Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NO.[CH2:4]([O:6][C:7](=[O:21])[C:8]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][N:10](C)C)[CH3:5].C([O-])(=O)C.[Na+].CCOCC>CO>[CH2:4]([O:6][C:7]([C:8]1[CH:9]=[N:10][O:20][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCOCC
Product: CCOC(=O)c1cnoc1-c1ccccc1
Reaction time: 16 h
Yield: 31.6 %

Procedure:
Hydroxylamine hydrochloride (1.1 g.; 0.016 mol.) was added to a mixture of ethyl-2-benzoyl-3-dimethylaminopropenoate (3.71 g.; 0.015 mol.) and anhydrous sodium acetate (1.25 g.; 0.015 mol.) in 50 ml. of ether and 25 ml. of methanol at 25° C. After 16 hours, the solvent was removed by evaporation and the residue was extracted with five 50 ml. portions of ether. The ether extracts were combined, washed with water, dried, filtered, then concentrated to yield an oil which was further purified by evaporative distillation at 60° C. and 0.55 torr. to yield ethyl-5-phenyl-4-isoxazolecarboxylate (1.03 g.; 32% yield) as a colorless liquid having the following analysis:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][CH2:23][O:24][CH2:25][CH3:26]>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cnccc23)CC1
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccncc21
Yield: 62.6 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 1.05 g (3.84 mmol) of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 0.52 ml (4.61 mmol) of 2-bromoethylethyl ether. After standard work-up and purification, 0.83 g (63% yield) 4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@@H:12]3[CH2:19][NH:20][CH2:21][CH2:22][N:11]3[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33].Cl>C(Cl)(Cl)Cl.O1CCCC1>[C:30]([N:20]1[CH2:21][CH2:22][N:11]2[CH2:10][C@@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:18]3[C:13]([C@@H:12]2[CH2:19]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: c1ccc([C@@H]2CN3CCNC[C@H]3c3ccccc32)cc1
Reactant: CCCC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)N1CCN2C[C@@H](c3ccccc3)c3ccccc3[C@@H]2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
To a stirred solution of cis-1,3,4,6,7,11b-hexahydro-7-phenyl-2H-pyrazino[2,1-a]isoquinoline dihydrochloride (7.8 g, 0.023 m) and triethylamine (9.4 g, 0.93 m) in chloroform (100 ml) maintained at 0° under nitrogen was added dropwise butyryl chloride (3.8 g, 0.0356 m). The mixture was allowed to warm to ambient temperature and stirred for 3 hours, then treated with 10% HCl (50 ml). The layers were separated and the organic phase washed with 10% HCl (2×50 ml), water (50 ml), and dried over MgSO4. Evaporation of the solvent gave an oily residue which was dissolved in tetrahydrofuran (100 ml) and a white solid crystallized which was collected by filtration to give 5.1 g of cis-1,3,4,6,7,11b-hexahydro-2-butyryl-7-phenyl-2H-pyrazino[2,1-a]isoquinoline, m.p. 212°-213°. An additional 3.5 of good purity product was recovered from the tetrahydrofuran to give a total of 8.6 g (93%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([O:14]CC)=O)[NH:9]2)=[CH:5][CH:4]=1)#[N:2].[NH3:17].CO>>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([NH2:17])=[O:14])[NH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Reactant: N
Solvent: CO
Product: N#Cc1ccc2cc(C(N)=O)[nH]c2c1
Yield: 88.6 %

Procedure:
Treat 6-cyano-1H-indole-2-carboxylic acid ethyl ester 5a (m=0, 1.0 g, 4.67 mmol) with 7 N NH3/MeOH as described in General Procedure IV to afford the title compound as an ivory colored solid (766 mg, 88.6%), mp 241-242° C.; 1H NMR (DMSO-d6) δ 11.5 (brs, 1H), 8.16 (brs, 1H), 7.83 (s, 1H), 7.80 (d, 1H, J=8.0 Hz), 7.58 (brs, 1H), 7.35 (d, 1H, J=8.0 Hz), 7.23 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[C:8](SC)[N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1>CN(C)C(=O)C.[Ni]>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:12])[CH:11]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Agent: [Ni]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 80 °C
Yield: 81.5 %

Procedure:
Methyl 3-[4-[(2,4-difluorobenzyl)oxy]-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (87 g, 0.20 mol) was dissolved in N,N-dimethylacetamide (870 mL) and heated to 80° C. Raney Ni was added and slight exotherm and off-gasing were observed. Reaction was complete. Heat and stirring were turned off. Since product had begun to precipitate from the cooled reaction mixture, heat was turned back on to 70° C. and stirring resumed. After redissolving the precipitate, the reaction mixture was allowed to cool for 15 min and then filtered through celite. Rinsed with 50° C. DMA and water, being careful not to let the celite pad go dry. The filtrate was added to 2 L of water and stirred. Product filtered, rinsed with water, and dried in the vacuum oven. When found to still be wet with DMA, slurried with water and stirred 1 h before filtering and redrying. Obtained the product as a white solid (63 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.28 (s, 1H), 8.04 (m, 1H), 7.90 (s, 1H), 7.55 (m, 2H), 6.99 (m, 2H), 5.87 (s, 1H), 5.39 (s, 2H), 3.88 (s, 3H), 2.19 (s, 3H). ESHRMS m/z 387.1195 (M+H calculated for C20H17F2N2O4 requires 387.1151).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.Cl.[O:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:22]2[CH2:23][CH2:24][CH:19]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1ccc(OC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(Oc3ccccc3)CC2)cc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
A solution of 1-fluoro-4-nitrobenzene (0.15 g, 1.063 mmol) and 4-phenoxypiperidine hydrochloride (0.250 g, 1.169 mmol) in dimethylformamide (2.126 ml) was treated with potassium carbonate (0.367 g, 2.66 mmol). The suspension was stirred at ambient temperature 2 hours, at 55° C. for 4 hours and at ambient temperature for 16 hours. The reaction was poured into water and the suspension was filtered and vacuum dried to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[O:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[O:19]1[C:23]2([CH2:28][CH2:27][N:26]([C:16]([C:13]3[S:14][CH:15]=[C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])[N:12]=3)=[O:17])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC4(CC3)OCCO4)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 1,4-Dioxa-8-azaspiro[4.5]decane (Aldrich) (0.06 ml; 0.53 mmol; 1 eq.) and triethylamine (0.15 ml; 1.06 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by precipitation in MeOH, affording Compound (38) as a beige solid (64.9 mg, 30%). 1H NMR (DMSO-d6, 300 MHz) δ 1.73 (m, 4H), 2.13 (s, 3H), 2.48 (s, 3H), 3.72 (m, 2H), 3.93 (m, 4H), 4.28 (m, 2H), 7.99 (s, 1H), 12.16 (s, 1H). M− (ESI): 407.10; M+ (ESI): 409.21. HPLC (method A), Rt: 2.86 min (purity: 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:26][NH2:27])[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:22]([O:26][N:27]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:7])[CH2:23][CH2:24][CH3:25]
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Reactant: CCCCON
Solvent: CCO
Product: CCCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reaction time: 12 h

Procedure:
A mixture of 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (210 mg), O-n-butylhydroxylamine (620 mg) and ethanol (8.4 ml) was stirred for 12 hrs. at 90° C. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure to give 2-butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:15]3[O:17][CH:16]3[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O>[CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH:16]([OH:17])[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCC1OC1c1cccc(NCC2CCCCC2)c1
Solvent: O=CO
Product: CC(C)(C)OC(=O)NCC(O)Cc1cccc(NCC2CCCCC2)c1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl (3-(3-(cyclohexylmethylamino)phenyl)oxiran-2-yl)methylcarbamate, HCOOH.Et3N complex (5:2), Pd/C (10% wt) in absolute EtOH is degassed by applying vacuum/argon 3 times. The reaction mixture is stirred at room temperature until no starting material is seen by TLC, then concentrated under reduced pressure. Purification by flash chromatography (EtOAc—hexanes gradient) gives tert-butyl 3-(3-(cyclohexylmethylamino)phenyl)-2-hydroxypropylcarbamate.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH2:11].[I:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:6][CH:5]([CH3:7])[CH2:4][N:3]1[CH2:8][CH2:9][CH2:10][NH:11][S:19]([C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC1CC(C)N(CCCN)C1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Solvent: c1ccccc1
Product: CC1CC(C)N(CCCNS(=O)(=O)c2ccc(I)cc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2,4-dimethyl-1-(3-aminopropyl)pyrrolidine (4.7 g, 0.03 mol) in benzene (20 ml) was added dropwise to a solution of 4-iodobenzenesulphonylchloride (9.1 g, 0.03 mol) benzene (80 ml). After stirring the resulting mixture for six hours at room temperature, the reaction product separated as an oil. The reaction mixture was evaporated, and the residue was dissolved in absolute alcohol (800 ml) and boiled with charcoal.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:25]([O:29][C:30]([N:32]1[CH2:36][CH:35]([OH:37])[CH:34]([NH2:38])[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[C:25]([O:29][C:30]([N:32]1[CH2:36][C:35](=[O:37])[CH:34]([NH:38][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[O:24])[CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(=O)C(NC(=O)C(CC(=O)N2CCOCC2)CS(=O)(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (120 mg, 0.34 mmol), 3-amino-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.74 mmol), prepared as in reference 13, EDC (0.3 g, 1.6 mmol), and HOBt (150 mg, 0.96 mmol) were combined. Dichloromethyl (10 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200 mL) the solution was washed with 1N aqueous HCl (50 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried with MgSO4 and evaporated under vacuum. The pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DMSO (5 mL). Triethylamine (0.5 mL) and then SO3 pyridine complex (150 mg) were added and the mixture was stiffed at ambient temperature for 3 hours. After dilution with ethyl acetate (100 mL), the solution was washed with water (50 mL) and brine, dried with MgSO4 and evaporated under vacuum. The residue was purified by flash chromatography on silica gel. Eluent: 5% methanol in ethyl acetate. Yield: 40 mg 3-(4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyrylamino)-4-oxo-1-pyrrolidine-1-carboxylic acid tert-butyl ester as white solid as mixture of diastereomers; 1H NMR: (DMSO) 8.80–8.66 (m, 1H), 7.42–7.34 (m, 5H), 4.52–4.41 (m, 2H), 4.34–4.20 (m, 1H), 3.98–3.88 (m, 1H), 3.82 (d, J=18.5 Hz, 1H), 3.70–3.05 (m, 13H), 2.70–2.52 (m, 2H), 1.41 (s, 9H); MS: (M+H)+ 538.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH2:28]([NH:30][CH3:31])[CH3:29].CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH2:28]([N:30]([CH3:31])[C:25]([C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH:8][C:9]1[CH:14]=[CH:13][N:12]2[N:15]=[C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:17]=[C:11]2[CH:10]=1)=[O:24])=[O:27])[CH3:29]
Reactant: CCNC
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(C)C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (600 mg, 1.66 mmol), N-ethylmethylamine (427 ul, 4.97 mmole), N-diisopropylethylamine (868 ul, 4.97 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 2.44 ml, 4.14 mmol) in tetrahydrofurane (30 ml) is stirred for 2 hours at 70° C. The cooled solution is diluted with ethyl acetate, washed once with sat. aqueous sodium bicarbonate solution, once with brine, dried with magnesium sulfate and evaporated to dryness. Two successive crystallizations of the residue (680 mg white solid) from ethyl acetate afford N4-ethyl-N4,1-dimethyl-N5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (365 mg, 54.6%) as a white solid. mp.: 193-4° C. MS: m/z=404.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 70 °C
Yield: 94 %

Procedure:
To a Solution of 4-chloro-3-nitrobenzoic acid (5.0 g, 24.81 mmol) in 50 ml of methanol was added H2SO4 (2 ml, 37.02 mmol) and the reaction mixture was heated at 70° C. for 5 h. After completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure. Water (50 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was, dried (Na2SO4), filtered and concentrated to give the desired product (5.04 g, 94%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:10][C:11]1[C:17](F)=[CH:16][C:14]([NH2:15])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.O>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][O:6][C:17]1[C:11]([F:10])=[CH:12][C:13]([N+:19]([O-:21])=[O:20])=[C:14]([NH2:15])[CH:16]=1
Reactant: CN(C)CCCO
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
In a 250 ml three-necked flask under an argon atmosphere, 5.3 g of 3-dimethylamino-1-propanol, in solution in 100 ml of tetrahydrofuran, are cooled to 0° C. using an ice bath and then introduce 2.3 g of sodium hydride at 50% in liquid petroleum jelly. After stirring for 1 hour at 0° C., rapidly add a solution of 3 g of 4,5-difluoro-2-nitroaniline in 100 ml of tetrahydrofuran and then heat in the region of 70° C. for 1 hour. The reaction mixture is poured into 100 ml of water and extracted with three times 100 ml of ethyl acetate. The organic phase is dried over magnesium sulphate and brought to dryness under reduced pressure. The solid obtained is washed with pentane, filtered, and dried under a hood. In this way, we obtain 3.5 g of 5-(3-dimethylaminopropoxy)-4-fluoro-2-nitrophenylamine, in the form of a yellow solid with the following characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH:12]C(OC(C)(C)C)=O)[C@@H:9]([N:20]=[N+]=[N-])[C@H:8]([O:23][CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH:7]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].Br.C(O)(=O)C.[OH-].[Na+].[P:50](=[O:54])([OH:53])([OH:52])[OH:51]>C(OCC)(=O)C.[Co].C(O)C>[P:50](=[O:51])([OH:54])([OH:53])[OH:52].[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@H:10]([NH2:12])[C@@H:9]([NH:20][C:36](=[O:38])[CH3:37])[C@H:8]([O:23][CH:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](N=[N+]=[N-])[C@@H](NC(=O)OC(C)(C)C)C1
Agent: [Co]
Agent: Br
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a solution of 3.96 g (3R,4R,5S)-4-azido-5-tert.-butoxycarbonylamino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid ethylester (10 mmol) in 50 ml ethyl acetate were added 2.0 g wet Raney-Cobalt catalyst and the suspension was stirred and hydrogenated at room temperature for 20 h (˜1.1 bar H2; 500 rpm). After removing the catalyst by filtration, 1.53 ml triethylamine (11 mmol =1.11 g) and 0.99 ml acetic anhydride (10.5 mmol =1.07 g) were added all at once and the colorless solution was stirred at room temperature for 1 h. Then 5.26 ml 5.7 M HBr/acetic acid (30 mmol HBr) were added to the colorless solution and the reaction mixture was stirred at room temperature for 20 h. Then ca. 55 ml 2 N NaOH (pH ca. 9.5) were added under stirring and the organic layer was separated and washed twice with 30 ml, a total of 60 ml 20% brine. All three aqueous layers were extracted sequentially and twice with 30 ml, a total of 60 ml ethyl acetate and the combined organic layers were dried (Na2SO4). After filtration and removal of the solvent by rotary evaporation (50°/≧1 mbar) the yellowish, viscous residue (3.47 g) was dissolved in 20 ml ethanol and added under stirring to a 50° C. warm solution of 0.98 g ortho-phosphoric acid (10 mmol) in 40 ml ethanol over 30 min (after the addition of two third, the 50° C. warm solution was seeded with pure title product). The white suspension was cooled down (2 h) and stirred at 0° C. for 3 h. The crystals were filtered, washed with ca. 20 ml acetone and dried (50°/10 mbar/16 h) affording 3.41 g (83.2%) white, crystalline phosphoric acid salt, m.p. 198-199° C. (dec.).
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[N:15]1([CH2:21][CH2:22][C:23]2[CH:32]=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[O:30]=[C:27]1[C:26]2[CH:31]=[CH:32][C:23]([CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][N:18]([CH2:1][CH:3]4[C:12]5[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=5)[O:6][CH2:5][CH2:4]4)[CH2:17][CH2:16]3)=[CH:24][C:25]=2[CH2:29][O:28]1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)OCCC2CN1CCN(CCc2ccc3c(c2)COC3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 12 mL reaction vial was added 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol), 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (66 mg, 0.27 mmol) and dichloromethane (3 mL). The solution was stirred at RT under N2 for 10 min. To above solution was added sodium tris(acetoxy) borohydride (224 mg, 1.1 mmol). The reaction was stirred at RT for 18 hours under N2, extracted with DCM, washed with brine and water. The organic phase was dried over MgSO4, filtered and purified by flash column chromatography. LC-MS (IE, m/z): 418.1 [M+1]+. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.84 (1H, d, J=7.8 Hz), 7.38 (1H, d, J=7.8 Hz), 7.32 (2H, m), 7.11 (1H, dxd, J=8.0 Hz, J=1.6 Hz), 7.08 (1H, d, J=1.6 Hz), 5.60 (2H, s), 4.4 (2H, m), 3.0 (4H, m), 2.4-2.8 (10H, m), 2.0 (2H, m). (0.092 μM)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:8]([O:19][CH2:20][CH3:21])[CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[CH2:20]([O:19][C:8]1[CH:7]=[C:6]([CH2:4][OH:3])[CH:11]=[CH:10][C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2ccc(F)cc2)c(OCC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CCOc1cc(CO)ccc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-ethoxy-4′-fluoro-biphenyl-4-carboxylic acid ethyl ester (0.50 g, 1.73 mmol, 1.0 equiv) in anhydrous THF (10 mL) was added dropwise at −10° C. diisobutylaluminum hydride (5.2 mL, 5.20 mmol, 3.0 equiv; 1 M solution in hexane) and the ccolong bath removed. After stirring for an additional time period of 60 min at rt, the reaction mixture was carefully poured on crashed ice/diluted HCl, extracted twice with ethyl acetate, the combined organic phases washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The title compound was isolated in quantitative yield (0.43 g) as a colorless viscous oil, sufficiently pure for the next step. MS (ISP): 229.3 [M+H−H2O]1.