Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(C(C2C=CC=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.C(OC1N=NC(C(C2C=CC([F:92])=CC=2)=C)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]2([C:26]3[CH:31]=[CH:30][C:29]([F:92])=[CH:28][CH:27]=3)[CH2:24][CH2:25]2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(c1ccc(F)cc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Agent: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Product: Fc1ccc(C2(c3cc(OCc4ccccc4)c(OCc4ccccc4)nn3)CC2)cc1
Yield: 16 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine (Intermediate 26) from 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 41) in 16% yield.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:22][CH3:23])=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:26]([BH3-])#[N:27].[Na+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>C(O)(=O)C.CO>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[CH3:23][O:22][C:4]1[C:3]([CH2:1][NH:27][CH3:26])=[CH:21][CH:20]=[CH:19][C:5]=1[O:6][C:7]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: [BH3-]C#N
Reactant: COc1c(C=O)cccc1Oc1nc(C(F)(F)F)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C(F)(F)F)ccc2C#N)c1OC
Yield: 64.5 %

Procedure:
2-(3-Formyl-2-methoxyphenoxy)-6-(trifluoromethyl)nicotinonitrile (0.50 g, 1.6 mmol), methylamine (33% in ethanol, 0.9 mL, 7.2 mmol) and sodium cyanoborohydride (120 mg, 1.9 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (80 mL) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.20 g, 1.7 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-trifluoromethyl-nicotinonitrile fumarate (468 mg, 67%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[C:15]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])([CH3:18])([CH3:17])[CH3:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:23])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)cc2)CC1
Reactant: C=CC(=O)OC(C)(C)C
Product: COC(=O)C1(c2ccc(OCCC(=O)OC(C)(C)C)cc2)CC1
Temperature: 110 °C
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic methyl ester (7.0 g, 3.6 mmol) in acrylic tert-butyl ester (50 mL) was added Na (42 mg, 1.8 mmol) at room temperature. The mixture was heated at 110° C. for 1 h. After cooling to room temperature, the resulting mixture was quenched with water and extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 54%) and unreacted start material (3.0 g). 1H NMR (300 MHz, CDCl3) δ 7.24 (d, J=8.7 Hz, 2 H), 6.84 (d, J=8.7 Hz, 2 H), 4.20 (t, J=6.6 Hz, 2H), 3.62 (s, 3 H), 2.69 (t, J=6.6 Hz, 2 H), 1.59-1.56 (m, 2 H), 1.47 (s, 9 H), 1.17-1.42 (m, 2 H).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)#[N:4].[CH3:13][O:14][C:15]([CH2:17]P(OC)(OC)=O)=[O:16]>O1CCCC1>[C:3]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:17]/[C:15]([O:14][CH3:13])=[O:16])=[CH:7][CH:6]=1)#[N:4]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(C#N)cc1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
To a stirring suspension of NaH (6.1 g of 60% oil suspension, 153 mmol) and p-cyanobenzaldehyde (20 g, 153 mmol) in tetrahydrofuran (250 mL) at 0° C. was added via addition funnel a solution of trimethyl phosphonoacetate (28 g, 153 mmol) in tetrahydrofuran (50 mL). After stirring for 48 hours, the solvent was removed in vacuo and the crude residue was dissolved in ethyl acetate (500 mL). The ethyl acetate solution was washed once with water, three times with saturated aqueous NaHSO3 and once with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give 28 g (98%) of a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:21])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:6][C:5]=1[F:22])(=[O:3])[CH3:2].C(O[CH:28](OC(C)(C)C)[N:29]([CH3:31])[CH3:30])(C)(C)C>CN(C)C=O>[CH2:19]([O:18][C:16]([C:9]1[C:8](=[O:21])[C:7]2[C:12](=[CH:13][C:4]([C:1]([CH:2]=[CH:28][N:29]([CH3:31])[CH3:30])=[O:3])=[C:5]([F:22])[CH:6]=2)[N:11]([CH2:14][CH3:15])[CH:10]=1)=[O:17])[CH3:20]
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: CCOC(=O)c1cn(CC)c2cc(C(C)=O)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2cc(C(=O)C=CN(C)C)c(F)cc2c1=O
Temperature: 70 °C

Procedure:
To 2.0 (6.5 mmol) of ethyl 7-acetyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 50 ml of dimethylformamide was added 1.71 ml (1.25 eq) of bis-t-butoxydimethylaminomethane. The mixture was heated at 70° C. for 18 hours. The mixture was then concentrated and the residue treated with ether and filtered to give 1.95 g of 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester, mp 176°-179° C.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][C:25]1=[O:40].Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[C:25](=[O:40])[CH2:26]4)=[N:35][CH:34]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1cnc(N2CCN(C)C(=O)C2)nc1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(=O)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 44.7 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) and methyl 2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-5-carboxylate (246 mg, 0.98 mmol) in toluene (5.00 mL) at 25° C. The resulting solution was stirred at 60° C. for 24 h. The reaction mixture was added to methanol (100 mL), then treated with HCl (2N aqueous solution, until pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (204 mg, 45%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5](=[O:20])N[C@H](C1SC=CN=1)CC1C=CC=CC=1.FC(F)(F)C(O)=[O:37]>ClCCl>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:21])[C:5]([OH:20])=[O:37])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Synthesis of (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)-pyrrolidin-2-yl]propanamide, trifluoroacetic acid salt (#19). According to general procedure B, from #16 (607 mg, 1.28 mmol, 1 eq.), dichloromethane (10 mL, 0.13 M) and trifluoroacetic acid (2 mL) was synthesized #19 (640 mg, quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.96-9.07 (br m, 1H), 8.89 (d, J=8.8 Hz, 1H), 7.87-8.00 (br m, 1H), 7.80 (d, J=3.2 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.28-7.34 (m, 4H), 7.20-7.27 (m, 1H), 5.43 (ddd, J=11.3, 8.6, 4.2 Hz, 1H), 3.42-3.50 (m, 2H), 3.36 (s, 3H), 3.04-3.14 (br m, 1H), 2.99 (dd, J=14.2, 11.5 Hz, 1H), 2.92-3.02 (m, 1H), 2.78-2.88 (br m, 1H), 2.34-2.42 (m, 1H), 1.73-1.84 (br m, 1H), 1.55-1.68 (m, 1H), 1.38-1.53 (m, 2H), 1.15 (d, J=6.9 Hz, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10](=[O:31])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:30])([F:29])[F:28])=[N:18][C:19]([C:20]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)(C)(C)C.[ClH:43]>C(OCC)(=O)C>[ClH:43].[NH2:7][C@H:8]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[CH:35][C:34]=1[F:41])[CH2:9][C:10]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:27]([F:30])([F:29])[F:28])=[N:18][C:19]([C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])=[C:13]2[CH2:12]1)=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCCC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
(R)-[3-Oxo-3-[1-(pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 12a (0.12 g, 0.199 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-(pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 12 (0.10 g, yield 94%) as a white solid.
Reaction SMILES: [CH:1]1([O:4][C:5]2[N:10]=[C:9](S(C)(=O)=O)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1.C([Li])CCC.[OH:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[CH:1]1([O:4][C:5]2[N:10]=[C:9]([O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[C:8]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:6]=2)[CH2:3][CH2:2]1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)c1nc(OC2CC2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OC3CC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Cyclopropyloxy-4-methylsulfonyl-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (Middle Rf product) (Example 55, Step A), (28 mg, 0.06 mmol) was reacted with 1 equivalent each of n-butyl lithium and 3-hydroxypyridine by the procedure described in Reference Examples 6 and 7. Workup and flash column chromatography on silica gel (eluted with 80/20 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=498 (M+−1); Rt=4.30 min. 1H-NMR 500 MHz (CDCl3): δ 0.30 (m, 2H), 0.59 (m, 2H), 1.26 (m, J=5 Hz, 1H), 4.09 (s, 2H), 7.18-7.30 (m, 6H), 7.36 (d, J=2 Hz, 1H), 7.40 (dd, J=7 Hz, J=5 Hz, 1H), 7.57 (d, J=7 Hz, 1H), 8.53 (d, J=5 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]1[C:16]([C:17]2[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:15]([F:24])[C:14]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:13]1)(=[O:11])=[O:10])#[N:2].C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.C(O)C>[ClH:41].[F:24][C:15]1[C:14]([CH2:25][NH:26][CH3:27])=[CH:13][N:12]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])(=[O:11])=[O:10])[C:16]=1[C:17]1[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccccc2C#N)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
tert-Butyl {[1-[(2-cyanophenyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (238 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=3:1 to give the title compound as colorless crystals (yield 186 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:13][C:14]1[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1>>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:19][C:17]2[S:18][C:14]([Cl:13])=[CH:15][CH:16]=2)=[CH:12][CH:11]=1)[CH3:10]
Reactant: O=Cc1ccc(Cl)s1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NCc2ccc(Cl)s2)cc1

Procedure:
4-(((5-chloro-2-thienyl)methyl)amino)benzoic acid ethyl ester was prepared from ethyl p-aminobenzoate and 5-chloro-2-thiophenecarboxaldehyde. Melting point was 108°-109° C.
Reaction SMILES: CS(O[CH:6]([C:15]1[CH:16]=[N:17][C:18]([NH:21][C:22]([C:24]2([C:27]3[CH:35]=[CH:34][C:30]4[O:31][CH2:32][O:33][C:29]=4[CH:28]=3)[CH2:26][CH2:25]2)=[O:23])=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])(=O)=O.[CH3:36][NH:37][CH2:38][CH3:39].O1C2C=CC(C3(C(NC4C=CC(C(N(C)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:31]1[C:30]2[CH:34]=[CH:35][C:27]([C:24]3([C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([CH:6]([N:37]([CH2:38][CH3:39])[CH3:36])[C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=5[O:13][CH3:14])=[CH:16][N:17]=4)=[O:23])[CH2:25][CH2:26]3)=[CH:28][C:29]=2[O:33][CH2:32]1
Reactant: COc1ccccc1C(OS(C)(=O)=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Reactant: CCNC
Agent: COc1ccccc1C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)N(C)C
Product: CCN(C)C(c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1)c1ccccc1OC

Procedure:
1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((ethyl(methyl)amino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from (6-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-3-yl)(2-methoxyphenyl)methyl methanesulfonate and N-methylethanamine in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((dimethylamino)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: Cl[CH:2]([C:7]1[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[N:9][N:8]=1)[CH2:3][CH:4]1[CH2:6][CH2:5]1.[N-:18]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.O>[CH:4]1([CH2:3][CH:2]([C:7]2[N:11]([CH3:12])[C:10]([S:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[N:9][N:8]=2)[NH2:18])[CH2:6][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(SCC2CC2)nnc1C(Cl)CC1CC1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(SCC2CC2)nnc1C(N)CC1CC1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a crude solution of the 3-(1-chloro-2-cyclopropylethyl)-5-[(cyclopropylmethyl)thio]-4-methyl-4H-1,2,4-triazole from step d in DMF (3 mL) under nitrogen was added sodium azide (1.0 g, 15 mmol). The mixture was stirred at 65° C. for 20 h, then cooled to room temperature, diluted with water and extracted into ethyl acetate. The organic extract was washed with water and then brine before being dried (MgSO4) and concentrated. The residue was taken up in THF (10 mL), and water (2 mL) was added followed by triphenylphosphine (1.6 g, 6.1 mmol). The reaction mixture was stirred under nitrogen for 5 h, then concentrated in vacuo. The residue was dissolved in methanol and applied to an SCX cartridge. Elution with methanol afforded organophosphorus residues and subsequent elution with 2M ammonia in methanol provided the title amine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:27]([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.O>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:17]=1)[C:14]([O:16][CH:27]([CH3:29])[CH3:28])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(-c2noc(C)n2)c(C(=O)OC(C)C)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (308 mg), 2-iodopropane (0.225 mL), potassium carbonate (312 mg) and N,N-dimethylformamide (2.6 mL) was stirred at 60° C. for 2.5 hours. After cooling to room temperature, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (342 mg).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:13])[CH3:12])[CH:6]=1.N1C=CC=CC=1.[S:21](Cl)(Cl)=[O:22].[CH3:25][NH:26][S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[C:30]1([S:27]([N:26]([CH3:25])[S:21]([N:2]([CH3:1])[C:3](=[O:14])[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([CH3:12])[CH3:13])[CH:6]=2)=[O:22])(=[O:29])=[O:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Reactant: CNC(=O)Oc1cccc(C(C)C)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(OC(=O)N(C)S(=O)N(C)S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-isopropylphenyl methylcarbamate (3.9 g, 0.02 mol) in dry tetrahydrofuran (15 ml), was added pyridine (2.0 g, 0.025 mol) and thionyl chloride (2.5 g, 0.021 mol). The mixture was stirred at room temperature for 4 hours. Pyridine hydrochloride was filtered rapidly and N-methylbenzenesulfonamide (3.5 g, 0.02 mol) was added. The mixture was cooled in an ice-water bath and triethylamine (2.2 g, 0.022 mol) was added dropwise. After the complete addition of the amine the mixture was stirred at room temperature for an additional half hour.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30](Cl)=[O:31])=[CH:25][CH:24]=1>O1CCCC1>[C:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:30](=[O:31])[CH2:29][C:26]3[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CC2CCCNC2)cc1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2CCCC(Cc3ccccc3)C2)cc1
Yield: 68.9 %

Procedure:
To a solution of the 3-phenylmethylpiperidine (1.75 g, 10 mmol) obtained in Example 1 (ii) and triethylamine (2.1 ml, 15 mmol) in tetrahydrofuran (10 ml) at 0° C. was added dropwise a solution of 4-methoxyphenylacetyl chloride (2.21 g, 12 mmol) in tetrahydrofuran (10 ml). The resultant mixture was stirred for 2 hours and the precipitate filtered off. The filtrate was then washed with saturated aqueous sodium bicarbonate (5 ml), dried with sodium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel using 1:1 then 2:1 ethyl acetate: hexane as eluant to give 3-phenylmethyl-N-(4'-methoxyphenyl)acetylpiperidine as a light yellow syrup (2.23 g), M+ found: 324.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([O:15][B:16](OC(C)C)[O:17]C(C)C)(C)C.C([Li])CCC.CCCCCC>O1CCCC1>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[N:4][CH:3]=[C:2]([B:16]([OH:17])[OH:15])[CH:7]=1
Reactant: FC(F)(F)c1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cncc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)pyridine (2.5 g, 11.06 mmol) and triisopropylborate (3.06 mL, 13.27 mmol) in anhydrous tetrahydrofuran (20 mL) at −78° C. under nitrogen was added dropwise a solution of n-butyl lithium in hexane (2.5 M, 4.9 mL, 12.17 mmol) The reaction was stirred at −78° C. for 3 hours then allowed to warm slowly to −10° C. The reaction mixture was then quenched by the addition of water (20 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous phase was diluted with water (40 mL) and washed with ether (2×40 mL). The aqueous phase was then acidified to pH 5 by the addition of acetic acid and the resulting suspension extracted with ethyl acetate (80 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to give 3-(trifluoromethyl)pyridine-5-boronic acid (2.022 g, 96% yield) as a tan solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1.[C:29]1([C:43]([OH:44])=[C:39]([N+:40]([O-:42])=[O:41])[CH:38]=[C:34]([N+:35]([O-:37])=[O:36])[CH:33]=1)[N+:30]([O-:32])=[O:31].[CH:45]1C=CC=C[CH:46]=1>C(O)C>[C:39]1([C:43]([OH:44])=[C:29]([N+:30]([O-:32])=[O:31])[CH:33]=[C:34]([N+:35]([O-:37])=[O:36])[CH:38]=1)[N+:40]([O-:42])=[O:41].[CH2:45]([N:40]([CH2:39][CH3:43])[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[C:11](/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12](\[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)/[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1)[CH3:46]
Reactant: c1ccccc1
Reactant: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Agent: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCN(CC)CCOc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
5.37 g (12 mmoles) of (E)-1-[4-(2-bromoethoxy)-phenyl]-1,2-diphenyl-3,3,3-trifluoro-propene, prepared as described in Example 7, are boiled with 8.8 g of diethylamino for 5 hours. The reaction mixture is diluted with 50 ml of benzene, washed with water until neutral, dried and evaporated. The residue is dissolved in 20 ml of 95% ethanol, and a solution of 3.22 g (14 mmoles) of picric acid in 32 ml of 95% ethanol is added. The separated crystals are filtered off, washed with ethanol and ether. 6.46 g (80.4%) of the aimed compound are obtained; m.p.: 131°-135° C.