Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([O:12][CH3:13])=[O:11])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)ccn1
Reaction time: 8 h
Yield: 94.1 %

Procedure:
A solution of methyl 4-nitropyridin-2-ylcarboxylate (0.7 g) (Deady et. al., Aus. J. Chem. 24 (1971)385-390) in methanol (30 ml) was treated with 10% Pd/C (0.3 g) and stirred under hydrogen at atmospheric pressure overnight. The solution was filtered and evaporated to yield the title compound (0.55 g). NMR δ(CDCl3) 3.97(3H,s), 4.34(2H, broad), 6.65(1H,dd), 7.39(1H,d), 8.32(1H,d).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C[Sn](C)(C)[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]([N:29]2[CH2:32][CH2:31][CH2:30]2)=[O:28])[CH:26]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]([N:29]4[CH2:30][CH2:31][CH2:32]4)=[O:28])[CH:26]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Reactant: C[Sn](C)(C)c1cncc(C(=O)N2CCC2)c1
Product: CCCNC(=O)c1nnc2c(-c3cncc(C(=O)N4CCC4)c3)cccc2c1N
Yield: 43.9 %

Procedure:
Using method D, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.28 mmol) and 3-trimethylstannyl-5-(azetidin-1-ylcarbonyl)-pyridine (182 mg, of 80%, 0.45 mmol) were reacted to afford the title compound (48 mg, 44.0% yield) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.89 (s, 1H), 8.51 (br, 1H), 8.40 (s, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.72-7.88 (m, 2H), 4.46 (br, 2H), 4.28 (br, 2H), 3.48 (q, J=6.7 Hz, 2H), 2.40 (m, J=7.8 Hz, 2H), 1.69 (m, J=7.3 Hz, 2H), 1.02 (t, J=7.4 Hz, 3H). MS APCI, m/z=391 (M+H). HPLC 1.74 min.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[N:14])=[N:11][CH:12]=2)[CH2:3]1.[OH:15][Li].O>OO>[OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH2:14])=[O:15])=[N:11][CH:12]=2)[CH2:3]1
Reactant: N#Cc1ccc(N2CCC(O)C2)cn1
Reactant: [Li]O
Agent: OO
Solvent: O
Product: NC(=O)c1ccc(N2CCC(O)C2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
A mixture of 5-(3-hydroxypyrrolidin-1-yl)picolinonitrile (2.7 g, 14.3 mmol) in H2O2 (30 mL) was added LiOH.H2O (1.8 g, 42.9 mmol) and the mixture was stirred at rt for 16 h. The precipitate was collected by filtration and the cake was washed with water (20 mL) to give the desired product (2.2 g, 74%) as a yellow solid. [LCMS: RtA=1.05 min, m/z 208.2 [M+H]+].
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=[CH:16][C:3]1=2.[CH2:20]([N-:22][CH2:23][CH3:24])[CH3:21]>>[CH2:20]([N:22]([CH2:23][CH3:24])[C:17]([C:14]1[CH:15]=[CH:16][C:3]2[C:2](=[O:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=1)=[O:18])[CH3:21]
Reactant: O=C(O)c1ccc2c(c1)OCc1ccccc1C2=O
Reactant: CC[N-]CC
Product: CCN(CC)C(=O)c1ccc2c(c1)OCc1ccccc1C2=O

Procedure:
A sample of compound 4c (5.5 g, 21.6 mmol) was converted to its corresponding diethylamide (4.28 g, 13.8 mmol) following an adaptation of Procedure 6.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13]OC(OC)N(C)C>CN(C)C=O>[CH3:13][N:7]1[C:8]2[C:3](=[C:2]([CH3:1])[N:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:12]
Reactant: COC(OC)N(C)C
Reactant: Cc1nccc2[nH]c(=O)ccc12
Solvent: CN(C)C=O
Product: Cc1nccc2c1ccc(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
E-9. 1,5-Dimethyl-1,6-naphthyridin-2(1H)-one--A mixture containing 4.5 g of 5-methyl-1,6-naphthyridin-2(1H)-one, 15 ml of dimethylformamide and 4 ml of dimethylformamide dimethyl acetal was stirred at room temperature overnight, then heated on a steam bath for 7 hours and then evaporated to dryness on a rotary evaporator. The solid residue was recrystallized from isopropyl alcohol and dried at 90°-95° C. to yield 3.5 g of 1,5-dimethyl-1,6-naphthyridin-2(1H)-one, m.p. 203°-205° C.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][N:13]=[C:12]2[NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:22]([CH3:33])[CH:21]=1)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C1(C)C=CC=CC=1>[CH3:33][C:22]1[CH:21]=[C:20]([NH:19][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([C:8]#[C:7][CH2:6][NH:5][C:3](=[O:4])[CH2:2][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[CH:10]=3)[N:15]=[CH:14][N:13]=2)[CH:25]=[CH:24][C:23]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CCl)cc23)ccc1Oc1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2ncnc3ccc(C#CCNC(=O)CN4CCOCC4)cc23)ccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-Chloro-N-{3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide (63 mg; 0.12 mmol) in toluene (10 ml) was added 3 equivalents of morpholine (31 mg) and the mixture heated at reflux overnight. The reaction was cooled to room temperature and the morpholine salts were filtered out and the solvent removed from the filtrate. The residue was redissolved in CH2Cl2 with a small amount of methanol and HCl gas was bubbled through the solution for 2-3 minutes. The solution was then concentrated to 2-3 ml, diluted with ethyl acetate and filtered to obtain N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-2-morpholin-4-yl-acetamide as a yellow/brown solid (65 mg; 94%). 1H NMR (400 MHz; CD3OD) δ 2.27 (3H, s), 3.21 (2H, m), 3.56 (2H, m), 3.87 (2H, m), 4.04 (2H, m), 4.09 (2H, s), 4.36 (2H, s), 6.93 (3H, d, J=8.4), 7.09 (1H, t, J=7.4 Hz), 7.34 (2H, t, J=8 Hz), 7.54 (1H, dd), 7.65 (1 H, s), 7.82 (1H, d, J=8.8 Hz), 8.06 (1H, d, J=8.4 Hz), 8.76 (1H, s), 8.80 (1H, s). Irms(M+): 508.0; (M−): 506.0.
Reaction SMILES: O[C@H:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CCN(S(F)(F)[F:25])CC>C(Cl)Cl>[F:25][CH:2]1[C@H:6]([O:7][CH3:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: CO[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: ClCCl
Product: CO[C@@H]1CN(C(=O)OCc2ccccc2)CC1F
Temperature: -20 °C
Yield: 66.7 %

Procedure:
To a solution of benzyl (3R,4R)-3-hydroxy-4-methoxypyrrolidine-1-carboxylate (0.818 g, 3.26 mmol) in 20 mL CH2Cl2 at −20° C. was added DAST (0.946 mL, 7.16 mmol). The reaction mixture was stirred at −20 ° C. and then room temperature overnight. The reaction mixture was quenched with 30 mL half saturated NaHCO3, stirred at room temperature for 15 min and extracted with EtOAc (2×30 mL). The organic layer was dried and concentrated. The residue was purified by flash column chromatography (25% EtOAc in Hexane) to give pale yellow solid (0.551 g, 67%). 1H NMR (CDCl3) δ 7.36-7.29 (5H, m), 5.13 (2H, s), 5.09, 4.92 (1H, m), 3.95-3.91 (1H, m), 3.74-3.35 (4H, m), 3.37 (3H, s).
Reaction SMILES: Br[CH2:2][CH2:3][S:4]([O-:7])(=[O:6])=[O:5].[Na+].[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O>[S:4]([CH2:3][CH2:2][NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=1)([OH:7])(=[O:6])=[O:5]
Reactant: O=S(=O)([O-])CCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCS(=O)(=O)O)cc1

Procedure:
A solution of 4.1 g. of sodium 2-bromoethanesulfonate and 7.9 g. of ethyl 4-aminobenzoate in 110 ml. of hexamethylphosphoramide is stirred at 125° for 18 hours and then poured into dilute hydrochloric acid. The solid is collected by filtration, dried and recrystallized from acetonitrile to yield ethyl 4-(2-sulfoethylamino)benzoate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:20](O)=[O:21])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].S(Cl)(Cl)=O.Cl[CH2:28][CH2:29]Cl>CN(C)C=O>[CH2:12]([N:8]([CH2:7][C:29]1[CH:28]=[CH:4][CH:6]=[CH:10][CH:9]=1)[C:20]([C:6]1([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:9](=[O:11])[N:8]([C@@H:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(C(=O)O)CC(=O)N([C@@H](C)c2ccccc2)C1
Reactant: ClCCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)N(Cc2ccccc2)Cc2ccccc2)CC(=O)N([C@@H](C)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(RS)-3-Ethoxycarbonyl-1-((S)-α-methylbenzyl)-5-oxopyrrolidine-3-carboxylic acid (30.5 g) was dissolved in 1,2-dichloroethane (92 ml), and thionyl chloride (11 ml) and one drop of N,N-dimethylformamide were added. The mixture was refluxed for 2 hours and the reaction mixture was concentrated under reduced pressure. The obtained oil was dissolved in toluene (39 ml) and the mixture was dropwise added to a solution of dibenzylamine (23.7 g) and triethylamine (12.2 g) in toluene (130 ml) under ice-cooling. The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, a sodium hydrogencarbonate-10% aqueous hydrochloric acid solution and water, and dried over anhydrous magnesium sulfate to give the object compound.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Brc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(Cn2ccc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of sodium hydride (60% oil dispersion, 112 mg, 2.81 mmol) in THF (12 mL) was stirred at rt and treated with a solution of 4-bromo-1H-indole (500 mg, 2.55 mmol) in THF (3 mL). After 1-2 min, the mixture was treated with 4-fluorobenzyl bromide (0.318 mL, 2.55 mmol) and the slightly cloudy solution was stirred at rt. After 20 h, the mixture was concentrated. The residue was partitioned between EtOAc and 0.1 M hydrochloric acid, and the aqueous phase was again extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 90:10 to 50:50 hexane-EtOAc) to provide 4-bromo-1-(4-fluorobenzyl)-1H-indole as a colorless oil (461.4 mg, 85% purity, 51%) contaminated by ca. 15% by weight of 4-bromo-1,3-bis(4-fluorobenzyl)-1H-indole. 1H NMR (400 MHz, chloroform-d) δ 7.28 (1 H, dd, J=7.6, 0.8 Hz), 7.19 (1 H, d, J=8.4 Hz), 7.16 (1 H, d, J=3.3 Hz), 6.94-7.09 (5 H, m), 6.60 (1 H, dd, J=3.1, 0.9 Hz), 5.28 (2 H, s). Mass spectrum m/z 304, 306 (M+H)+.
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]/[C:9]([OH:11])=O.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>ClCCl>[OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]/[C:9]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:11]
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)O)CO
Reactant: C1COCCN1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/C(=O)N1CCOCC1)CO

Procedure:
Following the same manner as in Example 5, the reaction and after-treatment were conducted by using 400 mg of (E,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid, 0.16 ml of triethylamine, 0.13 ml of ethyl chlorocarbonate and 0.20 ml of morpholine in 10 ml of dichloromethane to afford 210 mg of the end product.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2].[S:20](Cl)(=[O:23])(=[O:22])[NH2:21]>>[C:1]([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[C:16]#[N:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(C)(C)COc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CC(=O)OCC(C)(C)COc1cccc(NS(N)(=O)=O)c1C#N
Yield: 60 %

Procedure:
Prepared as in Example 215a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Example 233b) and sulfamoyl chloride in 60% yield. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (s, 6H), 1.98 (s, 3H), 3.85 (s, 2H), 3.91 (s, 2H), 6.91 (d, J=8.4 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 7.23 (s, 2H), 7.52 (t, J=8.0 Hz, 1H), 9.45 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:15])=[C:4]([C:11](=O)[CH2:12][CH3:13])[C:5](=[O:10])[O:6][C:7]=1[CH2:8][CH3:9].[CH2:16]([O:18][NH2:19])[CH3:17]>C(O)C>[Br:1][C:2]1[C:3](=[O:15])[C:4](=[C:11]([NH:19][O:18][CH2:16][CH3:17])[CH2:12][CH3:13])[C:5](=[O:10])[O:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCC(=O)c1c(O)c(Br)c(CC)oc1=O
Reactant: CCON
Solvent: CCO
Product: CCONC(CC)=C1C(=O)OC(CC)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.4 g of 5-bromo-6-ethyl-4-hydroxy-3-propionyl-pyrone (a melting point of 76.5° C to 77.5° C) was dissolved in 10 c.c. of ethanol and further 0.5 g of ethoxyamine was added in it and the resulting solution was agitated at room temperature during 4 hours. Further, it was agitated at a temperature of 40°-50° C during 30 minutes. Then, above ethanol was distilled off from the resulting reaction mixture under a reduced pressure and thereby, a crude white crystal was obtained. Further, the crude white crystal was recrystallized by using n-hexane and thus, a white spicular crystal was obtained as an objective compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](Cl)=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=C([C@@H](CC2CCCC2)[C:49]([NH:51]C2C=CN(CC3C=C(C=CC=3)C(N)=O)N=2)=O)C=CC=1S(C)(=O)=O.CN.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:51][CH3:49])=[O:26])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(=O)Cl)c3)n2)cc1Cl
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(C(N)=O)c3)n2)cc1Cl
Agent: CN
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a 0.166 M solution of crude 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoyl chloride in methylene chloride (prepared in Example 63, 1.71 mL, 0.28 mmol) was added a 40% solution of methylamine in water (250 μL, 0.32 mmol) and the reaction stirred at 25° C. for 30 min. The solution was diluted with methylene chloride (40 mL), washed with water (2×20 mL), saturated aqueous brine solution (2×20 mL), dried over magnesium sulfate and concentrated in vacuo to an off white foam. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 0% ethyl acetate/methylene chloride to 100% ethyl acetate/methylene chloride) afforded 3-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-methyl-benzamide (61 mg, 39%) as a white powder: ESI-LRMS m/e calcd for C27H31ClN4O4S [M+] 542.18, found 543.16 [M+H+]; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.15 (m, 2H, CH2), 1.34-1.79 (m, 8H, 4×CH2), 2.00-2.17 (m, 1H, CH), 2.75 (d, J, 4.5 Hz, 3H, NCH3), 3.32 (s, 3H, SO2CH3), 3.82-3.90 (m, 1H, CH), 5.21 (s, 2H, NCH2), 6.45 (d, J=2.3 Hz, 1H, Ar), 7.28-7.34 (m, 1H, Ar), 7.38 (t, J=7.8 Hz, 1H, Ar), 7.55 (dd, Jo=8.3, Jm=1.6 Hz, 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.67-7.71 (m, 2H, Ar), 7.72 (d, J=2.3 Hz, 1H, Ar), 7.97 (d, Jo=8.3 Hz, 1H, Ar), 8.33-8.45 (brm, 1H, NH), 10.76 (s, 1H, NH).
Reaction SMILES: [CH2:1]([OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16]C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:18][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:21])[CH3:20]
Reactant: CCCCC/C=C\CCCCCCCCCCO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC/C=C\CCCCCCCCCCOC(C)=O
Yield: 40 %

Procedure:
The obtained (Z)-11-hexadecenol (Formula II, R=H) is added to a mixture of 5 ml. of dry pyridine and 4 ml. of acetic anhydride, and the mixture is stirred at 0° C. for 3 hours. The solution is poured onto ice and extracted with methylene chloride. The extract is washed with water, 3% aqueous sulfuric acid and again with water, dried over magnesium sulfate, filtered, and the solvent is evaporated. The residue is distilled in fine vacuo. 2.2 g (40%) of (Z)-11-hexadecenyl acetate (Formula I, R=H) are obtained; the product is identical with the substance obtained according to step (A) above.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:23]2.O[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH3:35][CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1)=[CH:28][CH:27]=2)[C:31]([OH:33])=[O:32]
Reactant: COC(=O)C(C)Cc1cc2cc(O)ccc2[nH]1
Reactant: OCCCNc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.7 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.13 g, 0.57 mmol) was added to the solution of methyl 3-(5-hydroxyindolyl)-2-methylpropanoate (0.062 g, 0.27 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.06 g, 0.40 mmol), as prepared in step b of Example 1, and tri-n-butylphosphine (0.11 g, 0.53 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated and the residue was purified by flash chromatography on silica gel (10%-50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.015 g, 15%). 1H-NMR (400 MHz, CDCl3) δ 8.07 (m, 1H), 7.40 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.04 (d, J=3.1 Hz, 1H), 6.88 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.41 (m, 1H), 4.89 (br s, 1H), 4.45 (dd, J=14.2, 7.3 Hz, 1H), 4.10 (m, 4H), 3.63 (s, 3H), 5.52 (q, J=6.5 Hz, 2H), 2.13 (m, 2H), 1.66 (m, 1H), 1.52 (m, 1H), 1.16 (d, J=7.1 Hz, 3H), 0.93 (m, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:13][N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:11][CH:10]2[CH2:34][O:35][CH3:36])=[CH:5][CH:4]=1.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)[CH2:13][N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:11][CH:10]2[CH2:34][O:35][CH3:36])=[CH:5][CH:4]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: BrCc1ccccc1
Reactant: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(CO)cc1
Product: COCC1CN(C(=O)OC(C)(C)C)CC(OCc2ccc3ccccc3c2)C1c1ccc(COCc2ccccc2)cc1

Procedure:
(ddd) In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3SR,4RS,5RS)-4-(4-hydroxymethyl-phenyl)-3-methoxymethyl-5-(naphthalen-2-yl-methoxy)-piperidine-1-carboxylate with benzyl bromide there was obtained tert-butyl (3SR,4RS,5RS)-4-(4-benzyloxymethyl-phenyl)-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 582 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[Cl:14][C@H:15]1[C@H:19]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@@H:18]([CH2:29][O:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=2)[C@H:17]([OH:39])[CH2:16]1.O[CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(Cl)Cl>[N:43]1([CH2:42][CH2:41][O:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23]/[CH:22]=[CH:21]\[CH2:20][C@H:19]2[C@H:15]([Cl:14])[CH2:16][C@@H:17]([OH:39])[C@@H:18]2[CH2:29][O:30][C:31]2[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1
Reactant: OCCN1CCOCC1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC/C=C\C[C@@H]1[C@@H](COc2cc(Cl)cc(Cl)c2)[C@H](O)C[C@H]1Cl)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 20.3 %

Procedure:
Triethylamine (6.5 μL, 0.047 mmol) and ethyl chloroformate (7 μL, 0.073 mmol) were added sequentially to a solution of (Z)-7-[(1R,2S,3R,5R)-5-chloro-2-(3,5-dichloro-phenoxymethyl)-3-hydroxy-cyclopentyl]-hept-5-enoic acid (see U.S. 60/644,069, 20 mg, 0.047 mmol) in CH2Cl2 (0.47 mL) at room temperature. After 2.5 h, triethylamine (6.5 μL, 0.047 mmol) and 4-(2-hydroxyethyl)-morpholine (58 μL, 0.47 mmol) were added. After stirring overnight at room temperature, the reaction mixture was partitioned between H2O (5 mL) and CH2Cl2 (5 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×5 mL). The combined organic phase was washed with 1 N HCl (5 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (5% MeOH/CH2Cl2) afforded 5.1 mg (20%) of the title compound (2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][NH2:7].[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:38])[C:20]2[CH:25]=[N:24][C:23](S(C)(=O)=O)=[N:22][C:21]=2[N:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19](=[O:38])[C:20]2[CH:25]=[N:24][C:23]([NH:7][CH2:6][C:5]3[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:22][C:21]=2[N:30]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)=[O:17])[CH3:14]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: COc1cc(CN)cc(OC)c1
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCc3cc(OC)cc(OC)c3)ncc2c1=O

Procedure:
Using the procedure outlined in Example 28 Step F, the title compound was prepared from 3,5-dimethoxy-benzylamine and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (33 mg, 0.08 mmol). 8-Cyclohexyl-5-oxo-2-(3,5-dimethoxy-benzylamino)-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid (29 mg, 90%). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H30N4O5: 467.22 (M+H). Found: 467.2.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:15])[CH2:10][CH2:9]2)C=CC=CC=1.C>C(O)(=O)C>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(C1CCN(Cc2ccccc2)CC1)N1CCc2ccccc2C1
Solvent: CC(=O)O
Product: O=C(C1CCNCC1)N1CCc2ccccc2C1

Procedure:
115 g (0.34 mol) of 2-[(1-phenylmethyl-4-piperidyl)carbonyl]-1,2,3,4-tetrahydroisoquinoline are dissolved in 1 l of acetic acid, 4 g of palladinized charcoal (10% palladium) are added and the mixture is subjected to a hydrogenation at 75° C. under 0.35 MPa.