Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH2:19]([NH:26][C:27]([N:16]1[CH2:17][CH2:18][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCNCC2)cc1
Reactant: O=C=NCc1ccccc1
Solvent: c1ccncc1
Product: O=C(NCc1ccccc1)N1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 50 °C
Yield: 47.5 %

Procedure:
To a solution of 1-(4-Nitro-benzenesulfonyl)-piperazine (1.0 g, 2.6 mmol) in pyridine (10 ml) was added benzyl isocyanate (0.35 ml, 2.85 mmol) in one portion. The resulting mixture was then heated at 50° C. for 2 hours before being cooled to room temperature and concentrated under vacuum. The resulting residue was dissolved in ethyl acetate (50 ml) and washed with 1M HCl (100 ml), the organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum to give the title compound (0.5 g, 47% yield) as a yellow solid which was used without further purification. Tr=1.86 min, m/z (ES+) (M+H)+ 405.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1.BrC1C(NC(C(C)C)CNC(=O)OC(C)(C)C)=NC(Cl)=NC=1>>[Br:15][C:16]1[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][CH2:4][C@@H:3]2[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:18][C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(Cl)ncc1Br

Procedure:
tert-butyl N-[(1S,2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]cyclopentyl]carbamate was synthesized by treating tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.27 (s, 9H) 1.42-1.54 (m, 2H) 1.56-1.65 (m, 2H) 1.80-1.88 (m, 1H) 1.96-2.01 (m, 1H) 3.88-3.96 (m, 1H) 4.03-4.09 (m, 1H) 6.91 (d, J=8.20 Hz, 1H) 7.41 (d, J=7.32 Hz, 1H) 8.18 (s, 1H). LCMS (ESI) 391 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4]CC(Cl)=O.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[F:21].C1C[O:25][CH2:24][CH2:23]1>>[Cl:1][CH2:2][CH2:3][O:4][N:9]([C:24](=[O:25])[CH3:23])[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[F:21]
Reactant: CCOC(=O)c1ccc(N)c(F)c1
Reactant: O=C(Cl)COCCCl
Reactant: C1CCOC1
Product: CCOC(=O)c1ccc(N(OCCCl)C(C)=O)c(F)c1

Procedure:
Prepared analogously to Example 46a from (2-chloro-ethoxy)-acetylchloride and ethyl 4-amino-3-fluoro-benzoate with TEA in THF.
Reaction SMILES: [CH3:1][C:2]([N+:9]#[C-:10])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[I:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]=[CH2:19])=[N:16][CH:17]=1>CO>[I:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:10]([NH:9][C:2]([CH3:8])([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:19][N:18]=2)[CH:17]=1
Reactant: C=Nc1ccc(I)cn1
Reactant: [C-]#[N+]C(C)(C)CC(C)(C)C
Solvent: CO
Product: CC(C)(C)CC(C)(C)Nc1cnc2ccc(I)cn12
Yield: 39.6 %

Procedure:
Add 1,1,3,3-tetramethylbutyl isocyanide (Aldrich; 0.57 g, 4.06 mmol) to a solution of (5-iodo-pyridin-2-yl)-methylene-amine (Preparation 15a; 0.8 g, 3.4 mmol) in methanol (20 mL). Reflux for 36 h and concentrate. Purify by flash chromatography eluting with a gradient of 100% hexanes to 50% EtOAc/50% hexanes (45 mL/min, 44 min) giving 0.5 g (40%) of the title compound as a dark brown semi-solid. ES+ m/e 371.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>C(O)C.O>[O:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCCCCCCOc1ccccc1
Solvent: O
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCOc2ccccc2)cc1

Procedure:
A mixture of 16.5 g of ethyl p-aminobenzoate, 10.3 g of 11-phenoxy-1-undecanol O-methanesulfonate and 50 ml of hexamethylphosphoramide is heated at 100°-110° C. for 20 hours, chilled, and diluted with 30 ml of ethanol and 10 ml of water. Chilling and filtering gives a solid which is washed with ethanol-water (1:1) and with water to give yellow crystals, mp 83°-87° C. Recrystallization from ethanol gives yellow needles, mp 89°-90° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH:18]=[N:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[C:21]([CH3:24])([OH:23])[CH3:22])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[H][H]>CO.[Ni]>[F:1][C:2]1[C:3]([CH2:18][NH:19][C@H:20]([CH:25]([CH3:27])[CH3:26])[C:21]([CH3:22])([OH:23])[CH3:24])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)[C@@H](N=Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)(C)O
Agent: [Ni]
Solvent: CO
Product: CC(C)[C@@H](NCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1F)C(C)(C)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.5 %

Procedure:
Example 17A (800 mg, 2.97 mmol) and Example 105C (498 mg, 2.97 mmol) were dissolved in methanol (20 mL) and triethylamine (0.453 mL, 3.27 mmol). The yellow solution was stirred at ambient temperature for 90 minutes, followed by the addition of sodium borohydride (247 mg, 6.54 mmol). The reaction mixture was stirred over the weekend at ambient temperature, quenched with 100 mL 1.0 N NaOH, and extracted twice with 100 mL dichloromethane, dried over Na2SO4, filtered, and concentrated to obtain (R)-3-[({3-fluoro-6-[4-(trifluoromethyl)phenyl]pyridin-2-yl}methylene)amino]-2,4-dimethylpentan-2-ol (1.147 g, 3.00 mmol) as an orange oil. The imine (1.147 g, 3.00 mmol) in methanol (20 mL) was added to Raney Nickel (1.147 g) in a 50 mL pressure bottle. The mixture was pressurized with hydrogen (30 psi), and stirred for 48 hours at ambient temperature. The mixture was filtered through a nylon membrane, concentrated, and chromatographed on a Grace Reveleris 40 g column, eluted with 0-20% EtOAc in dichloromethane (30 mL/min) to provide the title compound (0.629 g, 1.636 mmol, 54.6% yield) as a colorless oil. MS (ESI+) m/z 385.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=8.2, 2H), 8.06 (dd, J=8.7, 3.7, 1H), 7.92-7.78 (m, 3H), 4.25 (s, 1H), 4.16-3.99 (m, 2H), 2.36 (q, J=6.2, 1H), 2.26 (dd, J=5.9, 2.4, 1H), 2.03-1.89 (m, 1H), 1.11 (d, J=9.2, 6H), 0.93 (dd, J=6.8, 5.8, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:14]2[C:22]3[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)([CH2:12][CH3:13])[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)cccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CCC(CCO)(c1ccc(Cl)cc1)c1c[nH]c2c(CS(C)=O)cccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60 mg (0.16 mmol) of the compound from Example 140 were introduced into 6 ml of dichloromethane at 0° C., 40 mg (0.16 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 62 mg (99% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]([C:21]([O:23]CC)=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][S:2][C:3]1[O:4][C:5]([C:21]([OH:23])=[O:22])=[C:6]2[C:20]=1[C:10]1[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:13][C:9]=1[CH2:8][CH2:7]2
Reactant: CCOC(=O)c1oc(SC)c2c1CCc1sc(-c3ccccc3)nc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1oc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
Ethyl 4,5-dihydro-8-methylthio-2-phenylfuro[3,4-e]benzothiazole-6-carboxylate (1.32 g) was suspended in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (15 ml); a 2 N aqueous solution of sodium hydroxide (5.3 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 1.5 hours, the solution obtained was poured over water (300 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-8-methylthio-2-phenylfuro[3,4-e]benzothiazole-6-carboxylic acid (1.14 g, 93.4%), which was then recrystallized from chloroform-methanol. Colorless prisms. Melting point 206-207° C. (decomposed).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[C:11]([CH2:13][OH:14])[N:12]=1.C(=O)(O)[O-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[C:11]([CH:13]=[O:14])[N:12]=1
Reactant: OCc1c[nH]c(-c2ccccc2Cl)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1c[nH]c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.3 %

Procedure:
To a solution of [2-(2-chlorophenyl)-1H-imidazol-4-yl]methanol (1.0 g, 4.81 mmol) in CH2Cl2 (50 mL) at to 25° C. is added sodium bicarbonate (1.21 g, 14.4 mmol) followed by Dess-Martin periodinane (2.29 g, 5.29 mmol). The reaction mixture is then stirred at to 25° C. for 1 hour. Subsequently, the reaction mixture is poured into a separatory funnel, diluted with CH2Cl2 and washed with a saturated sodium sulfite solution. The organic layer is dried over sodium sulfate and concentrated. The crude product is purified by column chromatography (50% ethyl acetate in hexanes) to afford 182 mg of 2-(2-chlorophenyl)-1H-imidazole-4-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](/[N:8]=[CH:9]/[C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=2)[CH2:20][CH2:19]1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[O:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=2)[CH2:22][CH2:23]1
Reactant: Cn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 85.8 %

Procedure:
5-[1-(2-Fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (9f, 0.42 g, 1 mmol) on reduction with sodium cyanoboro hydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-3-methyl-2,3-dihydro-1,3,4-oxadiazol-2-one (10f, 358 mg, 86%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14](Cl)(=[O:16])=[O:15])[CH2:6]1)=[O:4].[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][C@H:30]([CH3:32])[NH:29][C@H:28]([CH3:33])[CH2:27]2)[CH:22]=[CH:23][C:24]=1[Cl:25].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Br:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:27][C@@H:28]([CH3:33])[N:29]([S:14]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)(=[O:16])=[O:15])[C@@H:30]([CH3:32])[CH2:31]2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: C[C@@H]1CN(c2ccc(Cl)c(Br)c2)C[C@H](C)N1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COC(=O)C1Cc2cccc(S(=O)(=O)N3[C@H](C)CN(c4ccc(Cl)c(Br)c4)C[C@@H]3C)c2C1
Temperature: 55 °C

Procedure:
4-Chlorosulfonyl-indan-2(R,S)-carboxylic acid methyl ester (225 mg, 0.82 mmol) was added to a mixture of 1-(3-bromo-4-chlorophenyl)-cis-3,5-dimethylpiperazine (569 mg, 1.87 mmol), potassium carbonate (500 mg, 3.6 mmol), and acetonitrile (8 mL) at rt under nitrogen, and the reaction was heated at 55° C. for 3 h. After allowing the reaction to cool to rt, it was poured into water (40 mL) and extracted with dichloromethane (40 mL×2). The combined organic extracts were dried, filtered, concentrated, and purified by silica gel chromatography (9:1→3:1; hexanes:ethyl acetate) to give methyl 4-(4-(3-bromo-4-chlorophenyl)-cis-2,6-dimethylpiperazin-1-ylsulfonyl)-2,3-dihydro-1H-indene-2(R,S)-carboxylate: MS (ESI): 541.2 (M+H).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=O)[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH2:8]\1.[NH2:12][NH2:13]>CO>[CH3:9][C:7]1([CH3:10])[CH2:6][CH2:5][C:4]2[NH:13][N:12]=[CH:2][C:3]=2[CH2:8]1
Reactant: CC1(C)CCC(=O)/C(=C\O)C1
Reactant: NN
Solvent: CO
Product: CC1(C)CCc2[nH]ncc2C1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 82.9 %

Procedure:
In a 100 ml round-bottomed flask, 2-[1-hydroxy-meth-(Z)-ylidene]-4,4-dimethyl-cyclohexanone (1.30 g, 8.43 mmol) was dissolved in methanol (8.5 ml). Hydrazine (0.27 ml, 8.43 mmol) was added very slowly which resulted in an exothermic reaction. The reaction mixture was stirred at room temperature for 50 min then concentrated. The residue was triturated with petroleum ether to afford 1.05 g (83%) of 5,5-dimethyl-4,5,6,7-tetrahydro-1H-indazole as a light brown solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.28 (s, 1H), 2.67 (t, J=6.6 Hz, 2H), 2.32 (s, 2H), 1.60 (t, J=6.6 Hz, 2H), 0.99 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:27]=[CH:26][C:13]([CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1>O1CCOCC1.[Pd]>[O:1]=[C:2]1[N:6]([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:26][CH:27]=2)[C:5]2[CH:28]=[CH:29][CH:30]=[CH:31][C:4]=2[O:3]1
Reactant: CCOC(=O)C(=Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)OCC
Agent: [Pd]
Solvent: C1COCCO1
Product: CCOC(=O)C(Cc1ccc(OCCn2c(=O)oc3ccccc32)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 76 h

Procedure:
Dissolve the compound obtained in Example 1 (6.7 g) in a dioxane/absolute ethanol mixture (100 ml/20 ml) and add palladium-on-carbon (0.5 g). Stir magnetically at ambient temperature under a hydrogen atmosphere for 76 hours. Remove the palladium-on-carbon by filtration and remove the mixture of solvents by evaporation under reduced pressure. Crystallise the resulting oil by trituration in isopropyl ether. Recrystallise the resulting precipitate from a 9/1 cyclohexane/toluene mixture.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][S:3][CH:2]1[C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[CH3:12][I:13]>C(#N)C>[I-:13].[CH3:12][N+:10]1[CH:11]=[C:6]([CH:2]2[S:3][CH2:4][CH2:5][O:1]2)[CH:7]=[N:8][CH:9]=1
Reactant: CI
Reactant: c1ncc(C2OCCS2)cn1
Solvent: CC#N
Product: C[n+]1cncc(C2OCCS2)c1
Product: [I-]
Reaction time: 8 h
Yield: 83.4 %

Procedure:
5-(1,3-oxathiolan-2-yl)pyrimidine (0.780 g, 5.1 mmol) and acetonitrile (3 ml) are stirred under dry nitrogen in a bomb tube with rubber seal. Methyl iodide (0.7 ml, 11.30 mmol) is added, the bomb properly sealed, and stirring continued at room temperature overnight. This results in a yellow suspension which is vacuum-filtered to obtain yellow powdery crystals. The powder is put in a drying pistol to give 1.32 g (84%) yellow crystals. Recrystallization from ethanol gives fine crystals identified by 300 MHz nmr.
Reaction SMILES: C([O:5][C:6]([CH:8]1[C:13](=[O:14])[CH:12]([CH2:15][CH:16]=[CH2:17])[C:11]2[C:18]3[C:23]([CH:24]=[CH:25][C:10]=2[N:9]1[OH:26])=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:7])(C)(C)C.Cl(O)(=O)(=O)=O>C(#N)C>[CH2:15]([CH:12]1[C:11]2[C:18]3[C:23]([CH:24]=[CH:25][C:10]=2[N:9]([OH:26])[CH:8]([C:6]([OH:7])=[O:5])[C:13]1=[O:14])=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]=[CH2:17]
Reactant: C=CCC1C(=O)C(C(=O)OC(C)(C)C)N(O)c2ccc3ccccc3c21
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Product: C=CCC1C(=O)C(C(=O)O)N(O)c2ccc3ccccc3c21

Procedure:
A solution of 2.2 g. of 1-allyl-4-hydroxy-naphthpyridine-2(1H)-one-3-carboxylic acid t-butyl ester in 25 ml. of acetonitrile is treated with 0.75 ml. of 60% aqueous perchloric acid at 0° C. The resulting precipitate is filtered off and cooled with ester to obtain 1-allyl-4-hydroxy-naphthpyridine-2(1H)-one-3-carboxylic acid.
Reaction SMILES: [F:1][C:2]([P:8]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])(=[O:12])[O:9]CC)([F:7])[C:3]([F:6])([F:5])[F:4].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:7][C:2]([P:8]([C:13]([F:18])([F:19])[C:14]([F:17])([F:16])[F:15])(=[O:9])[O-:12])([F:1])[C:3]([F:6])([F:5])[F:4].[CH2:25]([N+:20]1[CH:14]=[CH:13][CH:23]=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCOP(=O)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: c1ccncc1
Product: CC[n+]1ccccc1
Product: O=P([O-])(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Ethyl bis(pentafluoroethyl)phosphinate, (C2F5)2P(O)OC2H5, (3.956 g; 12.0 mmol) is slowly added dropwise to dry and cooled (0° C.) pyridine (0.941 g; 11.9 mmol) in a 25 ml glass flask. A pale-yellow, more highly viscous solution forms spontaneously. After 30 minutes at 0° C. and 6 h at room temperature, the reaction solution is a brown-orange colour. The readily volatile constituents are removed in vacuo (10−3 mbar) at 40° C. N-Ethylpyridinium bis(pentafluoroethyl)phosphinate, [EPy][(C2F5)2P(O)O], (4.845 g; 11.8 mmol) can be isolated as highly viscous, intensely brown-orange liquid in quantitative yield and a purity of 99%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].[N+]([CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O-])=O>CCO>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][N:19]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][C:12]=2[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:28]1
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])C=Cc1ccccc1
Solvent: CCO
Product: Clc1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)c(Cl)c1

Procedure:
The title compound (0.43 g) was prepared from 0.55 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 370 μL of 2,4-dichlorobenzylamine, and 0.41 g of (2-nitro-vinyl)-benzene, using EtOH as the solvent. MS (ESI): exact mass calculated for C20H18Cl2N2, 356.08; found, m/z 357.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.55-7.50 (m, 2H), 7.37-7.29 (m, 4H), 7.22-7.18 (m, 1H), 7.07 (s, 1H), 6.77 (d, J=8.5 Hz, 1H), 5.23 (s, 2H), 4.38 (s, 2H), 3.54 (t, J=6.3 Hz, 2H), 2.86 (t, J=6.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53]1>CN(C=O)C>[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]([C:7]([C:6]3[C:5]([O:4][C:3]4[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=4[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=3)=[O:9])[CH2:57][CH2:56]2)[CH2:54][CH2:53]1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: c1ccc2c(c1)NCCN2C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (70 mg, 0.25 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.4 mL) was added N-ethyldiisopropylamine (96 mg, 126 μL, 0.74 mmol, 3.0 equiv; [CAS RN 7087-68-5]) and HATU (112 mg, 0.30 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt. After 15 min, 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (52 mg, 0.30 mmol, 1.2 equiv) was added and stirring at rt continued over night. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 38 mg (35%) of the title compound. MS (ISP): 440.1 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.S(Cl)([Cl:11])=O.[CH3:13]O>>[Cl-:11].[CH3:13][O:7][C:6]([CH:4]1[CH2:5][S:1][CH2:2][NH2+:3]1)=[O:8]
Reactant: O=C(O)C1CSCN1
Reactant: O=S(Cl)Cl
Reactant: CO
Product: COC(=O)C1CSC[NH2+]1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
The commercially available starting material, thiazolidine-4-carboxylic acid (1.3 g, 9.59 mmol) was dissolved in anhydrous methanol (19.18 mL) and cooled to 0° C. in an ice bath. Thionyl chloride (1.40 mL, 19.18 mmol) was added drop wise and the reaction stirred for 30 minutes. The ice bath was removed and stirring continued either for 4-5 hours or overnight. The solvent was stripped and the product placed on the high vacuum to give 4-(methoxycarbonyl)thiazolidin-3-ium chloride. Without further purification and assuming 100% yield, the 4-(methoxycarbonyl)thiazolidin-3-ium chloride (1.761 g, 9.59 mmol) and compound 4 (3.39 g, 10.55 mmol) were each dissolved separately in tetrahydrofuran (32.0 mL) and cooled to 0° C. Triethylamine (4.41 mL, 31.6 mmol) was added to the solution with 4-(methoxycarbonyl)thiazolidin-3-ium chloride and then compound 4 was added quickly via canula. After 20 minutes, the pH of the solution was checked to ensure it was basic. The reaction stirred at 0° C. for 1.5 hours and then at room temperature for 30 minutes and was checked by MS. It was quenched with cold 5% hydrochloric acid and diluted with cold ethyl acetate and water. The solution was extracted with ethyl acetate three times and the combined organic washed with brine, saturated sodium bicarbonate and then brine again. It was dried over sodium sulfate, filtered and stripped. The crude material was purified by silica gel chromatography using a gradient of 50% to 75% ethyl acetate in hexanes to give compound 261a (4.1 g, yield=99%). 1H NMR (400 Hz, CDCl3): the compound appears as a pair of distinct rotomers. δ 7.78 (s, 0.6H), 7.74 (s, 0.4H), 7.48-7.35 (m, 5H), 6.96 (s, 0.4H), 6.92 (s, 0.6H), 5.40 (dd, J1=7.0 Hz, J2=3.4 Hz, 0.6H), 5.31-5.22 (m, 2H), 5.13 (d, 9.6Hz, 0.4H), 4.60 (d, J=9.6 Hz, 0.4H), 4.46 (dd, J1=4.4 Hz, J2=3.2 Hz, 0.4 H), 4.36 (d, J=8.4 Hz, 0.6H), 4.26 (d, J=8.4 Hz, 0.6H), 4.02 (s, 1.8H), 3.96 (s, 1.2H), 3.86 (s, 1.8H), 3.71 (s, 1.2H), 3.48-3.43 (m, 0.6H), 3.36-3.29 (m, 1.4H); MS (m/z), found 455.3 (M+Na)+.