Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:30])[C:3]([N:5]1[C@@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:30][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([S:24]([CH3:27])(=[NH:26])=[O:25])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(S(C)(=N)=O)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=N)(=O)c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.7 %

Procedure:
To a stirred solution of 2,2-difluoro-1-((4R,5R)-4-(fluoromethyl)-2,2-dimethyl-5-(4-(6-(methylsulfonimidoyl)pyridin-3-yl)phenyl)oxazolidin-3-yl)ethanone (250 mg, 0.567 mmol) in DCM (8 mL) is added TFA (1 mL) at 0° C. The reaction mixture is allowed to stir at room temperature for 4 h. Volatiles are removed under reduced pressure and crude is diluted using aqueous sodium bicarbonate and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, concentrated and purified by silica gel column chromatography (100-200 mesh size) using 8% methanol in DCM as an eluent to afford the title compound (170 mg) as a brown solid. 1NMR (400 MHz, DMSO) δ: 3.19 (d, 3H, J=0.76 Hz), 4.32-4.37 (m, 1.5H), 4.42-4.46 (m, 0.5H), 4.48 (bs, 1H), 4.53-4.56 (m, 0.5H), 4.66-4.69 (m, 0.5H), 4.91 (t, 1H), 5.97 (d, 1H, J=4.48 Hz), 6.20 (t, 1H, J=53.72 Hz), 7.51 (d, 2H, J=8.24 Hz), 7.79 (d, 2H, J=8.28 Hz), 8.12 (d, 1H, J=8.24 Hz), 8.36-8.39 (dd, 1H, J1=2.32 Hz, J2=8.24 Hz), 8.87 (d, 1H, J=8.64 Hz), 9.03 (d, 1H, J=1.76 Hz). LC-MS (m/z): M+H=402.1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:35])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[C:28]2[CH3:31])[CH:24]([CH3:32])[CH2:23][C:22]([CH3:34])([CH3:33])[N:21]3[CH:20]=1)=O>>[CH3:34][C:22]1([CH3:33])[CH2:23][CH:24]([CH3:32])[C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:35])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]13)[C:28]([CH3:31])=[CH:27][CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(ccc(C)c13)C(C)CC2(C)C
Product: Cc1ccc2c3c1c(C1=C(c4c[nH]c5ccccc45)C(=O)NC1=O)cn3C(C)(C)CC2C

Procedure:
Beginning with (indol-3-yl)acetamide and (4,4,6,9-tetramethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:73][C@H:74]([NH2:81])[C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1>C(#N)C.C(Cl)Cl>[C:1]([NH:8][C@H:9]([C:24]([NH:81][C@@H:74]([C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH3:73])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 8 h

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.0 g; 13 mmol), BOP reagent (6.0 g; 13 mmol), HOBT (1.8 g; 13 mmol) and DiPEA (7.1 mL; 40 mmol) 100 mL of acetonitrile:CH2Cl2 (1:1), followed by (S)-α-methylbenzylamine (1.8 mL; 13 mmol), then stirred overnight. After work up, the crude product was purified by passing it through a plug of silica gel with EtOAc to give 5.9 g (92%) of the sub-title as a light yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[C:9](S(C)(=O)=O)[N:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]1=[O:16].[CH:17]([NH2:20])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:9]1[N:10]=[CH:11][C:6]2[CH:5]=[CH:4][C:3](=[O:16])[N:2]([CH3:1])[C:7]=2[N:8]=1)([CH3:19])[CH3:18]
Reactant: Cn1c(=O)ccc2cnc(S(C)(=O)=O)nc21
Reactant: CC(C)N
Product: CC(C)Nc1ncc2ccc(=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
A mixture of 8-methyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (194 mg, 0.81 mmol) and 2 mL of isopropylamine was stirred at room temperature for 15 minutes. Excess amine was removed in vacuo, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate, followed by brine, dried over magnesium sulfate, and concentrated to give 168 mg (95%) of 2-isopropylamino-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 148-149° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[CH:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].C(S([C:28]1[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])=[CH:30][N:29]=1)(=O)=O)C.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH2:37][CH3:38])(=[O:35])=[O:36])=[CH:30][N:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:16])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: COC(=O)c1cc(O)c2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(=O)OC)cc3ccc(Br)cc23)nc1
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 6-bromo-4-hydroxy-naphthalene-2-carboxylic acid methyl ester (423 mg, 1.5 mmol), potassium carbonate (414 mg, 3 mmol), 2,5-bis-ethanesulfonyl-pyridine (420 mg, 1.6 mmol) and N,N-dimethylformamide (4 mL) was vigorously stirred and heated at 100° C. overnight under an argon atmosphere, then cooled to room temperature, and diluted with ethyl acetate (10 mL). The resulting mixture was washed with water (10 mL×3). The combined aqueous layers were extracted with ethyl acetate (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to give 6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalene-2-carboxylic acid methyl ester (280 mg, 41%, crude yield) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([NH:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]C(CC)C.[Cl:29]C(Cl)(Cl)C(Cl)(Cl)Cl.Cl>C1COCC1.C1CCCCC1.C(Cl)Cl.O>[Cl:29][C:12]1[CH:13]=[CH:14][CH:15]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]=1[C:7]([NH:9][CH2:10][CH3:11])=[O:8]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CCNC(=O)c1ccccc1C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)CC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)c1c(Cl)cccc1C(C)(C)C
Temperature: -30 °C
Reaction time: 0.83 h

Procedure:
To a solution of 2-tert-butyl-N-ethylbenzamide (44 g, 215 mmol) and TMEDA (70 mL, 446 mmol) in 500 mL THF at -70° C. under a positive nitrogen atmosphere was added at a rapid stream 520 mL 1.3M s-BuLi in cyclohexane, maintaining the temperature at below -60° C. After the addition was complete, the resulting reaction solution was warmed to -30° C. and stirred at between -30° C. and -26° C. for 50 min. The solution was then cooled to below -70° C. and a solution of hexachloroethane (80 g) in 250 mL THF was added at between -70 and -65° C. Stirring at below -70° C. was continued for 0.5 h. The resulting reaction solution was then poured into water. CH2Cl2 and 3N HCl were added. The aq layer was separated and extracted with CH2Cl2. The combined organic layers were washed with water, dried and concentrated in vacuo. The solid was triturated with hexane and then purified by flash chromatography with 15% ethyl acetate/hexane as eluent to give the desired product as a white solid. m.p. 121-123° C.
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].ClCCl.FC(F)(F)S(O)(=O)=O>C1CCCCC1>[O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8]
Reactant: CC(=O)CCCCC(=O)O
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CC(=O)CCCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.0 g (about 90% pure, 62.4 mmol) of 6-oxoheptanoic acid were initially charged in 71.8 ml of cyclohexane, and 20.46 g (93.6 mmol) of tert-butyl 2,2,2-trichloroacetimidate and 15 ml of dichloromethane were added. At −10° C. 0.55 ml (6.24 mmol) of trifluoromethanesulfonic acid were slowly added dropwise to the solution. The resulting suspension was stirred overnight with warming to RT. The insoluble precipitate was then removed by filtration. The filtrate was washed twice with sodium bicarbonate solution and with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). On standing overnight, a solid precipitated from the product obtained in this manner. This solid was removed by filtration with suction and discarded. The target product, obtained in the form of the filtrate, was not purified any further. This gave 4.51 g (36.1% of theory) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:18]=2[NH:17][CH2:16][CH2:15]3)=[O:9])=[CH:4][CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:28]=[N:29][C:30]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=[CH:22][N:21]=1.C(OCC)(=O)C.O>CS(C)=O>[NH:17]1[C:18]2[C:14](=[CH:13][CH:12]=[CH:11][C:10]=2[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[N:29][C:30]5[C:35]([CH:36]=4)=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:23]=[CH:22][N:21]=3)=[CH:7][CH:6]=2)=[O:9])[CH2:15][CH2:16]1
Reactant: Nc1ccc(C(=O)c2cccc3c2NCC3)cc1
Reactant: Clc1nccc(Nc2cnc3ccccc3c2)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(c1ccc(Nc2nccc(Nc3cnc4ccccc4c3)n2)cc1)c1cccc2c1NCC2

Procedure:
200 mg (0.84 mmol) of (4-aminophenyl)-(2,3-dihydro-1H-indol-7-yl)methanone and 215 mg (0.84 mmol) of (2-chloropyrimidin-4-yl)quinolin-3-ylamine are warmed at 120° C. for 2 h in 2 ml of DMSO. The organic phase is stirred with ethyl acetate and water and purified by chromatography over silica gel after phase separation, drying and evaporation, giving 500 mg of (2,3-di-hydro-1H-indol-7-yl)-{4-[4-(quinolin-3ylaminopyrimidin-2-ylamino]phenyl}-methanone. (M.p.: 235-238° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.C(OC([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:34]3[CH:35]=[N:31][NH:32][CH:33]=3)=[CH:17][C:9]1=2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(-c3cn[nH]c3)cc21
Yield: 44 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydro-pyrido[2,3-b]pyrazine (109 mg) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylic acid-tert-butyl ester as in General Procedure 4B, then added 6 mL CH2Cl2 and TFA (0.6 mL), and purified on normal phase silica gel chromatography to give the title compound as an off-white solid (44% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].[Br:17][C:18]1[C:19]([F:28])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[S:21][C:22]=1Br>>[Br:17][C:18]1[C:19]([F:28])=[C:20]([C:24]([O:26][CH3:27])=[O:25])[S:21][C:22]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=1
Reactant: COC(=O)c1sc(Br)c(Br)c1F
Reactant: CC(C)COc1ccc(B(O)O)cc1C#N
Product: COC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)c(Br)c1F

Procedure:
Using (3-cyano-4-isobutoxyphenyl)boronic acid and methyl 4,5-dibromo-3-fluorothiophene-2-carboxylate, methyl 4-bromo-5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate was obtained in accordance with the method of Preparation Example 1(1). To an ethanol (60 ml) suspension of 1.75 g of the compound was added 1.00 g of 10% palladium-carbon, followed by stirring at room temperature for 4 hours under a hydrogen atmosphere at normal pressure. After insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 5:1) to obtain 0.39 g of methyl 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate. (2) The compound was dissolved in 15 ml of THF, and 2.5 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 60° C. for 5 hours. After cooling to room temperature, 2.5 ml of 1M hydrochloric acid and water were added thereto, followed by extraction with ethyl acetate. The resulting organic layer was dried and concentrated under reduced pressure. The resulting solid was recrystallized from ethyl acetate and hexane to obtain 252 mg of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid. (3) Then, 215 mg of sodium hydroxide was added to an ethanol (60 ml) solution of 1.81 g of 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylic acid, followed by stirring at 80° C. overnight. After the reaction solution was cooled to room temperature, the precipitate was collected by filtration to obtain 1.60 g of sodium 5-(3-cyano-4-isobutoxyphenyl)-3-fluorothiophene-2-carboxylate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[C:11](B(O)O)=[CH:12][S:13][CH:14]=1)=[O:9].ClC1C=CC(CC2SC(C=O)=CC=2)=CC=1>>[C:2]1([C:11]2[C:10]([CH:8]=[O:9])=[CH:14][S:13][CH:12]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cscc1B(O)O
Reactant: Ic1ccccc1
Agent: O=Cc1ccc(Cc2ccc(Cl)cc2)s1
Product: O=Cc1cscc1-c1ccccc1
Yield: 48 %

Procedure:
The title compound was synthesized from iodobenzene and 4-formylthiophen-3-ylboronic acid using the conditions to synthesize 5-(4-chlorobenzyl)thiophene-2-carbaldehyde. Double elution by prep-TLC (10% heptane/DCM) allowed for the isolation of 4-phenylthiophene-3-carbaldehyde (300 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (d, J=3.29 Hz, 1H), 7.39-7.50 (m, 5H), 8.27 (d, J=3.29 Hz, 1H), 9.87 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 185.80, 143.82, 138.91, 134.68, 134.28, 129.30, 128.58, 128.05, 124.76.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([B-](F)(F)F)[S:12][C:13]=2[C:14]2[N:18]=[CH:17][N:16](C3CCCCO3)[N:15]=2)=[CH:4][CH:3]=1.[K+].Br[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OCCC)=CC=CC=2OCCC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.O1CCOCC1.C(O)(C)(C)C.Cl>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:29])[C:9]2[CH:10]=[C:11]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=3)[S:12][C:13]=2[C:14]2[NH:18][CH:17]=[N:16][N:15]=2)=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc([B-](F)(F)F)sc1-c1ncn(C2CCCCO2)n1
Reactant: N#Cc1cc(Br)ccn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCOc1cccc(OCCC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CCO
Product: N#Cc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 85 °C
Yield: 11.4 %

Procedure:
A mixture of potassium (4-((4-chlorophenyl)(hydroxy)methyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-2-yl)trifluoroborate (0.133 g, 0.276 mmol), 4-bromo-pyridine-2-carbonitrile (60.6 mg, 0.331 mmol), 2-dicyclohexylphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (24.8 mg, 0.0533 mmol), palladium acetate (4.6 mg, 0.020 mmol) and sodium carbonate (77 mg, 0.73 mmol) in ethanol (6.2 mL, 110 mmol) was degassed with argon and then heated at 85° C. for 13 h. The mixture was absorbed on silica gel and purified by chromatography to afford an intermediate. LCMS: (AA) ES+ 478.1, 480.0. This intermediate in 1,4-dioxane (2.0 mL, 26 mmol), tert-butyl alcohol (2.0 mL, 21 mmol) and 4.00 M HCl in dioxane (3.0 mL, 14 mmol) was heated at 60° C. for 1 h. The mixture was evaporated to dryness and then purified by HPLC to afford 4-(4-((4-chlorophenyl)(hydroxy)methyl)-5-(4H-1,2,4-triazol-3-yl)thiophen-2-yl)picolinonitrile (12.4 mg, 11.4%). LCMS: (FA) ES+ 394.3, 396.1. 1H NMR (400 MHz, d6-DMSO) δ: 14.69-13.48 (br, 1H), 8.69 (d, J=6.79 Hz, 2H), 8.45 (s, 1H), 8.08-7.88 (m, 2H), 7.56 (d, J=8.39 Hz, 2H), 7.35 (d, J=8.40 Hz, 2H), 6.79 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:12]1([CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCC2CCCCC2)cc1
Temperature: 100 °C
Yield: 82.5 %

Procedure:
A solution of 4-hydroxybenzaldehyde (0.244 g, 2.00 mmol) in CH3CN (4.0 mL) was treated with bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol). The reaction mixture was heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Additional bromomethylcyclohexane (0.279 g, 2.00 mmol) and K2CO3 (0.332 g, 2.40 mmol) were added and the reaction mixture was again heated to 100° C. for 1 h in a Biotage Initiator microwave synthesizer. Following cooling, the reaction mixture was filtered and concentrated in vacuo. Purification via flash column chromatography (10% EtOAc/hexanes) gave the title compound as a white solid (0.360 g; 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1H) 7.85 (d, J=8.8 Hz, 2H) 7.11 (d, J=8.8 Hz, 2H) 3.89 (d, J=6.3 Hz, 2H) 1.80 (d, J=12.6 Hz, 2H) 1.61-1.79 (m, 4H) 1.13-1.32 (m, 3H) 1.07 (dd, J=12.6, 2.6 Hz, 1H) 1.01 (dd, J=11.9, 2.5 Hz, 1H). MS (ES+) m/e 219 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CN(C)C=O>[CH2:21]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[CH:11]=[O:12])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: O=Cc1c(O)ccc2c1OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1C=O)OCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-hydroxy-1,3-benzodioxole-4-carbaldehyde (0.166 g, 1.00 mmol) and K2CO3 (1.00 mmol) in dry N,N-dimethylformamide (2 ml) was added allylbromide (1.00 mmol) under argon. The mixture was stirred at room temperature for 18 h until the starting material was consumed (monitored by TLC). Then the mixture was poured onto ice-water (15 ml). The aqueous phase was filtered off, the precipitated product was washed with water and n-heptane and dried to give analytically pure crystals.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:3]1.[CH2:20]=O.[BH4-].[Na+]>C(O)C.C(#N)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:8][CH:6]1[N:7]([CH3:20])[CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CCOC(=O)c1ccc(N2CC(C)NC(C)C2)cc1
Reactant: C=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CC(C)N(C)C(C)C2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 112.2 %

Procedure:
Titanium(IV) isopropoxide (0.598 mL, 2.00 mmol) was added to ethyl 4-(3,5-dimethylpiperazin-1-yl)benzoate (0.262 g, 1 mmol), and paraformaldehyde (0.120 g, 4.00 mmol) in ethanol (5 mL). The resulting solution was stirred at 60° C. under nitrogen for 30 mins. This was cooled to 20° C. and sodium borohydride (0.095 g, 2.5 mmol) was added in one portion. The solution was heated at 60° C. for 24 h. The reaction mixture was quenched with 0.880 ammonia (0.5 mL), filtered, washed with diethyl ether (2×5 mL) and the organic extracts were evaporated. The crude product was purified by silica column chromatography, eluting with a gradient of 0-5% MeOH in DCM containing 0.1% ammonia. Fractions were evaporated to dryness to afford an oil. This was dissolved in acetonitrile (20 ml), polymer supported isocyante resin (1 mmol/g, 2 g) was added and the suspension was stirred overnight. The resin was filtered off and the solution evaporated to dryness to give ethyl 4-(3,4,5-trimethylpiperazin-1-yl)benzoate (0.310 g, 112%) as a white solid. MS: m/z 278 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27].N1C=CC=CC=1>C(O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=[N:26][OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
A mixture of 2,4-dibenzyloxybenzaldehyde (2 g), hydroxylamine hydrochloride (0.45 g) and pyridine (0.53 mL) in ethanol (20 mL) is heated at reflux for 1 hour. The solvent is then removed in vacuo, the residue dissolved in ethyl acetate and the solution washed with 1 N hydrochloric acid then with brine. Removal of the solvent in vacuo gives a beige coloured solid which crystallises from a mixture of ether and petroleum ether to give 2,4-dibenzyloxybenzaldehyde oxime in the form of a white solid, m.p., 130° C. [Elemental analysis:- C,76.1; H,5.75; N,4.28%. Calculated:- C,75.7; H,5.74; N,4.20%].
Reaction SMILES: [C:1]([N:11]([C@@H:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1)[CH3:12])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C(O)C.Cl>[C:1]([N:11]([C@@H:13]([CH3:23])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[CH3:12])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: C[C@@H](c1ccc([N+](=O)[O-])cc1)N(C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Product: C[C@@H](c1ccc(N)cc1)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
α-A solution of (S)-(-)-N-carbobenzyloxy-N-methyl-methyl-4-nitrobenzylamine (6.6 gm, 21 imol) in 100% ethanol (100 mL) was cooled in an ice bath while a solution of stannous chloride dihydrate (14.2 gm, 63 mmol) in conc. hydrochloric acid (25 mL) was added. The reaction was allowed to warm to rt over 14 hrs and was then quenched into a solution of ice, 5N sodium hydroxide (100 mL) and ether and the pH adjusted to 9-10. The layers were separated and the ether layer was washed with brine. The aqueous layers were consecutively extracted with a second portion of ether and the pooled ether layers were dried over sodium sulfate and evaporated. The residue was partially purified by flash chromatography using 20-30% ethyl acetate/hexanes, then 5% methanol/30% ethyl acetate/65% hexanes to give 6.0 gm of impure title compound containing variable amounts of benzyloxycarbonylmethylamine.