Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:34]([O:36][CH3:37])=[O:35])=[N:12][C:13]([C@@H:17]2[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].S(OC)(O[CH3:44])(=O)=O.Cl>O1CCOCC1>[CH3:37][O:36][C:34]([C:11]1[N:12]=[C:13]([C@@H:17]2[CH2:21][C@@H:20]([O:22][CH3:23])[CH2:19][N:18]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[N:14]([CH3:44])[C:15](=[O:16])[C:10]=1[O:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:35]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1nc([C@@H]2C[C@@H](OC)CN2C(=O)OCc2ccccc2)nc(O)c1OC(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COC(=O)c1nc([C@@H]2C[C@@H](OC)CN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 38 °C
Reaction time: 0.67 h

Procedure:
To methyl 5-(benzoyloxy)-2-{(2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxypyrrolidin-2-yl}-6-hydroxypyrimidine-4-carboxylate, dissolved in dioxane, LiH (1.4 eq.) was added and the reaction mixture stirred at 38° C. for 40 minutes. The temperature was raised to 60° C. and dimethyl sulphate (1.3 eq.) was added dropwise. After two hours the reaction mixture was cooled down to 0° C. and HCl 1 N was added to quench the reaction. The reaction mixture was extracted with ethyl acetate and the organic phase washed with HCl 1N, saturated aqueous NaHCO3 and brine, dried on Na2SO4, filtered and concentrated in vacuo. The desired product was isolated by flash chromatography on silica gel (eluent ethyl acetate:petroleum ether=30:70) as a 1:1 mixture of rotamers by NMR:
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:23]([C:21]3[N:22]=[C:18]([CH3:17])[O:19][C:20]=3[C:26]3[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=3)=[O:24])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC(F)(F)c1ccc(Cn2ncc(N)n2)o1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)n2)c1

Procedure:
Following general procedure A, starting from 2-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Na].[C:14]([NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=S)#[N:15]>O1CCCC1>[NH2:15][C:14]1[N:1]=[C:2]2[N:6]([C:17](=[N:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=1)[C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[S:3]2
Reactant: COc1ccc2nc(N)sc2c1
Reactant: N#CNC(=S)Nc1ccccc1
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)sc1nc(N)nc(=Nc3ccccc3)n12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-amino-6-methoxy benzothiazole (9.0 g) in dry tetrahydrofuran was treated with the sodium salt of N-cyano-N'-phenyl thiourea (5.0 g) and finely powdered mercuric chloride (6.75 g) and the mixture stirred at room temperature for 24 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[ClH:9].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13].[Cl-].[Zn+2:16].[Cl-]>C(O)CCC>[ClH:1].[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[CH:4][CH:3]=1)[N:6]=[C:12]([CH3:13])[CH:11]=[CH:10]2.[Cl-:9].[Zn+2:16].[Cl-:1]
Reactant: Nc1ccc(Cl)cc1
Reactant: C/C=C/C=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCO
Product: Cc1ccc2cc(Cl)ccc2n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 62 %

Procedure:
(Method A) 4-Chloroaniline (2.55 g, 20 mmol), concentrated hydrochloric acid (5 cm3), tetrachloro-1-4-benzoquinone (5.9 g, 20 mmol), and n-butanol (5 cm3) were mixed and heated to reflux giving a yellow suspension. Crotonaldehyde (1.68 g, 24 mmol) in butanol (2 cm3) was added over 1 hr giving a dark brown solution. After a further 30 mins reflux, zinc chloride (0.5M in THF, 40 cm3, 20 mmol) was added in three portions and reflux continued for 20 mins before cooling slowly to 0° C. and standing for 1 hr. The dark solid was filtered off, washed with ether, IPA and THF before drying in vacuo to give 6-chloro-2-methylquinoline hydrochloride/zinc chloride salt (3 g, 10.6 mmol, 62%). See, for example, Song et al., 1993.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([N:22]=[N+]=[N-])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.O>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH:8]=[CH:9][C@:10]2([NH2:22])[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1[C@@H]2C=C[C@](N)(C(=O)OCc3ccccc3)[C@@H]21
Temperature: 60 °C
Reaction time: 19 h
Yield: 31.2 %

Procedure:
To a solution of (1S,2R,5R,6S)-2-azido-bicyclo [3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVI) (66 mg, 0.202 mmol) in THF (4.5 mL) and H2O (0.5 mL) was added polymer supported PPh3 (130 mg, 0.404 mmol, 3.1 mmollg) and the mixture was stirred at 60° C. for 19 h. The resin was filtered off and washed with DCM. Removal of the solvent in vacuum left a yellow oil which was purified by silica gel column chromatography with hexane/ethyl acetate 1:3 to give (1S,2R,5R,6S) -2-amino-bicyclo [3.1.0] hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXVII) (19 mg, 31%) as a colorless oil. 1H-NMR (250 MHz, CDCl3) □1.25 (3H, t, J=7.2 Hz), 1.55 (1H, t, J=2.9 Hz), 1.78 (2H, bs), 2.53 (2H, m),4.12 (2H, q,J=7.2 Hz), 5.21 (2H, s), 5.37 (1H, d,J=5.3 Hz), 6.07 (1H, dd,J=5.3, 2 Hz), 7.35 (5H, s); MS[ISP] 302 (M+H+); □D20 -322.98 (c=0.77, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.O>[CH:12]1([C:10]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:8][N:9]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NNc1ccc(F)cn1)C1CCCCC1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1ccc2nnc(C3CCCCC3)n2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31.2 %

Procedure:
To a solution of Intermediate 34a (1.15 g, 4.83 mmol), triphenylphosphine (2.54 g, 9.67 mmol), and triethylamine (2.68 mL, 19.3 mmol) in dry THF (17 mL) at 0° C. under N2 was added hexachloroethane (2.28 g, 9.67 mmol), and the mixture stirred at 0° C. for 15 min, and at RT for 6 h. Water was added, then the organics washed with brine, dried (MgSO4) and concentrated in vacuo. Flash chromatography (silica gel, 0-100% EtOAc in cyclohexane) gave the title compound as an off-white solid (330 mg, 31%). 1H NMR (400 MHz, CDCl3): 1.36-1.55 (3H, m), 1.78-2.00 (5H, m), 2.05-2.14 (2H, m), 2.97 (1H, tt, J=11.5, 3.5 Hz), 7.16 (1H, ddd, J=10.0, 7.5, 2.3 Hz), 7.76 (1H, dd, J=10.0, 4.9, 0.9 Hz), 7.85 (1H, ddd, J=3.5, 2.2, 0.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(N(CC)CC)C.C(O)C>[CH3:20][C:19]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][C:11]=2[N:16]=[CH:17][CH:18]=1
Reactant: CC#CCN
Reactant: O=C1CC(=O)CC(c2ccccn2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1ccccn1)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 5-(2-pyridyl)cyclohexane-1,3-dione (2.0 g), 1-amino-2-butyne hydrochloride (0.1.1 g), molecular sieves 4A (2 g), tetrahydrofuran (30 ml) and ethanol (10 ml) was added triethylamine (2.1 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 4 hours and cooled. Insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) to give solid. The solid was stirred for 10 hours at 220° C., to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane) to give oil of 4-methyl-7-(2-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.28 g).
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](=[S:14])[NH2:13])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:15]I>CC(C)=O>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]([S:14][CH3:15])=[NH:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CI
Reactant: CCCCCNc1nc[nH]c1C(N)=S
Solvent: CC(C)=O
Product: CCCCCNc1nc[nH]c1C(=N)SC
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
To a solution of 4-(pentylamino)-1H-imidazole-5-carbothioamide (1.0 g, 4.7 mmol) in acetone (40 mL) was added methyl iodide (0.80 g, 5.6 mmol) dropwise. The mixture was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water and ethyl acetate. The organic layer was washed with water and brine, dried and concentrated to yield the crude product (1.2 g), which was used for next step without further purification. LCMS calculated for C10H19N4S (M+H): 227.1; found: 227.1.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([C@:21]2([CH3:27])[CH2:25][O:24]C(=O)[NH:22]2)[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.O.[OH-].[Li+].O>>[NH2:22][C@@:21]([C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH:7]3[CH2:6][CH2:5][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]3)[CH:12]=2)[CH:17]=1)([CH3:27])[CH2:25][OH:24]
Reactant: CC(C)C1CCC(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)C1CCC(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)CC1
Yield: 32.8 %

Procedure:
The compound was prepared in a manner similar as to that described above using (R)-4-[6-(4-isopropyl-cyclohexyloxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (200 mg, 0.0005 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 56 mg of the desired compound as a yellow brown solid (30%). ESI-MS: 325 (M−16)+. 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.67 (br. s., 1H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.35-1.75 (m, 4H), 1.68-1.08 (m, 10H), 1.01-0.68 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([OH:16])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1.Br[CH2:26][CH2:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([O:16][CH2:26][CH2:27][CH3:28])[CH:14]=3)[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3ncc(O)cc23)cn1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1cnc2c(c1)c(-c1cnn(C)c1)cn2COCC[Si](C)(C)C
Yield: 59.5 %

Procedure:
According to the general procedure using: 27 (60 mg, 0.174 mmol), 1-bromopropane (129 mg, 1.74 mmol), K2CO3 (241 mg, 1.74 mmol) and n-Bu4M (6.4 mg, 17 μmol) in acetone (4.0 mL) were heated at reflux for 18 h. Purification by PTLC using AcOEt:hexane=6:4 (v/v) as eluent gave 28i as a clear oil (40 mg, 59%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([O:8]C)=[O:7])#[N:2].[Li+].[OH-]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cc1ccc(C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of methyl 3-cyano-4-(2-methylpropyl)benzoate (D23) (800 mg) in methanol (30 mL) and water (5 mL) at room temperature was added LiOH (441 mg). Then the reaction mixture was stirred at 25° C. for 4 h. Methanol was removed under reduced pressure and water (30 mL) was added. 2N HCl was added to the solution until pH=5. After filtration, the solid was dried to give 3-cyano-4-(2-methylpropyl)benzoic acid (D24) (735 mg) as a white solid. MS (ES): C12H13NO2 requires 203. found 204.1 (M+H+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[N:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13](O)=[CH:12]2.IC.C(OCC)(=O)C>CC(C)=O>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][C:13]([O:4][CH3:1])=[CH:14][N:15]=2)[N:10]=1
Reactant: COc1ccc2ncc(O)cc2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cnc2ccc(OC)nc2c1
Reaction time: 4 h
Yield: 54.6 %

Procedure:
Potassium carbonate (13.84 g, 100.1 mmol, 2.0 eq) is added at room temperature to a stirred solution of 6-methoxy-[1,5]naphthyridin-3-ol (9.8 g, 50.06 mmol, 1.0 eq) in acetone (300 mL), followed by iodomethane (3.74 mL, 60.1 mmol, 1.2 eq). After 4 hours stirring under reflux conditions, the solid is removed by filtration and the filtrate is concentrated to give a residue that is extracted with ethyl acetate (3×100 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford 2,7-dimethoxy-[1,5]naphthyridine as a yellow solid (5.2 g, 52% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[C@H:4]([O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.[Cl-].[NH4+].O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])([OH:13])[CH:4]([O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:5]
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Reactant: Fc1ccc([Mg]Br)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.08 h
Yield: 71 %

Procedure:
A solution of 0.41 g (2.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 5 mL of toluene was cooled to 0° C., and 3.2 mL (2.2 mmol) of a 0.69 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain 0.54 g of a crude product. The resulting product was purified by column on silica gel to obtain 0.450 g of the title compound (yield: 71%) ((2S,3R)/(2R,3R)=93/7 (the diastereomeric ratio was measured by HPLC under the same HPLC measurement conditions as those in Example 19)).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([O:20]CC)=[O:19])[C:15]2[CH:23]=[CH:24][S:25][C:14]=2[C:13](=[O:26])[N:12]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:16]([CH2:17][C:18]([OH:20])=[O:19])[C:15]2[CH:23]=[CH:24][S:25][C:14]=2[C:13](=[O:26])[N:12]=1
Reactant: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2sccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2sccc21

Procedure:
Ethyl 2-(2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-4H-thieno[3,2-d]pyrimidin-1-yl)acetate (Int B57) (375 mg) as a suspension in dioxan (2-3 ml) was treated with 0.5M solution of aqueous sodium hydroxide (1.98 ml) at room temperature. After 1h the solution was concentrated to a small volume and acidified with 2M hydrochloric acid. The precipitate was filtered off, washed with water and dried in vacuo at 40° C. overnight. The title compound was obtained as a white solid (308 mgs, 89%); 1H-NMR (DMSO) δ 3.09 (4H, m), 5.19 (2H, s), 7.05-7.31 (3H, m), 7.49 (1H, d, J5.2 Hz) and 8.14 (1H, d, J5.2 Hz). (APCI+) Found (M+1)=351, C16H12F2N2O3S requires 350.
Reaction SMILES: [CH2:1]([OH:17])[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][CH3:16].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[C:25]([O:31][CH3:32])=[CH:24][C:23]=1[N+]([O-])=O>CN(C)C=O.O.C(O)(=O)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([O:17][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][CH3:16])[C:22]([O:21][CH3:20])=[CH:27][C:26]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1cc([N+](=O)[O-])c(OC)cc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cc(OC)c([N+](=O)[O-])cc1OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 12.7 g (0.0525 mole) of hexadecylalcohol and 2.50 g of a 55% by weight oily suspension of sodium hydride (0.057 mole) in 100 ml of dimethylformamide was stirred for 1 h at 50° C. (formation of foam). Thereafter 11.4 g (0.05 mole) of 1,4-dimethoxy-2,5-dinitrobenzene prepared as illustrated hereinbefore was added and the mixture was stirred for 1 h at 50° C. The mixture was poured in 500 ml of water and 10 ml of acetic acid. The precipitate which was formed, was filtered off and washed with water, dried and recrystallized from methanol. Yield: 60%; melting point: 71° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.Cl.Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([C:30]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)=[O:31])[CH2:25]2)=[N:21][C:22]=1[NH2:23].S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].C(N(CC)CC)C>O.C(O)C>[N:32]1([C:30]([C@@H:26]2[CH2:27][CH2:28][CH2:29][N:24]([C:20]3[N:21]=[C:22]4[NH:23][C:1]([C:3]5[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=5)=[N:16][C:17]4=[CH:18][CH:19]=3)[CH2:25]2)=[O:31])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: COC(=O)Cc1cccc(C=O)c1
Agent: Cl
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)Cc1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Into a vial was added methyl 2-(3-formylphenyl)acetate (98 mg, 0.55 mmol), (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (Intermediate 1, Step 3) (140 mg, 0.45 mmol) and ethanol (1.5 mL). Then sodium dithionate (388 mg, 2.23 mmol) and water (0.5 mL) were added to the mixture. The vial was sealed. The reaction mixture was heated to 110° C. for 18 h. The solution was cooled to room temperature. Triethylamine (0.15 mL, 1.1 mmol) was added and the solution was stirred at 100° C. for 18 h. A sample (0.8 mL) of the solution was removed and concentrated to dryness, and the resulting residue was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 448.2; HPLC retention time 2.28 min (Method A).
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[N:25][CH:26]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:36])[F:19])=[CH:26][N:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 262 Step B for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.63 (s, 1H), 8.37 (d, J=7.5, 1H), 7.68 (dd, J=8.9, 2.5, 1H), 6.40 (d, J=8.9, 1H), 4.49-4.38 (m, 1H), 3.83 (d, J=10.7, 1H), 3.68 (dd, J=11.0, 7.3, 1H), 3.63-3.52 (m, 1H), 3.33 (d, J=8.2, 1H), 3.27 (dd, J=8.3, 5.9, 1H), 2.77 (h, J=8.8, 2H), 2.45 (s, 3H), 2.17 (dt, J=12.4, 7.1, 1H), 2.14-1.98 (m, 1H), 2.02-1.86 (m, 2H), 1.79-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.48-1.36 (m, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 399 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:25]([CH3:27])[CH3:26])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][C:9]=2[Cl:24])=[O:4].[I-].[Li+]>N1C=CC=CC=1>[Cl:23][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([Cl:24])[CH:10]=1)[N:7]=[C:6]([CH:25]([CH3:26])[CH3:27])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2c(Cl)cc(Cl)cc2c1-c1ccc(F)c(Cl)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1nc2c(Cl)cc(Cl)cc2c(-c2ccc(F)c(Cl)c2)c1C(=O)O
Yield: 86.2 %

Procedure:
A solution of 6,8-dichloro-4-(3-chloro-4-fluoro-phenyl)-2-isopropyl-quinoline-3-carboxylic acid methyl ester (42.0 mg, 0.0984 mmol, Eq: 1.00) and lithium iodide (132 mg, 0.984 mmol, Eq: 10.0) in pyridine (1.5 ml) was heated to 135° C. overnight. The pyridine was then removed in vacuo and the remaining residue was diluted with water. The pH was adjusted to 12 by addition of 0.1N NaOH and the mixture was extracted with diethylether/heptane (60:40) (3×). The aqueous layer was acidified with 0.1N HCl to pH 3 and extracted with CHCl3 (3×). The combined CHCl3 layers were dried with Na2SO4 and evaporated to yield the title compound as white foam (35 mg). MS (ESI): 412.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>C(O)(=O)C>[NH2:1][C:2]1[C:10]([Br:12])=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: BrBr
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: CC(=O)O
Product: Cc1cc(Br)c(N)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of 2-amino-5-methylbenzoic acid (25.0 g, 170 mmol) in acetic acid (250 ml) was added bromine (10 ml, 195 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was filtered and the solid material was washed with water and cyclohexane and dried to give the title compound (33.4 g).