Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C@H:11]([O:14][CH2:15][O:16][CH3:17])[CH:12]=[CH2:13])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].[CH2:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]CC>C(Cl)Cl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C@H:11]([O:14][CH2:15][O:16][CH3:17])/[CH:12]=[CH:13]/[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19])[CH2:9][OH:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C[C@@H](OCOC)[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C=CCCCCCCCCCCCCC
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: CCCCCCCCCCCCC/C=C/[C@@H](OCOC)[C@H](CO)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
To a solution of alcohol 6 (230 mg, 0.88 mmol) in CH2Cl2 (8 mL) was added 1-pentadecene (741 mg, 3.52 mmol). The solution was degassed twice using N2 (2×10 min). To the reaction mixture was added benzylidene[1,3-bis(2,4,6-trimethyl -phenyl)-2-imidazolidinylidene]dichloro-(tricyclohexylphosphine)ruthenium catalyst (22.4 mg, 0.026 mmol) at rt under N2. After the reaction mixture was stirred for 4 h under reflux, the solvent was removed and the product was purified by chromatography (hexane/EtOAc 4:1) to afford 7 (280 mg, 72%): Rf0.45 (EtOAc/hexane 1:3); 1H NMR (CDCl3) δ 0.88 (t, 3H, J=7.0 Hz), 1.25 (m, 24H), 1.44 (m, 9H), 2.06 (q, 2H, J=7.7 Hz), 2.89 (d, 1H, J=5.2 Hz), 3.38 (s, 3H), 3.67 (m, 2H), 3.94 (dt, 1H, J=3.2, 11.1 Hz), 4.22 (dd, 1H, J=5.0, 7.6 Hz), 4.53 (d, 1H, J=6.6 Hz), 4.67 (d, 1H, J=6.6 Hz), 5.26 (d, 1H,J =7.6 Hz), 5.36 (dd, 1H, J=8.0, 15.4 Hz), 5.75 (dt, 1H, J=6.6, 14.6 Hz); 13C NMR (CDCl3) δ 14.1, 22.7, 28.4, 29.0, 29.1, 29.3, 29.4, 29.6, 29.7, 31.9, 32.3, 54.9, 55.6, 62.3, 76.1, 78.3, 79.4, 93.8, 125.9, 136.9, 155.9; ESI-HRMS [M+Na]+C25H49NO5Na calcd for m/z 466.3508, found 466.3514.
Reaction SMILES: CN1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[S:25]1CCC(=O)CC1>>[CH3:13][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:14][CH2:15][C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[C:5]3[CH2:23][CH2:24][S:25][CH2:3][C:4]=3[C:12]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Reactant: O=C1CCSCC1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCSC1

Procedure:
The method was the same as for Dimebon, using tetrahydro-thiopyran-4-one in place of 1-methylpiperid-4-one. The desired product was isolated as a glassy yellow oil (13.1 mg, 8.7% over three steps based on 2-methyl-5-(N-nitroso-2-p-tolylaminoethyl)pyridine starting material) by column chromatography on SiO2, eluting with 4:1 EtOAc/MeOH.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14]Br)[CH3:11]>C1(C)C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:11]
Reactant: CCOC(CBr)OCC
Reactant: CCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOCC(OCC)OCC
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Hexanol (200 g, 1.96 mol) and toluene (600 ml) were added to a 3 liter flask fitted with a mechanical stirrer and a reflux condenser. Sodium hydride (51.6 g, 2.15 mol) was added slowly to the resulting mixture, and then bromoacetaldehyde diethylacetal (385.7 g, 1.96 mol) was added dropwise. The mixture was heated to reflux temperature and maintained at that temperature for 6 hours. The mixture was then cooled to ambient temperature and was filtered to remove the resulting solids. Toluene was removed from the filtrate under reduced pressure, and the resulting product was distilled (85°-88° C.) to give 189.4 g of 2-hexyloxyacetaldehyde diethylacetal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[Cl:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: COC(=O)COc1ccc(F)c(N)c1
Reactant: CCC(=O)C(Cc1ccc(F)cc1Cl)C(=O)OC
Solvent: O
Solvent: C1COCCO1
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(F)cc1Cl
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (1.1 g), 2-(2-chloro-4-fluorobenzyl)-3-oxopentanoic acid methyl ester (2.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the solid washed with diethyl ether and dried to afford title compound, 1.5 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C([Li])CCC.[C:15](#[N:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][C:15](=[NH:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:6]1
Reactant: N#Cc1ccccc1
Reactant: NCCN1CCOCC1
Agent: [Li]CCCC
Solvent: O
Product: N=C(NCCN1CCOCC1)c1ccccc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Procedure as described for Amidine I using the following amounts and modifications: 6.6 mL of 4-(2-aminoethyl) morpholine (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.20 mL of benzonitrile (51.0 mmol). After refluxing overnight, the solution was green-brown. Addition of water yielded a light brown solution with suspended solid. Solution was filtered, taken to dryness, resuspended in 100 mL of pentane and stirred vigorously for 1 hour. A white solid deposited, which was filtered, washed with 10 mL of pentane and dried in vacuo yielding 8.17 g (70%) of white powder. NMR (400 MHz, CDCl3): 7.57 (br, 2H), 7.43 (m, 3H), 6.4 (br, 1H), 5.3 (br, 1H), 3.71 (m, 4H), 3.47 (br, 2H), 2.65 (m, 2H), 2.51 (br, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:38])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:26]=1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:38])[CH:30]=[CH:29][C:28]=3[CH3:31])[CH2:33][CH2:34]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 505.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10](=O)[CH2:11][C:12]([O:14]CC)=O)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:29][C:30]1[NH:34][N:33]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[N:31]=1>CCCCO>[NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[NH:29][C:30]4[N:34]([N:33]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[N:31]=4)[C:12](=[O:14])[CH:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1n[nH]c(N)n1
Reactant: CCOC(=O)CC(=O)c1ccc2nn[nH]c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: COC(=O)c1nc2[nH]c(-c3ccc4nn[nH]c4c3)cc(=O)n2n1
Temperature: 130 °C
Reaction time: 20 h
Yield: 36.5 %

Procedure:
To a solution of ethyl 3-(1H-benzo[d][1,2,3]triazol-6-yl)-3-oxopropanoate (246 mg, 1.5eq) in n-BuOH (5 ml) was added TsOH (10 mg, 0.1eq) and methyl 5-amino-1H-1,2,4-triazole-3-carboxylate (100 mg, 1.0 eq), and the reaction mixture was stirred for 20 h at 130° C. The solids were collected by filtration and washed with methanol (10 ml) to afford methyl 5-(1H-benzo[d][1,2,3]triazol-6-yl)-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-α]pyrimidine-2-carboxylate (80 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH:17]=O)=[O:16])=[CH:11][C:10]=1[CH2:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1C=CC(CCN)=CC=1)(OC)=O.[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([CH3:48])([CH3:47])[NH2:46])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][C:45]([NH:46][CH2:17][CH:15]([OH:16])[C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:10]([CH2:19][OH:20])[CH:11]=2)([CH3:47])[CH3:48])=[CH:40][CH:39]=1)([O:36][CH3:37])=[O:35]
Reactant: O=CC(=O)c1ccc(OCc2ccccc2)c(CO)c1
Reactant: COC(=O)c1ccc(CC(C)(C)N)cc1
Agent: COC(=O)c1ccc(CCN)cc1
Product: COC(=O)c1ccc(CC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c(CO)c2)cc1

Procedure:
The title compound was prepared by the process of Example 25, replacing phenyl glyoxal by 4-benzyloxy-3-hydroxymethylphenyl glyoxal and 2-(4-carbomethoxyphenyl) ethanamine by 2-(4-carbomethoxyphenyl)-1,1-dimethylethanamine. τ (d6DMSO) 9.06 (6H, s), 7.10-7.60 (5H, m), 6.20 (3H, s), 5.39 (2H, s), 5.00 (1H, m), 4.88 (2H, s), 3.04 (2H, d, J=8 Hz), 2.40-3.00 (10H, m), 2.12 (2H, d, J=8 Hz).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[CH2:13]1[S:19][C:17](=[O:18])[NH:16][C:14]1=[O:15]>>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:13]3[S:19][C:17](=[O:18])[NH:16][C:14]3=[O:15])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc2nccnc2c1
Product: O=C1NC(=O)C(=Cc2ccc3nccnc3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from quinoxaline-6-carbaldehyde (intermediate 55) and thiazolidinedione, the title compound was obtained.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].CO[C:11](=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[N:20]=[CH:21]N(C)C>C1COCC1>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[NH:20][CH:21]=[C:6]([C:7]#[N:8])[C:11]2=[O:25]
Reactant: COC(=O)c1cccc(OC)c1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)c(C#N)c[nH]c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 35.0 mL of THF was added 26.6 mL (66.4 mmol ) of n-BuLi solution during 5 min at −78° C. To the stirred solution was added a solution of 3.55 mL (67.9 mmol) of CH3CN in 65 mL of THF during 10 min which time the solution became white suspension, and then continued to stir for 15 min at −78° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2-(Dimethylamino-methyleneamino)-3-methoxy-benzoic acid methyl ester in 45 mL of THF during 30 min, and then continued to stir 30 min at −78° C. during which time the mixture gradually became clear. The solution was quenched with 8.5 mL of HOAc. The resulting thick slurry was stirred and warmed to room temperature. After most of the solvent was evaporated, the residue was diluted with cold water. The separate solid was collected by filtration and washed with water. After drying in vacuo, this afforded 3.8 g of the product as an off white solid in 77.6% of yield, m.p. 270° C. (dec.), mass spectrum (electrospray, m/e): M+H 201.1
Reaction SMILES: C([O:3][C:4]([C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[NH3:14]>>[C:12]([C:6]1([C:4]([NH2:14])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)#[N:13]
Reactant: CCOC(=O)C1(C#N)CCCCC1
Reactant: N
Product: N#CC1(C(N)=O)CCCCC1
Temperature: -78 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
1-Cyano-cyclohexanecarboxylic acid ethyl ester (11.4 g, 63.0 mmol) was placed into a glass pressure vessel and cooled to −78° C. It was charged with ammonia via needle until the total volume had doubled. The vessel was sealed and allowed to stir at room temperature for 20 hours. The solvent was evaporated and the resulting slurry triturated with ethyl acetate. The solids were collected by filtration and then filtered through a silica funnel (50 g silica), washing with ethyl acetate. The filtrate was concentrated to give the product (2.51 g, 26%) as a white solid. [M+H]+ 153.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[Br:37]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23](=[O:24])[C:22]4[C:21](=[CH:28][C:27]([NH2:29])=[C:26]([Br:37])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)ccc4c3=O)cc2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(N)c(Br)cc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a suspension of {1-[4-(7-amino-4-oxo-2-phenyl-4H-1-benzopyran-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (48 mg, 0.10 mmol) in chloroform (1.0 mL), was added N-bromosuccinimide (18 mg, 0.10 mmol) and the reaction mixture was stirred at RT for 1 hour. After this time, the mixture was poured into water and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, gradient 0 to 80% EtOAc in pentane) to yield the title compound as a yellow solid (34 mg, 61%). LCMS (Method B): RT=4.96 min, [M+H]+=561/563.
Reaction SMILES: C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH2:26])[CH3:25])=[C:20]([C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH:19]=1.[CH3:36][C:37]1[N:38]=[CH:39][N:40]([C:42]2[C:51](=[O:52])[N:50]3[C:45]([C:46](=[O:53])[O:47][CH2:48][CH2:49]3)=[CH:44][CH:43]=2)[CH:41]=1>O1CCCC1>[Cl:17][C:18]1[CH:28]=[CH:27][C:21]([O:22][CH2:23][C@@H:24]([NH:26][C:46]([C:45]2[N:50]([CH2:49][CH2:48][OH:47])[C:51](=[O:52])[C:42]([N:40]3[CH:41]=[C:37]([CH3:36])[N:38]=[CH:39]3)=[CH:43][CH:44]=2)=[O:53])[CH3:25])=[C:20]([C:29]([CH3:34])([CH3:35])[C:30]([F:31])([F:32])[F:33])[CH:19]=1
Reactant: C[C@H](N)COc1ccc(Cl)cc1C(C)(C)C(F)(F)F
Reactant: Cc1cn(-c2ccc3n(c2=O)CCOC3=O)cn1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Solvent: C1CCOC1
Product: Cc1cn(-c2ccc(C(=O)N[C@@H](C)COc3ccc(Cl)cc3C(C)(C)C(F)(F)F)n(CCO)c2=O)cn1
Temperature: 40 °C

Procedure:
Bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct (97%, 398 mg, 1.51 mmol) was added portion-wise over 5 minutes to a solution of (2S)-1-[4-chloro-2-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]propan-2-amine (C50) (400 mg, 1.51 mmol) in tetrahydrofuran (8 mL), and the reaction mixture was heated to 40° C. for 45 minutes. 7-(4-Methyl-1H-imidazol-1-yl)-3,4-dihydropyrido[2,1-c][1,4]oxazine-1,6-dione (P14) (555 mg, 2.26 mmol) was then added portion-wise over a period of approximately 5 minutes, and the reaction mixture was heated to 70° C. for 6 hours, whereupon it was cooled to 0° C. and slowly quenched with aqueous hydrochloric acid (1 M, 1 mL). After addition of water, the mixture was extracted three times with dichloromethane; the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the product as a pale yellow solid, which was used in the next step without additional purification. Yield: 690 mg, 1.28 mmol, 85%. LCMS m/z 541.3, 543.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 1.41 (d, J=6.8 Hz, 3H), 1.69 (br s, 6H), 2.23 (d, J=1.0 Hz, 3H), 3.85 (t, J=5.8 Hz, 2H), 4.05 (dd, half of ABX pattern, J=9.6, 5.4 Hz, 1H), 4.14 (dd, half of ABX pattern, J=9.6, 6.6 Hz, 1H), 4.41 (t, J=5.8 Hz, 2H), 4.48-4.57 (m, 1H), 6.54 (d, J=7.5 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 7.24-7.26 (m, 1H), 7.31 (dd, J=8.8, 2.6 Hz, 1H), 7.37-7.40 (m, 1H), 7.67 (d, J=7.5 Hz, 1H), 8.19 (d, J=1.4 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32](CC)[C:33]2[C:38](NCC)=CC=CN=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:19]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]([CH2:33][CH3:38])[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: CCNc1cccnc1N(CC)C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1ncnc(Cl)c1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
4,6-Dichloro-5-nitropyrimidine (8.88 g) is dissolved in 400 ml of methylene chloride and cooled to -78°. Then triethylamine (6.7 ml) and 1-benzyl-4-N-ethylaminopiperidine (EXAMPLE 205, 10.00 g) is added and the reaction is stirred 1 hr at -78° and slowly warmed to 20°-25°. The reaction is poured into saturated aqueous sodium bicarbonate, extracted with methylene chloride, washed with saline, dried and concentrated under reduced pressure. Purification by flash column chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[CH:32]([C:35]1[CH:36]=[CH:37][C:38]([S:41](Cl)(=[O:43])=[O:42])=[N:39][CH:40]=1)([CH3:34])[CH3:33]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:41]([C:38]1[CH:37]=[CH:36][C:35]([CH:32]([CH3:34])[CH3:33])=[CH:40][N:39]=1)(=[O:42])=[O:43]
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)C)cn2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.12 g of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in a mixture of toluene/pyridine (20 ml/30 ml) treated dropwise while cooling with ice with a solution of 1.05 g of 5-isopropylpyridine-2-sulphonyl chloride in toluene (30 ml) and subsequently stirred at room temperature for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was washed with water and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(5-isopropyl-pyridine-2-sulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)(=[O:8])=[O:7])([CH3:4])[CH3:3].[H][H]>[Pd].C(O)C>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][S:6]([NH:5][C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:8])=[O:7]
Reactant: [H][H]
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NS(=O)(=O)Cc1ccccc1N
Yield: 94.7 %

Procedure:
A mixture of 12 g (0.044 mol) of N-(1,1-dimethylethyl)-2-nitrobenzenemethanesulfonamide and 1 g of 10% palladium on carbon in 175 mL ethanol was reduced by shaking in a hydrogen atmosphere at 50 psi for 30 minutes. The catalyst was removed by filtration through a pad of diatomaceous earth with ethanol rinsing. The filtrate was then evaporated under reduced pressure and the residue crystallized from n-butyl chloride and hexanes to afford 10.1 g of the title compound, m.p. 115°-117° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7](Cl)[N:8]=[CH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][NH2:15].C(=O)([O-])[O-].[K+].[K+]>COCCOCCOC.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:15][CH3:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Clc1cc2ccc(Br)cc2cn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOCCOC
Product: CNc1cc2ccc(Br)cc2cn1
Temperature: 150 °C
Reaction time: 60 h
Yield: 86.5 %

Procedure:
A mixture of 7-bromo-3-chloroisoquinoline (100 mg, 0.4 mmol), methylamine hydrochloride (139 mg, 2.06 mmol), and potassium carbonate (456 mg, 3.30 mmol) in 1-methoxy-2-(2-methoxyethoxy)ethane (1 mL) was heated to 150° C. and stirred for 60 hours. Additional methylamine hydrochloride (100 mg, 1.5 mmol) and potassium carbonate (200 mg, 1.4 mmol) were added and heating was continued for another 40 hours. The reaction was cooled to room temperature and diluted with water. The mixture was stirred for 30 minutes. The resulting solid was filtered off, rinsed with water and dried under vacuum. Purification by flash column chromatography (10-30% ethyl acetate/heptanes) gave the title compound (82 mg) as a pale yellow solid. −APCI (M−H+1) 237.8; 1H NMR (400 MHz, CDCl3, δ): 8.70 (s, 1H), 7.84 (d, J=1.95 Hz, 1H), 7.48 (dd, J=8.97, 2.15 Hz, 1H), 7.38 (d, J=8.97 Hz, 1H), 6.39 (s, 1H), 2.92 (s, 3H).
Reaction SMILES: [C:1]([NH:20][CH:21]([CH2:26][O:27][C@@H:28]1[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]1[O:30][C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:22]([O:24]C)=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[I-].[Li+].C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:1]([NH:20][CH:21]([CH2:26][O:27][C@@H:28]1[O:60][C@H:59]([CH2:61][O:62][C:63](=[O:70])[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@H:49]([O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:39]([O:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@H:29]1[O:30][C:31](=[O:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:22]([OH:24])=[O:23])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)OC
Agent: [I-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)O
Yield: 68.1 %

Procedure:
In 26 mL of pyridine was dissolved 1.4 g of methyl 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy)propionate, 1.7 g of lithium iodide was added to the solution, and the resulting mixture was refluxed under nitrogen atmosphere for 4 hours. Chloroform was added to the reaction mixture, the resulting mixture was washed with 2 mol/L of hydrochloric acid, the chloroform layer was dried over anhydrous magnesium sulfate, and then, the solvent was removed under reduced pressure. The finally obtained residue was purified by silica gel chromatography (Eluent; chloroform: methanol=60:1) to obtain 940 mg of 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy) propionic acid.