)cc1
Product: FC(F)(F)c1cccc(C2(Cl)CN(C(c3ccccc3)c3ccccc3)C2)c1

Procedure:
This compound was prepared from compound (32) using the procedure described for compound (10).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[S:29]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][NH:30]1>>[O:34]=[S:29]1(=[O:35])[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 54.1 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and isothiazolidine 1,1-dioxide (158 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (274 mg) was obtained.
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=1)[C:3](OCC)=[O:4].[H][H]>CO.[Pd]>[OH:1][CH:2]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:18][CH3:19])[N:10]=2)[NH:15][C:3]1=[O:4]
Reactant: CCOC(=O)C(O)Cc1nc(OC)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(n1)CC(O)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A roundbottom flask was charged with a solution of ethyl 2-hydroxy-3-(6-methoxy-3-nitropyridin-2-yl)propanoate (37 mmol) in methanol (500 ml). To the mixture was added 10% palladium on carbon (3 g). The solution was shaken under 40 psi of hydrogen for 12 hours. The resulting solution was then allowed to react, with stirring, for 5 hours while the temperature was maintained at room temperature. The mixture was then filtered and the filtrate was diluted with 100 ml of water. Hydrochloric acid was added until the pH=5. The mixture was filtered and the filtrate was adjusted to pH=8 by the addition of sodium carbonate. The solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: C(C1(CC)OC2C=CC=CC=2C=C1)C.BrN1C(=O)CCC1=O.Br[C@@H:24]1[C:29]([CH2:32][CH3:33])([CH2:30][CH3:31])[O:28][C:27]2[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=2[C@H:25]1[OH:38].[OH-].[K+]>C(OCC)C>[O:38]1[CH:25]2[C:26]3[CH:37]=[CH:36][CH:35]=[CH:34][C:27]=3[O:28][C:29]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH:24]12
Reactant: CCC1(CC)Oc2ccccc2[C@@H](O)[C@@H]1Br
Agent: CCC1(CC)C=Cc2ccccc2O1
Agent: O=C1CCC(=O)N1Br
Agent: [K+]
Solvent: CCOCC
Product: CCC1(CC)Oc2ccccc2C2OC21

Procedure:
2,2-Diethyl-2H-benzo[b]pyran (3.86 g.) was treated with N-bromosuccinimide (7.40 g.) under the conditions described in Example 5 yielding trans-3-bromo-3,4-dihydro-2,2-diethyl-2H-benzo[b]pyran-4-ol (5.70 g.), as a pale yellow solid m.p. 75° - 77° after trituration with 60°-80° petroleum ether. Reaction of this bromohydrin (5.60 g.) with potassium hydroxide pellets (6.38 g.) in diethyl ether (300 ml.) for 4.5 days following Example 7 gave 3,4-epoxy-3,4-dihydro-2,2-diethyl-2H-benzo[b]pyran as a colourless liquid (4.28 g.) displaying signals centred at δ 3.66 and 3.78 (doublets, of coupling constant J = 4Hz) in its p.m.r. spectrum (CDCl3, with TMS as internal standard) corresponding to protons located at C-3 and C-4. Treatment of this epoxide (1.40 g.) with isopropylamine (3.50 g., an excess) and work-up as in Example 1, gave trans-4-isopropylamino-3,4-dihydro-2,2-diethyl-2H-benzo[b]pyran-3-ol hydrochloride (1.67 g.) m.p. 200° - 202°.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)CC)C.[C:31]([NH:39][C@@H:40]1[CH2:45][CH2:44][O:43][CH2:42][C@@H:41]1[C:46]([O:48][CH3:49])=[O:47])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[C:31]([NH:39][C@H:40]1[CH2:45][CH2:44][O:43][CH2:42][C@H:41]1[C:46]([O:48][CH3:49])=[O:47])(=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)[C@H]1COCC[C@H]1NC(=O)c1ccccc1
Agent: O=C(O)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1COCC[C@@H]1NC(=O)c1ccccc1
Reaction time: 20 h
Yield: 91 %

Procedure:
A mixture of (3S,4S)- and (3R,4R)-methyl 4-aminotetrahydro-2H-pyran-3-carboxylate, HBr (prepared in a similar manner as described in International Patent application No. WO 2003/024899, 500 mg, 2.083 mmol), benzoic acid (254 mg, 2.083 mmol), HOBt (383 mg, 2.499 mmol), EDC (479 mg, 2.499 mmol) and triethylamine (0.581 mL, 4.17 mmol) were mixed in methylene chloride (10 mL) at 25° C. and stirred for 20 hours. At the conclusion of this period, the reaction was worked up by adding methylene chloride and then rinsing the mixture with saturated sodium carbonate (1×). The methylene chloride layer was dried over sodium sulfate and concentrated to give an off-white solid. The off-white solid was purified over silica gel in 3:1 to 1:1 hexanes/EtOAc to 100% EtOAc to yield a mixture of (3R,4R)-methyl 4-benzamidotetrahydro-2H-pyran-3-carboxylate and (3S,4S)-methyl 4-benzamidotetrahydro-2H-pyran-3-carboxylate (500 mg, 1.899 mmol, 91% yield) as a white solid. MS (ESI+)=264.24 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]([CH2:23][C:24]#[N:25])[CH:16]=1)[CH3:2].Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:16]=[C:17]([CH2:23][C:24]#[N:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:1][CH3:2])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC#N)ccc1OC)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetonitrile and benzyl chloroformate.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].[CH3:5][O:6][C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]=O.[OH-].[Na+]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]1[S:4][CH2:1][CH2:2][S:3]1
Reactant: SCCS
Reactant: COC(=O)Cc1ccccc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1C1SCCS1
Temperature: 20 °C
Reaction time: 48 h
Yield: 97.3 %

Procedure:
10 ml of 1,2-ethanedithiol (0.12 moles) and 115 ml of trifluoro diboro diethyletherate are added to a solution of 22 g (0.12 moles) of 2-formyl-phenylacetic acid methyl ester in 100 ml of methylene chloride at 20° C. The system is agitated at 20° C. for 48 hours. 152 ml of 5% sodium hydroxide are added, the phases are separated, the organic phase is dried over magnesium sulphate and the solvent is evaporated under vacuum at +30° C. In this manner 29.7 g of 2-(1,3-dithiolan-2-yl)-phenylacetic acid methyl ester are obtained in the form of a yellow liquid. This crude product is saponified without the need for further purification.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12](Cl)[C:13]([O:15]CC)=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[NH2:19][C:20]([NH2:22])=[S:21].C([O-])(=O)C.[Na+]>COCCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]2[S:21][C:20](=[NH:19])[NH:22][C:13]2=[O:15])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(CC(C)=O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CC(=O)Cc1ccc(CC2SC(=N)NC2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of ethyl 3-(4-acetonylphenyl)-2-chloropropionate, ethylene ketal (4.86 g), thiourea (1.19 g) and sodium acetate (1.29 g) in 2-methoxyethanol (25 ml) was stirred and heated at 100 ° C. for 16 h. The solvent was evaporated and the residue was diluted with 50:50 water/hexane (50 ml). The resulting solid was filtered, dried and purified by chromatography on silica gel. Elution with methanol:chloroform (4:96) gave 5-(4-acetonylbenzyl)-2-iminothiazolidine-4-one as a white solid, mp 196°-198° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[CH:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[CH:40]1([C:46]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)C1CCCCC1
Product: CC(C)(C)OC(=O)NC1CCCOCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)C3CCCCC3)CN2C1=O
Yield: 26.7 %

Procedure:
Prepared by way of method I of example 27 using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (50 mg, 0.088 mmol) and cyclohexanecarbonyl chloride (35 μL, 0.26 mmol). The final trituration (diethyl ether/petroleum ether) and filtration gave 16 mg (27%) of 18-cyclohexanecarbonyloxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-10-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 96.1% pure (HPLC), MS m/z 679 (M−H)−, HRMS: calcd. 679.3013 and found 679.3007 (M−H)−, mp 128-130° C.
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][C:5]([CH3:10])([CH3:9])[C:6](=[O:8])[CH3:7].C(OCC)(=O)C.O>CO>[Br:1][CH2:7][C:6](=[O:8])[C:5]([CH3:10])([CH3:9])[CH2:4][OH:3]
Reactant: CC(=O)C(C)(C)CO
Reactant: BrBr
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(CO)C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.3 %

Procedure:
Bromine (182.0 g, 1.1 mol) is slowly added at −10° C. to a solution of 4-hydroxy-3,3-dimethyl-butan-2-one (120.0 g, 1.0 mol) in 700.0 mL of MeOH. The solution is slowly warmed up to room temperature and the reaction mixture is stirred for 2 h. Ethyl acetate and water are added to the reaction mixture, the two phases are separated, and the organic layer is washed with 10% K2CO3 solution. The organic layer is dried over anhydrous Na2SO4 and after filtration the solvent is removed under reduced pressure to afford the crude product that is purified by silica gel chromatography to afford 100.0 g of 1-bromo-4-hydroxy-3,3-dimethyl-butan-2-one as a brown liquid. Yield: 44%, over two steps; m/z 197 [M+H].