Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[CH:25]=[C:24](S(C)=O)[N:23]=[CH:22][N:21]=2)=[N:18][CH:17]=[CH:16][N:15]=1.[NH3:29].CC(O)C>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[NH:13][C:14]1[C:19]([C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH2:29])[CH:25]=2)=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: COc1cc(OC)c(Cl)c(Nc2nccnc2-c2cc(S(C)=O)ncn2)c1Cl
Reactant: N
Solvent: CC(C)O
Product: COc1cc(OC)c(Cl)c(Nc2nccnc2-c2cc(N)ncn2)c1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
(2,6-Dichloro-3,5-dimethoxy-phenyl)-[3-(6-methanesulfinyl-pyrimidin-4-yl)-pyrazin-2-yl]-amine 7 (200 mg, 0.414 mmol) is suspended in ammonia/2-propanol solution (2M, 3 mL, 6 mmol) in a sealed tube. After stirring at 100° C. overnight, the reaction is cooled to room temperature. The light yellow solid is collected by filtration, washed with water and 2-propanol, and dried to afford the desired product (6-[3-(2,6-dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-ylamine (40). The filtrate can be used for further purification to give an additional product.
Reaction SMILES: [F:1][C:2]1[C:16](=[O:17])[NH:15][C:5]2[N:6]=[C:7](S(C)(=O)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[C:18]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH2:36][CH2:37][OH:38])[CH2:30][CH2:29]2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[F:1][C:2]1[C:16](=[O:17])[NH:15][C:5]2[N:6]=[C:7]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][N:31]3[CH2:32][CH2:33][N:28]([C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[CH:21]=[CH:20][CH:19]=4)[CH2:29][CH2:30]3)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1
Reactant: OCCCCN1CCN(c2cccc3ccccc23)CC1
Reactant: Cc1nc(S(C)(=O)=O)nc2[nH]c(=O)c(F)cc12
Product: Cc1nc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc2[nH]c(=O)c(F)cc12

Procedure:
Following the same procedure as in Example H12 and starting from 6-fluoro-2-methanesulfonyl-4-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (300 mg, 1.166 mmol, U.S. Pat. No. 6,498,163) and 4-(4-naphthalen-1-yl-piperazin-1-yl)-butan-1-ol (331 mg, 1.166 mmol), the title compound was made as a solid (323 mg, 0.684 mmol, 58.7%). MS: APCI: M+1: 462.1 (Exact Mass: 461.22).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.[CH:17]1[CH:18]=[CH:19][N:20]2[CH2:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[NH:23][CH2:22][C:21]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[CH2:26][N:20]4[CH:19]=[CH:18][CH:17]=[C:21]4[CH2:22]3)=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)n(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
The 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.75 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.55 g) and diisopropylethylamine (0.42 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.79 g) was obtained as an amorphous solid, MS m/z: 383 (M+H)+.
Reaction SMILES: O.[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[CH2:14][CH2:15][CH:16]1[O:20][CH2:19][CH2:18][O:17]1.N>CN(C=O)C>[CH2:19]1[O:20][CH:16]([CH2:15][CH2:14][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:11])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:17][CH2:18]1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: BrCCC1OCCO1
Agent: N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)CCC2OCCO2)cc1
Temperature: 0 °C
Yield: 65.9 %

Procedure:
A mixture of sodium 4-toluenesulphinate monohydrate (37.2 g, 0.19 mole) and 2-(2-bromoethyl)-1,3-dioxolane (20 ml, 0.17 mole) in dry DMF (100 ml) was stirred at room temperature for 64h, resulting in a homogenous solution. This was poured into ice/water (1 liter) containing conc. ammonia solution (100 ml) and stirred vigorously until a white precipitate formed. The solid was filtered off, washed with water, dried and recrystallised from propan-2-ol/ether to give the title compound (D24) as a white solid (28.7 g, 66%) m.p. 78°-80° C.
Reaction SMILES: C[C@H](CCCC1C=CC=CC=1)C(O)=O.[CH3:15][C@@H:16]([CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[CH3:15][C@H:16]([CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)[C@@H](C)CCCc1ccccc1
Agent: C[C@H](CCCc1ccccc1)C(=O)O
Product: CCOC(=O)[C@H](C)CCCc1ccccc1
Yield: 88 %

Procedure:
(R)-(−)-Ethyl 2-methyl-5-phenylpentanoate was prepared from 20mc(i) (20.8 g) in the same manner (S)-(+)-ethyl 2-methyl-5-phenylpentanoate was prepared from 20mb(i) as described above. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (5:95 v/v) afforded the title compound (21.0 g, 88%) as a clear oil; TLC Rf 0.66 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic acid); MS (ESI+) m/z 221.2 (M+H)+; 1H-NMR (CDCl3) δ 7.32-7.26 (m, 2H), 7.20-7.14 (m, 3H), 4.11 (q, J=7.32 Hz, 2H), 2.64-2.57 (m, 2H), 2.48-2.39 (m, 1H), 1.75-1.53 (m, 3H), 1.52-1.41 (m, 1H), 1.27-1.21 (m, 3H), 1.13 (d, J=6.96 Hz, 3H,); [α]Tλ=α/cl, [α]21.9D=−0.114/(0.01771 g/1.5 mL)(0.5)=−19.31° (c=1.18, CHCl3).
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH2:34])=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][NH:34][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])=[CH:28][CH:27]=1
Reactant: Cc1ccc(CCN)cc1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccc(CCNC(=O)[C@H](CCCNC(=O)OC(C)(C)C)N(C)Cc2ccccc2)cc1

Procedure:
Nα-Benzyl-Nδ-Boc-Nα-methylornithine (200 mg) and 2-(4-methylphenyl)ethylamine were coupled to afford the titled compound (108 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.45 (s, 9H), 1.58 (m, 1H), 1.65 (m, 2H), 1.75 (m, 1H), 2.13 (s, 3H), 2.35 (s, 3H), 2.81 (t, J=5.8 Hz, 2H), 3.02 (m, 1H), 3.15 (m, 2H), 3.58 (m, 4H), 7.09 (m, 6H), and 7.27 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH:33]([CH3:35])[CH3:34]>C(OCC)(=O)C.CCCCCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][CH:33]([CH3:35])[CH3:34])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COc1cccc(C=C2Oc3cc(OC(C)C)ccc3C2=O)c1
Reaction time: 4 h
Yield: 32.4 %

Procedure:
To a solution of 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g, potassium carbonate 0.58 g and dimethylformamide 5 ml, 2-bromopropane 0.306 g was added. After the mixture was refluxed for 2.5 hours, water 50 ml was added. The resulting compound was extracted with ethyl acetate 50 ml twice. The ethyl acetate solution was washed with a saturated sodium chloride solution 20 ml twice, dehydrated with anhysrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dissolved in ethyl acetate 2 ml and hexane 10 ml, and the solution was allowed to stand at room temperature for four hours. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 187.2 mg.
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=O>>[CH3:43][N:42]([CH3:44])[CH2:40][CH2:39][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN(C)C)cc2)c1
Yield: 123.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-N,N-dimethylacetamide (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (17 mg) was obtained.
Reaction SMILES: [N:1]1([CH:6]([C:13]2[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][CH:23]=1.[OH-].[NH4+]>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]2[NH:19][C:16]3[CH:17]=[CH:18][C:13]([CH:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:14][C:15]=3[N:20]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: CCCCCCC(c1ccc(N)c(N)c1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCCC(c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1)n1ccnc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of 9 parts of 4-[1-(1H-imidazol-1-yl)heptyl]-1,2-benzenediamine, 5 parts of 4-fluorobenzoic acid and 100 parts of polyphosphoric acid was stirred for 2 hours at 100° C. After cooling, the reaction mixture was poured into ice water and treated with ammonium hydroxide. The product was extracted three times with 120 parts of trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 1,1'-oxybisethane. The product was filtered off and dried, yielding 5.8 parts (47%) of 2-(4-fluorophenyl)-5-[1-(1H-imidazol-1-yl)heptyl]-1H-benzimidazole; mp. 121.9° C. (compound 39).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:12]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=3)=[N:11][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38].[NH3:39]>CO>[NH2:39][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:12]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]([F:36])([F:35])[F:34])[CH:27]=3)=[N:11][C:10]=2[N:9]([CH3:37])[C:8]1=[O:38]
Reactant: N
Reactant: Cn1c(=O)n(CCOCCBr)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: CO
Product: Cn1c(=O)n(CCOCCN)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 39 %

Procedure:
1-(2-(2-bromoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.16 mmol) was dissolved in a preformed solution of ammonia in methanol (15 mL). The reaction was heated at 60° C. overnight in a sealed tube. The reaction was cooled to room temperature and the solvent was evaporated. The residue was purified by preparative HPLC to give 1-(2-(2-aminoethoxy)ethyl)-7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (35 mg, 39% yield) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]([CH3:27])([CH3:26])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH:19][S@@](C(C)(C)C)=O)[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[ClH:29]>CO.O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:28])[C:4]([CH3:27])([CH3:26])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]([C@H:17]([NH2:19])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N[S@](=O)C(C)(C)C)nc2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)C(C)(C)/C=C/c1ccc2ccc([C@@H](C)N)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (E)-2,2-dimethyl-4-{2-[(R)-1-((R)-2-methyl-propane-2-sulfinylamino)-ethyl]-quinolin-7-yl}-but-3-enoic acid methyl ester (700 mg, 1.74 mmol) in methanol (20 mL) was treated with hydrochloric acid in 1,4-dioxane (4 M, 10 mL). After stirring at room temperature for 2 h, the volatiles were removed in vacuo. The residual solvent was azeotroped off with toluene (3×15 mL) to give crude (E)-4-[2-((R)-1-amino-ethyl)-quinolin-7-yl]-2,2-dimethyl-but-3-enoic acid methyl ester hydrochloride.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1cccc(-c2ccccc2F)n1
Yield: 93 %

Procedure:
Method 1 was followed using 6-bromopicolinic acid (1.0 equiv.) and 2-fluorophenylboronic acid (1.5 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(2-fluorophenyl)picolinic acid in 93% yield. LC/MS=218.0 (M+H), Rt=0.66 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:13][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH2:23][O:22][CH2:21][CH2:20][C:18]=3[N:19]=2)C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.C(OCC)C>Cl.O1CCOCC1>[CH:1]1([CH2:4][NH:5][CH2:13][C:14]2[NH:15][C:16](=[O:24])[C:17]3[CH2:23][O:22][CH2:21][CH2:20][C:18]=3[N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1nc2c(c(=O)[nH]1)COCC2)CC1CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1[nH]c(CNCC2CC2)nc2c1COCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 121.8 %

Procedure:
tert-butyl cyclopropylmethyl((4-oxo-4,5,7,8-tetrahydro-3H-pyrano[4,3-d]pyrimidin-2-yl)methyl)carbamate (5.639 g, 16.81 mmol) was dissolved in 4 N HCl in dioxane (40 mL) and stirred at room temperature after approximately 5 min a white suspension formed and the reaction was allowed to stir overnight. 100 mL diethyl ether was added and the reaction mixture was filtered, washed with diethyl ether (2×25 mL) and dried in vacuo to yield the title compound as a white solid (4.819 g).
Reaction SMILES: C([O:9][CH2:10][CH:11]([CH2:30][C:31]#[N:32])[CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=O)C1C=CC=CC=1.[OH-].[Na+]>CO.O1CCCC1>[C:31]([CH2:30][CH:11]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][OH:9])#[N:32]
Reactant: CCCCCCCCCCCCCCCCOCC(CC#N)COC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCOCC(CO)CC#N
Yield: 67.6 %

Procedure:
A mixture of 12.42 g of 2-cyanomethyl-3-hexadecyloxypropyl benzoate n3' and 15.5 ml (31.0 mM) of 2N aqueous sodium hydroxide in 60 ml of methanol and 100 ml of tetrahydrofuran is stirred at room temperature for 1 hour and solvents are evaporated. The product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and evaporated. Purification by column silica gel chromatography using n-hexane-ethyl acetate (4:1) affords 6.430 g (67.8% yield) of the titled compound Vn1.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:24]I.[H-].[Na+]>>[CH3:24][N:5]([C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][C:9]2[C:10](=[O:14])[CH:11]=[CH:12][O:13][C:8]=2[CH:7]=1)[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: CI
Reactant: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CN(c1cc2occc(=O)c2cc1Oc1ccccc1)S(C)(=O)=O

Procedure:
7-Methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with methyl iodide in the presence of sodium hydride to obtain 7-(N-methyl-N-methylsulfonylamino)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18]C(=O)OCC2C=CC=CC=2)[CH:12]=[N:13][CH:14]=1.B(Br)(Br)Br.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].[NH4+].[Cl-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:12]=[N:13][CH:14]=1
Reactant: O=C(NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1)OCc1ccccc1
Reactant: CCS(=O)(=O)Cl
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a solution of benzyl 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropylcarbamate (94 mg, 0.227 mmol) in DCM (3 ml) was added BBr3 (0.682 ml, 0.682 mmol) at 0° C. This reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by addition of saturated NaHCO3 solution, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in pyridine (3.00 ml), and ethanesulfonyl chloride (0.086 ml, 0.910 mmol) was added to the solution. This reaction mixture was stirred at room temperature. After 1 h, saturated NH4Cl solution in water was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (EtOAc/Heptane=0-50%, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide (6.2 mg, 0.017 mmol, 7% yield). ESI-MS m/z: 371[M+1]+. 1H NMR (CDCl3, 400 MHz) 1.31 (t, J=7.2 Hz, 3H), 1.38-1.43 (m, 2H), 2.35-2.38 (m, 1H), 2.86-2.91 (m, 1H), 3.14 (q, J=7.2 Hz, 2H), 7.41 (dd, J=7.6, 2.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.57 (t, J=2.0 Hz, 1H), 7.65 (dd, J=7.6, 2.0 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1F.[C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].C(O)(=O)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[CH:13]([C:12]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: Fc1nc(F)c(Cl)c(F)c1Cl
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1c(Cl)c(F)nc(F)c1Cl
Reaction time: 17 h
Yield: 107.5 %

Procedure:
3,5-dichloro-2,4,6-trifluoropyridine (25 g, 15.4 mL, 123.7 mmol) and dibenzyl malonate (35.8 g, 31.5 mL, 126 mmol, Aldrich) were dissolved in anhydrous DMF (240 mL) under nitrogen atmosphere. The mixture was then cooled in an ice bath. To a stirred mixture, was added 60% sodium hydride (10 g, 250 mmol) portionwise (2 g) for 2 hr. The mixture was then stirred in a water bath for ca. 17 hr. Glacial acetic acid was added and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and dried in vacuo to give 62 g of dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate as a yellow oil. dibenzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)malonate (62 g) was then dissolved in dimethyl sulfoxide (DMSO) (120 mL) and stirred with water (10 mL) in an oil bath (130-140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether (Sometimes addition of EA is necessary to dissolve product completely). The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light yellow solid. The crude product was recrystallized from MC/Hexane three times to afford 30.9 g (75% for two steps) of benzyl 2-(3,5-dichloro-2,6-difluoropyridin-4-yl)acetate as a white solid. m.p. 98-101° C. 1H NMR (200 MHz, CDCl3) δ 4.11 (2H, s), 5.19 (2H, s), 7.30-7.38 (5H, m).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8]CC)=O.[C:17]([N:36]1[CH:40]=[C:39]([CH:41]=O)[N:38]=[CH:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[BH4-].[Na+]>O.C(Cl)Cl.CO>[C:11]1([CH:4]2[CH2:3][N:2]([CH2:41][C:39]3[N:38]=[CH:37][N:36]([C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:40]=3)[C:6](=[O:8])[CH2:5]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(CN)c1ccccc1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=C1CC(c2ccccc2)CN1Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Yield: 36 %

Procedure:
In a 500 ml, three-necked flask fitted with a magnetic stirrer and a reflux condenser under inert atmosphere, ethyl 4-amino-3-phenylbutanoate hydrochloride x42 (synthesized as described in patent application EP1265862, 6.2 g, 38 mmol), 1-trityl-1H-imidazole-4-carbaldehyde x43 (Dolensky B., Kirk K. L., Collect. Czech. Chem. Commun. (2002), 67, 1335-1344; 8.2 g, 36.1 mmol) and MeOH (150 ml) are stirred at room temperature. Triethylamine (3.9 ml, 41.85 mmol) and NaBH4 (1.06 g, 41.8 mmol) are added by portions. The mixture is stirred at 45° C. for 3 h, then at room temperature overnight. CH2Cl2 (300 ml) and water (300 ml) are added, the aqueous phase is extracted with CH2Cl2 (2×200 ml). The combined organic phases are washed with a saturated solution of NH4Cl (2×150 ml), dried, filtered and concentrated in vacuo. The crude product is recrystallized from AcOEt to afford 4-phenyl-1-[(1-trityl-1H-imidazol-4-yl)methyl]pyrrolidin-2-one x44.