Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:20])=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[S:15][C:9]=2[CH2:8][CH2:7]1)=O)C.CCO.[OH-].[K+]>O>[C:16]([C:14]1[S:15][C:9]2[CH2:8][CH2:7][NH:6][CH2:12][CH2:11][C:10]=2[C:13]=1[CH3:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)N1CCc2sc(C(C)(C)C)c(C)c2CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(C)(C)C)sc2c1CCNCC2
Temperature: 100 °C

Procedure:
The product of step b) was treated with 2 mL each of EtOH and 40% aqueous KOH. After heating to 100° C. for 12 hours, the reaction was cooled, diluted with water, and extracted 2× into DCM. The title product was purified by preparative HPLC-MS. MS: ESI (positive): 224 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=2)=[N:6][N:7]=1.[I-].[K+].[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[I:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[N:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: ClCc1nnc(-c2ccc(I)cc2)o1
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Product: Ic1ccc(-c2nnc(CN3CCOCC3)o2)cc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
2-Chloromethyl-5-(4-iodophenyl)-[1,3,4]oxadiazole (Intermediate 7) (48 mg, 0.15 mmol) and potassium iodide (25 mg, 0.15 mmol) were dissolved in morpholine (2 ml) and stirred for 18 hours at 20° C. The amine was then removed in vacuo and the product was purified on a 10 g silica SPE cartridge (stepped solvent gradient 80:20 ethyl acetate:cyclohexane, 100% ethyl acetate, 95:5 ethyl acetate:methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=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]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[C:12]1[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:11]=1[CH3:10]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: Cc1cc(C(F)(F)F)ccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Temperature: 25 °C

Procedure:
3-Chloro-4-iodoaniline (3.0 g, 11.8 mmol), (2-methyl-4-(trifluoromethyl)phenyl)boronic acid (2.9 g, 14.2 mmol), Pd(dppf)Cl2 (1.0 g, 1.2 mmol), and K2CO3 (3.3 g, 23.7 mmol) were dissolved in 1,4-dioxane (40 mL) and water (10 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([Br:29])[CH:31]=[CH:32][C:33]=3[O:38][CH3:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(Br)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 5-bromo-2 methoxybenzaldehyde. MS (ESI) m/z 577.
Reaction SMILES: Cl.[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][NH:19][C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[CH2:35]([C:41]1[CH:49]=[CH:48][C:44]([C:45](Cl)=[O:46])=[CH:43][CH:42]=1)[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]2[CH:34]=[CH:33][C:17]([CH2:18][N:19]([C:20]3[CH:32]=[CH:31][C:23]4[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=4[CH:21]=3)[C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:42][CH:43]=3)=[CH:16][CH:15]=2)=[CH:10][CH:11]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Reactant: CCCCCCc1ccc(C(=O)Cl)cc1
Agent: Cl
Product: CCCCCCc1ccc(C(=O)N(Cc2ccc(C#Cc3ccc(CCCC)cc3)cc2)c2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The titled compound was prepared following the procedure K using 6-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one hydrochloride and 4-hexylbenzoyl chloride as a yellow oil (85%). HPLC, Rt: 6.45 min (Purity: 99.8%).
Reaction SMILES: C1(C[O:8][C:9]2[C:14]([O:15]CC3C=CC=CC=3)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:38]=2)[C:33]([OH:35])=[O:34])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[OH:8][C:9]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH:38]=1)[C:33]([OH:35])=[O:34]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 4 h
Yield: 91.5 %

Procedure:
A mixture of 1.66 g of 3-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]-5-(tetradecyloxy)benzoic acid and 0.3 g of 10% palladium on carbon in 75 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 4 hours. The usual workup followed by trituration with hexane and filtration gave 1.14 g (91% yield, mp 92°-94°) of 3-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]-5-(tetradecyloxy) benzoic acid.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[N:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([C:17]2[CH:18]=[N:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: COc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ncc(Br)cc2[N+](=O)[O-])cn1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
A stirred mixture of 2,5-dibromo-3-nitropyridine (1.57 g, 5.57 mmol), 6-methoxypyridin-3-ylboronic acid (1.03 g, 6.73 mmol), trans-dichlorobis(triphenylphosphine)palladium (II) (0.2 g, 0.28 mmol), and 2.0M sodium carbonate (8.4 mL, 16.8 mmol) in 1,4-dioxane (27 mL) was heated to 90° C. After 19 h, the reaction was cooled to rt then diluted with water. After extraction with EtOAc, the organic extraction was dried over anhydrous sodium sulfate. After filtration and concentration, the residue was purified on silica gel (0-20% EtOAc in hexanes) to afford a light yellow solid as 5-bromo-6′-methoxy-3-nitro-2,3′-bipyridine. 1H NMR (400 MHz, CDCl3) δ ppm 8.92 (1H, d, J=2.2 Hz), 8.40 (1H, dd, J=2.5, 0.6 Hz), 8.32 (1H, d, J=2.2 Hz), 7.78 (1H, dd, J=8.6, 2.5 Hz), 6.85 (1H, dd, J=8.7, 0.7 Hz), 4.02 (3H, s).
Reaction SMILES: [I-].[CH3:2][N+:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C.O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])[CH2:5][CH2:4]1
Reactant: C[n+]1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCC(c2cccc(N)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of 1-methyl-4-(3-nitrophenyl)pyridinium iodide (D5, 4.0 g, 11.7 mmol) in ethanol (100 ml) and water (100 ml) at 0° C. was added sodium borohydride (665 mg, 17.6 mmol) portionwise over 0.5 h, before allowing to warm to room temperature while stirring for 2h. To the mixture was added 10% NaOH solution (100 ml) and the product extracted with dichloromethane (2×), dried (Na2SO4) and evaporated in vacuo to a brown oil (2.6 g). The oil was dissolved in ethanol (100 ml) and hydrogenated over 10% Pd--C at 50 psi and 50° C. for 48 h. Filtration and evaporation in vacuo of the filtrate gave the title compound as a yellow oil (2.1 g, 93%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[N:13]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=Cc1ccc(-c2ncccn2)cc1
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-c2ncccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrimidin-2-yl-benzaldehyde, of Preparation 21, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, 2H), 8.37 (d, 2H), 7.42 (d, 2H), 7.16 (t, 1H), 3.85 (s, 2H), 3.64 (s, 3H), 2.62 (t, 2H), 2.28 (t, 2H), 1.55 (m, 4H), 1.32 (m, 4H); MS 328 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:10]([CH:17]([CH3:19])[CH3:18])[NH:11]2.Cl[CH:35]([F:37])[F:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:35]([F:37])[F:36])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12
Product: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(OC(F)F)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-chloro-2-isopropyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:31])[C:8]([CH2:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)=[CH:13][CH:12]=1)=[O:5])[CH3:2].O.O.[Sn](Cl)Cl>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:31])[C:8]([CH2:29][CH3:30])=[C:9]([C:27]#[N:28])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccc(Oc3ccccc3[N+](=O)[O-])cc2)c(C#N)c(CC)n1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(-c2ccc(Oc3ccccc3N)cc2)c(C#N)c(CC)n1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combine 4-cyano-5-ethyl-3-[4-(2-nitro-phenoxy)-phenyl]-1-methyl-1H-pyrole-2-carboxylic acid ethyl ester (prepared in example E-230) and tin(II) chloride dihydrate (5 Eq.) in absolute ethanol (20 mL), and heat at reflux with stirring under a nitrogen atmosphere for 3 hours. Cool the reaction mixture to room temperature and dilute with ethyl acetate. Wash the organic layer with water, dry over potassium carbonate, filter, and concentrate under reduced vacuum. Purify the material by silica gel chromatography eluting with methylene chloride to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[NH2:1][C:2]1[N:7]=[C:6]([Cl:15])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)nc(N)n1
Product: CC(C)(C)c1cc(Cl)nc(N)n1

Procedure:
2-Amino-4-hydroxy-6-tert-butylpyrimidine (8.35 g) was dissolved in 50 mL of phosphorus oxychloride and the solution refluxed for 2 hours. Excess phosphorus oxychloride was removed under vacuum and the residue dissolved in 100 mL of ethanol. The solution was adjusted to pH 8 with ice-cold concentrated ammonium hydroxide, and solvent removed under reduced pressure. The residue was filtered to give a white solid, which was recrystallized from ethanol-water to give 2-amino-4-chloro-6-tert-butylpyrimidine (3.66 g), m.p. 87.7-88.90° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][CH:75]([N:78]3[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]3)[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:77][CH2:76][CH:75]([N:78]5[CH2:79][CH2:80][N:81]([CH3:84])[CH2:82][CH2:83]5)[CH2:74][CH2:73]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 60 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-benzaldehyde were reacted to produce the title compound (60%). 1H NMR (d-chloroform): 10.62 (br s, 1H), 8.22 (d, J=9 Hz, 1H), 7.98 (s, 1H), 6.66 (m, 2H), 6.50 (s, 1H), 6.33 (d, J=10 Hz, 2H), 5.07-5.19 (m, 2H), 4.03 (s, 3H), 3.90 (d, J=11 Hz, 2H), 3.49 (s, 2H), 3.17 (s, 1H), 2.89 (m, 4H), 2.65 (m, 4H), 2.46 (m, 4H), 232 (m, 1H), 2.31 (s, 3H), 1.97 (d, J=11 Hz, 2H), 1.60-1.79 (m, 3H). MS: 592.22 (M+H). HPLC retention time: 1.76 minutes (G Method).
Reaction SMILES: Br[C:2]1[S:6][C:5]2[C:7]3[C:27]([C:28](=[O:29])[C:4]=2[C:3]=1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:26][C:25]1[C:12]2[S:13][C:14](Br)=[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:11]=2[C:10](=[O:30])[C:9]=1[CH:8]=3.[CH2:39]([C:47]1[CH:51]=[C:50]([Sn](C)(C)C)[S:49][CH:48]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>[Pd]>[CH2:39]([C:47]1[CH:51]=[C:50]([C:14]2[S:13][C:12]3[C:25]4[C:9]([C:10](=[O:30])[C:11]=3[C:15]=2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][C:7]2[C:5]3[S:6][C:2]([C:2]5[S:6][CH:5]=[C:4]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:9][CH2:10][CH2:11][CH3:12])[CH:3]=5)=[C:3]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:4]=3[C:28](=[O:29])[C:27]=2[CH:26]=4)[S:49][CH:48]=1)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCc1csc([Sn](C)(C)C)c1
Reactant: CCCCCCCCc1c(Br)sc2c1c(=O)c1cc3c(cc12)c(=O)c1c(CCCCCCCC)c(Br)sc13
Agent: [Pd]
Product: CCCCCCCCc1csc(-c2sc3c(c2CCCCCCCC)c(=O)c2cc4c(cc23)c(=O)c2c(CCCCCCCC)c(-c3cc(CCCCCCCC)cs3)sc24)c1
Yield: 72 %

Procedure:
This product is synthesised from 2,7-dibromo-3.8-dioctyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b′]dithiophene-4,9-dione (FL128, 0.65 g, 0.96 mmol) and 3-octyl-5-trimethylstannylthiophene (2.5 eq.) according to the Stille palladium catalysed coupling method as described previously. After which, the product is purified on chromatography column (silica gel, hexane/CHCl3, 7:3) to give 0.62 g (72%) of a green-blue solid.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2]CCCCCCCCCCCC.[CH3:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[C:18]1([C@H:1]([OH:15])[CH3:2])[CH:17]=[CH:16][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCCCCCCCCCCCO
Reactant: CCCCCC
Product: C[C@@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 87 %

Procedure:
To the distillation residue were added 270 g of n-tetradecanol, 450 ml of hexane, and 10 g of Lipase OF. After regulating the particle size of the lipase by ultrasonication in the same manner as above, the mixture was stirred at 50° C. and 350 rpm for 72 hours to carry out interesterification. Hexane was evaporated under reduced pressure from the reaction mixture, and the residue was subjected to simple distillation at 90° C. and 3 mmHg to give highly pure (R)-(+)-1-phenylethanol in a free form (yield: 87%; chemical purity: 100%; optical purity: 100% ee).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[C:8]1([C:7]2[CH:6]=[C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:4]=[N:3][C:2]=2[N:29]2[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1nnc(-c2ccccc2)cc1-c1ccccc1
Reactant: c1cnc(N2CCNCC2)nc1
Product: c1ccc(-c2cc(-c3ccccc3)c(N3CCN(c4ncccn4)CC3)nn2)cc1
Temperature: 130 °C
Reaction time: 72 h
Yield: 81.1 %

Procedure:
A mixture of 3-chloro-4,6-diphenylpyridazine (267 mg, 1.0 mmol), 1-(2-pyrimidyl)piperazine (656 mg, 4.0 mmol) in 3 ml of 1-BuOH was heated with stirring at 130° C. for 3 days. The solvent was removed by evaporation in vacuo the residue was treated with water to give a suspension. The solid was then filtered off, washed with water, dried over filter funnel in vacuo to give light pink solid. (320 mg, 0.81 mmol, yield 81.1%). ESI-MS: m/z 395.5 (M+H+). HRMS calcd 395.1979. Found 395.1973; 1H NMR (CDCl3): d 8.329 (d, J=5.0, 2H), 8.101 (d, J=7.5, 2H), 7.734 (d, J=7.5, 2H), 7.655 (s, 1H), 7.509 (m, 6H), 6.530 (t, 1H), 3.836 (t, J=4.5, J=5.0, 4H), 3.394 (t, J=5.0, J=4.5, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](S)[NH:11][C:12]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][C:12]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc(S)[nH]c2-c2cccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: O
Product: Fc1ccc(-c2nc[nH]c2-c2cccnc2)cc1
Reaction time: 8 h
Yield: 73.3 %

Procedure:
4-(4-Fluorophenyl)-5-(3-pyridyl)-1H-2-imidazolethiol (8.2 g) was added portionwise to a mixture of 30 ml. of 35% nitric acid at room temperature. After stirring overnight, the reaction mixture was diluted with water and made basic with sodium carbonate. The product was extracted into ethyl acetate, which, after drying over potassium carbonate was evaporated to yield 5.3 g of 4-(4-fluorophenyl)-5-(3-pyridyl)imidazole.
Reaction SMILES: [ClH:1].N1C=CC=CC=1.Cl.[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:26]C)=[C:19]([O:24]C)[CH:20]=3)[C:15]=12)#[N:10].Cl>O>[OH2:24].[OH2:24].[ClH:1].[C:9]([C:11]1[S:12][C:13](=[NH:28])[N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([OH:26])=[C:19]([OH:24])[CH:20]=3)[C:15]=12)#[N:10]
Reactant: COc1cc2c(cc1OC)-c1c(C#N)sc(=N)n1CC2
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1sc(=N)n2c1-c1cc(O)c(O)cc1CC2

Procedure:
20.0 g. of pyridine hydrochloride are added to 6.0 g. of 1-cyano-3-imino-8,9-dimethoxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride, and the mixture is kept for 2 hours in an oil bath of 210°-220° C. The mixture is cooled and a mixture of 6 ml. of concentrated hydrochloric acid and 14 ml. of water is added. 5.2 g. of crystalline 1-cyano-3-imino-8,9-dihydroxy-3,4,5,6-tetrahydro-1,3-thiazolo[4,3-a]isoquinoline hydrochloride dihydrate are obtained; m.p.: gradually decomposes from 280° C. (after recryltallization from hot water).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH2:6]1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1coc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 80 °C
Reaction time: 17 h
Yield: 72.2 %

Procedure:
To a mixture of methyl((3S)-6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetate (367 mg) in toluene (5.0 mL) was added DDQ (272 mg). The mixture was stirred at 80° C. for 17 h. After cooling, the insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (263.6 mg).
Reaction SMILES: C(O[C@H]1CNC[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH2:29]([C:31]1[C:32]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:55][CH3:56])[CH2:52][N:51](C(OCC3C=CC=CC=3)=O)[CH2:50]2)=[N:33][C:34]([CH2:46][CH3:47])=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[CH3:45])[N:36]=1)[CH3:30]>>[CH2:55]([O:54][C@H:53]1[CH2:52][NH:51][CH2:50][C@H:49]1[NH:48][C:32]1[C:31]([CH2:29][CH3:30])=[N:36][C:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][C:38]=2[CH3:45])=[C:34]([CH2:46][CH3:47])[N:33]=1)[CH3:56]
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting benzyl (3R,4S)-3-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an amber oil. 1H NMR (CDCl3) δ 1.12, 1.30, 2.12, 2.46, 2.72, 2.92–3.14, 3.36, 3.52, 3.63–3.82, 3.84, 4.18–4.24, 4.71–4.86, 5.11–5.22, 6.78, 6.83, 7.09; IR (diffuse reflectance) 2970 (s), 2933 (s), 2875, 2835, 2493 (b), 2467 (b), 2439 (b), 2353, 2338 (w), 1568 (s), 1563, 1482 (s), 1397 (s), 1393, 1242 (s) cm−1 HRMS (ESI) calcd for C22H32N4O2+H1 385.2603. found 385.2603.