Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([C:7]([F:10])([F:9])[F:8])[CH2:3][CH2:4][CH2:5][OH:6].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:11])([F:1])[C:7]([F:8])([F:9])[F:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
A mixture of 4,4,5,5,5-pentafluoropentan-1-ol (1 g, 5.6 mmol), p-toluenesulfonylchloride (1.3 g, 6.8 mmol), and triethylamine (1.2 mL, 8.4 mmol) in DCM (20 mL) was stirred at room temperature for 18 h. Water was added to the reaction mixture, the two layers were separated, and the aqueous layer was extracted with DCM (2×). The organics were combined, dried over sodium sulfate, and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with 0 to 20% EtOAc/hexanes to afford 1.7 g of 4,4,5,5,5-pentafluoropentyl 4-methylbenzenesulfonate as a colorless oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)C(Cc1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc(Cl)cc1)C(Cc1ccccc1)c1ccccc1

Procedure:
A 20% sodium hydroxide solution (10 ml.) is added to a stirred solution of p-chlorobenzaldehyde (19.4 g., 0.138 mole) and 3,4-diphenyl-2-butanone (31.06 g., 0.138 mole) in ethanol (400 ml.). The cream-colored solid that separates is collected, washed with water, and dried at 90°C., yield 41.13 g., m.p. 113°-115°C. Recrystallization from ethanol gives material with m.p. 117°-118.5 C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCC(NC(=O)c2ccc(N)nc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
6-Aminonicotinic acid (Aldrich; 2 g, 14.48 mmol) and 4-amino-1-methylpiperidine (Fluorochem; 1.82 g, 15.92 g) were suspended in DMF (20 mL), DIPEA (7.5 mL, 43.44 mmol) and HATU (6.05 g, 15.92 mmol) were added and the reaction stirred at ambient temperature for 18 hrs. The solvent was evaporated and the residues stirred with water (50 mL for 1 hr filtered, acidified with 2M aq HCl and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) then the crude product eluted with 2M ammonia in MeOH and evaporated. The residue was dissolved in DCM with a little MeOH to help solubility and purified on silica eluting with a gradient of 10-20% 2M ammonia in MeOH/DCM. Fractions containing product combined and evaporated to give the title compound as a cream solid (1.75 g, 52%)
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[C:27]=1[F:34]
Reactant: CC(C)N
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1cc(F)cc(F)c1F
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: C[C@H]1NC(=O)C(NC(=O)OC(C)(C)C)C[C@H]1c1cc(F)cc(F)c1F
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of NaBO3.4H2O (1.5 g, 3.9 mmol) in H2O (18.2 g) was charged isopropylamine (1.16 g, 19.6 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.2-10.3 by 6N HCl. PLP (0.042 g, 0.27 mmol) and ATA-412 (1.0 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 45 (2 g, 4.7 mmoL) in DMSO (10 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (10 mL), and then partitioned with water and IPAc. The organic solution was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 46 (1.45 g, 85% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.95-7.78 (m, 1H), 6.95 (m, 1H), 3.01 (t, 1H), 1.36 (s, 9H), 1.17-1.10 (br, 4H), 1.12 (m, 3H); MS (ESI) m/e [M+H]+: 359.15.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:14][C:15]1[N:20]=[C:19]([C:21]2[O:22][C:23](Br)=[CH:24][CH:25]=2)[C:18]([C:27]#[N:28])=[C:17]([S:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:16]=1>C1COCC1>[NH2:14][C:15]1[N:20]=[C:19]([C:21]2[O:22][C:23]([CH2:2][C:1]#[N:3])=[CH:24][CH:25]=2)[C:18]([C:27]#[N:28])=[C:17]([S:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:16]=1
Reactant: CC#N
Reactant: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(Br)o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a stirred solution of 0.2 ml (3.72 mmol) acetonitrile in 25 ml dry THF under argon at −78° C. was added dropwise 3.3 ml (1,65 mmol) potassium bis(trimethylsilyl)amide solution (0.5M in toluene) and stirring continued for 1 hour. The solution was then transferred dropwise via cannula to a solution of 300 mg (0.75 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile in 25 ml THF at −78° C. and stirring continued for 5 h at −78° C. and 1 h at −40° C. The reaction mixture was then quenched by addition of saturated aqueous ammonium chloride solution. The mixtured was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 4/1 then ethyl acetate) afforded 22 mg (8%) 2-amino-4-(5-cyanomethyl-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a brown crystalline solid. ES-MS m/e (%): 385 (M+Na+, 45), 363 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](O)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4].CN(C=O)C.C(Cl)(=O)C([Cl:29])=O>C(Cl)Cl>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([Cl:29])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[S:6]1(=[O:20])=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(O)=C(c2ccc(Cl)cc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCN1C(=O)C(Cl)=C(c2ccc(Cl)cc2)S1(=O)=O
Yield: 86.8 %

Procedure:
2-Butyl-5-(4-chlorophenyl)-4-hydroxyisothiazol-3(2H)-one 1,1-dioxide (0.9 g, ca. 60%, 1.71 mmol) was dissolved in DCM (50 mL). DMF (0.13 mL) was added. Under nitrogen atmosphere, oxalyl chloride (0.434 g, 3.42 mmol) was dropped in. The mixture was then heated to reflux for 2 h and then evaporated to dry. Water (30 mL) was added into the residue. It was then extracted with DCM (20 mL×3). The extracts were combined and washed with water (50 mL×3) and brine (20 mL), dried (MgSO4) and evaporated. The residue was then purified by column chromatography (ISOLUTE SI, 20 g/70 mL), eluting with DCM:heptane (25:75), to give the title compound (0.496 g, 87%); 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H), 7.54 (d, 2H), 3.76 (t; 2H), 1.85-1.77 (m, 2H), 1.48-1.39 (m, 2H), 0.98 (t, 3H); 13C NMR (100 MHz, CDCl3): δ 155.8, 142.4, 139.0, 130.2, 129.9, 127.7, 121.8, 40.8, 30.2, 19.9, 13.4.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:13]=[C:14]([O:19][CH3:20])[C:15]([NH2:18])=[N:16][CH:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([O:19][CH3:20])[C:15]([NH:18][S:7]([C:5]2[S:6][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])=[N:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)s1
Reactant: COc1nc(Cl)cnc1N
Product: COc1nc(Cl)cnc1NS(=O)(=O)c1ccc(C)s1

Procedure:
Prepared by the method of Example 1 using 5-methylthiophenesulphonyl chloride and 5-chloro-3-methoxy-2-pyrazinamine.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Br:27])[CH:14]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI.CN(C)C=O>O>[CH3:29][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:28])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([Br:27])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg), potassium carbonate (95 mg), methyl iodide (43 μl) and N,N-dimethylformamide (DMF) (5 ml) was stirred at room temperature for 3 hrs. After diluting with water, the mixture was extracted with ether and the extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and ethyl acetate and n-hexane was added to the residue and the mixture was crystallized to give the title compound (96 mg, 62%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-:28].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)COc1ccc(CC(C)NCCc2csc(C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCC(=O)O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 16 by reaction of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine (diastereomer A) in methanol with 1N sodium hydroxide solution. After the mixture has been neutralised with 1N hydrochloric acid it is extracted by shaking with methylene chloride, the extract is evaporated to dryness, and the remaining residue is triturated with petroleum ether and filtered off with suction.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19](C)(C)[O:20][SiH2]C(C)(C)C)[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=3)[CH2:31][NH:32][C:33]([C:35]3[C:36](=[O:50])[N:37]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][CH:40]=3)=[O:34])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O>C(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([CH2:19][OH:20])[CH:18]=[C:13]3[C:12]([C:28]3[CH:29]=[C:30]([CH:51]=[CH:52][CH:53]=3)[CH2:31][NH:32][C:33]([C:35]3[C:36](=[O:50])[N:37]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=4)[CH:38]=[CH:39][CH:40]=3)=[O:34])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CO)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 1-neck round-bottom flask was dissolved 1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-[1-benzenesulfonyl-5-(tert-butyl-dimethyl-silanyloxymethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-benzylamide (0.17 mmol, 0.00017 mol) in ethanol (3.00 mL, Fisher;). To this was added 12 M of hydrogen chloride in water (1.00 mL, 0.012 mol; Fisher) and the reaction was stirred at room temperature for 1 h and then evaporated to give the crude product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](N)[C:3]=1[NH:9][CH2:10][CH2:11][OH:12].Cl.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[CH:22]([OH:27])[C:23](=[NH:26])OC>C(O)C.C(=O)([O-])O.[Na+]>[NH2:1][C:2]1[C:3]2[N:9]([CH2:10][CH2:11][OH:12])[C:23]([CH:22]([C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[Cl:14])[OH:27])=[N:26][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=N)C(O)c1ccc(Cl)cc1Cl
Reactant: Nc1cccc(N)c1NCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCO)c12
Reaction time: 12 h
Yield: 99.1 %

Procedure:
To a stirred solution of 2-[(2,6-diaminophenyl)amino]ethanol (3.63 g, 21.7 mmol) in ethanol (43 mL) was added methyl 2-(2,4-dichlorophenyl)-2-hydroxyethanimidoate hydrochloride (7.04 g, 26.0 mmol) at room temperature. After 12 h, the reaction mixture was diluted with aqueous sodium hydrogen carbonate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give the title compound as an orange amorphous solid (7.58 g, 21.5 mmol, 99%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[O:8][CH3:9].C1(P(C2CCCCC2)C2C=CC=CC=2C2C3C(C4C=CC=CC=4C=2)=CC=CC=3)CCCCC1.[Cl:54][C:55]1[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[Cl:54][C:55]1[CH:60]=[C:59]([Cl:61])[CH:58]=[CH:57][C:56]=1[C:2]1[N:3]=[CH:4][C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Temperature: 110 °C
Yield: 30.5 %

Procedure:
A Kimble vial was charged with (1R,2S)-1-[(5-bromo-6-methoxypyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol (0.55 g, 1.63 mmol), Pd2(dba)3 (33 mg, 35 μmol), dicyclohexyl[2-(9-phenanthryl)phenyl]phosphine (64 mg), 2,4-dichlorophenylboronic acid (567 mg, 2.67 mmol), K3PO4 (1.13 g, 5.34 mmol) and toluene (15 mL). The vial was flushed with N2, sealed and heated at 110° C. for 6 hr. Cool to rt, add additional Pd2(dba)3 (33 mg) and 2,4-dichlorophenylboronic acid (0.5 g, 2.7 mmol). Continue heating overnight. Add additional Pd2(dba)3 (33 mg) and 2,4-dichlorophenylboronic acid (0.5 g, 2.7 mmol) and continue heating for 5 hr. Add additional Pd2(dba)3 (33 mg) and 2,4-dichlorophenylboronic acid (0.5 g, 2.7 mmol) and continue heating overnight. The reaction was cooled to rt, diluted with CH2Cl2, washed with sat. aq NaHCO3 and sat. aq. NaCl. Dry organic extract over MgSO4, filter and concentrate. Purify by biotage MPLC (90 g column, 30% ethyl acetate/hexanes) to afford 0.2 g (31%) of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-6-methoxypyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol as an oil: 1H NMR (CDCl3) δ 3.06-3.10, 3.26-3.32, 3.92, 4.79, 5.33, 5.49-5.50, 7.28-7.41, 7.50, 7.74; MS (ESI+) for C20H17Cl2N3O2 m/z 402 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH:17](Br)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9](=[O:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Li+].[Li+]>CN(C)C=O>[C:9]1(=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCCCCCC(Br)C(Br)CCCCCC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C1CCCCCC=CC=CCCCCCC1
Reaction time: 14 h

Procedure:
The crude 8,9-dibromocyclohexadecanone was fed into a reaction vessel containing a slurry of dimethylformamide (DMF) 700 ml and lithium carbonate (111 g 1.5 mole) at 150° C. The mass was aged for 14 hrs. The reaction was washed with 2 L water then 10% aqueous acetic acid (500 ml). Distillation over caustic (2% NaOH ) affords 54 g of 7,9-cyclohexadecadien-1-one and 86 g of a mixture of 8-cyclohexadecenone and 7,9-cyclohexadecadien-1-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:27]([O:29]CC4C=CC=CC=4)=[O:28])([CH3:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:24]([C:27]([OH:29])=[O:28])([CH3:26])[CH3:25])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)OCc4ccccc4)c3)cnc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(C(C)(C)C(=O)O)c3)cnc21
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a stirred solution of 6-[5-(1-benzyloxycarbonyl-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (500 mg, 1.0 mmol) in MeOH (25 mL) is added 10% Pd/C (250 mg). The reaction mixture is stirred under 40 psi H2 for 16 h. The catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated to afford 160 mg of 6-[5-(1-carboxy-1-methyl-ethyl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]3[C:13]([NH:16][C:25](=[O:26])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:17]3)=[CH:14][CH:15]=2)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Solvent: CCO
Product: CCOC(=O)c1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Yield: 14 %

Procedure:
A solution of 15 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine and 12.5 parts of diethyl 2-oxo-1,3-propanedioate in 80 parts of ethanol was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 3.1 parts (14.0%) of ethyl 3,4-dihydro-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-3-oxo-2-quinoxalinecarboxylate; mp. 229.7° C. (comp. 107).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:16])[CH2:14]C)=[CH:7][C:5]=2[N:6]=1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:16])[CH2:14][N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][C:5]=2[N:6]=1
Reactant: CC[C@@H](O)COc1ccc2sc(C)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol, as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [CH2:1]([CH:8]([O:10][P:11]([CH2:14][C:15]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1)([OH:13])=[O:12])C)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:8]([O:10][P:11]([CH2:14][C:15]1([C:20]([OH:22])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19]1)([OH:13])=[O:12])[CH3:1]
Reactant: [H][H]
Reactant: CC(Cc1ccccc1)OP(=O)(O)CC1(C(=O)O)CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(O)CC1(C(=O)O)CCCC1
Yield: 102.6 %

Procedure:
3.5 g of 1-benzylethylphosphonomethyl-1-cyclopentanecarboxylic acid (preparation see Example 3E)) were dissolved in 150 ml of ethanol and treated with 1.0 g of 5% strength Pd catalyst on active carbon. The mixture was then hydrogenated at a hydrogen pressure of 2.1 bar for 4 hours. The catalyst was filtered out twice, the filtrate was evaporated in vacuo, and the residue was dried in a high vacuum. 2.60 g of oily 1-ethylphosphonomethyl-1-cyclopentanecarboxylic acid were obtained, which was reacted without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1.[CH3:19][NH:20][CH3:21].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:19][N:20]([CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:17][CH3:18])[CH:9]=2)=[N:6][N:7]=1)[CH3:21]
Reactant: CNC
Reactant: COc1cc(-c2nnc(CCl)o2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2nnc(CN(C)C)o2)ccc1N
Temperature: 60 °C
Yield: 89.2 %

Procedure:
To 2-(chloromethyl)-5-[3-(methyloxy)-4-nitrophenyl]-1,3,4-oxadiazole (0.399 g, 1.48 mmol) in dioxane (10 mL) was added dimethylamine (1.87 mL, 40% weight in H2O, 14.8 mmol). The reaction was heated at 60° C. overnight. The reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. The residue was taken up in EtOAc (20 mL) and Pd on carbon was added in one portion. The mixture was stirred at rt under H2 (1 atm.) until complete by TLC. The reaction was filtered through Celite® and concentrated to provide the title compound of step D (0.326 g, 1.32 mmol, 89% over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.18-2.23 (m, 6H), 3.67-3.72 (m, 2H), 3.76-3.82 (m, 3H), 5.47-5.56 (m, 2H), 6.64-6.72 (m, 1H), 7.25 (d, J=2.0 Hz, 1H), 7.30 (dt, J=8.1, 2.1 Hz, 1H).