Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.[Br:31]N1C(=O)CCC1=O>O.C(=O)(O)[O-].[Na+]>[Br:31][C:13]1[S:12][C:11]([C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccc(Cl)cc1)c1ccsc1-c1ncn(C2CCCCO2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C

Procedure:
To a mixture of (4-chlorophenyl){2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanone (20.2 g, 54.0 mmol) in N,N-dimethylformamide (350 mL, 4500 mmol) was added dropwise a solution of N-bromosuccinimide (14.42 g, 81.05 mmol) in N,N-dimethylformamide (50 mL, 600 mmol) under argon. The mixture was stirred at rt with care taken to block the reaction from exposure to ambient light. After 3 h reaction, LCMS showed both starting material and product. Additional N-bromosuccinimide (6.732 g, 37.82 mmol) was added and the mixture was stirred at rt again. After stirring overnight, the mixture was diluted with water and sodium bicarbonate solution and then the mixture was extracted with EtOAc. The organic layer was washed with water and brine. The EtOAc layer was dried and evaporated in vacuum to a residue, which was purified by chromatography to afford (5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanone as a white solid (18.0, 73.5%). LCMS: (FA) ES+ 451.9, 453.9
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([C:27]([O:29]C)=[O:28])[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:31])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:19]3[N:20]4[CH:26]=[C:25]([C:27]([OH:29])=[O:28])[CH:24]=[CH:23][C:21]4=[N:22][C:18]=3[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:31])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Agent: Cl
Product: O=C(O)c1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A suspension of compound 11 (1.0 equiv., 0.060 mmol, 0.025 g) in a concentrated aqueous HCl solution (1 ml) was stirred at 60° C. overnight. The solvent was concentrated under reduced pressure to give the hydrochloride salt of 5,6-dihydro-6-(4-nitrophenyl)-5-oxo-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-9-carboxylic acid (71), which was further dried under high vacuum (0.024 g, yield=91%, purity (LC)=98%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[C:15]([C:16](OC)=[O:17])=[CH:14][N:13]=1.[BH4-].[Na+]>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:13]=[CH:14][C:15]([CH2:16][OH:17])=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=1
Reactant: COCCCc1ccccc1-c1cc(C(F)(F)F)c(C(=O)OC)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCc1ccccc1-c1cc(C(F)(F)F)c(CO)cn1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
To a solution of methyl 6-[2-(3-methoxypropyl)phenyl]-4-(trifluoromethyl)nicotinate (1 eq.) from step 1, in MeOH (0.14M) was added portion wise sodium borohydride (9.3 eq.). The mixture was stirred at 65° C. for 12 h, cooled to room temperature, poured in water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel, eluting with Hex/EtOAc 20% afforded the desired compound as an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:5][CH:4]=1.[C:32](O)(=[O:36])[CH:33]([CH3:35])[CH3:34]>CN(C=O)C>[F:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:21]3[CH:22]=[N:23][N:24]([CH:26]4[CH2:31][CH2:30][N:29]([C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:28][CH2:27]4)[CH:25]=3)=[CH:8][N:9]2[S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(C3CCNCC3)c2)c2ccc(F)cc21
Reactant: CC(C)C(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)C(=O)N1CCC(n2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Yield: 94.9 %

Procedure:
Following the general method as outlined in Example 83, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 17; 271 mg; 0.59 mmol) and isobutyric acid (104 mg; 1.18 mmol) in DMF (15 mL), 277 mg (90%) of the title compound was obtained as a yellow oil after purification by a silica gel chromatography (DCM/MeOH=20/1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:13][N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](=[O:18])[C@@H:10]([NH:19]C(=O)OC(C)(C)C)[CH2:9]1>C(OCC)(=O)C>[NH2:19][C@H:10]1[CH2:9][C@@H:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:13][N:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:11]1=[O:18]
Reactant: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](NC(=O)OC(C)(C)C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](N)C1=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl [(3S,5S)-5-(2-fluorophenyl)-1-(2-methylpropyl)-2-oxopiperidin-3-yl]carbamate (150 mg, 0.41 mmol) in ethyl acetate (20 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=265.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:11][CH2:12][CH2:13][CH2:14][OH:15])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[C:16](=S)=[S:17].Cl>C(O)C>[F:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]2[N:11]([CH2:12][CH2:13][CH2:14][OH:15])[C:16](=[S:17])[NH:1][CH2:2]2)=[CH:9][CH:8]=1
Reactant: NCC(NCCCO)c1ccc(F)cc1
Reactant: S=C=S
Agent: Cl
Solvent: CCO
Product: OCCCN1C(=S)NCC1c1ccc(F)cc1

Procedure:
Dissolve 5.3 g of the product of Step B in 50 ml of 80% aqueous ethanol, then add 2.02 g of carbon disulfide and reflux the mixture for one (1) hour. Cool the solution then treat with 0.2 ml of concentrated hydrochloric acid and reflux the mixture for sixteen (16) hours. Concentrate the reaction mixture in vacuo, extract with methylene chloride and dry the extract. Concentrate the extract to a residue and triturate with isopropyl ether to obtain the product of this step. Yield 5.2 g M.P. 104°-106° C. Recrystallize the product from ethanol petroleum ether to obtain the product as a colorless solid. M.P. 105°-106°.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CS([Cl:17])(=O)=O>C(Cl)Cl>[Cl:17][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CO)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCl)cc1
Temperature: 25 °C

Procedure:
To a solution of 100 g (0.60175 moles) of methyl 4-hydroxymethylbenzoate in 600 mL of dry CH2Cl2. add 109 mL (79.1 g) of TEA and cool the so-formed reaction mixture to 0° C. Add, dropwise over a 2 hour period, 55.8 mL (0.722 mole, 1.2 eq) of methanesulfonyl chloride in 150 mL of dry CH2Cl2. Allow the so-formed stirred reaction mixture to warm slowly to room temperature over a 48 hr period. TLC shows no starting material remains. Add water, separate the layers and wash the organic layer successively with water, saturated NaHCO3 and brine. Dry the organic layer over Na2SO4. Remove the organic solvent under reduced pressure to produce 98.45 g of (88.6 % of theory) of the title compound as a crystalline solid. ##STR120##
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]1.[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[OH:34]>>[Cl:27][C:28]1[CH:29]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][CH:16]2[CH2:21][CH2:20][CH:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:18][CH2:17]2)[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: CCN(CC)C1CCC(Nc2c(C(C)=O)cnc3ccc(-c4ccc(O)c(Cl)c4)cc23)CC1
Yield: 58.7 %

Procedure:
Following general procedure D, 1-{6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}ethanone (30 mg, 0.072 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (34 mg, 0.200 mmol) to afford the desired product (19.7 mg, 59%) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD) δ 8.95 (s, 1H), 8.34 (d, J=1.8 Hz, 1H), 8.02 (dd, J=8.7, 1.9 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.71 (d, J=2.3 Hz, 1H), 7.53 (dd, J=8.4, 2.3 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 4.31 (s, 1H), 3.52-3.43 (m, 1H), 3.22 (q, J=7.2 Hz, 4H), 2.70 (s, 3H), 2.46 (d, J=12.3 Hz, 2H), 2.20 (d, J=11.9 Hz, 2H), 1.88-1.65 (m, 4H), 1.41-1.30 (m, 6H); ESI MS m/z 466 [C27H32ClN3O2+H]+; HPLC 97.7% (AUC), tR=10.44 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]([OH:23])[CH3:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25].Cl>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]([O:23][C:24](=[O:26])[CH3:25])[CH3:22])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CC(O)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)c1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
6.09 g (20 mmol) of (+)-4-benzyloxy-4'-(1-hydroxyethyl)biphenyl was dissolved in 100 ml of dry pyridine, followed by dropwise addition of 1.73 g (22 mmol) of acetyl chloride. The mixture was stirred at room temperature for one hour, then poured into 1 liter of 2N hydrochloric acid and extracted with 300 ml of toluene. The toluene layer was washed with water, then with a 7% sodium bicarbonate solution and again with water successively in that order and then dried over anhydrous magnesium sulfate. This toluene solution was distilled under reduced pressure to remove the solvent and the residual white solid was purified by column chromatography packed with 200 g of silica gel to obtain 6.86 g of (+)-4-benzyloxy-4'-(1-acetoxyethyl)biphenyl in a 99% yield. It was further purified by recrystallization from ethanol. [α]D25 =+56.3° (c=1, CHCl3); melting point: 137° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([Br:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[Br:18][C:16]1[CH:17]=[C:12]([C:10]([C:9]2[C:8]3[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=3[O:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])[CH:13]=[C:14]([Br:20])[C:15]=1[O:19][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(OCC(=O)O)c(Br)c1

Procedure:
This compound was prepared from (2-butyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2, and was obtained as an off-white solid, mp 92-94° C.; MS m/e 508 (M+); Analysis for: C21H18Br2O5 Calc'd: C, 49.44; H, 3.56 Found: C, 47.24; H, 3.59
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1.C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([CH:54]6[CH2:55][CH2:56][O:51][CH2:52][CH2:53]6)[CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC2CCN(C3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 24.7 %

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide (Intermediate 12) (35 mg, 0.07 mmol, 1 eq) and sodium triacetoxyborohydride (18 mg, 0.084 mmol, 1.2 eq) in DCM (0.5 mL) were reacted with tetrahydropyran-4-one (6.5 μL, 0.07 mmol, 1 eq) at rt for 2 days. Further and sodium triacetoxyborohydride (18 mg, 1.2 eq), tetrahydropyran-4-one (6.5 μL, 1 eq) were added and acetic acid (4 μL, 1 eq). After two days the RM was diluted with DCM, washed with water and the organic layer concentrated in vacuo. The resulting residue was purified by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-benzamide (10 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[C:13]1([C:4]([C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: c1ccccc1
Solvent: O
Product: O=C(c1ccccc1)c1c(F)cc(F)cc1F
Temperature: 25 °C

Procedure:
2,4,6-trifluorobenzoyl chloride (5.0 g), benzene (5 ml) and ferric chloride (1.39 g) were heated at 80° C. for 16 h, then allowed to cool to room temperature. The reaction mixture was diluted with water, extracted with ethyl acetate (×2) and the combined organic extracts washed with brine, dried (MgSO4) and evaporated under reduced pressure (5.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:22][CH:21]1[CH2:20][NH:19][CH2:18]2>>[CH:17]12[CH2:22][CH:21]1[CH2:20][N:19]([C:14]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16])[CH2:18]2
Reactant: C1NCC2CC12
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CC3CC3C2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 3-azabicyclo[3.1.0]hexane by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][N:10](C)C)=[C:4]([C:13]#[N:14])[CH:3]=1.N[C:16]1[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:17]=1[CH3:23].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:9][N:10]=[C:13]2[NH:14][C:18]1[CH:19]=[C:20]([OH:22])[CH:21]=[CH:16][C:17]=1[CH3:23]
Reactant: CN(C)C=Nc1ccc(Br)cc1C#N
Reactant: Cc1ccc(O)cc1N
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(O)cc1Nc1ncnc2ccc(Br)cc12
Yield: 101.4 %

Procedure:
6.0 g (23.9 mmol) of N′-(4-bromo-2-cyanophenyl)-N,N-dimethylformamidine and 3.24 g (26.3 mmol) of 2-amino-4-hydroxytoluene are suspended in 40 ml of acetic acid and heated under reflux for 1 h. The resulting mixture is cooled and then added to 100 ml of water and extracted with ethyl acetate. The combined organic phases are washed with water and sat. aqueous sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated. 8.0 g (100%) of the desired product are obtained.
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][C@H:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=1>>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][C@H:23]([N:28]2[CH2:29][CH2:30][N:31]([S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])[CH2:32][CH2:33]2)[C:24]([O:26][CH3:27])=[O:25])=[O:20])=[CH:17][CH:16]=1
Reactant: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCNCC2)cc1
Reactant: CC(C)S(=O)(=O)Cl
Product: COCCOCOc1ccc(C(=O)NC[C@@H](C(=O)OC)N2CCN(S(=O)(=O)C(C)C)CC2)cc1
Yield: 66.5 %

Procedure:
In a manner similar to example 2-1, starting from 0.2 ml (1.9 mmol) of 2-propanesulphonyl chloride and from 0.7 g (1.8 mmol) of methyl (S)-3-[4-(2-methoxy-ethoxymethoxy)benzoylamino]-2-piperazin-1-ylpropanoate, 0.6 g (68%) of methyl (S)-3-[4-(2-methoxyethoxy-methoxy)benzoylamino]-2-[4-(propane-2-sulphonyl)-piperazin-1-yl]propanoate is obtained in the form of a colourless oil.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[NH:20][N:21]=[CH:22][C:14]=12.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1>C1COCC1.C(Cl)Cl>[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[N:16]=[C:15]2[N:20]([CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][O:23]3)[N:21]=[CH:22][C:14]=12
Reactant: C1=COCCC1
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
p-Toluene sulfonic acid (p-TsOH, 30.2 mg, 0.159 mmol) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 1.587 mmol) and 3,4-dihydro-2H-pyran (200 mg, 2.381 mmol) in a mixture of THF:CH2Cl2 (1:1, 10 mL). The reaction mixture was stirred for 12 h at room temperature after which the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (20 mL) and poured in water (20 mL). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (20 mL). The combined organic phases were washed with water (40 mL), then washed with brine (40 mL), dried over Na2SO4 and concentrated. The resulting crude material was purified by flash chromatography (CH2Cl2/CH3OH, 99/1 increasing) to yield the title compound (397 mg, 1.454 mmol, 92% yield) as a pale white oil which was used without further purification.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].S(Cl)([Cl:15])=O>>[Cl:15][CH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=1
Reactant: CS(=O)(=O)c1cccc(CO)c1
Reactant: O=S(Cl)Cl
Product: CS(=O)(=O)c1cccc(CCl)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of (3-methanesulfonyl)phenyl methanol (0.21 g, 1.1 mmol) in thionyl chloride (3 mL) was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure to provide 1-chloromethyl-3-methanesulfonylbenzene as a yellow oil (0.23 g, 95%): 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.70 (d, J=8 Hz, 1H), 7.59 (t, J=8 Hz, 1H), 4.65 (s, 2H), 3.08 (s, 3H).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][OH:9].[H-].[Na+].[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16]>CN(C)C=O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([O:9][CH2:8][CH:2]2[CH2:3][CH:4]3[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1c(F)cccc1F
Reactant: OCC1CC2CCC1C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC2CC3CCC2C3)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 2-norbornane methanol (1.3 g, 10.3 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (450 mg, 11.33 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warned to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.58 g, 11.33 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed-ice water, stirred. The reaction mixture was extracted with ethyl acetate, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) yielded 986 mg of 2-fluoro-5-(bicyclo[2.2.1]hept-2-ylmethoxy)benzonitrile.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13].[H][H]>CO.[Pd]>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)Nc1ccccc1C#CC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccccc1CCC(C)(C)C
Yield: 94.2 %

Procedure:
3.23 g (15 mmol) of N-[2-(3,3-dimethylbut-1-ynyl)phenyl]acetamide (XIII-1) were initially charged in 40 ml of methanol. 0.5 g of palladium-on-carbon (5%) was added, and the mixture is then hydrogenated in an autoclave at a hydrogen pressure of 4 bar for 20 h. Removal of the catalyst and the solvent gave 3.1 g (94% of theory) of N-[2-(3,3-dimethylbutyl)phenyl]acetamide of logP (pH 2.3)=2.69.
Reaction SMILES: [CH:1]1([CH:7]([CH2:18][C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=O)[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O.C[N:31](C)C=O>>[CH:1]1([C:7]2[CH:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:31]=[C:9]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CC(CC(=O)c1ccco1)C1CCCCC1)c1cccc(O)c1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1cccc(-c2cc(C3CCCCC3)cc(-c3ccco3)n2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-cyclohexyl-1-(3-hydroxyphenyl)-5-(furan-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.90 mmol), NH4OAc (1.7 g), and AcOH (1.7 mL) in dimethylformamide (30 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 3-(4-cyclohexyl-6-furan-2-yl-pyridin-2-yl)-phenol; 1H NMR (DMSO-d6) d 1.42 (m, 4H), 1.71 (m, 2H), 1.85 (m, 4H), 2.64 (m, 1H), 6.67 (dd, J=3.3, 1.5 Hz, 1 H), 6.85 (dd, J=8.1, 1.8 Hz, 1H); 7.18 (d, J=3.3 Hz, 1H), 7.29 (m, 1H), 7.57 (m, 3H), 7.63 (s, 1H), 7.85 (s, 1H), 9.54 (s, 1H); IR (KBr) 1607 cm−1; MS [M+H]+ m/z 320. Anal. calcd for C21H21NO2.0.6 C4H8O2: C, 75.52; H, 6.94; N, 3.77; Found: C, 75.72; H, 6.72; N, 3.55.