Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CSc1nc(N)nc(-c2ccc(F)cc2)c1C#N
Temperature: 25 °C
Yield: 54 %

Procedure:
To a stirred suspension of 0.50 g (2,49 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 10 ml toluene under argon at room temperature were added 384 mg (2.74 mmol)p-fluorobenzeneboronic acid, 288 mg (0.25 mmol) tetrakis(triphenyl-phosphine)palladium(O) and 638 mg (4.98 mmol) anhydrous potassium carbonate. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Chromatography (1/1 ethyl acetate/hexane) followed trituration in ether/hexane afforded 350 mg (54%) 2-amino-4-(4-fluoro-phenyl)-6-methylsulfanyl-pyrimidine-5-carbonitrile as a yellow crystalline solid. EI-MS m/e (%): 260 (M+, 37), 259 ([M—H]+, 100).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([C:19]([CH3:21])=[CH2:20])[CH2:13][CH2:12]2)C1C=CC=CC=1.C(OC1C=C2C(=CC=1)CC(=C(C)C)CC2)C1C=CC=CC=1>CCO.[Pd]>[CH:19]([CH:14]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:16]=2[CH2:15]1)([CH3:21])[CH3:20]
Reactant: C=C(C)C1CCc2cc(OCc3ccccc3)ccc2C1
Agent: [Pd]
Agent: CC(C)=C1CCc2cc(OCc3ccccc3)ccc2C1
Solvent: CCO
Product: CC(C)C1CCc2cc(O)ccc2C1
Reaction time: 24 h

Procedure:
To the mixture of 6-benzyloxy-2-isopropenyl-1,2,3,4-tetrahydronaphthalene and 6-benzyloxy-2-isopropylidene-1,2,3,4-tetrahydronaphthalene (2.37 g, crude) in EtOH (30 mL) is added 10% Pd/C (550 mg) and it is hydrogenated at RT and at 1 atm for 24 h. The mixture is filtered through Celite, and the filtrate is concentrated and purified to give the title compound: 1H NMR (CDCl3) δ 0.95 (d, J=6 Hz, 6H), 1.31-1.41 (m, 1H), 1.42-1.46 (m, 1H), 1.56-1.62 (m, 1H), 1.87-1.92 (m, 1H), 2.39-2.45 (m, 1H), 2.69-2.77 (m, 3H), 4.43 (s, 2H), 6.55 (d, J=2.5 Hz, 1H), 6.58 (d, J=2.5, 8 Hz, 1H), 6.93 (d, J=8 Hz, 1H), 7.31-7.43 (m, 5H); (M−H)−=189.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1.[OH-].[K+].O>CO>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]([C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[OH:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccc(OCc2ccc(Cl)cc2)c(F)c1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (94, 100.0 mg, 0.85 mmol) in methanol (50.0 mL) were added 4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde (599, 250.0 mg, 0.94 mmol, prepared as described in Example 34) and potassium hydroxide (1.00 g, 17.82 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (P-1895, 55 mg, 17.0%). MS (ESI) [M+H+]+=383.3.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([I:15])=[CH:14][C:6]1=2.[H-].[Na+].I[CH3:24]>CN(C)C=O>[Cl:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:24])[C:7]2[N:11]=[CH:12][C:13]([I:15])=[CH:14][C:6]1=2
Reactant: Clc1ccc(Cl)c(CN2CCNc3ncc(I)cc32)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(Cl)ccc2Cl)c2cc(I)cnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 56 %

Procedure:
To a solution of 1-(2,5-dichlorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (305 mg) in anhydrous N,N-dimethylformamide was added NaH (1.6 eq) followed by iodomethane (1.4 eq). The reaction mixture was stirred at room temperature for 48 hours and then concentrated. Column chromatography gave the title compound as a yellow solid (56% yield). LCMS: m/z=434.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.09 (3H, s), 3.42 (2H, m), 3.48 (2H, m), 4.36 (2H, s), 6.54 (1H, d, J=1.8 Hz), 7.17 (1H, d, J=2.3 Hz), 7.21 (1H, dd, J=8.6, 2.5 Hz), 7.34 (1H, d, J=4.3 Hz), 7.72 (1H, d, J=1.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:37])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=4[O:25][CH3:26])[C:20]#[N:21])[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[CH:9]2[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH:7]=1.[N-:38]=[N+:39]=[N-:40].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:37])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[CH:13]=[C:12]([C:17]4[CH:18]=[C:19]([C:20]5[NH:40][N:39]=[N:38][N:21]=5)[CH:22]=[CH:23][C:24]=4[O:25][CH3:26])[N:11]([CH:27]([CH3:29])[CH3:28])[C:10]=3[CH:9]2[C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C#N)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnn[nH]2)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)ccc1C)C2=O
Temperature: 25 °C

Procedure:
A solution of 3-[5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-benzonitrile (Example 17) (0.126 mmol), sodium azide (0.534 mmol) and ammonium chloride (0.534 mmol) in DMF (2 mL) was stirred at 120° C. for 36 h. The mixture was cooled to rt and poured onto ice-H2O and acidified with 1N aqueous HCl. The resulting suspension was filtered. The solid was washed with H2O and dried. The residue was purified by SFC to afford the title compound as a white solid. tR: 4.98 min (HPLC 1); ESI-MS: tR=1.25 min, [M+H]+ 573/575 (LC-MS 1); TLC: Rf=0.21 (9:1 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): (rotamers) 8.14 (d, 1H), 7.96 (s, 1H), 7.80 (s, 1H), 7.35-7.47 (m, 3H), 7.26 (m, 2H), 7.16 (m, 1H), 7.11 (m, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 3.97 (m, 1H), 3.86 (s, 3H), 1.94 (s, 3H), 1.33 (m, 3H), 0.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=O.[CH2:12]1[C@H:21]2[C@H:16]([CH2:17][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=32)[NH:15][CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:15]2[C@@H:16]3[C@@H:21]([C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[CH2:18][CH2:17]3)[CH2:12][CH2:13][CH2:14]2)=[O:7])[CH:8]=[CH:9][C:10]=1[OH:11]
Reactant: c1ccc2c(c1)CC[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc(O)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(O)c(Cl)c1)N1CCC[C@@H]2c3ccccc3CC[C@@H]21
Yield: 42 %

Procedure:
The title compound is prepared from 3-chloro-4-hydroxy-benzoic acid and cis-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate is used]. Yield: 42% of theory; LC (method 4): tR=1.98 min; Mass spectrum (ESI+): m/z=342/344 (Cl) [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Na+].[CH2:6]([S:8]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O-])=[O:17])=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:7].[OH-].[Na+]>O>[CH2:6]([S:8]([NH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([Cl:3])=[O:17])=[CH:14][CH:13]=1)(=[O:10])=[O:9])[CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)Nc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
To 100 mL of thionyl chloride at 0° C. is added 25.1 g (0.1 mol) of 4-[(ethylsulfonyl)amino]benzoic acid sodium salt (prepared from the acid and sodium hydroxide in water and evaporation of solvent) under a nitrogen atmosphere. Reflux the reaction mixture for 24-40 hr. then remove the excess thionyl chloride in vacuo. Dissolve the crude material in tetrahydrofuran, filter through celite and evaporate the solvent to obtain the title compound.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:8]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]1=O.[C:20]([NH2:28])(=[S:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([C:20]2[S:27][C:2]3[CH2:11][CH2:10][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][C:8]=4[O:12][CH2:13][C:14]([OH:16])=[O:15])[C:3]=3[N:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(Br)C2=O
Reactant: NC(=S)c1ccccc1
Product: O=C(O)COc1cccc2c1CCc1sc(-c3ccccc3)nc1-2
Yield: 27 %

Procedure:
Using ethyl [(6-bromo-5,6,7,8-tetrahydro-5-oxo-1-naphthalenyl)oxy]acetate and thiobenzamide, the procedure of Example 52 was otherwise repeated to synthesize the title compound. Yield 27%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[C:27]2([CH2:32][CH2:31][CH:30]([N:33]3[C:37]4=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]4[C:35](I)=[N:34]3)[CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)C>[O:23]1[C:27]2([CH2:28][CH2:29][CH:30]([N:33]3[C:37]4=[N:38][CH:39]=[N:40][C:41]([NH2:42])=[C:36]4[C:35]([C:11]4[CH:10]=[N:9][C:8]([O:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:13][CH:12]=4)=[N:34]3)[CH2:31][CH2:32]2)[O:26][CH2:25][CH2:24]1
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC#N
Solvent: CCOCC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)nc1)nn2C1CCC2(CC1)OCCO2
Temperature: 25 °C
Yield: 71.9 %

Procedure:
A mixture of 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate AG) (1.1 g, 0.0037 mol), 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate N) (1.29 g, 0.0032 mol), tetrakis(triphenylphosphine)palladium (0.22 g, 0.00019 mol) and sodium carbonate (0.85 g, 0.008 mol) was heated in a mixture of ethylene glycol dimethyl ether (40 mL) and water (20 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and ethylene glycol dimethyl ether was removed under reduced pressure. The precipitate was collected by filtration, washed with water once, acetonitrile twice and diethyl ether twice to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off-white solid (1.03 g, 0.0023 mol): 1H NMR (DMSO-d6, 400 MHz) 8.36 (s, 1H), 8.24 (s, 1H), 8.03 (d, 1H), 7.45 (t, 2H), 7.22 (m, 3H), 7.16 (d, 1H), 4.81 (m, 1H), 3.93 (s, 4H), 2.24 (m, 2H), 1.88 (m, 6H); MS: MH+ 445.
Reaction SMILES: [CH2:1]([N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7])[CH:2]=[CH2:3].B.CSC.B1([O-])O[O:36]1.O.O.O.O.[Na+].O>C1COCC1>[OH:36][CH2:3][CH2:2][CH2:1][N:4]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1)(=[O:22])=[O:21])[C@@H:5]([C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CCN([C@@H](C(=O)OCc1ccccc1)C(C)(C)C)S(=O)(=O)c1cccc(OC)c1
Reactant: [O-]B1OO1
Agent: B
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: COc1cccc(S(=O)(=O)N(CCCO)[C@@H](C(=O)OCc2ccccc2)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
To a solution of benzyl N-allyl-N-[(3-methoxyphenyl)sulfonyl]-3-methyl-D-valinate (12.7 g, 29.3 mmol) in THF (90 mL) cooled to 0° C., borane-DMS complex (5M in diethyl ether, 12 mL, 60.0 mmol) is added dropwise. The reaction mixture is slowly warmed up to rt and is allowed to stir at rt for 24 h. To the reaction mixture, sodium perborate tetrahydrate (27.1 g, 176 mmol) and de-ionized water (90 mL) are added in portions. The reaction mixture is stirred for additional 3 h. The reaction mixture is filtered to remove the white precipitates, then the aqueous layer is extracted with EtOAc. The organic extracts are combined, washed with brine, dried over sodium sulfate, and concentrated in vacuo to obtain a highly viscous yellow oil. The crude product is purified by column chromatography eluting with a gradient of 25-65% EtOAc/heptane to obtain the desired alcohol as a colorless oil (9.08 g). Mass spectrum (450.46; M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:13]=1[C:14]#[N:15]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:16]2[CH:17]=[CH:18][CH:19]=[C:12]([F:11])[C:13]=2[C:14]#[N:15])=[CH:4][CH:3]=1
Reactant: N#Cc1c(F)cccc1F
Reactant: Sc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1Sc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
4-Chlorobenzenethiol (1.14 g; 7.9 mmol) in anhydrous DMF is added over 1 hour to an ice-cooled suspension of sodium hydride, 60% dispersion in mineral oil (316 mg; 7.9 mmol), in anhydrous DMF. The reaction is allowed to room temperature over 30 minutes. This material is then added over 30 minutes to an ice-cooled solution of 2,6-difluorobenzonitrile (1.0 g; 7.2 mmol) in anhydrous DMF. After the addition the reaction is allowed to room temperature and stirred for 2 hours. The reaction mixture is then poured slowly into vigorously stirred ice water to give a white paste, which becomes solid with continued stirring. The solid is filtered, washed with water, and dried under vacuum at 30° C. overnight to yield 1.66 grams of 2-(4-chlorophenylsulfanyl)-6-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH2:13][CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[C:21]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)([CH3:24])([CH3:23])[CH3:22].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:21]([C:25]1[CH:29]=[C:28]([C:30]([NH:16][CH:14]([CH3:15])[CH2:13][C:11]2[O:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:17]([F:20])([F:18])[F:19])[CH:4]=3)=[CH:9][CH:10]=2)=[O:31])[NH:27][N:26]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(N)Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1
Reactant: CC(C)(C)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(Cc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)o1)NC(=O)c1cc(C(C)(C)C)n[nH]1
Yield: 92.3 %

Procedure:
3-tert-butyl-N-(1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-yl)-1H-pyrazole-5-carboxamide was prepared from 1-(5-(4-chloro-3-(trifluoromethyl)phenyl)furan-2-yl)propan-2-amine (0.500 g, 1.651 mmol), 3-tert-butyl-1H-pyrazole-5-carboxylic acid (0.306 g, 1.817 mmol), HOBt (0.246 g, 1.817 mmol), DIPEA (0.576 ml, 3.303 mmol) and EDCI (0.349 g, 1.817 mmol) using the method of Example 1(d) producing 0.692 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 1.26 (s, 9H), 2.87-2.92 (m, 1H), 2.96-3.00 (m, 1H), 4.29-4.37 (m, 1H), 6.29-6.32 (m, 1H), 7.04-7.10 (m, 1H), 7.57-7.73 (m, 1H), 7.88-7.98 (m, 3H), 12.84 (m, 1H).
Reaction SMILES: CC1NC(=O)C2C(=CC(C)=C(C)C=2)N=1.C(OCCl)(=O)C(C)(C)C.CC1NC(=O)C2C(=CC=C(C)C=2)N=1.[C:37]([O:43][CH2:44][N:45]1[C:54](=[O:55])[C:53]2[C:48](=[CH:49][C:50]([CH3:57])=[C:51]([CH3:56])[CH:52]=2)[N:47]=[C:46]1[CH3:58])(=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].[Br:59]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:59][CH2:56][C:51]1[CH:52]=[C:53]2[C:48](=[CH:49][C:50]=1[CH3:57])[N:47]=[C:46]([CH3:58])[N:45]([CH2:44][O:43][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:54]2=[O:55]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2cc1C
Agent: CC(C)(C)C(=O)OCCl
Agent: Cc1ccc2nc(C)[nH]c(=O)c2c1
Agent: Cc1nc2cc(C)c(C)cc2c(=O)[nH]1
Product: Cc1cc2nc(C)n(COC(=O)C(C)(C)C)c(=O)c2cc1CBr
Yield: 57 %

Procedure:
2,6,7-Trimethyl-3,4-dihydroquinazolin-4-one (European Patent Specification No. 0284338) was reacted with chloromethyl pivalate using the procedure described in European Patent Specification No. 0239362 for the corresponding reaction of 2,6-dimethyl-3,4-dihydroquinazolin-4-one. There was thus obtained 3-(pivaloyloxymethyl)-2,6,7-trimethyl-3,4-dihydroquinazolin-4-one. The product so obtained was reacted with N-bromosuccinimide in the presence of benzoyl peroxide using the procedure described in European Patent Specification No. 0284338 to give 6-bromomethyl-2,7-dimethyl-3-(pivaloyloxymethyl)-3,4-dihydroquinazolin-4-one in 57% yield, m.p. 149°-152° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:6][NH:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17]
Reactant: C1CCNC1
Reactant: CNc1ccc(C=O)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.55 g (78.0 mmol) pyrrolidine are added to a solution of 4.70 g (26.1 mmol) 4-methylamino-3-nitro-benzaldehyde in 100 mL THF and the reaction mixture is acidified with glacial acetic acid. 6.36 g (30.0 mmol) NaBH(OAc)3 are added and the reaction mixture is stirred overnight at RT. The mixture is combined with saturated NaHCO3 solution and the aqueous phase is extracted twice with EtOAc. The combined organic extracts are washed with 200 mL semisaturated NaHCO3 solution and dried over MgSO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: DCM to DCM/MeOH 9:1).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][N:7]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8](=[O:20])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.Cl.Cl.NCCC1C2SC(=O)NC=2C(O)=CC=1.C([BH3-])#N.[Na+].N>O1CCOCC1.CO.O.C(O)(=O)C.ClCCl>[O:3]=[CH:4][CH2:5][CH2:6][N:7]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8](=[O:20])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(CCN(CCc1ccccc1)C(=O)CCOCCc1ccccc1)OCC
Agent: Cl
Agent: N
Agent: NCCc1ccc(O)c2[nH]c(=O)sc12
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: O=CCCN(CCc1ccccc1)C(=O)CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of N-(3,3-diethoxypropyl)-N-phenethyl-3-phenethyloxy-propanamide (Example 8b), 0.127 g) in dioxane (10 mL) was treated with concentrated hydrochloric acid (1 mL) and stirred at room temperature for 30 minutes. After this time the solution was diluted (dichloromethane 30 mL), washed with water (2×20 mL), brine (20 mL), dried over magnesium sulfate and concentrated to give the crude aldehyde product (0.13 g) which was used immediately. The crude aldehyde was dissolved in methanol (20 mL) and 7-(2-aminoethyl)-4-hydroxy-3H-benzothiazol-2-one hydrochloride (0.078 g) was added along with acetic acid (0.1 mL) and water (0.1 mL). After stirring at room temperature for 30 minutes, sodium cyanoborohydride (0.012 g) was added and the reaction mixture stirred overnight. Ammonia (7N in methanol, 1 mL) was added and the mixture was concentrated. The resulting residue was taken up in ethyl acetate (50 mL), washed with water (2×20 mL), brine (20 mL), dried over magnesium sulfate and concentrated to give the crude product which was purified by flash column chromatography eluting with 1% ammonia; 5% methanol in dichloromethane to afford the titled compound as a white solid (0.078 g).
Reaction SMILES: [CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4].[O:19]1[CH2:43][CH:20]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH:40]3[O:42][CH2:41]3)=[CH:34][CH:33]=2)([CH3:31])[CH3:30])=[CH:25][CH:24]=1>C(O)(C)(C)C>[CH2:1]([N:5]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:41][CH:40]([OH:42])[CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]([C:26]3[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH:20]([OH:19])[CH2:43][N:12]4[C:13]([CH3:15])([CH3:16])[CH2:14][CH:9]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6](=[O:8])[CH3:7])[CH2:10][C:11]4([CH3:17])[CH3:18])=[CH:24][CH:25]=3)([CH3:31])[CH3:30])=[CH:33][CH:34]=2)[C:11]([CH3:17])([CH3:18])[CH2:10]1)[C:6](=[O:8])[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Reactant: CCCCN(C(C)=O)C1CC(C)(C)NC(C)(C)C1
Solvent: CC(C)(C)O
Product: CCCCN(C(C)=O)C1CC(C)(C)N(CC(O)COc2ccc(C(C)(C)c3ccc(OCC(O)CN4C(C)(C)CC(N(CCCC)C(C)=O)CC4(C)C)cc3)cc2)C(C)(C)C1

Procedure:
To 20 ml of t-butanol were added 5.0 g of 4-(N-butylacetamido)-2,2,6,6-tetramethylpiperidine and 2.8 g of 2,2-bis[p-(2,3-epoxypropoxy)phenyl]propane, and the mixture was reacted following the procedure described in Example 1 to give the desired Compound No. 234 in the form of a white vitreous mass. The compound had an Rf value of 0.54 on thin-layer chromatography on silica gel developed with a 20:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].[N:17]([O-:19])=[O:18].[Na+].C(O)(=O)C.[N+]([O-])(O)=O>O>[CH3:16][O:15][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:9]([CH:8]=1)[C:10]([OH:12])=[O:11]
Reactant: O=N[O-]
Reactant: COc1cc(C(=O)O)ccc1OCCCCl
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCCl
Temperature: 40 °C
Yield: 944.9 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer and a dropping funnel were placed 16.2 g (65.4 mmol) of 4-(3-chloropropoxy)-3-methoxybenzoic acid (purity: 98%) obtained in Reference Example III-7, 0.45 g (6.54 mmol) of sodium nitrite, and 20 mL of acetic acid. The resulting mixture was heated to 40° C. under stirring. To the reaction mixture was dropwise added slowly 27.6 g (262.0 mmol) of nitric acid (60 wt. %), and the mixture was heated at the same temperature for 5 hours. After the reaction was complete, 20 mL of water was added to the reaction mixture, and the aqueous mixture was cooled to 20° C., precipitating a crystalline product. The crystalline product was collected by filtration, washed with 30 mL of water, and dried under reduced pressure, to give 17.9 g (isolated yield: 93.0%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoic acid as a white crystalline product.