Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15](Br)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]2[C:20](=[O:21])[CH:19]=[C:18]3[C:13]([N:14]=[C:15]([C:32]#[C:31][CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:17]3)=[CH:12]2)[CH:5]=1
Reactant: C#CCc1ccccc1
Reactant: COC(=O)c1cccc(Cn2cc3nc(Br)ccc3cc2=O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2cc3nc(C#CCc4ccccc4)ccc3cc2=O)c1

Procedure:
The coupling of 3-(7-bromo-3-oxo-2H-8-azaisoquinolin-2-ylmethyl)benzoic acid methyl ester (1.20 g, 3.22 mmol) with 3-phenyl-1-propyne (1.00 mL, 8.06 mmol) using triethylamine (0.92 mL, 6.60 mmol), CuI (0.044 g, 0.23 mmol), and Pd(Ph3P)4 (0.15 g, 0.13 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). A portion of the resulting red oil is purified on the preparatory HPLC using 80:20 acetonitrile/water (0.1% TFA), evaporated to dryness, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, dried over MgSO4 and evaporated to dryness. Drying will afford the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:12][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[NH:1][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: Nc1c(O)ccc2ccccc12
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccccc1Br)Nc1c(O)ccc2ccccc12
Yield: 8.4 %

Procedure:
The urea was prepared from 1-amino 2-hydroxy napthalene(195 mg, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound(0.030 g, 8%). EI-MS m/z 357(M+H)+
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[OH-].[Na+].CS(C)=O.CC#N>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=3[CH3:24])=[CH:11][CH:12]=2)[C@H:7]([NH:25][C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCO
Solvent: CS(C)=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3C)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution of methyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoate (for a preparation see Intermediate 108) (20 mg, 0.046 mmol) in ethanol (0.5 mL) was treated with NaOH (1M in water, 0.182 mL, 0.182 mmol) and the resulting mixture was stirred at room temperature for 30 min. It was then made up to 0.9 mL by addition of 1:1 solvent mixture of DMSO/CH3CN and purified by MDAP to give 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]-3-methylbenzoic acid (16 mg, 0.038 mmol, 83%) as a white solid. LCMS (method A): Retention time 0.91 min, [M+H]+=425.18
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[N:8])[N:2]=1.[ClH:9].[H][H]>CO.[Pd]>[ClH:9].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[N:2]=1
Reactant: [H][H]
Reactant: N#Cc1cccnn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1cccnn1

Procedure:
To a solution of the intermediate from Step B (5.96 g, 56.7 mmol) in MeOH (35 mL) was added 6N HCl (20.89 mL, 125 mmol) followed by Pd/C (0.905 g, 8.51 mmol). The reaction mixture was kept on Parr shaker for 2 hours at 40 psig hydrogen. The reaction mixture was filtered through Celite™ (diatomaceous earth) and washed with 600 mL of MeOH and the filtrate concentrated. The residue was azeotroped several times with toluene. A dark brown solid was obtained. m/z=110 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].C(OCC)(=O)C>CN(C=O)C.O>[CH3:20][O:19][C:17](=[O:18])[CH2:16][NH:12][C:11]1[CH:13]=[CH:14][C:8]([Br:7])=[CH:9][CH:10]=1
Reactant: COC(=O)CBr
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(Br)cc1
Temperature: 100 °C
Yield: 33.2 %

Procedure:
Potassium carbonate (2.41 g, 17.4 mmol) is added to a stirred solution of 4-bromo-aniline (2.00 g, 11.6 mmol) and methyl bromoacetate (1.78 g, 11.6 mmol) in dry DMF (20 mL) at ambient temperature. The mixture is heated at 100° C. for 1 hour. At ambient temperature ethyl acetate (60 mL) and water (60 mL) are added to the mixture. The organic layer is separated, washed with half-saturated brine, dried, filtered and concentrated. After MPLC separation on silica (gradient 0-15% ethyl acetate in hexane), 0.94 g (33% yield) of the title compound is obtained. 1H NMR (DMSO-d6): δ3.62 (s, 3H), 3.87 (d, J=6.4 Hz, 2H), 6.22 (t, J=6.4 Hz, 1H), 6.49 (d, J=8.8 Hz, 2H), 7.19 (d, J=8.8 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:33]([O:37][C:38]([NH:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([NH:47][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)[CH2:45][CH2:46]1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: Brc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1
Temperature: 70 °C

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromoisoquinoline (100 mg), tris(dibenzylideneacetone)palladium(0) (23 mg), 2-(di-tert-butylphosphino)biphenyl (29 mg), Intermediate 40 (122 mg) and sodium tert-butoxide (66 mg) in toluene was stirred with heating at 70° C. for 3.5 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (69 mg).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:1]1(=[O:14])[O:13][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:12][C:10](=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCCCCCCCC(=O)O
Reactant: OCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCCCCCCCC(=O)OCCCCCCO1
Temperature: 165 °C

Procedure:
Crystalline poly (hexamethylene sebacate) was prepared using a kettle equipped with a stirrer, nitrogen gas inlet tube, thermometer and condenser by reacting sebacic acid with 1,6hexamethylene glycol in the presence of a p-toluenesulfonic acid catalyst as follows: sebacic acid and hexamethylene glycol were added to the reaction kettle in a respective 1.0 to 1.1 molar ratio along with 0.5 wt % p-toluenesulfonic acid. The 10 mole % excess of glycol was used to ensure the predominant presence of hydroxyl end groups in the reaction product. The mixture was heated to 165°C while stirring. At 165°C, an amount of xylene was added to assist refluxing and this temperature was maintained until water evolution ceased (4 hrs.). Afterwards, the condensers were removed and the excess glycol and catalyst were removed by sparging with nitrogen for 0.5 hours at 165°C. On cooling to room temperature, the poly (hexamethylene sebacate) crystallized into an off-white solid. Next, the poly (HMS) from above was purified by precipitation from a benzene solution into methanol using techniques well known in the art. The precipitated poly (HMS) was collected by filtration and dried in vacuo. Analytical data on this purified material indicate an acid number of 1.06, an hydroxyl number of 34.4, an Mn of 3165 g/mole, an MWD (Mw /Mn) of 1.41 by GPC in chloroform, a glass transition temperature of about -62°C and a crystalline melting point of about 65°C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[CH2:19][O:20][C:21]([CH3:23])=[O:22]>CS(C)=O.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:11]=[CH:10][C:9]([N:15]2[CH2:16][CH2:17][C:10]3([CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][CH2:11]3)[CH2:13][CH2:14]2)=[N:8][CH:6]=1)=[O:22]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCC3(CCN(C(=O)OC(C)(C)C)C3)CC2)nc1
Temperature: 85 °C

Procedure:
To a solution of methyl 6-chloronicontinate (200 mg, 1.16 mmol) in DMSO/PhMe (2 mL of a 1:1 solution) was added t-butyl-2,8-diazaspiro[4.5]decane-2-carboxylate (700 mg, 2.91 mmol). The reaction mixture was heated at 85° C. for 6 hours and then diluted with EtOAc (10 mL). The organic layer was washed with NaHCO3 (1×5 mL) and brine (1×5 mL), dried over Na2SO4, and then concentrated. The crude residue was purified by reverse-phase flash chromatography (10-100% MeCN/H2O with 0.05% TFA) to give t-butyl 8-[5-(methoxycarbonyl)pyridin-2-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate: MS (ESI+): cal'd [M+H]+ 376.2, obs'd 376.2. This intermediate was then treated with TFA (3 mL) in CH2Cl2 (6 mL). The reaction mixture was concentrated after 30 minutes of stirring at room temperature and the crude residue was purified by reverse-phase flash chromatography (10-75% MeCN/H2O with 0.05% TFA) to give the methyl 6-(2,8-diazaspiro[4.5]dec-8-yl)nicotinate: MS (ESI+): cal'd [M+H]+ 276.2, obs'd 276.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][NH:8][C:9]([C:12]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[N:15][O:14][N:13]=2)=[N:10][OH:11])[O:5][CH:6]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[C:22](=[O:23])[O:11][N:10]=[C:9]2[C:12]2[C:16]([NH:17][CH2:18][CH2:19][O:20][CH3:21])=[N:15][O:14][N:13]=2)[O:5][CH:6]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCNc1nonc1C(=NO)NCc1cc(Br)co1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1Cc1cc(Br)co1
Temperature: 65 °C
Yield: 52 %

Procedure:
N-[(4-Bromo-2-furyl)methyl]-N′-hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidamide (7.3 g, 20.4 mmol) and 1,1′-carbonyldiimidazole (5.0 g, 30.5 mmol) were dissolved in ethyl acetate (72 mL). The reaction mixture was heated at 65° C. for 15 minutes. Ethyl acetate (70 mL) was added and the crude reaction was washed with 0.1 N hydrogen chloride in water (2×70 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes gave the desired product (4.1 g, 90%). LCMS calculated for C12H13BrN5O5 (M+H)+: m/z=386.0, 388.0. 1H NMR (400 MHz, CD3OD): δ 7.88 (s, 1H), 6.67 (s, 1H), 6.39 (t, J=5.7 Hz, 1H), 5.07 (s, 2H), 3.50 (m, 2H), 3.41 (q, J=5.7 Hz, 2H), 3.25 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:15]=[N+:16]=[N-:17].[Na+].CO.C(OC)=O>O>[C:1]1([CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]([OH:13])[CH2:14][N:15]=[N+:16]=[N-:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCCc1ccccc1
Yield: 93.5 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 5.77 g of 3-phenylpropoxymethyloxirane (prepared as described in Preparation 52), 9.75 g of sodium azide, 160 ml of an 8:1 by volume mixture of methanol and water and 40 ml of methyl formate were used, to give 6.6 g of the title compound as a pale yellow oil having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:5 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-])=O)[C:7]=1[OH:16])(=[O:5])=[O:4]>C(OCC)(=O)C.[Pd]>[CH3:1][N:2]([CH3:17])[S:3]([C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]([NH2:13])[C:7]=1[OH:16])(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
To a solution of N,N-dimethyl-6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (140 mg, 0.50 mmol) in ethyl acetate, was added 10% Pd/C (50 mg). The mixture was flushed with hydrogen, then stirred under a hydrogen atmosphere at balloon pressure for 1.5 hours at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (100 mg, 80%). 1H NMR (DMSO-d6): δ 6.87 (d, 1H), 6.80 (d, 1H), 2.82 (s, 6H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3].ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:20][C:19](=[O:21])[C:18]2[C:13](=[C:14]([CH:22]3[O:37][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:2][CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCC=Cc1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Solvent: ClC(Cl)Cl
Product: CCCCCC1OC1c1cccc2c(=O)[nH]c(-c3ccccc3OCCC)nc12
Reaction time: 3 h

Procedure:
1.5 g (3.98 mmoles) of the compound from Example 1 is dissolved at 0° C. in 40 ml of dry chloroform. To it is added 0.98 g (3.98 mmoles) of 70% m-chloroperbenzoic acid. The mixture is allowed to come to room temperature and is stirred for 3 hours longer. It is washed 3 times with 30 ml portions of 10% sodium bisulfite solution and twice with 30 ml portions of 1 N NaOH solution, dried over MgSO4, and evaporated under vacuum. The residue (1.6 g) was chromatographed on silica gel with toluene/ethyl acetate 95:5 as eluant.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)=[CH:4][C:3]=1[F:17].[C:18]1([CH:24]([C:26]2[CH:27]=[CH:28][C:29]3[O:33][C:32](B(O)O)=[CH:31][C:30]=3[CH:37]=2)[CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[F:17][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8]2)[CH:15]=[CH:16][C:2]=1[C:32]1[O:33][C:29]2[CH:28]=[CH:27][C:26]([CH:24]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH3:25])=[CH:37][C:30]=2[CH:31]=1
Reactant: COC(=O)C1CN(Cc2ccc(Br)c(F)c2)C1
Reactant: CC(c1ccccc1)c1ccc2oc(B(O)O)cc2c1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(C)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
According to Scheme B2 and general procedure F, methyl 1-(4-bromo-3-fluorobenzyl)azetidine-3-carboxylate (0.241 g, 0.797 mmol) and 5-(1-phenylethyl)benzofuran-2-ylboronic acid (0.212 g, 0.797 mmol) were employed to give methyl 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate. According to Scheme B2 and general procedure H, methyl 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)-methyl)azetidine-3-carboxylate (0.275 g, 0.620 mmol) provided 1-((3-fluoro-4-(5-(1-phenylethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a white solid [hS1P1 EC50=99 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (t, J=8.0 Hz, 1H), 7.59 (s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.20-7.35 (m, 8H), 7.12-7.20 (m, 1H), 4.28 (q, J=7.0 Hz, 1H), 3.60 (s, 2H), 3.18-3.46 (m, 5H), 1.64 (d, J=7.5 Hz, 3H). MS (ESI) m/z: Calculated: 429.2; Observed: 430.2 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)(=[O:22])=[O:21].C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Cl:11][C:8]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2](=[NH:1])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)(=[O:22])=[O:21])[CH:9]=1
Reactant: O=S(=O)(c1ccccc1CBr)C1CCCC1
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cl
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)C1CCCC1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
(Step 4) A solution of 2-amino-5-chloronicotinamide (200 mg) and 1-(bromomethyl)-2-(cyclopentylsulfonyl)benzene obtained in Step 3 (530 mg) in DMF (5 ml) was stirred at 90° C. for 20 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in aqueous sodium hydrogen carbonate solution, and the solution was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=3:1). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (70 mg).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][C:5]2[S:8][C:9]([C:11]([O-:13])=O)=[N:10][C:4]=2[CH2:3]1.[Li+].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[ClH:16].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][N:33]([C:11]([C:9]3[S:8][C:5]4[CH2:6][NH:7][CH:2]([CH3:1])[CH2:3][C:4]=4[N:10]=3)=[O:13])[CH:32]([CH2:36][C:37]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[O:38])[CH2:31]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=C(CC1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1)N1CCOCC1
Reactant: CC1Cc2nc(C(=O)[O-])sc2CN1
Agent: Cl
Agent: [Li+]
Product: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3CC(=O)N3CCOCC3)sc2CN1

Procedure:
Starting materials: lithium 6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate, 1-[(6-chloronaphthalen-2-yl)sulfonyl]-3-[[(morpholin-4-yl)carbonyl]methyl]piperazine hydrochloride
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[NH:6]2.[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:29][C@@H:28]([NH2:40])[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)C(C)C)(C)C>C(O)C>[Si:18]([O:25][C@@H:26]1[C@H:30]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:29][C@@H:28]([NH:40][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[NH:6]3)[CH2:27]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2ncnc3[nH]c(-c4cccc(Cl)c4)nc23)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 83.5 %

Procedure:
A solution of 6-chloro-8-(3-chlorophenyl)-9H-purine (155 mg, 0.58 mmol), (1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentanamine (200 mg, 0.56 mmol) (Example 128, steps a-c), and N,N-diisopropylethylamine (0.20 mL, 1.17 mmol) in ethanol (2.00 mL) was microwaved at 160° C. for 30 minutes. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (275 mg, 76%) as a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C>C1COCC1.C1(C)C=CC=CC=1.O=[Pt]=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:22]=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: O=CO
Agent: O=[Pt]=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reaction time: 16 h
Yield: 63 %

Procedure:
A Parr hydrogenator was charged with PtO2 and 1-(4-benzyloxy-3-nitro-phenyl)-2-bromo-1-(R)-ethanol (4) (0.72 g, 2.04 mmol) dissolved in a mixed solvent of THF (8 mL) and toluene (8 mL). The mixture was hydrogenated at 55 psi at rt for 16 h. Then a mixture of formic acid (0.13 mL, 3.45 mmol) and acetic anhydride (0.22 mL, 2.33 mmol) was added and stirring was continued at rt for 66 h. The catalyst was filtered through a Celite pad and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by Biotage silica gel column chromatography eluting with ethyl acetate/dichloromethane (gradient 0% to 10%) to give the desired formamide 5 as a white solid (0.45 g, 63%): 1H NMR (300 MHz, CDCl3) δ 2.95 (s, 1H), 3.52 (m, 1H), 3.60 (m, 1H), 4.85 (m, 1H), 5.08 (s, 2H), 6.96 (d, 1H), 7.13 (dd, 1H), 7.39 (m, 5H), 7.88 (br, 1H), 8.37 (dd, 1H).
Reaction SMILES: CS(O[CH:6]1[C:10]([CH3:12])([CH3:11])[C:9](=[O:13])[N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34][C:35]([F:38])([F:37])[F:36])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[CH2:7]1)(=O)=O.[N-:47]=[N+:48]=[N-:49].[Na+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[N:47]([CH:6]1[CH2:7][N:8]([C:14]2[C:18]([NH:19][C:20]([C:22]3[N:23]=[C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:33]([CH2:34][C:35]([F:37])([F:38])[F:36])[C:39](=[O:40])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=4)[O:25][CH:26]=3)=[O:21])=[CH:17][N:16]([CH3:46])[N:15]=2)[C:9](=[O:13])[C:10]1([CH3:12])[CH3:11])=[N+:48]=[N-:49]
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(OS(C)(=O)=O)C(C)(C)C2=O)n1
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CC(N=[N+]=[N-])C(C)(C)C2=O)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.2 %

Procedure:
1-(4-(((2-(2-((tert-Butoxycarbonyl)(2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazol-4-yl)carbonyl)amino)-1-methyl-1H-pyrazol-3-yl)-4,4-dimethyl-5-oxopyrrolidin-3-yl methanesulfonate (15 mg) was dissolved in DMF (0.50 mL), sodium azide (22 mg) and 18-crown-6 (5.9 mg) were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate, and the mixture was washed three times with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.0 mg).