Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1.BrC1C=CC(CN2C=CN=C2)=CC=1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27][CH3:28])[S:22][C:21]=3[S:29]([NH2:32])(=[O:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: Brc1ccc(Cn2ccnc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reaction time: 30 h
Yield: 49 %

Procedure:
Trifluoroacetic acid was added (10 mL) to the crude 3-(4imidazol-1-ylmethylphenyl)-5-butyl-N-tert-butylthiophene-2-sulfonamide from step (c) above, and one drop (ca. 0.05 mL) of anisol was added to the mixture. The reaction mixture was stirred under N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (20:1)) to give sub-title compound (232 mg, 0.62 mmol) in 49% yield (from 1-(4-bromobenzyl)-1H-imidazole).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=O)N.[NH2:10][C@H:11](C(O)=O)[CH2:12]C1C=CC=CC=1.N[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:12][CH2:11][NH2:10]
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
Asn⇄Gln; and Phe⇄Trp⇄Tyr.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]([CH3:38])([CH3:37])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:36][CH2:35][C:19]2([O:24][CH2:23][CH2:22][N:21]([C:25]([C:27]3[N:28]=[C:29]([CH:32]([CH3:34])[CH3:33])[S:30][CH:31]=3)=[O:26])[CH2:20]2)[CH2:18][CH2:17]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH:32]([C:29]1[S:30][CH:31]=[C:27]([C:25]([N:21]2[CH2:20][C:19]3([CH2:35][CH2:36][N:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([CH3:38])([CH3:37])[CH:9]=[O:8])[CH2:17][CH2:18]3)[O:24][CH2:23][CH2:22]2)=[O:26])[N:28]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)CO)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(CCCCCC(C)(C)C=O)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (0.048 mL) was added to a solution of (9-(7-hydroxy-6,6-dimethylheptyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 102, step c) (0.28 g) in DCM (15 mL) at 0° C. under argon and the mixture stirred for 5 min before addition of Dess-Martin periodinane (0.39 g). The reaction mixture was stirred at RT for 1 h then was quenched by addition of saturated sodium bisulfite solution (10 mL) and saturated sodium bicarbonate solution (10 mL) then ethyl acetate was added and the mixture stirred for 5 min. The layers were separated and the aqueous solution was extracted with ethyl acetate (×2). The combined organic solutions were washed with saturated sodium bicarbonate solution. Acetic acid (0.053 mL) was added to the organic phase which was then dried over sodium sulphate, filtered and evaporated in vacuo to afford the crude subtitled compound as a yellow oil. Yield 0.33 g.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[CH:17]([C:19]1[CH:52]=[CH:51][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:31][CH2:30]2)=[O:24])=[CH:21][CH:20]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(C)C.C(O)(=O)C>[C:5]([CH:4]1[CH2:8][CH2:9][N:1]([CH2:17][C:19]2[CH:20]=[CH:21][C:22]([C:23]([CH2:25][NH:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36](=[O:50])[NH:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[CH2:31][CH2:30]3)=[O:24])=[CH:51][CH:52]=2)[CH2:2][CH2:3]1)(=[O:6])[NH2:7]
Reactant: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Reactant: NC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: NC(=O)C1CCN(Cc2ccc(C(=O)CNCCN3CCC(OC(=O)Nc4ccccc4-c4ccccc4)CC3)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a three-necked 2-L flask was added isonipecotamide (5.99 g, 40.0 mmol), acetic acid (2.57 mL), sodium sulfate (6.44 g) and isopropanol (400 mL). The reaction mixture was cooled to 0-10° C. with an ice bath and a solution of biphenyl-2-ylcarbamic acid 1-{2-[(4-formylbenzoyl)methylamino]ethyl}piperidin-4-yl ester (11 g, 22.7 mmol; prepared as described in Preparation 5) in isopropanol (300 mL) was slowly added. The reaction mixture was stirred at room temperature for 2 hours and then cooled to 0-10° C. Sodium triacetoxyborohydride (15.16 g, 68.5 mmol) was added portion wise and this mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated under reduced pressure to a volume of about 50 mL and this mixture was acidified with 1N HCl (200 mL) to pH 3. The resulting mixture was stirred at room temperature for 1 hour and then extracted with DCM (3×250 mL). The aqueous phase was then cooled to 0-5° C. with an ice bath and 50% aqueous NaOH solution was added to adjust the pH of the mixture to 10. This mixture was then extracted with isopropyl acetate (3×300 mL) and the combined organic layers were washed with water (100 mL), brine (2×50 mL), dried over sodium sulfate, filtered and concentrated to afford 10.8 g of the title compound (80% yield. MS m/z: [M+H+] calc'd for C35H43N5O4 598.3; found 598.6. Rf=2.32 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH2:12][CH:13](OC)[O:14][CH3:15])=[CH:7][N:6]=1)=[O:4].CCN(CC)CC.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([CH:12]=[CH:13][O:14][CH3:15])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CC(OC)OC)nc1N
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC=Cc1cnc(C(=O)OC)c(N)n1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 215.2 %

Procedure:
To a solution of 3-amino-5-(2,2-dimethoxy-ethyl)-pyrazine-2-carboxylic acid methyl ester (300 mg, 1.244 mmol) and Et3N (1.213 ml, 8.70 mmol) in DCM (10 ml) at −10° C. was added dropwise trimethylsilyl trifluoromethanesulfonate (0.809 ml, 4.48 mmol). The reaction mixture was stirred at room temperature for 100 min. A saturated solution of NaHCO3 was added and the mixture was extracted twice with DCM. The combined organic layers were washed with NH4Cl solution and brine, dried with Na2SO4, filtered and concentrated under reduced pressure to obtain a brown oil (560 mg). The resulting crude material (mixture of E and Z) was directly used in the next step without further purification.
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=O)(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:22][O:23][C:24](=[O:33])[C@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[NH2:26].C(N1CCOCC1)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O>[C:1]([S:5]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([NH:26][C@@H:25]([CH2:27][C:28]1[N:32]=[CH:31][NH:30][CH:29]=1)[C:24]([O:23][CH3:22])=[O:33])=[O:12])(=[O:6])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.7 (20 mmol) of (S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamic acid (EPA 0236734) 4.85 g (20 mmol) of L-histidine methyl ester dihydrochloride, 10.3 ml (81.7 mmol) of N-ethylmorpholine and 2.98 g (20 mmol) of HOBT in 85 ml of dimethylformamide is treated portionwise under argon at 0°-2° with 4.23 g (22 mmol) of EDC and subsequently stirred at room temperature overnight. Thereafter, the solvent is evaporated in a high vacuum, the residue is taken up in 100 ml of ethyl acetate and washed in sequence three times with 10 ml of 2N sodium bicarbonate solution, twice with 10 ml of saturated sodium chloride solution, twice with 10 ml of saturated ammonium chloride solution and twice with 5 ml of saturated sodium chloride solution. The aqueous phases are extracted three times with 20 ml of ethyl acetate and the pooled organic phases are dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product obtained (9.4 g) is chromatographed on 300 g of silica gel using a 95:5 mixture of methylene chloride and methanol as the eluent. There are obtained 8.6 g of methyl (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionate as a colourless foam; MS: 436 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4].[CH3:14][C:15]([O-:17])=[O:16].[Na+].O>CC(CC)=O>[C:15]([O:17][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1)=[O:4])(=[O:16])[CH3:14]
Reactant: CC(=O)[O-]
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 48 h
Yield: 87.5 %

Procedure:
2-Bromo-1-(3-nitrophenyl)ethanone (25 g) was dissolved in methylethyl ketone (150 mL). NaOAc (12.5 g) was added and the mixture stirred for 48 hours. Water (100 mL) was added and the reaction mixture extracted with DCM. The DCM layer was dried over Na2SO4 and concentrated to give the title compound (20 g, 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:19][NH2:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:20][CH3:19])=[O:5]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc([N+](=O)[O-])c(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 62.8 %

Procedure:
To a solution of 2,4-dichloro-5-nitrobenzoic acid (8 g, 33.9 mmol) in toluene (200 ml) was added thionyl chloride (12.4 ml, 169 mmol) at room temperature. The mixture was stirred at 80° C. for 5 h. The solvent was removed and the residue was dissolved with tetrahydrofurane (60 ml). The mixture was added 40% methylamine (1.4 ml, 33.9 mmol) at 0° C. and the mixture was stirred at room temperature for 2.5 h. The volatile component was removed under reduced pressure, and the residue was extracted with ethyl acetate (100 ml). The organic layer was washed with water (100 ml), brine (100 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with hexane/ethyl acetate (2:1/1:1/1:2) to afford 5.3 g (63%) of the title compound as pale yellow solids.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12]O)=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27].C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:9][CH2:8][CH:7]([NH:14][C:15]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)=[O:16])[C:6]1=[O:27]
Reactant: COC(=O)CN1CC(CO)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN1CC(CS(C)(=O)=O)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of {6-hydroxymethyl-3-[(isoquinoline-1-carbonyl)-amino]-2-oxo-2,3,4,7-tetrahydro-azepin-1-yl}-acetic acid methyl ester, 19, (1.35 g, 3.52 mmol) in 10 mL CH2Cl2is treated with triethyl amine (1.3 mL, 8.81 mmol) and methanesulfonyl chloride (0.61 mL, 7.93 mmol) at −78° C. After stirring at −78° C. for 2 hours, the reaction mixture is poured into a CH2Cl2/saturated NaCl solution. The organic layer is collected and washed with saturated NaHCO3, saturated NaCl, dried (Na2SO4) and concentrated in vacuo to afford the desired product which is used without further purification.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]2[C:23]=1[CH:24]=[C:25]([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)[NH:26]2
Reactant: COc1ccc(OC)c2[nH]ccc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: COc1ccc(OC)c2[nH]c(B3OC(C)(C)C(C)(C)O3)cc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 4,7-dimethoxy-1H-indole.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:28]=2[F:27])[CH:7]=1
Reactant: OCc1cc(F)c(F)cc1F
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)c(F)cc3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,4,5-trifluorobenzyl alcohol (123 mg; 0.736 mmol), example 75 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: CCC1(CCCCCl)C(=O)Nc2c(Cl)cc(Cl)cc21
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2c(Cl)cc(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 5,7-dichloro-3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-chloro-phenyl)-piperazine.
Reaction SMILES: O[C@@:2]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[C:26]([C:31]([NH:33][CH3:34])=[O:32])[CH:25]=[CH:24]2)([C:6]1[N:7]=[CH:8][N:9](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)[CH2:3][CH2:4]O.C(N(C(C)C)C(C)C)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH2:55]>C1COCC1>[OH:55][C:10]1[N:9]=[CH:8][N:7]2[CH2:4][CH2:3][C@@H:2]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]([NH:33][CH3:34])=[O:32])[CH:25]=[CH:24]4)[C:6]=12
Reactant: O
Reactant: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3cn(S(=O)(=O)c4ccc(C)cc4)cn3)ccc2c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2cc([C@@H]3CCn4cnc(O)c43)ccc2c1
Temperature: 10 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To THF (4.8 mL) was added 6-[(1S)-1,3-dihydroxy-1-(1-tosyl-1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (479.6 mg, 1.0 mmol). The reaction mixture was cooled to 10° C., and ethyldiisopropylamine (505.9 mg, 4.0 mmol) and methanesulfonyl chloride (458.8 mg, 4.0 mmol) were successively added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added a solution of sodium carbonate (530.0 mg, 5.0 mmol) in water (2 mL), and the mixture was warmed to 57° C., and stirred for 5 hr. The separated organic layer was concentrated under reduced pressure. Methanol (4 mL) and activated carbon (40 mg) were added thereto. The reaction mixture was stirred at the same temperature for 20 min, and the activated carbon was filtered off, and washed with methanol (2 mL). The filtrate and washing were concentrated under reduced pressure. Methanol (1 mL), ethyl acetate (5 mL), and THF (10 mL) were added to the residue, and the mixture was washed twice with 10% sodium chloride-containing 5 w/v % aqueous sodium bicarbonate solution (15 mL). The separated organic layer was concentrated under reduced pressure to give 6-((7S)-hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (135.4 mg, 0.44 mmol). yield 44%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][N:38]2[CH2:39][CH2:40][C:34]3([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]4[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=4)=[O:29])[CH2:35]3)[CH2:36][CH2:37]2)=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCc1cc(CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Reaction time: 8 h

Procedure:
A solution of 2-(5-(bromomethyl)-2-fluorophenyl)ethanol [Aromatic Intermediate 2] (5.17 g) in ethanol (20 mL) was added dropwise to a suspension of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate [Example 1, step b] (9.4 g) and potassium carbonate (6.75 g) in ethanol (75 mL) and the resulting mixture stirred overnight. The mixture was filtered, the filter cake was washed with ethanol (50 mL), and the filtrate and washings combined and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (250 mL). The phases were separated and the organic phase washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The residue was purified by flash silica chromatography using 95:5 ethyl acetate:triethylamine as solvent to give the subtitled compound as a clear oil. Yield 7.9 g.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:9][C:10](=[O:21])[CH2:11][C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8].[CH3:22][C:23]1[CH2:28][CH2:27][CH2:26][C:25]([CH3:30])([CH3:29])[C:24]=1[CH:31]=[CH:32][C:33](Cl)=[O:34]>C1COCC1.CCOCC>[CH2:3]([O:9][C:10](=[O:21])[CH:11]([C:33](=[O:34])[CH:32]=[CH:31][C:24]1[C:25]([CH3:29])([CH3:30])[CH2:26][CH2:27][CH2:28][C:23]=1[CH3:22])[C:12]([O:14][CH2:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20])=[O:13])[CH2:4][CH:5]=[CH:6][CH2:7][CH3:8]
Reactant: CC1=C(C=CC(=O)Cl)C(C)(C)CCC1
Reactant: CCC=CCCOC(=O)CC(=O)OCCC=CCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC=CCCOC(=O)C(C(=O)C=CC1=C(C)CCCC1(C)C)C(=O)OCCC=CCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a suspension of 2.10 g 60% sodium hydride in 20 ml of THF, a solution of 14.00 g malonic acid dihex-3-enyl ester in 20 ml of THF were dropped in at 0-5° C. The reaction mixture was stirred 1 hour at room temperature. Then a solution of 11.9 g 3-(2,6,6-trimethyl-cyclohex-1-enyl)-acryloyl chloride (Shimasaki et al., Chem. Pharm. Bull., 43 (1995) 1, 100-107) in 40 ml of THF was dropped in and the reaction mixture was stirred at room temperature for 21 hours. Then the reaction mixture was diluted with ether and the organic phase was washed with water, dried, filtered and evaporated to dryness. The resulting yellow oil was purified by chromatography to yield 4.22 g of a yellow oil.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][CH:10]=N1.[N:13]1([CH2:18][C:19]2[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH-:27])=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>C(OCC)(=O)C>[N:13]1([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][CH2:26][N:27]3[CH:10]=[CH:11][CH:12]=[N:8]3)=[CH:28][CH:29]=2)[CH:17]=[CH:16][CH:15]=[N:14]1
Reactant: c1cn[nH]c1
Reactant: [NH-]CCCOc1ccc(Cn2cccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cnn(CCCOc2ccc(Cn3cccn3)cc2)c1
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a mixture of anhydrous N,N-dimethylformamide (5 ml) and sodium hydride (60% oil dispersion) (62 mg) was added pyrazole (100 mg), and the mixture was stirred for 30 minutes. An anhydrous N,N-dimethylformamide solution (5 ml) of 3-[4-(1-pyrazolyl)methylphenoxy]propylamide (produced in Reference Production Example 1 described below) (434 mg) was then added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was then diluted with ethyl acetate (50 ml), which was washed twice with saturated aqueous ammonium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oil was subjected to silica gel column chromatography, which afforded 340 mg of 1-{3-[4-(1-pyrazolyl)methylphenoxy]propyl}pyrazole (compound 31) in colorless oil. Yield, 82%.
Reaction SMILES: [CH3:1][C:2](Cl)([CH2:4][CH2:5][C:6]([CH3:9])(Cl)[CH3:7])[CH3:3].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:18]>[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)CCl>[OH:17][C:16]1[C:15]2[C:6]([CH3:9])([CH3:7])[CH2:5][CH2:4][C:2]([CH3:3])([CH3:1])[C:14]=2[CH:13]=[C:12]([CH3:18])[CH:11]=1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: Cc1cccc(O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1cc(O)c2c(c1)C(C)(C)CCC2(C)C
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
2,5-Dimethyl-2,5-dichlorohexane (183 g, 1 mol) was stirred with m-cresol (129.6 g, 1.2 mol) and aluminum chloride (4 g) was added in one direction. The mixture was heated at 95° C., with stirring for 1.5 h, after which ethylene dichloride (100 mL) was added and then the heating was continued. After 1 h the mixture was cooled to 20° C. and poured onto an ice-water/hydrochloric acid mixture (150 mL, 10% HCl solution). The mixture was then extracted with toluene (500 mL). The organic layer was separated, washed with brine (3×50 mL) and dried (Na2SO4). The solvent was removed by distillation and the residue was crystallized from a hexane/benzene solvent mixture to give 1-hydroxy-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene (171 g), mp 133°-134° C., GLC purity 99%+. 1H-NMR (CDCl3) δ 6.82 (1H, broad s), 6.35 (1 H, d, J=1.4 Hz), 4.72 (1H, s), 2.30 (3H, s), 1.71 (4H, m), 1.49 (6H, s), 1.34 (6H, s). 13C-NMR (CDCl3) δ 154.2 (1C, s), 147.8 (1C, s), 135.7 (1C, s), 128.0 (1C, s), 120.2 (1C, d), 114.6 (1C, d), 37.9 (1C, t), 35.2 (1C, t), 34.6 (1C, s), 33.7 (1C, s), 32.0 (2C, q), 28.5 (2C, q), 20.8 (1C, q). IR (KBr) 3,503 cm-1, MS (m/e) 218 (M+, 24.7), 203 (100.0), 161 (55.1), 147 (23.9), 57 (10.9).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH:18](=[N:9][CH:10]([CH2:16][CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(N)CC
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)N=Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (2 moles) was added to a solution of the product from step (a) (1 mole) in toluene. When addition was complete, benzaldehyde (1 mole) was added. The mixture was azeotroped until no further water was collected, then cooled to room temperature and filtered. The filtrate was evaporated in vacuo to give the desired product as an oil.