Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:6])[CH:3]([CH3:5])[CH3:4].[CH2:19](Br)[C:20]#[CH:21].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:6][C:2]([NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:20]#[CH:19])=[C:11]([O:16][CH3:17])[CH:10]=1)([CH3:1])[CH:3]([CH3:5])[CH3:4]
Reactant: C#CCBr
Reactant: COc1cc(C(=O)NC(C)(C)C(C)C)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCOc1ccc(C(=O)NC(C)(C)C(C)C)cc1OC
Yield: 71.7 %

Procedure:
To 10 ml of DMF were added 0.4 g of N-(1,1,2-trimethylpropyl)-4-hydroxy-3-methoxybenzamide, 0.28 g of propargyl bromide and 0.78 g of cesium carbonate and the mixture was heated under reflux for 1 hour. Then, the reaction mixture was concentrated. Dilute hydrochloric acid was added to the residue and extracted with ethyl acetate. After the organic layer was dried over magnesium sulfate, it was concentrated under reduced pressure. The solid obtained was successively washed with hexane and methyl tert-butyl ether to obtain 0.33 g of N-(1,1,2-trimethylpropyl)-4-(2-propynyloxy)-3-methoxybenzamide (hereinafter, described as the compound 11 of the present invention) represented by the formula:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[N:16]=[C:10]2[CH:9]=1)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:15]2[N:16]=[C:10]3[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]3[N:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cccc(-c2nc3cc(NC(=O)OC(C)(C)C)ccn3n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cccc(-c2nc3cc(N)ccn3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.5 %

Procedure:
To a solution of [2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-carbamic acid tert-butyl ester (5.5 g, 16.2 mmol) in DCM (100 ml) was added a solution of HCl in dioxane (4 N, 20 ml). The resultant reaction mixture was stirred at 25° C. for 16 h. Volatiles were removed in vacuum, and the resultant residue was dried under vacuum to give 2-(3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine (5 g, quant) as light yellow solid. LC-MS: m/z=241.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][P:9]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23](O)=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:36])=O>ClCCl>[P:9]([O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([Cl:36])=[O:24])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(CCOP(=O)(OCc1ccccc1)OCc1ccccc1)C(=O)Cl

Procedure:
To a solution of the product from Example 11B (0.211 g, 0.538 mmol) in dichloromethane (1.35 mL) at 0° C. were added DMF (4 μL) and a solution of oxalyl chloride in dichloromethane (2M, 0.538 mL) and the mixture was stirred for 45 minutes at 0° C. The solvent was evaporated under reduced pressure and the residue was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1F.Cl.[CH3:37]CO>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[O:18][C@@:13]1([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH2:37]1
Reactant: CCO
Reactant: CCCC[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(F)c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc(F)c(O[C@@]2([C@H]3CCNC3)C=CC=CC2)cc1F
Temperature: 90 °C

Procedure:
(S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-carboxylic acid t-butyl ester (40.0 mg, 155 μmol) was dissolved in DMF (100 mL, 12.9 mmol). While stirring, 60% sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 311 μmol) was slowly added, and the mixture was stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 μL, 466 μmol) was added. The mixture was then heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H20F3NO, 288.15. found 288.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Product: CCOC(=O)CNc1cccc(C(=O)c2ccccc2)c1
Yield: 66 %

Procedure:
4.5 g Ethyl N-(3-benzoylphenyl)-glycinate, obtained at a 66% yield from 3-aminobenzophenone and ethyl bromoacetate by an analogous procedure to that of Example 1, are heated in the presence of 10 ml dimethyl sulphate and 2 ml water to 100° C. for 11/2 hours.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:24][CH2:25][CH2:26][Cl:27]>O1CCCC1>[C:1]([NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:24][CH2:25][CH2:26][Cl:27])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCN(CCCCl)CC1)c1ccccc1

Procedure:
A mixture of 4-benzamidopiperidine (3.2 g; preparation I11), triethylamine (5.67 ml) and 1-bromo-3-chloropropane (2.31 ml) in 150 ml of tetrahydrofuran was refluxed overnight, then concentrated to a small volume and treated with 100 ml of chloroform. The solution was washed with 50 ml of aqueous saturated solution of potassium carbonate, dried over sodium sulfate and concentrated to dryness. The residue (6 g) was purified by silica gel chromatography (eluent chloroform/methanol 9:1) to give, after recrystallization from 20 ml of diethyl ether, 1.63 g of the product, m.p. 145-147° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]([CH2:13][C:14]([O:16]CC)=O)[C:10]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C:9]=3[C:8]=2[CH:7]=[C:6](Cl)[CH:5]=1.[Cl:32]C1C2NC3CCN(C(OC(C)(C)C)=O)CCC=3C=2C=C(Cl)C=1.BrCC(OCC)=O>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:13][CH2:14][OH:16])[C:10]3[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:22][CH2:23][C:9]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[Cl:32]
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)cc(Cl)c31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)cc(Cl)cc3c2CC1
Agent: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3c(Cl)c(Cl)ccc23)CC1
Reaction time: 0.33 h
Yield: 107.3 %

Procedure:
Preparation of tert-Butyl 7,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) was added to a solution of tert-butyl 7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94 mL, 8.4 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 2 h and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40M) with heptane/EtOAc (3:1) to give 1.8 g (98%) of a white solid: mp 117.0-120.0° C.; IR (diffuse reflectance) 2972, 1744, 1690, 1464, 1409, 1377, 1366, 1349, 1294, 1222, 1204, 1190, 1167, 1111, 861 cm−1; MS (EI) m/z 440 (M+), 440, 386, 385, 384, 339, 311, 310, 300, 298, 57; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 56.97; H, 5.97; N, 6.19.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([O:31]CC)=O)[NH:23][C:22]2=[O:34])#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:78]2[CH:82]=[N:81][C:80]([CH2:83][O:84][CH2:85][C:86]3[CH:87]=[C:88]([CH2:92][NH2:93])[CH:89]=[CH:90][CH:91]=3)=[N:79]2)C=CC=CC=1>>[C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([C:29]([NH:93][CH2:92][C:88]1[CH:89]=[CH:90][CH:91]=[C:86]([CH2:85][O:84][CH2:83][C:80]3[N:81]=[CH:82][NH:78][N:79]=3)[CH:87]=1)=[O:31])[NH:23][C:22]2=[O:34])#[N:18]
Reactant: NCc1cccc(COCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(COCc4nc[nH]n4)c3)[nH]c(=O)c2c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[({[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]methyl}oxy)methyl]phenyl}methanamine obtained in Reference Example 38, the title compound was obtained as a white powder (20 mg, 6%).
Reaction SMILES: ClC1N=[CH:4][C:5]2[CH2:11][N:10]([C:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH2:9][CH2:8][C:6]=2N=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24].CCOC(C)=O.[CH:34](O)([CH3:36])[CH3:35]>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:34]2[CH:35]=[C:6]3[C:5](=[CH:4][CH:36]=2)[CH2:11][N:10]([C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:9][CH2:8]3)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(c1cccnc1)N1CCc2nc(Cl)ncc2C1
Reactant: CC(C)O
Solvent: CCOC(C)=O
Product: O=C(c1cccnc1)N1CCc2cc(Nc3cccc(F)c3)ccc2C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A solution of (2-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)(pyridin-3-yl)methanone, Intermediate 5 (0.025 g, 0.091 mmol) in isopropanol (0.1 mL) was treated with 3-fluoroaniline (0.011 g, 0.100 mmol). The resulting mixture was heated to 60° C. and allowed to stir overnight. After being allowed to cool to room temperature EtOAc (10 mL) was added to the reaction mixture, and the resulting solution was then washed twice with brine (10 mL). The combined aqueous layers were washed once with EtOAc (10 mL). The organic layers were combined, then dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The resulting crude residue was then purified over silica using a MeOH/CHCl3 gradient. The desired product was obtained in 75.5% yield (0.024 g, 0.069 mmol).
Reaction SMILES: COC1C=[C:5]([CH2:11][CH2:12][CH2:13][C:14](=O)C=C)[CH:6]=[C:7]([O:9]C)C=1.C[O:19]C1C=C(CCCC(=O)CCN(CC)CC)C=C(OC)C=1>[OH-].[K+]>[CH2:13]([CH:12]1[C:7](=[O:9])[CH2:6][CH2:5][C:11]1=[O:19])[CH3:14]
Reactant: CCN(CC)CCC(=O)CCCc1cc(OC)cc(OC)c1
Reactant: C=CC(=O)CCCc1cc(OC)cc(OC)c1
Agent: [K+]
Agent: [OH-]
Product: CCC1C(=O)CCC1=O

Procedure:
Reflux 6-(3,5-dimethoxyphenyl)hex-1-en-3-one, containing a small amount of 6-(3,5-dimethoxyphenyl)-1-diethylaminohexan-3-one (6 g, produced by slow distillation of the latter substance) with 2-ethylcyclopentane-1,3-dione (3.5 g) in 0.12% anhydrous methanolic potassium hyroxide (10 cc) for 10 hours. Work up the reaction mixture as for the preparation of 2-(6 -m-acetoxyphenyl-3-oxohexyl)-2-methylcyclopentane-1,3-dione to obtain 2-[6-(3,5-dimethoxyphenyl)-3-oxohexyl]-2-ethylcyclopentane-1,3-dione as a viscous gum; infrared absorption peaks at 5.80, 6.25 μ (split peak).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][C:6]2([CH3:14])[CH3:13].S(=O)(=O)(O)O.[N-:20]=[N+]=[N-].[Na+]>C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:20][CH2:7][C:6]2([CH3:14])[CH3:13]
Reactant: COc1ccc2c(c1)C(C)(C)CC2=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1ccc2c(c1)C(C)(C)CNC2=O
Temperature: 60 °C
Yield: 98 %

Procedure:
A solution of 5-methoxy-3,3-dimethyl-indane-1-one (Intermediate 16, 3.3 g, 17.4 mmol) in benzene (50 mL) was treated with concentrated sulfuric acid (10 mL) and heated to 60° C. Sodium azide (1.95 g, 30 mmol) was added in small portions and after the addition was complete, the reaction mixture was heated further for 4 h. It was then cooled, diluted with water and extracted with chloroform (×3). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a brown solid (3.5 g, quantitative by weight).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH2:12]([N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
Commercially available ethyl nipecotate (509.7 mg; 3.25 mmol) was dissolved in dichloromethane (12 ml). Dilsopropylethylamine (570 μl; 3.27 mmol) was added, followed by commercially available benzyl bromide (386 μl; 3.25 mmol) and the mixture stirred at ambient temperature for approximately 20 hours. The mixture was then evaporated at ambient temperature under reduced pressure. The crude product was purified by chromatography on silica eluting with 80% ethyl acetate in hexane, giving ethyl 1-benzyl-3-piperidinecarboxylate (634.4 mg) as a colorless oil. MS m/z (positive ion) 248 (MH+; 100).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:27])[C:18]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[N+:15]([O-:6])[CH:16]=[C:17]([Cl:27])[C:18]=1[CH2:19][O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cncc(Cl)c1COC1CCCCO1
Solvent: ClCCl
Product: [O-][n+]1cc(Cl)c(COC2CCCCO2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Chloroperoxybenzoic acid (mCPBA, 1.32 g, 7.66 mmol) was added to a stirred solution of 3,5-Dichloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine (200 mg, 0.766 mmol) in DCM (5 mL). After stirring for 3 h at RT the solvent was removed in vacuo and the residue was partitioned between DCM (50 mL) and 2 N NaOH solution (50 mL). After extraction of the organic layer with water (50 mL) the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 278.0 [M+H+].
Reaction SMILES: [CH2:1]([N:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[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].[CH2:39](Br)[CH:40]=[CH2:41].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C(Cl)(Cl)Cl>[CH2:41]([O:20][N:19]([CH2:1][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])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:40]=[CH2:39]
Reactant: CCCCCCCCCCCCCCCCCCN(O)CCCCCCCCCCCCCCCCCC
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=CCON(CCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCCC
Yield: 35.9 %

Procedure:
A mixture of 42.4 g (80 mmol) of N,N-dioctadecylhydroxylamine, 13 ml (150 mmol) of allyl bromide and 17.0 g (160 mmol) of sodium carbonate in 450 ml of ethanol is heated under reflux at approximately 80° to 85° C. The reaction is considered complete after 14 hours upon complete disappearance of the N,N-dioctadecylhydroxylamine as indicated by TLC analysis (silica gel, chloroform solvent). The reaction mixture is concentrated under reduced pressure and the resultant residue is triturated with 500 ml of chloroform. The insoluble salts are removed by filtration and the filtrate concentrated. The resultant residue is purified by flash chromatography (silica gel, chloroform solvent) to give 16.6 g (36% yield) of the title compound as a white solid melting at 60°-62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:23])([CH3:22])[C:11]#[C:12][CH2:13]O[Si](C(C)(C)C)(C)C)=[O:8].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.[C:54](OCC)(=[O:56])C>O1CCCC1>[Cl:29][C:27]1[CH:26]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:28]=1)[O:5][CH:6]([CH2:24][CH3:25])[C:7]([NH:9][C:10]([CH3:22])([CH3:23])[C:11]#[C:12][CH2:13][CH2:54][OH:56])=[O:8]
Reactant: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C
Reactant: CCOC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(Oc1cc(Cl)cc(Cl)c1)C(=O)NC(C)(C)C#CCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(3,5-Dichlorophenoxy)-N-(1-tert-butyldimethylsilyloxy-4-methylpent-2-yn-4-yl)butyramide (prepared as described in Example 1; 3.35 g) in tetrahydrofuran (60 ml) was stirred at 3-5° C. and a solution of tetra n-butylammonium fluoride (14.6 ml of 1M solution in tetrahydrofuran) was added dropwise over 5 minutes. On completion of the addition, the mixture was stirred for 0.5 hour at 0° C., 2 hours at ambient temperature and stored for 18 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic phase was separated, washed with aqueous ammonium chloride, brine, dried over magnesium sulphate and evaporated under reduced pressure to give a colourless solid that was fractionated by chromatography (silica; hexane/ethyl acetate, 2:1 by volume) to give the required product as a colourless solid (2.01 g) mp 104-106° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([O:17]CC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1C(=O)O
Reaction time: 48 h
Yield: 93.1 %

Procedure:
To 6.05 grams (22.3 mmol) of the ester of step 1 dissolved in 25 mL methanol was added 2.6 g (55.74 mmol) lithium hydroxide monohydrate dissolved in 10 mL water. The mixture was stirred for 48 hours, partitioned between ethyl acetate and 1 N HCl, dried over magnesium sulfate and concentrated to obtain 5.05 g of the crude (1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclohexanecarboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[O:9]=[CH:10][C:11]1[CH:19]=[CH:18][C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][C:16]=1[O:17][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)[CH:10]=[O:9]
Reactant: BrCc1cccnc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1cccnc1
Yield: 45.8 %

Procedure:
3-Bromomethylpyridine (0.30 mg, 1.2 mmol) was added to a suspension of vanillin (0.12 g, 0.79 mmol), potassium carbonate (0.33 g, 2.4 mmol) in acetone (5.0 mL) and treated according to Procedure 3. 3-Methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (88 mg, 46%) was obtained as a brown oil. Piperidine (36 μL, 0.36 mmol) was added to a suspension of 3-methoxy-4-(pyridin-3-ylmethoxy)benzaldehyde (0.88 mg, 0.36 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (73 mg, 0.33 mmol) in toluene (5 mL) and treated according to Procedure 2, acidifying with 20% AcOH. (E)-2-[[3-(3-Methoxy-4-(pyridin-3-ylmethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (58 mg, 44%) was obtained as a pure brown crystalline solid; mp 245-251° C.; δH (400 MHz, DMSO-d6) 3.84 (s, 3H, OCH3), 5.18 (s, 2H, OCH2), 6.80 (d, J=15.6 Hz, 1H, CH═CHCO), 7.12 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.24 (d, J5′,6′=8.0 Hz, 1H, H6′), 7.40-7.45 (m, 2H, H2′, Ar—H), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.87 (d, J=8.0 Hz, 1H, Ar—H), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.55-8.67 (m, 3H, H6, Ar—H), 11.32 (s, 1H, NH); δC (100 MHz, DMSO-d6) 55.7, 67.6, 110.8, 113.4, 116.7, 120.2, 120.3, 122.4, 122.7, 123.6, 127.9, 131.1, 132.4, 133.9, 135.9, 141.0, 141.5, 149.1, 149.2, 149.3, 164.2, 169.5; HRMS (ESI) calculated for C23H20N2O5 [M+H]+ 404.1445 found 404.1445; vmax 758, 1257, 1509, 1586, 1671, 2931 cm−1.
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C(O)=O.[CH2:19]([NH:23][NH2:24])[CH2:20][CH2:21][CH3:22]>C(O)(=O)C>[CH2:10]([C:9]1[N:23]([CH2:19][CH2:20][CH2:21][CH3:22])[N:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:8]=1)[CH3:11]
Reactant: CCCCNN
Reactant: CCOC(=O)C(=O)CC(=O)CC
Agent: O=C(O)C(=O)O
Solvent: CC(=O)O
Product: CCCCn1nc(C(=O)OCC)cc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.6 %

Procedure:
A solution of ethyl 2,4-dioxohexanoate (approximately 60% pure, 45.0 g, 0.232 mol), prepared as described in Part A of Example 10, in glacial acetic acid (150 mL) was cooled to 0° C. Butylhydrazine oxalate (25.0 g, 0.139 mol) was added slowly. The reaction was allowed to warm to ambient temperature, stirred overnight, and concentrated under reduced pressure. The residue was adjusted to pH 10 with the addition of 2 M aqueous sodium carbonate. The mixture was extracted with chloroform and an emulsion that contained solid material formed. The solid was isolated by filtration, and the filtrate was transferred to the separatory funnel. The organic layer was separated. The aqueous layer was extracted with chloroform three times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide an oil that was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with CMA in chloroform) to yield 13.27 g of ethyl 5-ethyl-1-butyl-1H-pyrazole-3-carboxylate as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (40 mg, 0.086 mmole) in CH2Cl2 (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 3 hours. All the solvents were evaporated. The mixture was purified by reverse phase preparative HPLC to give the title compound (14 mg, 40%) [hS1P1 EC50=160 nM, 261 nM]. 1H NMR (400 MHz, CD3OD) δ 7.77 (m, 2H), 7.42 (dd, 1H), 7.40 (s, 1H), 7.20-7.30 (m, 5H), 7.10 (m, 3H), 4.50 (s, 2H), 4.04 (s, 2H), 3.64 (dd, 2H), 3.55 (dd, 2H), 3.26 (dd, 2H), 2.90 (dd, 2H). MS (ESI) m/z: Calculated: 411.18; Observed: 412.10 (M++1).