Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:11]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:10]=2[S:9][N:8]=1.C(O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:10]2[S:9][N:8]=[C:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=3)[C:11]=2[CH:12]=1
Reactant: Cn1cccc1-c1nsc2ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cccc1-c1nsc2ccc(N)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a mixture of 3-(1-methylpyrrol-2-yl)-5-nitro-1,2-benzisothiazole(1.5 g, 5.79 mmol), ethyl acetate and ethanol is added tin(II) chloride dihydrate (6.5 g, 28.8 mmol). The resultant mixture is heated to reflux, stirred 30 min at reflux and cooled to room temperature. The mixture is diluted with ethyl acetate and slowly quenched with solid sodium bicarbonate and water. Brine is added and the resultant mixture stirred and allowed to stand until layer separation is complete. The organic layer is saved and the aqueous layer is extracted with ethyl acetate. The solids which form in the aqueous layer are triturated with ethyl acetate, filtered and the filtrate combined with the above organic layers. The combined organic layers are washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the title compound as a brown oil (1.10 g, 84.6%) identified by NMR spectral analysis.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]([CH2:19][C:20]([NH:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])=[C:27]([CH3:31])[CH2:28][S:29](=[O:30])[C@H:24]12)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.COP(OC)OC>CC(C)=O.C(OCC)(=O)C.O.O.O.[Ru](Cl)(Cl)Cl>[O:12]([CH2:19][C:20]([NH:22][CH:23]1[C:40](=[O:41])[N:25]2[C:26]([C:32]([O:34][CH2:35][C:36]([Cl:38])([Cl:39])[Cl:37])=[O:33])=[C:27]([CH3:31])[CH2:28][S:29](=[O:9])(=[O:30])[C@H:24]12)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)C1
Agent: Cl[Ru](Cl)Cl
Agent: COP(OC)OC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
A solution of 0.026 g (0.1 mM) of ruthenium trichloride trihydrate in 25 ml of acetone containing 0.5 mM of m-chloroperbenzoic acid was stirred for 10 minutes at 0° to -10° C. under a nitrogen atmosphere. To the stirred reaction mixture were added 4.94 g (10 mM) of 2,2,2-trichloroethyl 7-phenoxyacetamido-1-oxo-3-methyl-3-cephem-4-carboxylate in one portion, followed by the portion-wise addition over ten minutes of a solution of 8.0 g (40 mM) of m-chloroperbenzoic acid in 40 ml of acetone. Following the complete addition, the reaction mixture was warmed to room temperature and stirred for 4 hours. Thin-layer chromatographic analysis indicated that no starting material remained in the reaction mixture. Trimethylphosphite was added to the reaction mixture until a negative starch iodide test was obtained. The solvent was removed from the reaction mixture by evaporation under reduced pressure to provide a solid. The solid was dissolved in 100 ml of ethyl acetate and washed twice with 100 ml portions of dilute sodium carbonate and then with water and finally with brine. The solution was dried and the solvent was removed by evaporation under reduced pressure to provide an oil. Crystallization of the oil from 50 ml of methanol afforded 2.91 g of 2,2,2-trichloroethyl 7-phenoxyacetamido-1,1-dioxo-3-methyl-3-cephem-4-carboxylate. Yield 57%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH3:25])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:28]([NH:31][CH3:32])[CH:29]=[CH2:30]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:31]([CH2:28][CH:29]=[CH2:30])[CH3:32])[CH2:12][CH2:11]2)[CH3:25])=[CH:4][CH:3]=1
Reactant: C=CCNC
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Solvent: CO
Product: C=CCN(C)CCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1

Procedure:
A solution of 219 mg (0.524 mmol) of trans-Methanesulfonic acid 4-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-butyl ester and 0.48 ml of N-allyl methyl-amine in 1 ml of MeOH was stirred over night at RT, and for 2 h under reflux. After concentration of the reaction-mixture in vacuo, the crude product was purified by chromatography over silica gel with EtOAc/H2O/AcOH/Aceton (6:2:1:1) to give 165 mg (80%) of clean trans-{4-[4-(Allyl-methyl-amino)-butyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 393 (MH+, 1Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][O:20][C:19]2[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: O=C(CCl)Nc1ccc(Br)cc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COc1ccc(O)cc1)Nc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 15 %

Procedure:
A mixture of compound 7a (496 mg, 2 mmol), K2CO3 (553 mg, 4 mmol), and KI (66 mg, 0.4 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (440 mg, 4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hr. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc (3:1) to provide the intermediate 7b (100 mg, 0.3 mmol, 16% yield). 1H NMR (400 MHz, Chloroform-d) δ 8.30 (broad s, 1H), 7.56-7.46 (m, 4H), 6.94-6.87 (m, 2H), 6.87-6.80 (m, 2H), 4.57 (s, 2H).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:29]C)=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+].C(Cl)(Cl)Cl.C(O)(C)C>C(Cl)Cl>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=4)[CH:22]=[CH:21][C:20]=3[C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])=[O:18])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCCCC2)cc1)c1c(-c2cc(F)ccc2F)ccc2cc(O)ccc12
Yield: 46.1 %

Procedure:
Dissolve [4-(2-azepan-1-yl-ethoxy)-phenyl]-[2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-methanone (1.74 g, 3.37 mmol) in 20 mL methylene chloride and chill in ice. Add to this solution 2.0 mL of boron tribromide (5.3 g, 21.2 mmol) and allow to come to room temperature. Pour into a two phase solution of saturated sodium bicarbonate and 3/1 chloroform/isopropanol. Separate the organic layer, wash with water and dry over 3 Å sieves. Evaporate the solvent and purify on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to yield 780 mg (46%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13].C(OC([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CO.O>[Br:1][C:2]1[C:11]([O:12][C@H:23]2[CH2:24][CH2:25][CH2:26][NH:21][CH2:22]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Reactant: O=c1[nH]ccc2c(Br)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=c1[nH]ccc2c(Br)c(O[C@H]3CCCNC3)ccc12
Reaction time: 1 h

Procedure:
The crude 5-bromo-6-hydroxy-2H-isoquinolin-1-one (93 mg) was mixed with (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 4.3 mol eq), potassium carbonate (700 mg, 12 mol eq) and N, N-dimethylformamide (2 ml). The mixture was microwaved at 150° C. for 20 minutes. Water was added to the mixture and the crude product extracted out into ethyl acetate. The organic phase was washed with brine and dried (MgSO4). The organics were concentrated in vacuo then purified by prep-HPLC. Dichloromethane and trifluoroacetic acid (3:1, 2 ml) were added and the mixture stirred for 1 h then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford (S)-5-bromo-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one. The residue was purified by prep-HPLC (1.8 mg), El-MS: m/z=323.5 and 323.5 [M+H]+
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[C:7]=2[O:6]1)=[N+]=[N-]>[Pd]>[F:22][C:20]([F:21])([F:23])[C:16]1[CH:15]=[C:14]([C:13]2[C:7]3[O:6][CH:5]([CH2:4][NH2:1])[CH2:9][C:8]=3[CH:10]=[CH:11][CH:12]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1
Agent: [Pd]
Product: NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1
Yield: 69 %

Procedure:
Treatment of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (5.2 g, 11.57 mmol) with sodium azide (3.01 g, 46.3 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.375 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.64 g (69%) of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 172-174° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.09; H, 4.6; N, 4.03.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:20])=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH:21]1([NH2:24])[CH2:23][CH2:22]1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:20])=[N:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:10])[C:5]([NH:24][CH:21]2[CH2:23][CH2:22]2)=[N:6][CH:7]=1
Reactant: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1Cl
Reactant: NC1CC1
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1NC(=O)c1cc(Br)cnc1NC1CC1
Temperature: 0 °C
Yield: 74.2 %

Procedure:
A solution of 5-bromo-2-chloro-N-(2,6-dichloro-4-methyl-3-pyridinyl)-3-pyridinecarboxamide (3.00 g, 7.61 mmol) and cyclopropylamine (2.11 mL, 30.5 mmol) in xylenes was heated in a sealed tube at 120° C. for 24 h. The reaction was cooled to 0° C., diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by trituration (Et2O:hexane, 3:1) to give the title compound (2.35 g, 75% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[C:10](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)=[CH:9][N:8]=[N:7]1)=[O:4].ClCCl.[C:41]([OH:44])(=[S:43])[CH3:42].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>O.C1(C)C=CC=CC=1>[C:41]([S:43][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:10]1[N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[N:7]=[N:8][CH:9]=1)(=[O:44])[CH3:42]
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (6.27 g) in a mixed solvent of dichloromethane (100 ml) and toluene (100 ml) were added thioacetic acid (3.62 ml) and N,N-dimethylformamide dineopentyl acetal (14.0 ml). After the mixture was stirred at room temperature for 1 hour, water was added thereto and products were extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Concentration under reduced pressure followed by purification of the residue by silica gel chromatography using hexane, ethyl acetate, and dichloromethane (2:1:1) as an eluent afforded crude (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-1-(triphenylmethyl)piperidine (4.0 g).
Reaction SMILES: OC(C1C=C2C(=CC=1)C=C(C(O)=O)C=C2)C(C)CC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1.[OH:43][C:44]([C:72]1[CH:73]=[C:74]2[C:79](=[CH:80][CH:81]=1)[CH:78]=[C:77]([C:82](OC)=[O:83])[CH:76]=[CH:75]2)([C:48]1[N:49]=[CH:50][N:51](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:52]=1)[CH:45]([CH3:47])[CH3:46].Cl.[CH3:87][O:88][NH2:89].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.O>[OH:43][C:44]([C:72]1[CH:73]=[C:74]2[C:79](=[CH:80][CH:81]=1)[CH:78]=[C:77]([C:82]([NH:89][O:88][CH3:87])=[O:83])[CH:76]=[CH:75]2)([C:48]1[N:49]=[CH:50][NH:51][CH:52]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1
Reactant: CON
Agent: CC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CONC(=O)c1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 158.6 %

Procedure:
In a similar manner to that described in Example 9-(i), a crude mixture of 6-(1-hydroxy-2-methyl-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoic acid was obtained by the reaction using methyl 6-(1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-2-naphthoate (2.0 g). To a solution of the crude mixture in THF (30 mL) was added methoxyamine hydrochloride (354 mg), 1-hydroxybenzotriazole (594 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (744 mg) under ice cooling. The mixture was stirred at room temperature for 15 h, diluted with water and extracted with ethyl acetate. The extract was concentrated and purified by column chromatography (eluent; hexane:THF=1:2) followed by crystallization from hexane-ethyl acetate to give the titled compound (1.90 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:14]=[C:13]([S:15][CH2:16][C:17]2[S:21][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH3:32])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)COc1ccc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(SCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
Ethyl {2-methyl-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl sulfanyl]phenoxy}acetate obtained from Example 10 (5.0 g, 10.5 mmol) was dissolved in ethanol (200 ml) and 3N sodium hydroxide solution (35.0 ml) was added thereto. The reaction mixture was stirred for 30 minutes at room temperature. After completion of reaction, 2N HCl was added thereto for adjusting pH to be 2.0. Ethanol was evaporated by under reduced pressure and the reaction mixture was extracted with ethyl acetate and brine. Subsequently, the solvent was evaporated by under reduced pressure and the residue was purified by LH-20 column chromatography to thereby yield 4.71 g of the title compound (yield: 98.8%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH2:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])[CH3:13]>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:11][C:6]1[C:5]2[C:9](=[CH:10][C:2]([C:21]3[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=3)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:3][CH:4]=2)[NH:8][N:7]=1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Reactant: Nc1n[nH]c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2ccc3c(N)n[nH]c3c2)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
To a solution of 6-bromo-1H-indazol-3-amine (2.1 g, 10.0 mmol) in dioxane (100 mL) and sodium carbonate (1N, 40 mL) were added 3-(ethoxycarbonyl)phenylboronic acid (1.94 g, 10.0 mmol) and Pd(dppf)Cl2 (816 mg, 1.0 mmol). After the reaction was stirred at 100° C. for 4 hours and cooled to room temperature, the mixture was filtered through Celite and washed by ethyl acetate. The combined organic solution was washed by brine, dried with sodium sulfate and concentrated in vacuo. The crude residue was purified by flash chromatography with 50:1 (v/v) methylene chloride-methanol to afford the title product (1.46 g), MS m/z: 282.11 (M+1).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=Cc1ccc(F)cc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Product: O=Cc1ccc(Oc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 4-fluoro-3-(trifluoromethyl)phenol.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[N:5][CH:4]=[N:3]1.CN(C)C=O.[Br:17]N1C(=O)CCC1=O>O>[Br:17][C:9]1[S:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][N:5]=2)=[N:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ncnc1-c1nccs1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncnc1-c1ncc(Br)s1
Temperature: 22 °C
Reaction time: 18 h
Yield: 969 %

Procedure:
To a mixture of methyl-5-thiazol-2-yl-1H-[1,2,4]triazole (6.55 g; 39 4 mmol) and dimethylformamide (32 mL), add N-bromosuccinimide (14 g, 78.8 mmol) in three portions over 1 h. Stir the mixture at 22° C. for 18 h and then add to water (300 mL) chilled to 0-5° C. Separate the aqueous layer and extract with methyl-t-butyl ether (2×200 mL). Combine the organic layers and wash with 7% aqueous sodium hydrogen carbonate (100 mL) and then dry over sodium sulfate. Filter and evaporate the solvent to afford the title compound (9.5 g, 93%). ES/MS m/z (79Br/81Br) 245/247 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:12]([CH3:13])[O:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[N:23]1[CH:28]=[C:27](B(O)O)[CH:26]=[N:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]4[CH:28]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:3]=3)[CH:12]([CH3:13])[O:11][C:10]([NH2:14])=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(C2(c3cccc(Br)c3)N=C(N)OC2C)cc1
Reactant: OB(O)c1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(C2(c3cccc(-c4cncnc4)c3)N=C(N)OC2C)cc1
Temperature: 100 °C

Procedure:
A dried pressure tube was charged with (4RS,5RS)-4-(3-bromo-phenyl)-4-(4-methoxy-phenyl)-5-methyl-4,5-dihydro-oxazol-2-ylamine (Building Block AP, (64 mg, 0.2 mmol), pyrimidine-5-boronic acid (25 mg, 0.2 mmol), triphenylphosphine (10 mg, 0.04 mmol), 2 N sodium carbonate solution (0.4 mL), and 1,2-dimethoxyethane (2 mL). The mixture was purged with argon before palladium(II)acetate (4 mg, 0.018 mmol) was added. The sealed pressure tube was heated at 100° C. for 60 hours. The incomplete reaction was stopped, the reaction mixture was cooled and evaporated under reduced pressure. The residue was directly chromatographed on silica gel using a gradient of dichloromethane/methanol=100/0 to 85/15 as the eluent. The mixture of the diastereomeric racemates was chromatographed on a preparative silica gel LC-plate using a 9:1-mixture of dichloromethane/methanol as the eluent. There were obtained 2 fractions of the desired product: 5 mg of a 9:1-mixture of diastereomeric racemates (example 169) [Mass (calculated) C21H20N4O2 [360]; (found) [M+H]+=361 and 3 mg of a 6:4-mixture of diastereomeric racemates (example 170) [Mass (calculated) C21H20N4O2 [360]; (found) [M+H]+=361
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[CH3:11][CH:12]([CH2:20][CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)[C:24](O)=[O:25]>>[CH3:11][CH:12]([CH2:20][CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:24]=[O:25])=[CH:16][CH:15]=1
Reactant: CCC(C)Cc1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCC(C)Cc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
Trifluoroacetic acid (150 cc) was added to a flask containing 14.0 gm hexamethylenetetramine (HMTA). (+)2-methylbutylbenzene (14.8 gm) was then added and the mixture was refluxed for 21 hours. The deep orange mixture was distilled to remove excess trifluoroacetic acid. When about one third the volume remained, the mixture was poured into 600 ml ice water and stirred for 15 minutes. Sodium carbonate was added with stirring until the mixture was basic and the product was extracted with ether. The ether extract was washed with water and dried over sodium sulfate. The ether was removed leaving 18 gm crude (+)-4(-2-methylbutyl)benzaldehyde. This was vacuum distilled (78° C. at 0.07 mm Hg). The structure of the product was confirmed by NMR. The yield of the product was 78%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:7][CH:6]=3)[C:9]3[N:10]([N:33]=[CH:34][CH:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)CBr
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OCC(=O)OCC)cc2)c2ccnn12
Temperature: 70 °C
Reaction time: 15 h
Yield: 75 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added ethyl bromoacetate (0.66 mL) and cesium carbonate (1.3 g) and the mixture was stirred at 70° C. for 15 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.82 g, 75%).