Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:5]>[Pd].CO>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([C:4]([NH:6][CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:5])=[C:2]([F:1])[CH:17]=1
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(NC(=O)c2ccc(N)cc2F)CC1
Reaction time: 16 h

Procedure:
2-fluoro-N-(1-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 62; 1.62 g, 5.8 mmol), 10% Palladium on Carbon (160 mg) and Methanol (50 mL) were combined and stirred at 25 )C under Hydrogen at 5 bar pressure for 16 hours.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Oc1ccnc2cc(C(F)(F)F)ccc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 50.6 %

Procedure:
7-Trifluoromethyl-4-quinolinol (320 mg, 1.5 mmol), Cs2CO3 (500 mg, 1.5 mmol) and anhydrous DMF (3 mL) were stirred at 70° C. in a 50 ml round-bottomed flask equipped with a magnetic stirrer. After 20 min, 5-(5-bromopentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 10 (420 mg, 1.4 mmol) in DMF (2 mL) was added and the reaction mixture was stirred for 15 h at 75° C. DMF was evaporated at 60° C. and the reaction mixture was poured in 20 mL of H2O and extracted with EtOAc (3×100 mL). The organic layer was washed with brine (10 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=98:2 to 90:10) to give after evaporation 5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 12 (300 mg, 47% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:20])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([CH:17]=O)[C:11]=2[CH3:19])[CH:9]=1)[CH3:2].[NH2:21][CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[C:23]1=[O:28].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:20])=[C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12](/[CH:17]=[N:21]/[CH:22]3[CH2:26][CH2:25][N:24]([CH3:27])[C:23]3=[O:28])[C:11]=2[CH3:19])[CH:9]=1)[CH3:2]
Reactant: CN1CCC(N)C1=O
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C=O)c2C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOc1ccc(F)c(-c2cc(C)nc(/C=N/C3CCN(C)C3=O)c2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 241.4 %

Procedure:
To a stirred mixture of 4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-pyridine-2-carbaldehyde (which may be prepared as described in Description 141) (2980 mg, 10.904 mmol) and 3-amino-1-methyl-pyrrolidin-2-one (508.12 mg, 4.4514 mmol) in anhydrous DCM (10 mL) at room temperature, was added magnesium sulfate (3937.5 mg, 32.711 mmol). The resulting mixture was left to stir at room temperature for 3 h. The reaction mixture was filtered through a plug of cotton wool and the filtrate was washed with brine. The organic layer was collected by means of a PhaseSep cartridge. Evaporation of solvent under reduced pressure gave yellow oil, 3-[(E)-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]methyleneamino]-1-methyl-pyrrolidin-2-one (3.97 g, 10.746 mmol, 98.6% yield). To a portion of this material (3920 mg, 10.611 mmol) in anhydrous THF (35 mL) under nitrogen at room temperature, was added phenyl vinyl sulfone (2141.9 mg, 12.733 mmol) and silver acetate (1771.1 mg, 10.611 mmol). The resulting mixture was left to stir in the dark for 10 min. DBU (0.7932 mL, 5.3055 mmol) was added. The resulting mixture was left to stir in the dark for 2 h. The dark filtrate was evaporated and further dried under house vac. It was purified by silica gel chromatography (100 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%) followed by methanol in ethyl acetate (0-15%). Evaporation of desired fractions gave 3-(benzenesulfonyl)-2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (3880 mg, 7.2166 mmol, 68.0% yield) as brown solid. To a stirred solution of this material in anhydrous THF (30 mL) under nitrogen at 0° C., was added potassium tert-butoxide (4048.9 mg, 36.083 mmol). The resulting mixture was left to stir for 2 h and acetic acid (2.07 mL, 36.08 mmol) was added. Stirring was continued for 15 min at room temperature. Evaporation of solvent under reduced pressure gave a dark oily residue. It was purified by silica gel chromatography (50 g SiO2) eluting with ethyl acetate in iso-hexane (30-100%). Evaporation of desired fractions gave brown oil, 2-[4-(5-ethoxy-2-fluoro-phenyl)-3,6-dimethyl-2-pyridyl-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D142) (543 mg, 1.373 mmol, 19.0% yield);
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[F:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]1=O.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2].C([O-])(O)=O.[Na+]>CCOC(C)=O.CC(N(C)C)=O>[F:16][CH:17]1[C:22]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: O=C1CCCCC1F
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCCCC1F)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (66 mg, 0.30 mmol), 2-fluorocyclohexanone (0.10 mL, 0.90 mmol), CSA (7.0 mg, 0.030 mmol), MgSO4 (72 mg, 0.60 mmol) and DMA (1 mL) was stirred at 80° C. for 2 h. Then, saturated aqueous NaHCO3 and EtOAc were added to quench the reaction. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel 85:15 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/hexane) to give the title compound (53 mg, 55%) as a pale yellow solid:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[N:27]=[CH:26][N:25](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[N:24]=5)[CH:21]=4)[N:16](C4CCCCO4)[N:15]=3)[CH:9]=2)=[O:7])[CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[NH:24]1[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[C:10]2[CH:9]=[C:8]([C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[O:7])[CH:13]=[CH:12][CH:11]=2)=[N:27][CH:26]=[N:25]1
Reactant: O=C(NCC1CC1)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1cccc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 50 °C
Yield: 54.1 %

Procedure:
To a stirred solution of N-(cyclopropylmethyl)(3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl) (1,2,4-triazol-3-yl)](1H-indazol-3-yl)}phenyl)carboxamide (0.241 g, 0.352 mmol) was added dioxane (4.0 mL) and aqueous 6 N hydrochloric acid (4.0 mL) and the mixture heated at 50° C. for 4 h. The mixture was cooled and poured into aqueous saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated. Addition of ethyl acetate (5 mL) initiated crystal growth and the ethyl acetate phase was pipetted off. The crystals were filtered. Purification by preparative HPLC (30–80% acetonitrile/water) gave the title compound (0.0682 g, 54% yield). 1H NMR (CD3OD) δ 8.79 (s, 1H), 8.45 (m, 1H), 8.19 (dt, 1H), 8.11 (d, 1H), 7.90 (dt, 1H), 7.69 (d, 1H), 7.66 (t, 1H), 3.30 (m, 2H), 1.18 (m, 1H), 0.55 (m, 2H), 0.32 (m, 2H). ES-MS (m/z) 359 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[CH:4][C:3]=1[F:23].[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[F:23][C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)[CH:6]=[CH:7][C:2]=1[NH:1][CH3:24]
Reactant: C[C@H]1CN(Cc2ccc(N)c(F)c2)CCN1C(=O)OC(C)(C)C
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1F
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-3-fluorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D63) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to and after addition of sodium borohydride. δH (CDCl3, 400 MHz) 6.96 (2H, m), 6.61 (1H, m), 4.17 (1H, br.s), 3.89 (1H, br.s), 3.79 (1H, d), 3.41 (1H, d), 3.28 (1H, d), 3.08 (1H, td), 2.87 (3H, s), 2.74 (1H, m), 2.57 (1H, m), 2.08 (1H, dd), 1.95 (1H, m), 1.45 (9H, s), 1.22 (3H, d).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:29])=[CH:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCCO)C>[ClH:29].[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([OH:1])[CH:3]=3)=[CH:24][CH:25]=[N:26]2)=[CH:21][C:20]=1[O:30][CH3:31])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(N)cc1O
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: Cl
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ccnc2cc1OCc1ccccc1
Yield: 61.5 %

Procedure:
A solution of 3-hydroxy-4-methylaniline (68 mg, 0.55 mmol) and 7-benzyloxy-4-chloro-6-methoxyquinoline hydrochloride (168 mg, 0.5 mmol), (prepared as described for the starting material in Example 3), in 2-ethoxyethanol (5 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, the precipitate collected by filtration, washed with 2-ethoxyethanol and then ether and dried under vacuum to give 7-benzyloxy-4-(3-hydroxy-4-methylanilino)-6-methoxyquinoline hydrochloride (130 mg, 61%).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@H:4]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH2:21][CH2:22][C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34]CC4C=CC=CC=4)[CH:29]=3)[O:26][CH:27]=2)=[C:15]([Cl:42])[CH:14]=1)[NH:5]C(=O)C(F)(F)F.Cl>C(O)(=O)C>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:42])[C:16]=1[O:20][CH2:21][CH2:22][C:23]1[N:24]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)[O:26][CH:27]=1)[CH2:12][C@@H:4]([C:3]([OH:43])=[O:2])[NH2:5]
Reactant: COC(=O)[C@H](Cc1cc(Cl)c(OCCc2coc(-c3cccc(OCc4ccccc4)c3)n2)c(Cl)c1)NC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Product: N[C@@H](Cc1cc(Cl)c(OCCc2coc(-c3cccc(O)c3)n2)c(Cl)c1)C(=O)O
Temperature: 25 °C
Yield: 53 %

Procedure:
A mixture of O-[2-[2-(3-benzyloxyphenyl)-oxazol-4-yl]ethyl]-3,5-dichloro-N-trifluoroacetyl-L-tyrosine methyl ester (316 mg, 0.496 mmol), hydrochloric acid (3 ml) and acetic acid (1.5 ml) was heated under reflux for 6 hrs. The reaction mixture was cooled to room temperature and the solvent was distilled off under reduced pressure. Water (30 ml) was added to the residue and the mixture was adjusted to pH 4-5 with 10% aqueous sodium hydroxide. The precipitates were collected by filtration, washed with water, suspended in ethanol (20 ml) and triturated. The resultant product was collected by filtration, washed with ethanol and dried under reduced pressure to give 3,5-dichloro-O-[2-[2-(3-hydroxyphenyl)-oxazol-4-yl]ethyl]-L-tyrosine (115 mg, 52%) as a pale brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccn2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccn2)cc1N
Yield: 54.4 %

Procedure:
Prepared from (2-nitro-4-pyridin-2-ylethynyl-phenyl)-carbamic acid tert.-butyl ester (Example F8) (262 mg, 0.772 mmol) by reduction with SnCl2.2H2O (871 mg, 3.86 mmol) according to the general procedure G (method b). Obtained as a light brown solid (130 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:9](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:10]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][N:3]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cnc(Cl)cn1
Solvent: ClCCl
Product: S=C=Nc1cnc(Cl)cn1
Yield: 83 %

Procedure:
A solution of 5-chloropyrazin-2-amine (12.95 g, 100 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (27.9 g, 120 mmol) was stirred in DCM (200 mL) at room temperature for 1 h. The reaction was concentrated to ca. 100 mL volume and filtered through a pad of silica gel (1 L), washing with 10% EtOAc in hexanes. The filtrate was concentrated and dried to afford 2-chloro-5-isothiocyanatopyrazine (14.32 g, 83 mmol, 83% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.38 (d, J=1.26 Hz, 1H) 8.18 (d, J=1.26 Hz, 1H). MS (LC/MS) R.T.=1.84; [M+H]+=172.09.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[N:10]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:27][CH2:28][N:29]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[N:10]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1nccc2c1c(-c1ccc(N3CCNCC3)cc1)nn2-c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nccc2c1c(-c1ccc(N3CCN(S(C)(=O)=O)CC3)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-c]pyridine (260 mg) and triethylamine (112 mg) in dichloromethane (5 mL) was added methanesulfonyl chloride (99.0 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 2 hr, and diluted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (240 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=[O:8])[CH3:2].CO.[BH4-].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH2:7][OH:8])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOc1ccc(CO)cc1OCC
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
To a mixture of 3,4-diethoxybenzaldehyde (6.68 g) and methanol (100 ml) was added sodium borohydride (1.30 g) at 0° C. The resulting mixture was stirred at 0° C. for 45 minutes. The reaction mixture was mixed with water and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3,4-diethoxybenzyl alcohol (6.64 g) as a yellow oil.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:14]1C[CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.O>C(Cl)(=O)C=C.C1C=CC=CC=1>[C:15]([O:13][C@H:10]1[CH2:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)(=[O:14])[CH:16]=[CH2:17]
Reactant: O[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)O[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
First, 2.5 g of trans-4-phenylcyclohexanol, 50 ml of tetrahydrofuran, and 1.8 g of triethylamine were placed in a 100 ml flask. A solution in which 1.7 g of acryloyl chloride was dissolved in 5 ml of benzene was added dropwise to the mixture under ice water cooling. The mixture was allowed to warm to room temperature and stirred for 5 hours. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) and recrystallized from acetone to obtain 1.8 g of trans-4-phenylcyclohexyl acrylate (Y: 55.1%). The compound thus obtained had a purity of 99.7% by GC and 1 spot by TLC. Furthermore, the compound had an m.p. of 67.3° C.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:21][C:22]2[O:26][C:25]([C:27]([O:29]CC)=[O:28])=[CH:24][CH:23]=2)[NH:7][C:8]=1[NH:9][C:10](=[O:20])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].C(O)C.C1COCC1.[OH-].[Na+]>C(O)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:21][C:22]2[O:26][C:25]([C:27]([OH:29])=[O:28])=[CH:24][CH:23]=2)[NH:7][C:8]=1[NH:9][C:10](=[O:20])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH3:19])=[CH:15][CH:16]=1)(=[O:3])[NH2:2]
Reactant: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)OCC)o3)nc2C(N)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCCc1ccc(C(=O)Nc2[nH]c(Cc3ccc(C(=O)O)o3)nc2C(N)=O)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.8 g (4.24 mM) of ethyl 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylate are added to 10 ml of an ethanol/THF mixture (50-50). 4 ml of aqueous 3N sodium hydroxide solution are then added and the reaction medium is maintained at 40° C. with stirring for 2 hours. The reaction medium is allowed to cool and is acidified with acetic acid; a solid crystallizes. The solid is filtered off and washed with demineralized water to give, after drying, 1.7 g of 5-[4-carbamoyl-5-(4-propylbenzoylamino)-1H-imidazol-2-ylmethyl]furan-2-carboxylic acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:40][N:39]([CH3:41])[CH2:38][CH2:37][NH:36][S:33]([C:30]1[CH:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)cc1
Product: CN(C)CCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-(2-dimethylamino-ethyl)-benzenesulfonamide (example B.30) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (340 mg, 58%). MS (ISP) 582.2 [(M+H)+]; mp 193–194° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[CH:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:31].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>C(#N)C.O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH:17]1[CH:16]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:31])[N:8]1[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:1][S:33]([CH3:32])(=[O:35])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N)C1c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.25 g of ethyl (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 30 ml of acetonitrile were added 0.75 ml of methanesulfonyl chloride and 1.6 ml of diisopropylethylamine, followed by stirring at room temperature overnight. Ethyl acetate and water were added thereto to carry out a liquid separation operation, and the organic layer was washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and then evaporated under reduced pressure. The residue was added with diethyl ether for crystallization, and collected by filtration to obtain 2.02 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13](Br)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:17]2[C:12](=[C:13]([CH:26]=[O:27])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)c1cccc2c(Br)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cccc2c(C=O)cccc12
Temperature: -95 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-bromo-1-naphtoic acid tert-butyl ester (Example 9.2) (6.1 g) in dry tetrahydrofuran (54 ml) cooled to −100° C. was added a solution of butyl lithium (1.6M in hexane) (12.5 ml) dropwise at −100° C., followed by addition of dimethyl-formamide (“DMF”) (2.77 ml) at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured onto a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over sodium sulfate and concentrated to give 5-formyl-1-naphtoic acid tert-butyl ester (3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.35 (s, 1H), 9.50 (s, 1H), 9.18 (d, 1H), 8.15 (d, 1H), 8.00 (d, 1H), 7.65-7.75 (m, 2H), 1.65 (s, 9H).