Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([OH:11])=[O:10].S(Cl)(Cl)=O>O1CCCC1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH:8]([CH3:12])[C:9]([O:11][CH2:17][CH2:3][CH2:2][CH2:20][CH3:19])=[O:10]
Reactant: CC(Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCOC(=O)C(C)Oc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionic acid is dissolved in tetrahydrofuran, to this is added thionyl chloride while stirring, then, the mixture is heated while stirring under reflux condition. Then, the solution is allowed to cool, concentrated, then, dissolved in tetrahydrofuran (hereinafter, referred to as Solution A). Tetrahydrofuran is added to 1-pentyl alcohol, and Solution A is added to this, then, pyridine is added. The mixture is stirred at room temperature, then, 2% aqueous hydrochloric acid is poured into the reaction solution, and extracted with ethyl acetate. The organic layer is washed with saturated saline, and dried over magnesium sulfate, then, concentrated. The residue is subjected to silica gel column chromatography (eluent: hexane/ethyl acetate=5/1) to obtain pentyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]propionate [compound 3-189 of the present invention].
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH:29](C(OCC1C=CC=CC=1)=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:11][C:12](=[O:28])[C@H:13]([CH3:27])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([C:49]1[CH:50]=[CH:51][C:52]([C:55]([OH:57])=O)=[N:53][CH:54]=1)#[N:48]>>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[NH:11][C:12](=[O:28])[C@H:13]([CH2:27][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:46])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:55]([C:52]1[CH:51]=[CH:50][C:49]([C:47]#[N:48])=[CH:54][N:53]=1)=[O:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](NC(=O)CCNC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: N#Cc1ccc(C(=O)NCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)nc1

Procedure:
N-[3-[(Benzyloxy)carbonyl]-N-[N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester was deprotected and coupled with 5-cyano-2-pyridinecarboxylic acid to give N-[3-[(benzyloxy)carbonyl]-N-[N-[(5-cyano-2-pyridyl)carbonyl]-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 157°-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:12][CH3:13])[CH2:7][CH2:6][CH:5]([C:8](OC)=[O:9])[CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:13][O:12][C:3]1([O:2][CH3:1])[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4]1
Reactant: COC(=O)C1CCC(OC)(OC)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(OC)CCC(CO)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
A solution of methyl 3,3-dimethoxycyclopentanecarboxylate, methyl 3,3-dimethoxycyclopentanecarboxylate (14.68 g, 78 mmol), in THF (100 mL) was cooled (0° C. ice bath) and treated with 1.0N lithium aluminum hydride in THF (74.1 mL, 74.1 mmol) by dropwise addition. Upon completion of the addition, the reaction was warmed to room temperature and stirred for 6 hrs. The reaction was quenched by slow addition of Na2SO4-10H2O (17 g). The suspension was stirred for 1 hr, treated with anhyd. Na2SO4, and filtered. The filtrate was concentrated to afford the target compound (12.01 g, 75.0 mmol, 96% yield) as a colourless oil. 1H NMR (500 MHz, CDCl3) δ ppm 3.54 (2 H, s), 3.20 (3 H, s), 3.19 (3 H, s), 2.21-2.32 (1 H, m), 1.99 (1H, dd, J=13.28, 9.00 Hz), 1.85-1.91 (1 H, m), 1.78-1.85 (2 H, m), 1.73-1.78 (1 H, m), 1.56 (1 H, dd, J=13.12, 7.32 Hz), 1.40-1.48 (1 H, m).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[CH:10]([OH:14])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.N(C1CCN(C)C(C)(C)C1C)C(C)=O>ClCCl>[C:1]([C:5]1[CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]2[O:12][C:11](=[O:13])[C:10](=[O:14])[C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Agent: CC(=O)NC1CCN(C)C(C)(C)C1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2=O
Yield: 26.3 %

Procedure:
3.8 g (0.0146 mol) of 5,7-di-tert-butyl-3-hydroxy-benzofuranone, 6.1 g (0.032 mol) of p-toluenesulfonic acid and 6.9 g (0.032 mol) of 4-acetamino-tetramethylpiperidine (TEMPO) are stirred in 100 ml of dichloromethane at room temperature for 24 hours. The yellow solution is then washed three times with 200 ml of 5% hydrochloric acid each time, dried over magnesium sulfate and concentrated to dryness by evaporation. Crystallisation of the residue from hexane yields 1 g of the above-mentioned compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]([CH3:31])[C:28](Cl)=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:26][N:27]([CH3:31])[C:28](=[O:29])[O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione with N,N-dimethylcarbamoyl chloride and triethylamine in toluene there is obtained 2-[2-chloro-5-[3,6-dihydro-2,6 -dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4 -fluorophenoxy]-ethyl N,N-dimethylcarbamate, 1H-NMR (CDCl3, 400 MHz): 7.31 ppm (d,1H), 6.81 ppm (d,1H), 6.36 ppm (s,1H), 4.40°-4.47 ppm (m,2H), 4.16°-4.22 ppm (m,2H), 3.56 ppm (d,3H), 2.92 ppm (s,3H), 2.89 ppm (s,3H);
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[CH3:7][N:8]([CH3:31])[NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])[NH:16][C:17]2=[O:20])=[CH:12][CH:11]=1.C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:29][C:27]([F:28])([F:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:15]1[NH:16][C:17](=[O:20])[C:18]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([N:9]([CH3:3])[N:8]([CH3:31])[CH3:7])[CH:19]=2
Reactant: [BH3-]C#N
Reactant: CN(C)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)N(C)c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
0.1 ml of acetic acid, 26.2 μl of a 37% formalin aqueous solution, and 25.3 mg (0.403 mmol) of sodium cyanoborohydride were added to 1 ml of a methanol solution containing 28 mg of the 7-(2,2-dimethylhydrazino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 149. The obtained mixture was stirred at a room temperature overnight. Thereafter, a saturated sodium bicarbonate aqueous solution was added to the reaction solution. The mixture was extracted with ethyl acetate, and was then dried over anhydrous sodium sulfate. The extract was concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 2:1), so as to obtain 25.5 mg (88%) of 3-(2-trifluoromethylphenyl)-7-(1,2,2-trimethylhydrazino)-2H-isoquinolin-1-one in the form of a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([C:11](=[O:23])[C:12]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15])[C:6]([O:8]CC)=O)[CH3:2]>CS(O)(=O)=O>[OH:8][C:6]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH3:22])([CH2:13][CH2:14][CH3:15])[C:11](=[O:23])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:24]
Reactant: CCCC(C)(C(=O)C(C(=O)OCC)C(=O)OCC)c1ccccc1
Agent: CS(=O)(=O)O
Product: CCCC1(C)C(=O)C(C(=O)OCC)=C(O)c2ccccc21
Yield: 63.4 %

Procedure:
2-(2-methyl-2-phenyl-pentanoyl)-malonic acid diethyl ester (2.45 g, 7.33 mmol) was stirred in methanesulfonic acid (20 mL) at 25° C. for 3 hours. The solution was partitioned cold water and ethyl acetate and the aqueous phase was extracted three times with ethyl acetate. The ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 5%, 10%, and 20% ethyl acetate in hexane to give the title compound (1.34 g, 63%). 1H NMR (300 MHz, CDCl3) δ ppm 0.72 (m, 4 H) 0.96 (m, 1 H) 1.46 (m, 3 H) 1.63 (s, 3 H) 1.74 (m, 0.5 H) 1.92 (m, 0.5 H) 2.26 (m, 1 H) 4.47 (m, 2 H) 7.42 (m, 2 H) 7.59 (m, 1 H) 8.16 (m, 0.5 H) 8.23 (m, 0.5 H) 15.10 (s, 0.5 H) 15.16 (s, 0.5 H). (ESI+) m/z 289 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH:3]=[CH2:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH2:8][CH2:7]1.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([NH:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C=CCCNC(=O)CCC(=O)O
Reaction time: 16 h

Procedure:
A mixture of 0.71 g (10 mmol) but-3-enylamine and 1.0 g (10 mmol) succinic anhydride in 10 ml DCM is stirred for 16 h. The mixture is poured into 25 ml 1N NaOH, washed with TBME, acidified with 6 ml 6N HCl, saturated with NaCl and extracted with THF/EtOAc twice. The combined organic layers are dried with sodium sulfate and evaporated to yield the title compound.
Reaction SMILES: C([O-])(=O)C1C(=CC=CC=1)C(N)=[O:5].[CH2:13]([P+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].C1(=O)NC(=O)C2=CC=CC=C12>>[OH-:5].[CH2:26]([P+:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH3:29]
Reactant: NC(=O)c1ccccc1C(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C1NC(=O)c2ccccc21
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrabutylphosphonium phthalamate is also prepared in the following way. A solution of tetrabutylphosphonium hydroxide (12.5 g; 40% in water) is prepared. Then phthalimide (2.7 g) is added, and the reaction solution is stirred at room temperature overnight. The water is then removed in a rotary evaporator, and the residue is taken up in toluene. The toluene is removed in a rotary evaporator, and the residue is again taken up in toluene. This procedure is repeated 4-5 times. The solvent is then removed to dryness. 1H-NMR (d6-DMSO) 0.9 (t, 12 H), 1.42 (m, 16 H), 2.18 (m, 8 H), 7.05 (b, 1 H), 7.18 (m, 1 H), 7.29 (d, 2 H), 7.74 (d, 1 H), 10.35 (b, 1 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([NH:12][CH2:13][CH2:14][OH:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>ClCCl>[CH2:5]([N:12]([CH2:13][CH2:14][OH:15])[C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Cl
Reactant: OCCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.5 %

Procedure:
Acetyl chloride (0.858 g, 10.8 mmol) was added drop by drop to a solution of N-benzyl ethanol amine (1.5 g, 9.9 mmol) and triethylamine (1.5 g, 14.9 mmol) in dry dichloromethane (20 ml) at 0° C. under nitrogen atmosphere and stirred at room temperature overnight. The reaction was quenched with water and extracted with dichloromethane. The organic layer was washed with water, 10% aq. NaHCO3, brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel using 5% methanol in dichloromethane as eluent afforded 0.68 g of the desired product as an oil.
Reaction SMILES: Cl.[I:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].ClC1C(CO)=CC(F)=C(Cl)N=1>>[I:2][C:3]1[CH:11]=[N:10][CH:9]=[CH:8][C:4]=1[CH2:5][OH:6]
Reactant: O=C(O)c1ccncc1I
Agent: Cl
Agent: OCc1cc(F)c(Cl)nc1Cl
Product: OCc1ccncc1I
Yield: 33 %

Procedure:
Compound 24A (142 mg, 33%) was prepared from 3-iodo-isonicotinic acid hydrochloride (522 mg, 1.83 mmol) ) using a procedure similar to the synthesis of 1A. HPLC Rt=0.34 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: Nc1ccccc1B(O)O
Product: Nc1ccccc1-c1cccc(C(=O)O)n1

Procedure:
Preparation analogous to Ex. 10, A, using 110 mmol of 2-aminophenylboronic acid [5570-18-3] instead of 110 mmol of 3-carboxybenzeneboronic acid, and using 100 mmol of 6-bromopyridine-2-carboxylic acid [21190-87-4] instead of 100 mmol of 1-bromo-2-aminonaphthalene. Yield: 17.5 g (82 mmol), 81.7%; purity according to 1H-NMR about 99%.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([O:12][CH2:13][C@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3C(OC(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][C:3]1=2.FC(F)(F)C(O)=O>ClC(Cl)C>[NH:15]1[CH2:16][CH2:17][CH2:18][C@@H:14]1[CH2:13][O:12][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:8]=1[CH2:9][CH2:10][CH2:11][C:2]2=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc2c1CCCC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: O=C1CCCc2c(OC[C@H]3CCCN3)cccc21

Procedure:
13.2 6.5 g of tert-butyl (R)-2-(5-oxo-5,6,7,8-tetrahydronaphthalen-1-yloxy-methyl)pyrrolidine-1-carboxylate are reacted with trifluoroacetic acid in dichloroethane and worked up as described, giving 4.1 g of 5-((R)-1-pyrrolidin-2-ylmethoxy)-3,4-dihydro-2H-naphthalen-1-one; Rt.: 1.325 min; [M-1-H]+246.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:7][N:8]2[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CN1CC(CC(=O)OC)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1CC(CC(=O)OC)c2c(N)cccc21
Reaction time: 3 h

Procedure:
A mixture of (±)-ethyl methyl 2,2′-(4-nitro-2,3-dihydro-1H-indole-1,3-diyl)diacetate from Step C (550 mg, 1.7 mmol) and 10% Pd/C (40 mg) in EtOH (10 mL) was stirred under an atmosphere of hydrogen (ca. 1 atm). After 3 h, the reaction was filtered through a Celite pad and concentrated in vacuo to give the title compound. MS: m/z=293 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].CS(O[CH2:11][CH2:12][CH2:13][N:14]([C:16]([O:18][CH:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:17])[CH3:15])(=O)=O>CCO.C(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:11][CH2:12][CH2:13][N:14]([CH3:15])[C:16](=[O:17])[O:18][CH:19]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]/[CH:46]=[CH:47]\[CH2:48]/[CH:49]=[CH:50]\[CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCOS(C)(=O)=O
Reactant: CCNCC
Solvent: CCO
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)N(C)CCCN(CC)CC
Reaction time: 50 h
Yield: 42 %

Procedure:
A solution of diethylamine (2 mL) in EtOH (10 mL) was treated with 3-((((6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yloxy)carbonyl)(methyl)amino)propyl methanesulfonate (500 mg, 0.7 mmol) in CH2Cl2 (2.5 mL). The solution was stirred (50 h), concentrated and subjected to chromatography (EtOAc) to yield (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl (3-(diethylamino)propyl)(methyl)carbamate (207 mg, 42%) as a pale yellow oil. Rf 0.43 (10% CH3OH—CH2Cl2), 1H NMR (400 MHz, CDCl3, δH) 5.41-5.28 (m, 8H, C═CH×8), 4.79-4.70 (m, 1H, CHO2CNR2), 3.28 (br. s, 2H, CH2NCH3), 2.94-2.83 (br. s, 3H, CO2NCH3), 2.79 (app. t, 4H, bis-allylic CH2×2), 2.52 (q, 4H, N(CH2CH3)2), 2.09-2.01 (m, 8H, CH2HC═C×4), 1.75-1.65 (m 4H, CH2×2), 1.59-1.45 (m, 4H, CH2×2), 1.42-1.22 (m, 36H, CH2×18), 1.15 (t, 6H, N(CH2CH3)2), 0.90 (t, 6H, CH3×2). FW 699.19, C46H86N2O2.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH:10]=[C:11]3[N:15]([C:8]=2[CH:7]=[CH:6][N:5]=1)[CH2:14][CH2:13][C:12]3=O)([CH3:3])=[CH2:2].[H-].[Na+].[NH4+].[Cl-].[CH3:21][CH2:22][O:23][C:24]([CH3:26])=[O:25]>C1COCC1>[C:1]([C:4]1[C:9]2[CH:10]=[C:11]3[N:15]([C:8]=2[CH:7]=[CH:6][N:5]=1)[CH2:14][CH2:13]/[C:12]/3=[CH:26]\[C:24]([O:23][CH2:22][CH3:21])=[O:25])([CH3:3])=[CH2:2]
Reactant: CCOC(C)=O
Reactant: C=C(C)c1nccc2c1cc1n2CCC1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)c1nccc2c1cc1n2CC/C1=C\C(=O)OCC
Temperature: 0 °C

Procedure:
To a solution of 1-isopropenyl-6,7-dihydro-8H-pyrido[3,4-b]pyrrolizin-8-one (0.60 g, 2.8 mmol) and triethyl phosphonoacetate (1.00 g, 4.46 mmol) in THF (24 mL) at −78° C. was added 80% NaH (0.12 g, 4.00 mmol), the reaction mixture was allowed to warm to 0° C., then to room temperature. The reaction mixture was poured onto saturated NH4Cl and EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated. The title compound was purified by flash chromatography (40% EtOAc in Hexane).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:38])([S:34](F)(=[O:36])=[O:35])[C:24]([F:33])([F:32])[C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27].C(OC)(C)(C)C.N12CCCN=C1CCCCC2>O>[F:29][C:26]([F:27])([F:28])[C:25]([F:30])([F:31])[C:24]([F:32])([F:33])[C:23]([F:38])([F:22])[S:34]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1)(=[O:35])=[O:36]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCCCCc1cnc(-c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 16 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
A 12 liter flask fitted with a mechanical stirrer, a constant addition funnel, a thermometer, and a reflux condenser was charged with of 5-octyl-2-(4-hydroxyphenyl)pyrimidine (300 g, 1.05 mol), perfluorobutanesulfonyl fluoride (378 g, 1.25 mol), and tert-butylmethylether (3 L) under positive nitrogen pressure and was cooled with an ice bath to 16° C. 1,8-Diazabicyclo[5.4.0]undec-7-ene (180 g, 1.18 mol) was added to the resulting mixture over 25 minutes, while maintaining the temperature of the mixture below 20° C. After the addition was complete, the mixture was stirred at room temperature for 2 hours, and then 3 liters of water was added. The resulting aqueous phase was separated from the resulting organic phase, and the organic phase was washed with a mixture of 2.25 liters of water and 0.75 liters of concentrated HCl. The solvent was removed from the organic phase under reduced pressure to yield 697 g of crude product, which was recrystallized from ethanol to yield 4-(5-octyl pyrimidine-2-yl)phenyl nonafluorobutane sulfonate (499 g, 84% yield).
Reaction SMILES: [N:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:22][C:23]1[C:28]2[C:29](=[O:43])[N:30]3[CH2:42][CH2:41][C@H:31]3[C:32]3[N:33]([CH:34]=[N:35][C:36]=3[C:37](=[N:39]O)[NH2:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O>[Cl:22][C:23]1[C:28]2[C:29](=[O:43])[N:30]3[CH2:42][CH2:41][C@H:31]3[C:32]3[N:33]([CH:34]=[N:35][C:36]=3[C:37]3[N:39]=[C:7]([CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[O:9][N:38]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CN1CCCC1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CN4CCCC4)n3)c2[C@@H]2CCN12
Reaction time: 8 h
Yield: 31.7 %

Procedure:
2.55 g (13.5 mmol) of 1-pyrrolidine-acetic acid were dissolved in 20 ml of N,N-dimethylformamide and treated portionwise with 2.6 g (15.9 mmol) of 1,1'-carbonyldiimidazole. After stirring for 45 minutes 3.9 g (12.3 mmol) of (S)-8-chloro-12,12a-dihydro-9-oxo-9H,11H- azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° overnight. 0.2 g of p-toluenesulphonic acid was added and the mixture was stirred at 90° for a further 4 hours. The reaction mixture was concentrated. By chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 and recrystallization from ethyl acetate and hexane there were obtained 1.6 g (32%) of (S)-8-chloro-12,12a-dihydro-1-[5-(pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 117°-120°, which was converted into the hydrochloride.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:18])[CH2:6]1)C.Cl.[C:20]([NH2:25])(=[NH:24])[CH:21]([CH3:23])[CH3:22]>>[CH3:17][C:14]1[CH:15]=[CH:16][C:9]2[NH:8][C:7](=[O:18])[CH2:6][C:5]3[CH:4]=[N:24][C:20]([CH:21]([CH3:23])[CH3:22])=[N:25][C:11]=3[C:10]=2[CH:13]=1
Reactant: CC(C)C(=N)N
Reactant: Cc1ccc2c(c1)C(=O)C(=CN(C)C)CC(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)-c1nc(C(C)C)ncc1CC(=O)N2
Yield: 91 %

Procedure:
Analogous to Scheme 1 from 4-[(dimethylamino)methylene]-3,4-dihydro-7-methyl-1H-benzazepine-2,5-dione and isobutyramidine hydrochloride. Yield: 91%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15][N:16](C)C)[C:10]([O:12]CC)=O)=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([NH:36]N)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[C:10]([OH:12])=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[O:19][CH3:20])[CH:15]=[N:16]2)=[N:32][CH:31]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCc3ccccc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and N-benzyl-6-hydrazinylnicotinamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3 H) 4.53 (d, J=5.6 Hz, 2 H) 7.27 (d, J=3.8 Hz, 1 H) 7.36 (d, J=4.0 Hz, 5 H) 7.42-7.59 (m, 2 H) 8.47 (d, J=6.6 Hz, 1 H) 8.98 (s, 1 H) 9.28 (br. s., 1 H). MS m/z [M+H]+ 426.4.
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](O)=[O:6])([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>>[CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5]([Cl:17])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Reactant: O=S(Cl)Cl
Product: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1

Procedure:
10 g of the product of Step D were added to a mixture of 50 ml of petroleum ether (b.p.=35°-70° C.) and 20 ml of thionyl chloride and the mixture was refluxed for 4 hours and was then cooled. The mixture was evaporated to dryness to obtain 10.8 g of D 2-isopropyl-2-p-chlorophenyl acetyl chloride.