Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:36])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:28])[C:23]([OH:25])=[O:24].[CH2:37]1CCN2C(=NCCC2)CC1.S(OC)(OC)(=O)=O.O>CN(C=O)C>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:36])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:27]([C:29]1[CH:34]=[N:33][C:32]([CH3:35])=[CH:31][N:30]=1)=[O:28])[C:23]([O:25][CH3:37])=[O:24]
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cnc(C(=O)O[C@]2(C(=O)O)[C@H](C)CC3C4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]45O[C@H]5C[C@@]32C)cn1
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@]1(OC(=O)c2cnc(C)cn2)[C@H](C)CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@@]21C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The product of Step 1 (2.50 g) is dissolved in DMF (11 mL) and cooled to 0° C. DBU (1.68 g) is added, followed by dimethyl sulphate (953 mg) after 10 minutes. The reaction is stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The combined organic phases are washed with water and brine, then dried over sodium sulfate. Evaporation affords 5-methylpyrazine-2 carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Observed mass (M+H) 511.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[C:21](OC)=[O:22])=[CH:15][CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([CH2:17][C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=2)[CH2:21][OH:22])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
Methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate (0.002 mol) in tetrahydrofuran (50 ml) is added dropwise to a tetrahydrofuran (50 ml) suspension of lithium aluminium hydride (0.004 mol). After consumption of the ester, the remaining lithium aluminum hydride is quenched by the addition of water and filtration to remove the resulting salts. Evaporation of the solvent gives 3-(4-(2-quinolinylmethyloxy)benzyl)benzylalcohol.
Reaction SMILES: C(N)C1C=CC=CC=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14].[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1cccc(F)c1
Yield: 14 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 3-fluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 14% yield: mp 169-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (t, J=5.7 Hz, 1H), 7.50-7.00 (m, 9H), 4.54-4.34 (m, 4H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 164.2, 162.3, 161.0, 157.8, 155.5, 151.6, 143.1, 130.6, 129.1, 128.2, 127.9, 123.6, 118.0, 114.4, 114.1, 47.3, 42.6, 42.4, 42.0, 17.5; MS (ES+) m/z 425.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)=[CH:5][C:4]([C:27]2[C:32]([CH:33]=[O:34])=[C:31]([N:35]3[CH:47]=[CH:46][N:38]4[C:39]5[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=5[CH:45]=[C:37]4[C:36]3=[O:48])[N:30]=[CH:29][CH:28]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:34][CH2:33][C:32]1[C:31]([N:35]2[CH:47]=[CH:46][N:38]3[C:39]4[CH2:40][CH2:41][CH2:42][CH2:43][C:44]=4[CH:45]=[C:37]3[C:36]2=[O:48])=[N:30][CH:29]=[CH:28][C:27]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][O:24][CH2:23]4)[CH2:18][C@@H:17]3[CH3:26])=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(-n4ccn5c6c(cc5c4=O)CCCC6)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.9 %

Procedure:
A mixture of 176a (200 mg, 0.31 mmol), NaBH4 (47 mg, 1.20), and methanol (10 mL) was stirred at room temperature for 1 h. The reaction mixture was then quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 176 (42 mg, 28%). MS-ESI: [M+H]+ 649.3. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (d, J=2.5 Hz, 1H), 8.56 (d, J=5.5 Hz, 1H), 8.47 (s, 1H), 7.84 (d, J=2.5 Hz, 1H), 7.50-7.48 (m, 2H), 7.39-7.36 (m, 1H), 7.26-7.24 (m, 2H), 6.83-6.80 (m, 2H), 4.57-4.54 (m, 2H), 4.48-4.40 (m, 3H), 4.35-4.33 (m, 1H), 3.69-3.67 (m, 1H), 3.60 (s, 3H), 3.41-3.38 (m, 2H), 3.11-3.08 (m, 1H), 2.97-2.93 (m, 1H), 2.76-2.74 (m, 2H), 2.62-2.60 (m, 2H), 2.52-2.51 (m, 1H), 2.35-2.32 (m, 2H), 2.19-2.17 (m, 1H), 1.90-1.87 (m, 2H), 1.77-1.75 (m, 2H), 0.94 (d, J=6.5 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C@H:19]1[NH:24][C@@H:23]([CH3:25])[CH2:22][N:21]([C:26]([C:28]2[C:29]([CH3:36])=[C:30]([CH:34]=O)[NH:31][C:32]=2[CH3:33])=[O:27])[CH2:20]1>C(O)C.N1CCCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:30]2[NH:31][C:32]([CH3:33])=[C:28]([C:26]([N:21]4[CH2:20][C@H:19]([CH3:18])[NH:24][C@H:23]([CH3:25])[CH2:22]4)=[O:27])[C:29]=2[CH3:36])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: O=C1Cc2c(cccc2-c2ccc(Br)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Br)cc4)c32)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.5 %

Procedure:
To a solution of 4-(4-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-bromo-phenyl)-3-[4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (38 mg, 28%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Cl[CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(COCCl)cc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(COCc1ccc(OC)cc1)(C(=O)OCC)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of diethyl 3,4-difluorophenylmalonate (13 g, 48 mmol) in dry tetrahydrofuran (100 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (1.5 g, 50 mmol) of 80% oil dispersion). The mixture was allowed to warm to room temperature and then heated to reflux for 1hour. To the cooled mixture was added 4-methoxybenzyl chloromethyl ether (9.5 g, 51 mmol ref. Synthesis, 1983, 762) and reflux was continued overnight. The cooled mixture was partitioned between water and diethyl ether, the organic layer was separated, dried over anhydrous magnesium sulphate and evaporated to leave diethyl 2-(3,4-difluorophenyl)-2(4-methoxybenzyloxymethyl)malonate as a yellow oil Nmr δ7.35 (1H,m), 7.2 (2H,d), 7.15-7.00 (2H,m), 6.85 (2H,d), 4.45 (2H,s), 4.20 (4H,q), 4.10 (2H,s), 3.80 (3H,s), 1.25 (6H,t).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[BrH:12].BrBr>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:7]([Br:12])[CH:8]=1
Reactant: Br
Reactant: Nc1ccc(F)cc1[N+](=O)[O-]
Agent: BrBr
Solvent: O
Product: Nc1c(Br)cc(F)cc1[N+](=O)[O-]
Temperature: 7 °C
Reaction time: 1 h

Procedure:
Mix 4-fluoro-2-nitroaniline (15.6g, 0.1mol) in water (400mL) and add 48% hydrobromic acid (1kg). Add bromine (16g, 0.1mol) with stirring and stir for 1 hour. Dilute to 2L and cool to 7° C. Filter, wash with water and dry to give 4-fluoro-2-bromo-6-nitroaniline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:18]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]1[N:18]=[C:13]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:14]2[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[S:25][C:15]=2[N:16]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Reactant: NCc1cccc([N+](=O)[O-])c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccccn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3-nitrobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[S:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(CC=C)O1.C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].CN(C=O)C>[CH2:16]([C:2]1[S:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[CH:3]=1)[CH:12]=[CH2:11]
Reactant: O=C1OCc2cc(Br)sc21
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1cc2c(s1)C(=O)OC2
Temperature: 100 °C

Procedure:
In a 15 mL microwave reaction vial was added 2-bromothieno[2,3-c]furan-6(4H)-one (45 mg, 0.205 mmol), 4,4,5,5-tetramethyl-2-(prop-2-en-1-yl)-1,3,2-dioxaborolane (34.5 mg, 0.205 mmol, 1.0 eq), potassium carbonate (56.8 mg, 0.411 mmol, 2.0 eq) and palladium triphenylphosphane (1:4) (23.7 mg, 0.021 mmol, 0.1 eq). To above mixture was added DMF (1.0 mL), de-gas and filled with N2. The vial was heated to 100° C. for 60 min, cooled down, diluted with EtOAc, washed with aqueous sodium bicarbonate, brine and water. The organic phase was dried over anhydrous Na2SO4, filtered, concentrated. The crude product was purified by flash column chromatography. LC-MS (IE, m/z): 181.2 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2
Reactant: CC(C)(C)OC(=O)N1CCc2c(Br)cccc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2-c2ccccn2)C1
Temperature: 110 °C
Yield: 91 %

Procedure:
To a 350 mL sealable flask was added t-butyl 5-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.67 g, 11.77 mmol) and tri-n-butyl(2-pyridyl)tin (5.2 g, 14.12 mmol. The mixture was dissolved in dioxane (100 mL) and tetrakis(triphenylphosphine)palladium(0) (2.72 g, 2.354 mmol) was added. The mixture was flushed with N2 and the flask was sealed and heated to 110° C. After heating the mixture for 65 h, the mixture was cooled to rt and was filtered through a pad of CELITE® to remove the solids. The CELITE® was washed with MeOH and the organic solution was concentrated under reduced pressure. The residue was purified using BIOTAGE® flash chromatography and a 10-50% EtOAc in hexanes gradient. The expected product, tert-butyl 5-(pyridin-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.33 g, 10.72 mmol, 91% yield), was isolated as a thick yellow oil. LC/MS: m/z 311.02 (M+H)+, 2.257 min (method 1). 1H NMR (500 MHz, chloroform-d) δ ppm 8.70 (d, J=4.88 Hz, 1H) 7.77 (t, J=7.32 Hz, 1H) 7.40 (d, J=7.93 Hz, 1H) 7.23-7.32 (m, 3H) 7.19 (br. s., 1H) 4.64 (br. s., 2H) 3.55 (br. s., 2H) 2.86 (t, J=5.95 Hz, 2H) 1.48 (br. s., 9H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:22][OH:23])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.N1C=CN=C1.[Si:29](Cl)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]>CN(C=O)C>[Si:29]([O:23][CH2:22][C@H:2]([OH:1])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](c1ccc(C(F)(F)F)cc1)[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
tert-butyl (1R,2R)-2,3-dihydroxy-1-(4-(trifluoromethyl)phenyl)propylcarbamate (11 g, 32.8 mol) in 100 mL DMF was cooled in an ice-water bath. 1H-imidazole (8.2 mL, 72 mol) was added in one portion, and the mixture was stirred for 10 minutes under nitrogen. tert-butyldimethylsilylchloride (5.43 g, 36.0 mmol) in 20 mL DMF was added via syringe. The reaction was monitored by TLC. After 16 hours, DMF was evaporated under high vacuum. 150 mL distilled water was added, and the resulting mixture was extracted into diethyl ether (2×200 mL). The ether layer was washed with saturated aqueous ammonia chloride and dried over sodium sulfate. After removing the solvent, the product was obtained as a white solid (14.0 g, yield=95%). 1H NMR (400 MHz, CD3OD) δ ppm 0.08-0.12 (m, 6H) 0.97 (s, 9H) 1.43 (s, 9H) 3.50 (s, 1H) 3.63 (s, 1H) 3.85 (s, 1H) 4.81 (s, 1H) 7.53-7.58 (m, 2H) 7.60-7.66 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH2:14][OH:15])[CH3:2].CC1NC(C2C=CC=CC=2)=NC=1CO>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]=1[CH:14]=[O:15])[CH3:2]
Reactant: CCc1[nH]c(-c2ccccc2)nc1CO
Agent: Cc1[nH]c(-c2ccccc2)nc1CO
Product: CCc1[nH]c(-c2ccccc2)nc1C=O

Procedure:
The procedure of Example 18 is repeated substituting an equimolecular amount of 5-ethyl-2-phenyl-4-imidazolemethanol for the 5-methyl-2-phenyl-4-imidazolemethanol employed in that example. There is thus obtained the title compound in equally good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>C(#N)C>[CH3:1][O:2][C:3]1[C:4]([N+:28]([O-:30])=[O:29])=[CH:5][C:6]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)CCC(=O)CC2
Agent: [K+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCC(=O)CC2
Temperature: 25 °C

Procedure:
2-Methoxy-5,6,8,9-tetrahydro-benzocyclohepten-7-one (6.00 g, 0.0315 mol) was dissolved in Acetonitrile (280 mL, 5.4 mol) and was added to a mixture of Trifluoroacetic anhydride (13.4 mL, 0.0946 mol) in Acetonitrile at 0° C. Potassium nitrate (3.19 g, 0.0315 mol) was then added and the reaction was allowed to warm to room temperature. When HPLC showed consumption of starting material, the mixture was poured over saturated sodium bicarbonate, and organics were extracted with ethyl acetate/dichloromethane. Combined organics were dried over sodium sulfate, filtered and reduced en vacuo. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). The gradient run was 0% EA-50% EA. Combined fractions were reduced en vacuo to afford 3.62 (49%) of 2-Methoxy-3-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one and 1.80 grams (25%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[C:4](/[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:5]/[C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H][H]>CO>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]1[CH2:10][CH2:9][CH2:8][C:7]=1[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)/C(=C/C1=C(Oc2ccccc2)CCC1)NC(=O)c1ccccc1
Reactant: [H][H]
Solvent: CO
Product: COC(=O)[C@H](CC1=C(Oc2ccccc2)CCC1)NC(=O)c1ccccc1
Yield: 101.4 %

Procedure:
To a 2-L autoclave, a slurry of compound (V) (n=1, R=Ph, R1=PhO, R2=Me) (100 g, 0.27 mol) in methanol (900 mL) was charged and bubbled with nitrogen for 30 minutes. Then [Rh(COD)(ScRp-DuanPhos)]BF4 (135 mg, 0.2 mmol) was added under nitrogen. The autoclave was then charged hydrogen to 10 bar and stirred at room temperature overnight. The reaction was monitored with HPLC. After the reaction completed, pressure of the hydrogenator was released, and the solution was concentrated to provide the product as oil (100 g). The ee was >99% which was determined by HPLC using Chiralpak AD-H column.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[NH2:10][C:11](=S)[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Cl-].[NH4+]>C(O)C.[Cl-].[Na+].O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9][N:8]=1
Reactant: CCOC(=O)C(N)=S
Reactant: NNC(=O)c1nccs1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(-c2nccs2)n[nH]1
Temperature: 110 °C
Reaction time: 264 h
Yield: 37 %

Procedure:
A suspension of thiazole-2-carbohydrazide (4.2 mmol), ethyl 2-amino-2-thioxoacetate (1 equiv) and ammonium chloride (6 equiv) in ethanol (150 mL) was placed in a sealed tube and this was warmed to 110° C. and stirred at that temperature for 11 days. The reaction solution was cooled to rt and conc. Brine was added and the mixture was adjusted to pH-6 and extracted with EtOAc. The organic phases were dried over Na2SO4, filtered and conc. The crude product was purified using SiO2 chromatography and an appropriate solvent gradient (CH3CN/MeOH/CH2Cl2) to give ethyl 3-(thiazol-2-yl)-1H-1,2,4-triazole-5-carboxylate as an off-white solid (Intermediate-2, 37% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[C:27]([F:28])=[C:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CCCCCCOc1ccc(-c2ncc(Br)cn2)cn1
Reactant: CCCCCCCCc1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCc1ccc(-c2cnc(-c3ccc(OCCCCCC)nc3)nc2)c(F)c1F
Yield: 79.9 %

Procedure:
The reaction of 2 mmol of 5-bromo2-(6-hexyloxypyridin-3-yl)pyrimidine, 2.2 mmol of 2,3-difluoro-4-octylphenylboronic acid, 4 mmol of sodium carbonate and 0.02 mmol of tetrakis(triphenylphosphine)palladium(0) in 14 ml of toluene, 7 ml of ethanol and 7 ml of water is carried out Analogously to the procedure indicated for Example 1a). The crude product is separated off by column chromatography on silica gel 60 using n-heptane/ethyl acetate 9:1 (v/v) as eluent and is recrystallized from acetonitrile, giving 0.77 g (80%) of colorless crystals, X 104 SC 94 SA 129 I.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH3:25][CH2:26][CH2:27]Br.O>CN(C=O)C>[CH3:19][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:7]1[CH:20]=[CH:21][C:4]([O:3][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=1[N+:22]([O-:24])=[O:23]
Reactant: CCCBr
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 1.0 ml of DMF, 4′-hydroxy-N-methyl-2′-nitro-p-toluenesulfonanilide (0.32 g (0.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, n-propyl bromide (0.20 g (2.20 mmol)) was added dropwise and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated were filtered and washed to give 0.15 g (42%) of the title compound as pale yellow crystals.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=O)[C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1)C1C=CC=CC=1>CO.Cl.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:33]=[CH:32][C:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:31])[C:27]([F:28])([F:29])[F:30])[CH2:24][CH2:25][C:19]=3[CH:18]=2)[C:11](=[O:35])[CH:10]=1
Reactant: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To 5.00 g (10.3 mmol) 4-benzyloxy-1-{2-oxo-2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21a) in 100 mL MeOH and 9.8 mL 1 M aqueous HCl-solution is added 500 mg of 10% Pd/C. The reaction mixture is stirred under a hydrogen atmosphere of 5000 hPa at 50° C. for 18 h. After filtration and evaporation of the solvent, is the residue purified by HPLC (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95).