Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1.[CH3:23]S(C)=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH:14]([CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=2[CH3:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)C(C)c1cc(C)c(C(=O)c2ccc(Cl)cc2)n1C
Reaction time: 0.5 h

Procedure:
6.4 Grams (0.02 mole) of ethyl 5-(p-chlorobenzoyl)-1,4-dimethylpyrrole-2-acetate is dissolved in 100 ml. of dimethyl sulfoxide (DMSO) and added to a slurry of 0.48 g. (0.02 mole) of sodium hydride in approximately 30 ml. of DMSO. The mixture is stirred for 30 mins. before 2.84 g. (0.02 mole) of methyl iodide is added. Stirring is continued for 15 mins. The reaction mixture is then poured into water and the precipitate filtered off and recrystallized from 2-propanol to yield ethyl 5-(p-chlorobenzoyl)-1,4,α-trimethylpyrrole-2-acetate, m.p. 88°-90° C.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:44][C:45]1[O:46][C:47]([CH3:50])=[N:48][N:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:44][C:45]3[O:46][C:47]([CH3:50])=[N:48][N:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: Cc1nnc(Cn2nnc3c(N4CC5(COC5)C4)nc(C(C)(C)C)nc32)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as white solid. MS (m/e): 371.2 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6](=O)[NH:7][C:8]=1[CH3:9])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>O>[Cl:15][C:6]1[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]([CH2:1][CH3:2])=[C:8]([CH3:9])[N:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCc1cc([N+](=O)[O-])c(=O)[nH]c1C
Solvent: O
Product: CCc1cc([N+](=O)[O-])c(Cl)nc1C
Yield: 57.5 %

Procedure:
A mixture of 5-ethyl-6-methyl-3-nitro-2-(1H)-pyridinone (2.38 g, 13 mmol) and phosphorus pentachloride (3.3 g, 15.6 mmol) was heated under an atmosphere of nitrogen at 140°-150° C. for 15 minutes. The resultant brown oil was then treated with water and the product extracted into chloroform. The organic extract was washed three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure (15 torr). The residue was passed through a small plug of silica gel, eluted with 2% methanol in chloroform. Collection and concentration of appropriate fractions yielded 1.5 g (57.5%) of the corresponding chloropyridine as a clear pale brown oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[CH:29][C:24]2=[CH:23][N:22]=1>CN(C)C=O.O>[Cl:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([O:18][CH3:19])=[C:12]([Cl:20])[C:11]=1[C:21]1[N:26]=[C:25]2[NH:27][N:28]=[C:29]([I:1])[C:24]2=[CH:23][N:22]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3cn[nH]c3n2)c1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
N-Iodosuccinimide (0.23 g, 1.0 mmol) was added to a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.30 g) in N,N-dimethylformamide (5.0 mL). The reaction mixture was stirred at 40° C. overnight. The reaction mixture was diluted with water and quenched with aqueous Na2S2O3. The precipitates formed were filtered, washed with water, ether, and dried in vacuum to afford the desired product (0.33 g). LCMS (M+H)+=450.8/452.8.
Reaction SMILES: [N+:1]([C:4](=[C:8]1[NH:13][CH2:12][CH2:11][CH2:10][S:9]1)[C:5](=[O:7])[CH3:6])([O-:3])=[O:2].[Br:14]N1C(=O)CCC1=O.C(OCC)C>C(Cl)(Cl)(Cl)Cl>[Br:14][N:13]1[CH2:12][CH2:11][CH2:10][S:9][C:8]1=[C:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)C(=C1NCCCS1)[N+](=O)[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)C(=C1SCCCN1Br)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 10.1 g of 2 and 10.0 g of N-bromosuccinimide in 150 ml of carbon tetrachloride was stirred at room temperature for 18 hours. The resulting mixture was filtered and the filtrate stripped of solvent under reduced pressure to leave a slightly gummy yellow solid. The solid was treated with ethyl ether and the remaining solid collected (bright yellow solid, m.p.: 101°-104°), then dissolved in methylene chloride. The solution was treated with Norite, filtered and the solvent stripped under reduced pressure to leave a solid which on recrystallization from ethyl acetate gave 12 as a yellow solid, m.p.: 105°-109°.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:3][C@H:4]1[CH2:8][C@@H:7]([C:9]([N:11]([C:13]2[C:14]([Cl:24])=[N:15][N:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:17]=2)[CH3:12])=[O:10])[CH:6]=[CH:5]1)(=[O:34])[CH3:33]
Reactant: CN(C(=O)[C@H]1C=C[C@@H](N)C1)c1cn(-c2cccnc2)nc1Cl
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1C=C[C@H](C(=O)N(C)c2cn(-c3cccnc3)nc2Cl)C1
Reaction time: 24 h

Procedure:
To a suspension of (1R,4S)-4-amino-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-methylcyclopent-2-enecarboxamide dihydrochloride (0.065 g, 0.17 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.084 g, 0.83 mmol) followed by acetyl chloride (1 M in CH2Cl2, 0.25 mL, 0.25 mmol). After stirring for 24 hours, the reaction product was purified by direct application to silica gel chromatography eluting with MeOH/CH2Cl2 to provide the title compound F86 as yellow foam (0.040 g, 67%).
Reaction SMILES: [N:1]1[C:8]([NH2:9])=[N:7][C:5]([NH2:6])=[N:4][C:2]=1[NH2:3].[CH2:10]=[O:11]>>[CH2:10]([NH:3][C:2]1[N:4]=[C:5]([NH2:6])[N:7]=[C:8]([NH2:9])[N:1]=1)[OH:11]
Reactant: C=O
Reactant: Nc1nc(N)nc(N)n1
Product: Nc1nc(N)nc(NCO)n1

Procedure:
Applicant's copending application Ser. No. 08/704,259 of Aug. 26, 1996 which is a continuation of Ser. No. 08/468,141 filed Jun. 6, 1995 describes a method for preparing an A-stage stabilized phenolic resin melamine dispersion which includes reaction of a portion of the melamine with formaldehyde to produce methylolmelamine in the phenolic resin to reduce the free formaldehyde content in the resin to less than 0.5% by weight of the composition.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([S:47][CH2:48][CH:49]([CH2:53][C:54]1[C:62]([Cl:63])=[CH:61][C:57]2[O:58][CH2:59][O:60][C:56]=2[CH:55]=1)[C:50](O)=[O:51])(=O)C>C(Cl)Cl.C(N(CC)CC)C>[Cl:63][C:62]1[C:54]([CH2:53][CH:49]([CH2:48][SH:47])[C:50]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)=[O:51])=[CH:55][C:56]2[O:60][CH2:59][O:58][C:57]=2[CH:61]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)SCC(Cc1cc2c(cc1Cl)OCO2)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)Cc1cc2c(cc1Cl)OCO2
Yield: 63.9 %

Procedure:
The operation is carried out as in Stage 5 of Example 1, starting with 121 mg of L-Tryptophan in the form of the hydrochloride, 2 ml of anhydrous methylene chloride, 0.13 ml of triethylamine, 199 mg of BOP and 143 mg of the product obtained in Stage 5 above, dissolved in 3 ml of anhydrous methylene chloride. Purification is carried out by chromatography on silica with chloroform-ethyl acetate: 90-10 as eluant. In this way 133 mg of expected product (yellow gum) is obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[C:17](/[C:16]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=1)\[C:18]#[N:19]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1cc2ccccc2o1
Product: COc1ccc(/C(C#N)=C/c2cc3ccccc3o2)cc1OC
Yield: 76.5 %

Procedure:
2-Benzofurancarboxaldehyde (166 mg) was condensed with 3,4-dimethoxybenzyl cyanide (201 mg) through Method A (production step 2), to thereby yield the target product (yield: 265 mg, 77%).
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=O)C.O.[NH2:30]N>C(O)(=O)C>[N:24]1([CH2:23][CH2:22][CH2:21][O:20][C:17]2[CH:18]=[CH:19][C:14]([C:8]3([C:6]4[N:5]=[CH:4][NH:2][N:30]=4)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:15][CH:16]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: NN
Reactant: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CC(=O)O
Solvent: O
Product: c1nc(C2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)n[nH]1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
N-[(dimethylamino)methylene]-4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxamide (0.15 g, 0.39 mmol), hydrazine hydrate (0.048 mL, 0.98 mmol) and acetic acid (1 mL) were combined and heated at 100° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with 10% aqueous sodium carbonate (20 mL). The organic was dried over sodium sulphate and evaporated to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:0.8 to 90:10:1) to produce a clear oil which was triturated with diethyl ether (3 mL), a white solid was isolated as the title compound (0.034 g, 24%). 1H NMR (400 MHz, CDCl3) δ 1.82-1.95 (m, 4H), 2.0-2.10 (m, 2H), 2.30 (m, 2H), 2.60-2.70 (m, 2H), 2.70-2.80 (m, 6H), 3.62 (t, 2H), 3.89 (m, 2H), 3.95 (t, 2H), 6.80 (d, 2H), 7.20 (d, 2H), 7.95 (d, 1H). HRMS ESI+ m/z 357.2279 [MH]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH2:10])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C([O-])([O-])=O.[Na+].[Na+]>CC(O)(C)C.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: ClCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: c1cc2cc(N3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Yield: 53.7 %

Procedure:
A heterogeneous, tan solution of 1H-indol-5-amine (4.5547 g, 34.5 mmol), 1-chloro-2-(2-chloroethoxy)ethane (6.06 mL, 51.7 mmol) and Na2CO3 (14.61 g, 138 mmol) in t-BuOH (90 mL) in a sealed pressure tube was heated to 100° C. for 2 days. The reaction was cooled to room temperature, diluted with EtOAc and filtered through a pad of CELITE®, and the filtrate was concentrated in vacuo. Water (50 mL) was added to the residue and basified to pH ˜11 with saturated aqueous NaHCO3; this was extracted with CH2Cl2 (4×75 mL). The organic layers were combined and washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give crude product. This was triturated with Et2O to give the first crop of desired product (3.7495 g) as a tan solid. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography using an ISCO 120 g column eluting with 20-50% EtOAc/hexanes to give the second crop of the desired product (1.9458 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2].IC.[CH3:25]C([O-])(C)C.[K+]>C1COCC1>[C:1]([C:3]1[C:4]([C:19]([F:22])([F:21])[F:20])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH3:25])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:18])=[CH:6]2)#[N:2]
Reactant: COC(=O)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]propanoate (0.065 g, 0.209 mmol) in THF (1 mL) was added iodomethane (0.59 g, 4.18 mmol), followed by dropwise addition of t-BuOK (1M in THF, 0.63 mL, 6.3 mmol). After 10 min, the mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 325 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]([F:13])([F:12])[CH2:10][OH:11].C(N(CC)CC)C>O1CCCC1>[C:1]([O:11][CH2:10][C:9]([Br:8])([F:13])[F:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OCC(F)(F)Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCC(F)(F)Br

Procedure:
Pivalic acid chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl pivalate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(pivaloyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([O:7][CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:13][CH:14]=1)[O:7][CH2:8][CH2:9][C:10]2=[O:12]
Reactant: COc1ccc(OCCC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)C(=O)CCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclisation is carried out on the acid chloride generated starting from the acid. Heating the acid obtained in Step B (500 mg:2.55 mmol) at reflux of toluene (20 ml) for 3 hours in the presence of thionyl chloride (0.56 ml:7.65 mmol:3 eq.) allows easy access to the acid is chloride. The solvent and also the excess reagent are removed by concentrating the resulting yellow solution under reduced pressure. The dry residue is then taken up in 20 ml of anhydrous dichloromethane; aluminium chloride (465.9 mg:3.49 mmol:1.5 eq.) is then introduced cautiously. The reaction mixture is hydrolysed in the cold state after 1 hour of stirring at ambient temperature. The product is extracted, washed with water and then purified on a silica column (AcOEt/PE 3/7).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[C:31]3=[N:32][CH:33]=[CH:34][C:35](B4OC(C)(C)C(C)(C)O4)=[C:30]3[CH:29]=[CH:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:7][C:5]1[O:6][C:2]([C:35]2[CH:34]=[CH:33][N:32]=[C:31]3[N:27]([S:24]([C:21]4[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=4)(=[O:25])=[O:26])[CH:28]=[CH:29][C:30]=23)=[C:3]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: Cc1nc(-c2ccc([N+](=O)[O-])cc2)c(Br)o1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc32)cc1

Procedure:
Following the procedure described for Intermediate 6 with 5-bromo-2-methyl-4-(4-nitrophenyl)-1,3-oxazole and [(4-methylphenyl)sulfonyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine provided the title compound. ESMS [M+H]+: 476.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([NH:21][OH:22])([CH3:20])([CH3:19])[CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:21]([C:17]([CH3:20])([CH3:19])[CH3:18])[O-:22])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)[N+]([O-])=Cc1ccc(OCc2ccccc2)cc1
Yield: 89.3 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde, N-tert-butylhydroxylamine and catalytic amount of p-toluenesulfonic acid monohydrate in benzene was refluxed under argon atmosphere with a Dean-Stark trap to remove generated water. The mixture was then rotary evaporated to give a residue which was purified by recrystallization. The title compound was obtained in 89.3% yield as a white powder, m.p. 111.0° C. (Rf=0.66 on a silica gel plate using EtOAc as an eluant).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[OH:60])=[O:9]
Reactant: N[C@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:23])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:39](O)[CH2:40][C@H:41]([OH:43])[CH3:42]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH:24]([CH3:26])[CH3:25])[N:11](/[CH:20]=[CH:21]/[C@@H:22]3[O:43][C@H:41]([CH3:42])[CH2:40][CH2:39][O:23]3)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/C=O
Reactant: C[C@@H](O)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@H]1OCC[C@@H](C)O1
Yield: 73.5 %

Procedure:
A mixture of (E)-3-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-2-propenal (2.01 g), p-toluenesulphonic acid monohydrate (0.316 g) and (R)-(-)-butane-1,3-diol (98%, 1.37 g) in toluene (130 ml) was heated under reflux with a Dean-Stark trap for 20 h. The mixture was concentrated to ca. 30 ml and purified by FCC eluting with System A (1:4) to give the title product (1.78 g,) as a white solid. δ(CDCl3) 1.23 (d, J 6 Hz, 3H, CH3CH--O), 1.42 (d, J 7 Hz, 6H, (CH3)2CH), 1.55-1.8 (m, 2H, OCH(CH3)CH2CH2O), 3.20 (septet, J 7 Hz, 1H, (CH3)2CH), 3.7-3.9 (m, 2H, CH2O), 4.05-4.16 (m, 1H, O--CH(CH3)), 4.95 (d, J 5 Hz, 1H, CH=CHCH(O)2), 5.32 (dd, J 15 and 5 Hz, 1H, NCH=CH), 6.76 (dd, J 15 and 1 Hz, 1H, NCH=CH), 6.89 (t, J 9 Hz, 2H, C-3 and C-5 protons of 4-(4-fluorophenyl)), 7.11 (t, J 9 Hz, 2H, C-3 and C-5 protons of 5-(4-fluorophenyl)), 7.39 and 7.27 (2 dd, J 9 and 6 Hz, 4H, C-2 and C-6 protons of both 4-fluorophenyls).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28]>ClCCl>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 66 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of dichloromethane was cooled to −30° C. To it was added Et3N followed by the addition of isobutyl chloroformate dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-isobutyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (90 mg, 66% yield). LC/MS: m/z 363.3 (M+H)+ at 2.74 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])=[O:9].C1(C)C=CC=CC=1.[CH2:29]([O:31][SiH:32]([O:36][CH2:37][CH3:38])[O:33][CH2:34][CH3:35])[CH3:30]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][Si:32]([O:36][CH2:37][CH3:38])([O:33][CH2:34][CH3:35])[O:31][CH2:29][CH3:30])=[O:9]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=CCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CCO[Si](CCCCCCOC(=O)C=Cc1ccc(OC)c(OC)c1)(OCC)OCC
Temperature: 25 °C

Procedure:
A mixture of 0.50 g of hex-5-enyl 3,4-dimethoxycinnamate, 1.0 ml of toluene, 2.9 ml of triethoxysilane and 0.02 ml of a solution of 134 mg of hexachloro(IV) platinic acid hexahydrate in 10 ml of isopropanol is allowed to react overnight at 40° C. The reaction mixture is then cooled to room temperature and filtered over a silica gel pad and the filtrate is completely evaporated down. Chromatography of the residue over silica gel gives 6-triethoxysilanylhexyl 3,4-dimethoxycinnamate.