Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH2:33])[CH:23]=1.NC1C(N)=NC=CC=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([O:30][CH2:31][CH3:32])[N:25]=[C:24]([NH:33][C:12](=[O:14])[CH2:11][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])[CH:23]=1
Reactant: CCOc1nc(N)cc(N)c1C#N
Reactant: COc1cccc(CC(=O)O)c1OC
Agent: Nc1cccnc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1nc(NC(=O)Cc2cccc(OC)c2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
To 67 mg (0.34 mmol) of (2,3-dimethoxyphenyl)acetic acid in 1 mL of CH2Cl2 was added 32 μL (0.37 mmol) of oxalyl chloride. The solution was stirred at ambient temperature for 20 minutes then added to a solution of 60 mg (0.28 mmol) of 4,6-diamino-2-ethoxy-nicotinonitrile in 0.5 mL of pyridine. The mixture was complete within 5 minutes though some diaminopyridine remained. The solvent was removed under reduced pressure, then the residue was taken up in 10 mL of ethyl acetate and extracted with water (2×5 mL), saturated NaHCO3(aq.) (1×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to an oil. This was recrystallized from 8 mL of methanol to provide 35 mg (35%) of white crystals. 1H NMR (300 MHz, d6-DMSO) δ 10.22 (s, 1H), 7.15 (s, 1H), 6.97 (m, 2H), 6.88 (s, 2H), 6.81 (dd, 1H, J=7.1, 2.0 Hz), 4.35 (q, 2H, J=7.1 Hz), 3.79 (s, 3H), 3.71 (s, 2H), 3.68 (s, 3H), 1.31 (t, 3H, J=7.1 Hz); MS (ESI) m/e=327 (M−Et+H)+, 357 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[CH3:37])[C:28]([NH:30][CH:31]1[CH2:33][CH2:32]1)=[O:29].N1C=CC=CC=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:24][C:25]2[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=2[CH3:37])[C:28]([NH:30][CH:31]2[CH2:32][CH2:33]2)=[O:29])=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a solution of 4-benzyloxybenzoic acid (11.0 g, 48 mmol) in DCM (100 mL) at 0° C. was added oxalyl chloride (8.4 mL, 96 mmol) followed by DMF (two drops). The resulting mixture was stirred at room temperature for 2 hours. The mixture was evaporated giving a white solid which was dissolved in DCM (50 mL). The resulting solution was added portionwise to a stirred solution of 3-amino-N-cyclopropyl-4-methylbenzamide (7.61 g, 40 mmol) and pyridine (7.76 mL, 96 mmol) in DCM (100 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed three times with DCM to give the title compound as a white solid (13.9 g, 87%); NMR Spectrum: (DMSOd6) 0.60 (m, 4H), 2.25 (s, 3H), 2.84 (m, 1H), 5.20 (s, 2H), 7.14 (d, 2H), 7.39 (m, 6H), 7.63 (d, 1H), 7.79 (s, 1H), 7.97 (d, 2H), 8.37 (s, 1H), 9.82 (s, 1H); Mass Spectrum: M+H+ 399.
Reaction SMILES: NC(N)=O.[CH3:5][S:6][CH2:7][CH2:8][CH2:9][NH:10][S:11]([C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([NH2:21])[C:15]=1[OH:22])(=[O:13])=[O:12].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:32]([NH:31][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=2[Cl:23])=[O:33])=[C:15]([OH:22])[C:14]=1[S:11]([NH:10][CH2:9][CH2:8][CH2:7][S:6][CH3:5])(=[O:13])=[O:12]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CSCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Agent: NC(N)=O
Product: CSCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 69.7 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-(3-methylthiopropyl)-3-amino-6-chloro-2-hydroxybenzenesulfonamide (250 mg, 0.80 mmol) and 2,3dichlorophenylisocyanate (1 82 mg, 0.97 mmol) were coupled to form the desired urea (278 mg, 70%). 1H NMR (MeOD-d4): δ 8.29 (d, 1H), 8.06 (d, 1H), 7.24 (m, 2H), 7.05 (d, 1H), 3.07 (t, 2H), 2.48 (t, 2H), 1.98 (s, 3H) 1.74 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH2:19][OH:20])[NH:6][C:7]=1[C:8]1[C:9]([CH3:18])=[CH:10][C:11](C)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])#[N:2].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.CC1C=C(C)C(B2OC(C)(C)C(C)(C)O2)=CC=1C(OC)=O>>[C:1]([C:3]1[N:4]=[C:5]([CH2:19][OH:20])[NH:6][C:7]=1[C:8]1[CH:16]=[C:12]([CH:11]=[CH:10][C:9]=1[CH3:18])[C:13]([OH:15])=[O:14])#[N:2]
Reactant: Cc1cc(C)c(-c2[nH]c(CO)nc2C#N)cc1C(=O)O
Agent: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1ccc(C(=O)O)cc1-c1[nH]c(CO)nc1C#N

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 219.6, except methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) was used in place of methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O.FC(F)(F)S(O[C:73]1[CH2:78][C:77]([CH3:80])([CH3:79])[CH2:76][C:75]([CH3:82])([CH3:81])[CH:74]=1)(=O)=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[C:73]1[CH2:78][C:77]([CH3:80])([CH3:79])[CH2:76][C:75]([CH3:82])([CH3:81])[CH:74]=1
Reactant: CC1(C)C=C(OS(=O)(=O)C(F)(F)F)CC(C)(C)C1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C2=CC(C)(C)CC(C)(C)C2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.7 %

Procedure:
A screw-cap vial was charged with 66.31A (0.556 g, 1.94 mmol), THF (10 mL), 66.56A (0.500 g, 1.29 mmol), potassium phosphate (0.824 g, 3.88 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (commercially available from Aldrich) (0.165 g, 0.401 mmol), palladium(II) acetate (0.0291 g, 0.129 mmol), and water (0.117 mL, 6.47 mmol). The mixture was purged with argon and stirred for 48 hours at room temperature under an argon balloon. Additional 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.165 g, 0.401 mmol), palladium(II) acetate (0.0291 g, 0.129 mmol), and 69.31A (0.556 g, 1.94 mmol) were added, and stirring was continued for 16 hours at room temperature under argon. The mixture was filtered through silica gel (EtOAc) and concentrated. The crude product was purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 69.31B (0.300 g, 58% yield) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Na+].[ClH:36]>ClCCl>[ClH:36].[C:25]1([N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]2[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)[C@@H]1CCCN(CCCCCCN(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The ester prepared in Example 3 (3.4 g, 8.3 mmol) was dissolved into ethanol (10 ml) and a 12 N sodium hydroxide solution (1.5 ml) was added. The reaction mixture was stirred at room temperature for 6 h. A concentrated hydrochloric acid solution (2.3 ml) was added with cooling of the reaction vessel in an ice-bath and dichloromethane (300 ml) was added. The resulting emulsion was dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was crystallised from ethyl acetate. This afforded 2.8 g (81%) of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([C:15]([O:17]C)=O)=[C:13]([OH:19])[C:12]2[C:7](=[CH:8][C:9]([Cl:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].Cl.[C:22]1([NH:32][NH2:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(O)C.C(OCC)(=O)C>[Cl:20][C:9]1[CH:10]=[CH:11][C:12]2[C:13](=[O:19])[C:14]3[C:15]([OH:17])=[N:33][N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[C:3](=[O:4])[C:5]=3[NH:6][C:7]=2[CH:8]=1
Reactant: NNc1cccc2ccccc12
Reactant: COC(=O)c1nc2cc(Cl)ccc2c(O)c1C(=O)OC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=c1c2ccc(Cl)cc2[nH]c2c(=O)n(-c3cccc4ccccc34)nc(O)c12
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a stirred suspension of dimethyl7-chloro-4-hydroxyquinoline -2,3-dicarboxylate (2.00 g, 6.80 mM) and 1-naphthyl hydrazine hydrochloride (9.26 g, 47.6 mM) in ethanol (72 mL) was added triethylamine (7.60 mL) to give a brown solution. After refluxing for 4 days, the solution was cooled to room temperature and diluted with ethyl acetate (0.35 L) to give a tan suspension. This suspension was filtered to remove the solids which were discarded. The filtrate was then poured into ethyl acetate (500 mL) which was washed with hydrochloric acid (3×500 mL, 1N). The washed solution was diluted with ether (250 mL) to give a tan suspension. The solids were collected to give the 1-naphthyl hydrazine salt of the title compound as a tan powder (2.09 g). This material was refluxed in glacial acetic acid (50 mL) for 2 hours, cooled to room temperature and filtered. The collected solids were washed with glacial acetic acid and ether to give the title compound (1.44 g, 54%) as a tan powder, mp 368° C. (decomp.); MS(CI): 390 (M+H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH3:15])[CH2:3][CH2:2]1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: Cc1ccc(C(=O)N[C@@H](CC2CC2)C(N)=O)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=318.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>CCOC(C)=O.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH:3]=1
Reactant: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1cc(N)cc(Br)c1
Yield: 15.4 %

Procedure:
A solution of 5-(3-Bromo-5-nitro-phenyl)-1-methyl-1H-tetrazole (2.1 g) in EtOAc (100 ml) was hydrogenated on a H-cube® apparatus at 20° C., room pressure with a flow rate of 1 ml/min using a Raney-Ni cartridge. After reaction completion, the mixture was concentrated in vacuum and triturated with MeOH. The solid was filtered and further triturated and air-dried to give the title compound (290 mg). Rt 1.25 min (method D).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:4][CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COCc1cccc(Br)n1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(COCc1cccc(Br)n1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(6-bromopyridin-2-yl)methoxy]acetic acid (1.6 g, 7.5 mmol) and morpholine (0.65 g, 7.5 mmol) in dichloromethane at 0° C. was added N-ethyl-N-isopropylpropan-2-amine (3.9 mL, 22.5 mmol), 1-hydroxybenzotriazole hydrate (1.5 g, 11.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 11.25 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography, eluting with ethyl acetate:hexanes (3:7) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Si](C=[N+]=[N-])(C)(C)[CH3:16].C(O)(=O)C>CO.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-(trifluoromethyl)benzoic acid (260 mg, 1.25 mmol, 1 eq) in MeOH (0.5 mL) and CH2Cl2 (2 mL) was treated with TMSCHN2 (2M in hexanes, 0.85 mL, 1.70 mmol, 1A eq) dropwise with stirring at room temperature. After the reaction was stirred for 10 min, acetic acid was added until the yellow color disappeared. The mixture was concentrated to afford methyl 4-fluoro-3-(trifluoromethyl)benzoate, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[C:6]([F:12])[CH:5]=1>O.C(O)C>[Br:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:1][OH:2])=[C:6]([F:12])[CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)cc1F
Solvent: O
Solvent: CCO
Product: ON=Cc1ccc(Br)cc1F
Reaction time: 66 h

Procedure:
A solution of hydroxylamine in water (50%, 5 ml) was added to a solution of 4-bromo-2-fluorobenzaldehyde (1.0 g) in ethanol (5 ml) and the mixture was stirred at room temp. for 66 h. The ethanol was removed under vacuum and the aqueous residue as extracted with ethyl acetate (×2). The organic extracts were washed with water and brine, dried (MgSO4) and concentrated under vacuum. The residue was purified on a Varian Bond-Elut SPE cartridge (silica, 20 g) eluting with cyclohexane:ethyl acetate (100:0 to 50:50) to give the title compound as a white solid (0.94 g).
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])N.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>CC(O)=O>[C:4]1([C:5]([O:7][CH3:8])=[O:6])[C:3]2[NH:1][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccccc1NN
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: COC(=O)c1cccc2c3c([nH]c12)CCCC3
Temperature: 80 °C
Yield: 57 %

Procedure:
A 150-mL round-bottom flask was placed a solution of methyl 2-hydrazinylbenzoate (7.81 g, 1.00 equiv, 1%) in AcOH (70 mL). To this solution was added cyclohexanone (4.5 g, 45.92 mmol, 1.00 equiv) dropwise with stirring at 80° C. The resulting solution was heated to reflux for 2 hr in an oil bath. Upon completion, the reaction was then quenched with water (50 mL). The solids were collected by filtration and washed with H2O (2×50 mL) affording methyl 6,7,8,9-tetrahydro-5H-carbazole-1-carboxylate as white solid (6 g, 55.8%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([NH-])(C)C.[Li+].[CH3:14][Sb:15](Br)[CH3:16]>C1COCC1>[CH3:14][Sb:15]([CH3:16])[C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: C[Sb](C)Br
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)[Sb](C)C
Temperature: -78 °C
Yield: 50 %

Procedure:
A 3.48 g quantity (30 mmole) of ethyl isobutyrate was added to 50 ml of THF, and the mixture was chilled to −78° C. To the mixture was slowly added 16.5 ml (33 mmole) of lithium isopropylamide (product of Aldrich, 2.0M heptane-THF-ethylbenzene solution) over a period of 10 minutes. The reaction mixture was stirred while being held at −78° C. (for 1 hour). To the resulting solution was added 6.9 g (29.8 mmole) of dimethylstibanyl bromide at 0° C., followed by stirring at room temperature for 2 hours. After the completion of the reaction, the solvent was concentrated in a vacuum and subsequently distilled in a vacuum, giving 3.98 g of a colorless oily product (50.0% in yield), b.p. 53-55° C./1.6-1.8 mmHg. MS (HRMS), 1H-NMR and 13C-NMR revealed that the product was the desired one.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([S:11]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:13])=[O:12])([CH2:9][CH3:10])[CH3:8].[Cl:26][C:27]1[CH:28]=[C:29]([OH:35])[CH:30]=[N:31][C:32]=1[O:33][CH3:34]>CS(C)=O.O>[CH:7]([S:11]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:35][C:29]2[CH:30]=[N:31][C:32]([O:33][CH3:34])=[C:27]([Cl:26])[CH:28]=2)=[CH:18][C:17]=1[F:24])(=[O:13])=[O:12])([CH2:9][CH3:10])[CH3:8]
Reactant: COc1ncc(O)cc1Cl
Reactant: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)S(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(OC)c(Cl)c2)cc1F
Temperature: 90 °C
Yield: 52.1 %

Procedure:
Potassium carbonate (0.140 g, 1.01 mmol) was added to a stirred solution of N-(sec-butylsulfonyl)-2,4,5-trifluorobenzamide (Preparation 68, 0.090 g, 0.30 mmol) in DMSO (1 mL). After 10 minutes a solution of 5-chloro-6-methoxypyridin-3-ol (Preparation 77, 0.088 g, 0.51 mmol) in DMSO (2 mL) was added at room temperature. The mixture was heated at 90° C. for 72 hours. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×25 mL). The combined organics were washed with water (25 mL), dried over magnesium sulfate, filtered, evaporated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 66% EtOAc in heptane to yield the title compound (0.068 g):
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]#[N:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C#N)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Yield: 74.5 %

Procedure:
4-(2-Cyano-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.2 g) was dissolved in IMS (15 mL) and palladium on carbon (10%; 0.08 g) in water (0.5 mL) was added. Ammonium formate (0.3 g) was added and the mixture heated at reflux for 0.5 hour. The mixture was allowed to cool, filtered and the solvent removed by evaporation to give the title compound as a clear colourless oil (0.15 g). LCMS m/z 287.3[M+H]+. R.T.=4.63 min (Analytical Method 4).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][O-:13].[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:12])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1c(Br)cnc2[nH]ccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(Br)cnc2[nH]ccc12
Temperature: 175 °C
Yield: 26.4 %

Procedure:
5-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (500 mg, 2.16 mmol) was combined with sodium methoxide (583 mg, 10.8 mmol) and suspended in anhydrous methanol (10 mL). The reaction was heated in the microwave to 175° C. for 4 h. The reaction mixture was concentrated and purified by flash silica gel chromatography using a gradient of (ethyl acetate/methanol 9:1) in hexanes to afford 5-Bromo-4-methoxy-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.57 mmol, 27%) as a light yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 11.84 (bs, 1H), 8.14 (s, 1H), 7.40 (m, 1H), 6.80 (m, 1H), 4.30 (s, 3H). MS: m/z 226.9/228.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:23][N:24]2[CH2:27][CH:26]([C:28]([O:30]CC)=[O:29])[CH2:25]2)[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:13][C:11]=2[CH:12]=1.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:23][N:24]2[CH2:25][CH:26]([C:28]([OH:30])=[O:29])[CH2:27]2)[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([CH2:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CCOC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5nccs5)ccc4o3)c(F)c2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(Cc5nccs5)ccc4o3)c(F)c2)C1
Temperature: 24 °C

Procedure:
A mixture of ethyl 1-((3-fluoro-4-(5-(thiazol-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate (290 mg, 644 μmol) in THF (5 mL) was treated with a solution of LiOH (27 mg) in H2O (2 mL) and stirred at 24° C., neutralized with 0.1M aqueous HCl, and concentrated. The resulting solids were collected by filtration and purified by RP-HPLC to give 1-((3-fluoro-4-(5-(thiazol-2-ylmethyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylic acid as a white solid [hS1P1 EC50=76 nM]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.93-7.91 (m, 1H), 7.73 (s, 1H), 7.66-7.58 (m, 3H), 7.32-7.28 (m, 4H), 4.44 (s, 2H), 3.65 (br. s, 2H), 3.46 (br. s, 2H), 3.30-3.26 (m, 3H). MS (ESI) m/z: Calculated: 422.1; Observed: 423.2 (M++1).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34](O)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:34]([C:29]1[C:30]2[C:25](=[C:24]([Cl:23])[CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:27][CH:28]=1)=[O:35])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)c1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(tert-butyl)phenyl]-1-(3-chlorophenyl)-1-propanol (0.313 g, 0.985 mmol) in N,N-dimethylformamide (5 ml) were added 5-chloronaphthalene-1-carboxylic acid (0.214 g, 1.04 mmol) and 1-hydroxybenzotriazole monohydrate (0.160 g, 1.04 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g, 1.04 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(tert-butyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide (0.307 g, 62%) as colorless crystals.